DRUG REGISTRATION GUIDANCE DOCUMENT (DRGD) - BPFK

Drug Registration Guidance Document (DRGD)GUIDELINE HISTORYNo.GuidelineDescription ofAmendmentEffective date1.a) Guidelines for Application forRegistration ofPharmaceutical Products,Third Editionb) Permohonan PendaftaranKeluaran Ubat Tradisional,Second EditionInitial Publicationa) October1993b) December19982.Drug Registration GuidanceDocument (DRGD)Merging of1(a) and 1(b)* 20043.Drug Registration GuidanceDocument (DRGD),First Edition - January 2013Revision of DRGDNovember 20121 st January 2013* Note:There have been monthly updates of information in the DRGD. The last revision was inNovember 2012.National Pharmaceutical Control BureauFirst Edition, January 20132

Drug Registration Guidance Document (DRGD)This guidance document is issued by the Director ofPharmaceutical Services under Regulation 29,Control of Drugs and Cosmetics Regulations 1984.NPCB reserves the right to amend any part ofthe guidance document whichever it deems fit.All Rights Reserved.No part of this guidance document may be reproduced, stored in a retrieval system, ortransmitted, in any form or by any means, electronic, mechanical, microfilming,recording or otherwise, without written permission from the Senior Director ofPharmaceutical Services, Ministry of Health, Malaysia.National Pharmaceutical Control BureauFirst Edition, January 20133

Drug Registration Guidance Document (DRGD)Applicants shall familiarize with the contents of this guidance document and thegoverning legislations before they submit applications for medicinal productregistration.The Authority may request for information or specify conditions not described in thisdocument that is deemed necessary to ensure the quality, safety and efficacy of theproduct.An on-going review of regulatory policies will continue, taking into account the globalregulatory environment, to allow for timely and pertinent changes.For more information, please refer to Circulars and Newsletters.Applicants are advised to refer to NPCB‟s website for the latest updates of theDRGD and other related guidelines. Separate guidelines are available for Cosmeticand Veterinary products.The Authority reserves the right to amend any part of the DRGD whenever it deemsfit.Any enquiry on registration of products may be submitted to:Secretary,Drug Control Authority,National Pharmaceutical Control Bureau,Ministry of Health Malaysia,Jalan Universiti, P.O. Box 319,46730 Petaling Jaya, Selangor.National Pharmaceutical Control BureauFirst Edition, January 20135

Drug Registration Guidance Document (DRGD)ABBREVIATIONS AND ACRONYMSACCSQ-PPWGACTDACTRAMVANOVAAPIASEANATCBABEBETBMFBPBSECCLASEAN Consultative Committee on Standards and Quality/Pharmaceutical Product Working GroupASEAN Common Technical DossierASEAN Common Technical RequirementAnalytical Method ValidationAnalysis of VarianceActive Pharmaceutical Ingredient (Interchangeable with drug substance oractive substance). The term API Manufacturer is interchangeable withDMF Holder.Association of Southeast Asian NationsAnatomical Therapeutic ChemicalBioavailabilityBioequivalenceBacterial Endotoxins TestBatch Manufacturing FormulaBritish PharmacopoeiaBovine Spongiform EncephalopathyCentre for Compliance and LicensingCDCR Control of Drugs & Cosmetics Regulations 1984CEOChief Executive OfficerNational Pharmaceutical Control BureauFirst Edition, January 20136

Drug Registration Guidance Document (DRGD)CEPCFCCFSCICMCCoACOHCOMBOCOSCPPCTXCTILDCADEDMFDNADRGDEDQMELCEMAEPCertificate of Suitability(For Guideline on Registration of API, CEP is referring to Certificate ofSuitability of European Pharmacopoeia monographs issued by the EDQM)ChlorofluorocarbonsCertificate of Free SalesConfidence IntervalChemistry, Manufacturing And ControlsCertificate of AnalysisChange of Product Registration Holder (Previously known as Change ofMarketing Authorization Holder)Combination PackChange of Manufacturing SiteCertificate of Pharmaceutical ProductClinical Trial ExemptionClinical Trial Import LicenceDrug Control AuthorityData ExclusivityDrug Master File (interchangeable with Active Substance Master File)Deoxyribonucleic acidDrug Registration Guidance DocumentEuropean Directorate for the Quality of Medicine and HealthcareEndotoxin Limit ConcentrationEuropean Medicines AgencyEuropean PharmacopoeiaNational Pharmaceutical Control BureauFirst Edition, January 20137

Drug Registration Guidance Document (DRGD)FDAFDIFEOFPQCFSQDFTIRgGCGCPGDPGMPHACCPHBsAgHBVHCVHDPEHIVHPLCHSICHINNFood and Drug AdministrationFood-Drug InterfaceFor Export OnlyFinished Product SpecificationFood Safety and Quality DivisionFourier Transform InfraredgramGas ChromatographyGood Clinical PracticeGood Distribution PracticeGood Manufacturing PracticeHazard analysis and critical control pointsSurface Antigen of the Hepatitis B VirusHepatitis B VirusHepatitis C VirusHigh-density polyethyleneHuman immunodeficiency virusHigh Performance Liquid ChromatographyHealth SupplementInternational Conference on Harmonisation of Technical Requirements forRegistration of Pharmaceuticals for Human UseInternational Non-proprietary NamesNational Pharmaceutical Control BureauFirst Edition, January 20138

Drug Registration Guidance Document (DRGD)IPQCISOJAKIMJPLLALLOALOCLOImAbmaxMCBMDDCImLMPNMSMMVDNATNCENDPIn-Process Quality ControlInternational Organization for StandardizationMalaysia Department of Islamic Development(Jabatan Kemajuan Islam Malaysia)Japanese PharmacopoeiaLitreLimulus Amebocyte LysateLetter of AuthorizationLetter of CommitmentLetter of Intentmonoclonal antibodymaximumMaster Cell bankMedical Device-Drug-Cosmetic InterfacemillilitreMost-Probable NumberMethylsulphonylmethaneMaximum Valid DilutionNucleic Acid TestingNew Chemical EntityNew Drug ProductNational Pharmaceutical Control BureauFirst Edition, January 20139

Drug Registration Guidance Document (DRGD)NMTNPCBNRVOTCPh. Eur.PIPIC/SPILPMFPOAppmPRHPSURPVRNARSDSIRIMSPCspp.Syn.Not More ThanNational Pharmaceutical Control BureauNutrient Reference ValueOver-the-CounterEuropean PharmacopoeiaPackage InsertPharmaceutical Inspection Co-operation SchemePatient Information LeafletPlasma Master FileProtocol of Analysisparts per millionProduct Registration Holder(Previously known as Marketing Authorization Holder, MAH)Periodic Safety Update ReportProcess ValidationRibonucleic acidRelative Standard DeviationStandards and Industrial Research Institute of MalaysiaSummary of Product CharacteristicsSpeciesSynonymNational Pharmaceutical Control BureauFirst Edition, January 201310

Drug Registration Guidance Document (DRGD)TAMCTGATLCTSETYMCUSPUSPIUVVVMWCBWHOTotal Aerobic Microbial CountTherapeutic Goods AdministrationThin Layer ChromatographyTransmissible Spongiform EncephlopathiesTotal Yeasts and Moulds CountUnited State PharmacopeiaUS Package InsertUltra-VioletVaccine Vial MonitorWorking Cell BankWorld Health OrganisationNational Pharmaceutical Control BureauFirst Edition, January 201311

Drug Registration Guidance Document (DRGD)GLOSSARYIndigenous Medicine: As defined under Regulation 2, the CDCR 1984, indigenousmedicine means a system of treatment and prevention of disease established throughtraditional use of naturally occurring substancesLicensed importer: A person to whom an import license has been issued underRegulation 12, CDCR 1984 (as defined in Regulation 2, CDCR 1984)Licensed wholesaler: A person to whom a wholesaler's licence has been issuedRegulation 12, CDCR 1984 (as defined in Regulation 2, CDCR 1984)Manufacturer: A company that carries out at least one step of production as well as thefinal release of the finished product.Manufacturing: The definition of „manufacturing‟ includes:a) The making or assembling of the product;b) The enclosing or packing of the product in any container in a form suitable foradministration or application, and the labelling of the container and;c) The carrying out of any process in the course of any of the foregoing activities.(as defined in Regulation 2, CDCR 1984)Medicinal Product: The term refers to „product‟ as stated in Regulation 2, CDCR 1984which is applicable to pharmaceutical and natural productsOTC: Refers to Generic (Non-Scheduled Poison)Product Owner: A person, company or entity who is the legal/ registered owner of theproduct formulation and/or process with whom the marketing authorization holder has acontract (glossary used in ACTD and ACTR).Product Registration Holder: The company or corporate or legal entity in the field ofpharmaceuticals whose name the marketing authorization has been granted. This partyis responsible to all aspects of the product, including quality and compliance with theconditions of marketing authorization. The authorized holder must be subjected tolegislation in the country that issued the marketing authorization, which normally meansbeing physically located in that country (glossary used in ACTD and ACTR).National Pharmaceutical Control BureauFirst Edition, January 201312

Drug Registration Guidance Document (DRGD)The Authority: Refers to Drug Control Authority (DCA)The System: Refers to QUEST system in website of NPCBGlossary for Homeopathic Products:Active substance: Active substances are considered to be source materials processedby one or a sequence of homeopathic manufacturing procedures listed inpharmacopoeias in official use and other officially recognized documents (e.g. mothertinctures, dilutions or triturations).Diluent: Substance used for the preparation of a stock/ starting material or thepotentisation process and which may also represent the substance of the dosage form.Liquid diluents usually consist of purified water, aqueous solution, glycerol or ethanol ofa suitable concentration or for which there is an appropriate monograph. Thecommonest solid diluent is usually lactose monohydrate.Dilution: Dilution has two meanings in homeopathy:For a product, a dilution is a liquid homeopathic preparation which is potentised asdescribed below (see the definition of potentisation). Individual dilutions are alsocalled potencies;As a procedure, dilution means the de-concentration process of a liquid or a solidpreparation. One part of each stage in the preparation of a homeopathic medicinefrom its stock or previous dilution (potency) by adding one part of a previous solid orliquid phase to a predetermined weight or volume of the diluent (see Potentisationbelow). Dilution occurs at all stages of production of the homeopathic medicineswhether by addition of solid excipient in trituration or the addition of diluent in theliquid phase and succussion.Dosage form: a dosage form in homeopathy complies with any relevant specificationsfor that dosage form for which an appropriate characterization exists in apharmacopoeia in official use, or in other officially recognized documents. The mostcommonly encountered homeopathic dosage form, the globule (pillule or pellet), is asolid spherule which consists of lactose, sucrose or any other suitable vehicle. Usually,preformed globules are impregnated with a dilution or directly by a mother tincture. Thehomeopathic dosage form tablet is a solid preparation which complies with any relevantNational Pharmaceutical Control BureauFirst Edition, January 201313

Drug Registration Guidance Document (DRGD)characterization in the pharmacopoeia in official use (or in other officially recognizeddocuments) for tablets. Homeopathic medicines in tablet form are either prepared byimpregnation of preformed tablets or by compression of triturations with the vehicle. Themost commonly used liquid homeopathic medicines are either alcoholic solutions or oralliquids.Excipient: Substance needed for manufacturing a dosage form (used afterpotentisation) such as wheat starch and magnesium stearate for tablets. It may alsorepresent the substance of the dosage form.Homeopath: A qualified provider (practitioner) of homeopathic treatment.Homeopathic medicines: Any medicine prepared in accordance with a homeopathicmanufacturing procedure described by a pharmacopoeia in official use or other officiallyrecognized documents. A homeopathic medicine may contain a number of homeopathicpreparations.Homeopathy: Classical homeopathy is a system of medicine using preparations ofsubstances whose effects, when administered to healthy subjects, correspond to themanifestations of the disorder in the individual patients.Mother tincture (also called tincture): The initial homeopathic preparation made fromsource material that can be further potentised (also called “liquid stock”), sometimesused as homeopathic medicines, is regarded as the most concentrated form of afinished homeopathic medicine. Mother tinctures are obtained classically by macerationor percolation (sometimes also by digestion, infusion, decoction or fermentation)techniques from source materials according to a procedure prescribed by a recognizedhomeopathic pharmacopoeia. Sometimes a mother tincture corresponds to the firstdecimal dilution, “1D” or “1X” (10-1), mostly when dry plant material is used as startingmaterial.Nosodes: Homeopathic medicines prepared from disease products from humans oranimals; from pathogenic organisms or their metabolic products; or from decompositionproducts of animal organs.Potency: The denominated degree of serial trituration or dilution and succession that isreached for each homeopathic medicine. The degrees of dilution or potencies areNational Pharmaceutical Control BureauFirst Edition, January 201314

Drug Registration Guidance Document (DRGD)normally indicated by the letters D, DH or X for successive 1 to 10 (decimal) dilutions,the letters C, CH or K or CK for successive 1 to 100 (centesimal) dilutions while Q or LMdenote successive 1 to 50 000 (Hahnemannian quinquagintamillesimal) dilutions.Dilution by 1 to 10 denotes 1 part processed with 9 parts of diluent (Hahnemanniandecimal), dilution by 1 to 100, 1 part processed with 99 parts (Hahnemannian orKorsakovian centesimal), and so on. The number preceding the letters (e.g. D, C or LM)normally indicates the number of dilution steps employed (Table 1).As a consequence of different views in various approaches in homeotherapy andbecause the notion of these terms may depend on the nature of the starting materials,the terms “high potency” and “low potency” cannot be defined unambiguously.Potentisation (also called dinamization): The combined process of serial dilution andsuccussion or trituration at each step in the manufacture of homeopathic medicinesfrom stocks. (According to the tenet of homeopathy, potentisation represents theprocess by which the activity of a homeopathic medicine is developed.)Table 1: Potency tableDilution ratioCommondesignation(s)Examples1:10 a X 1X, 2X, 3X, etc.1:10 a D D1, D2, D3, etc.1:10 a DH DH1, DH2, DH3, etc.1:100 b C1C, 2C, 3C, etc.C1, C2, C3, etc.1:100 b CH1CH, 2CH, 3CH, etc.CH1, CH2, CH3, etc.1:100 b CK1:100 b K1CK, 2CK, 3CK, etc.CK1, CK2, CK3, etc.1K, 2K, 3K, etc.K1, K2, K3, etc.1:50 000 a LM 1LM, 2LM, 3LM, etc.1:50 000 a Q Q1, Q2, Q3, etc.National Pharmaceutical Control BureauFirst Edition, January 201315

Drug Registration Guidance Document (DRGD)a For 1:10 and 1:50 000 dilution ratios only the Hahnemannian method of manufacture(multi-flask method) is used.b For 1:100 dilution ratios a C potency is assumed to use the Hahnemannian method ofmanufacture (multi-flask method) and can also be denoted as CH. When theKorsakovian method of manufacture (single-flask method) is used, the potency isdesignated as CK or K.Sarcodes: Homeopathic medicines made from healthy animal tissues or secretions. InGreek, sarcode means fleshly.Source material (raw material, starting material, mother substance): Sourcematerial is the original raw material used for the production of homeopathic medicines.This material is obtained from natural sources, e.g. of botanical, zoological,microbiological, mineral, chemical, animal and human origin, or synthetic procedures.Source materials may undergo preliminary treatment in order to be further processed.Stock: Substances or preparations made from the source materials (e.g. bymaceration, succussion or trituration) used as starting points for the production ofhomeopathic medicines.National Pharmaceutical Control BureauFirst Edition, January 201316

Drug Registration Guidance Document (DRGD)CONTENTSGUIDELINE HISTORY……………………………………………………………………… 2PREAMBLE………………………………………………………………………………….. 4ABBREVIATIONS & ACRONYMS………………………………………………………... 6GLOSSARY…………………………………………………………………………………..12SECTION A: GENERAL OVERVIEW1. INTRODUCTION ............................................................................................. 241.1 REGISTRATION OF PRODUCTS ................................................................... 261.1.1 REGISTRABLE PRODUCTS .................................................................... 271.1.2 NON-REGISTRABLE PRODUCTS ........................................................... 271.1.3 EXEMPTIONS FOR PRODUCTS USED IN CLINICAL TRIALS ANDMANUFACTURING SAMPLES FOR REGISTRATION ............................. 301.2 CATEGORIES OF PRODUCT ......................................................................... 311.2.1 NEW DRUG PRODUCTS .......................................................................... 311.2.2 BIOLOGICS ............................................................................................... 331.2.3 GENERICS ................................................................................................ 341.2.4 HEALTH SUPPLEMENTS ......................................................................... 351.2.5 NATURAL PRODUCTS ............................................................................. 351.3 FOOD - DRUG - INTERFACE PRODUCTS .................................................... 371.3.1 INTRODUCTION ....................................................................................... 371.3.2 CLASSIFICATION OF FDI PRODUCTS ................................................... 381.3.3 PICTORIAL GUIDE TO CLASSIFICATION OF FOOD-DRUG INTERFACEPRODUCTS .............................................................................................. 411.3.4 ADDITIONAL GUIDANCE NOTES FOR FOOD PRODUCTS ................... 431.4 MEDICAL DEVICE - DRUG - COSMETIC INTERFACE PRODUCTS............. 451.4.1 INTRODUCTION ....................................................................................... 45National Pharmaceutical Control BureauFirst Edition, January 201317

Drug Registration Guidance Document (DRGD)1.4.2 CLASSIFICATION CRITERIA ................................................................... 452. DATA EXCLUSIVITY ...................................................................................... 502.1 HOW TO APPLY.............................................................................................. 502.2 APPLICABILITY AND DATE OF COMING INTO FORCE ............................... 512.3 GRANT OF DATA EXCLUSIVITY.................................................................... 512.4 CONSIDERATION OF OTHER APPLICATIONS UPON THE GRANT OF DATAEXCLUSIVITY ................................................................................................. 532.5 NON-APPLICATION OF DATA EXCLUSIVITY ............................................... 532.6 APPEAL ........................................................................................................... 543. APPLICATION FORMALITIES ....................................................................... 553.1 WHO CAN APPLY FOR PRODUCT REGISTRATION .................................... 553.2 RESPONSIBILITY OF APPLICANT................................................................. 553.3 HOW TO APPLY.............................................................................................. 564. FEES ............................................................................................................... 574.1 FEES IMPOSED .............................................................................................. 574.2 MODE OF PAYMENT ...................................................................................... 575. TYPES OF APPLICATION .............................................................................. 585.1 REGISTRATION OF PRODUCTS ................................................................... 585.1.1 APPLICATION FOR PRODUCT REGISTRATION FOR THE FOLLOWINGCATEGORIES: .......................................................................................... 585.1.2 REGISTRATION OF COMBINATION PACK (COMBO PACK) ................. 585.1.3 REGISTRATION OF PRODUCT FOR EXPORT ONLY (FEO) ................. 605.2 AMENDMENTS TO PARTICULARS OF A REGISTERED PRODUCT ........... 605.2.1 VARIATION ............................................................................................... 605.2.2 CHANGE IN MANUFACTURING SITE ..................................................... 615.2.3 CHANGE IN PRODUCT REGISTRATION HOLDER ................................ 615.2.4 NEW/ ADDITIONAL INDICATION ............................................................. 615.2.5 APPLICATION FOR A CONVENIENT PACK ............................................ 625.3 RENEWAL OF PRODUCT REGISTRATION ................................................... 62National Pharmaceutical Control BureauFirst Edition, January 201318

Drug Registration Guidance Document (DRGD)5.4 CERTIFICATES ............................................................................................... 625.4.1 CERTIFICATE OF PHARMACEUTICAL PRODUCT (CPP)...................... 625.4.2 GOOD MANUFACTURING PRACTICE (GMP) CERTIFICATE ................ 635.5 LICENSES ....................................................................................................... 635.6 CLINICAL TRIAL IMPORT LICENCE (CTIL)/ CLINICAL TRIAL EXEMPTION(CTX) ............................................................................................................... 646. GENERAL CONDITIONS FOR REGISTRATION OF DRUG PRODUCTSUNDER THE CONTROL OF DRUGS AND COSMETICS REGULATIONS1984 ................................................................................................................. 656.1 REGISTRATION NUMBER ............................................................................. 656.2 PRODUCT PARTICULAR ............................................................................... 656.3 LABELLING ..................................................................................................... 656.4 PRODUCT AUTHENTICATION ....................................................................... 656.5 INDICATIONS, SPECIAL CONDITIONS ......................................................... 666.6 ADVERSE REACTIONS, COMPLAINTS ......................................................... 666.7 HOLDER OF REGISTRATION CERTIFICATE ................................................ 666.8 WITHDRAWAL FROM REGISTRATION ......................................................... 666.9 CANCELLATION, SUSPENSION, AMENDMENT BY THE AUTHORITY ....... 676.10 DIRECTIVES ................................................................................................... 677. USE OF HALAL LOGO ................................................................................... 68SECTION B: PRODUCT REGISTRATION PROCESS8. FLOW OF REGISTRATION PROCESS .......................................................... 698.1 PRE-SUBMISSION OF APPLICATION ........................................................... 708.1.1 CATEGORY OF PRODUCT ...................................................................... 708.1.2 METHOD OF EVALUATION ..................................................................... 708.1.3 REQUIREMENTS FOR PRODUCT REGISTRATION ............................... 738.1.4 CONDITIONS APPLIED ON PRODUCT REGISTRATION ....................... 74National Pharmaceutical Control BureauFirst Edition, January 201319

Drug Registration Guidance Document (DRGD)8.1.5 MULTIPLE APPLICATIONS ...................................................................... 758.1.6 SECOND OR THIRD SOURCE ................................................................. 758.1.7 VARIANTS ................................................................................................. 768.1.8 LANGUAGE ............................................................................................... 768.2 SUBMISSION OF APPLICATION .................................................................... 778.3 SCREENING OF APPLICATION ..................................................................... 778.3.1 SATISFACTORY ....................................................................................... 778.3.2 NON-SATISFACTORY .............................................................................. 788.4 EVALUATION OF APPLICATION.................................................................... 788.4.1 INITIATION OF REVIEW ........................................................................... 788.4.2 CORRESPONDENCE ............................................................................... 788.4.3 STOP CLOCK ........................................................................................... 798.4.4 TIMELINE FOR PRODUCT REGISTRATION ........................................... 798.5 REGULATORY OUTCOME ............................................................................. 808.5.1 DECISIONS OF THE AUTHORITY ........................................................... 808.5.2 PRODUCT REGISTRATION NUMBER..................................................... 808.5.3 CERTIFICATE OF REGISTRATION ......................................................... 818.6 POST-REGISTRATION PROCESS ................................................................. 818.7 REJECTED APPLICATION ............................................................................. 828.7.1 PROCESS OF APPEAL FOR QUEST 2 PRODUCT ................................. 838.7.2 PROCESS OF APPEAL FOR QUEST 3 PRODUCT ................................. 848.7.3 TEMPLATE FOR APPEAL LETTER ......................................................... 85SECTION C: QUALITY CONTROL9. GUIDELINE FOR THE SUBMISSION OF PROTOCOL OF ANALYSIS ......... 879.1 GENERAL REQUIREMENTS .......................................................................... 879.2 SPECIFIC REQUIREMENTS .......................................................................... 88National Pharmaceutical Control BureauFirst Edition, January 201320

Drug Registration Guidance Document (DRGD)10. GUIDELINE FOR THE SUBMISSION OF ANALYTICAL METHODVALIDATION DOCUMENTS ........................................................................... 9310.1 TYPES OF ANALYTICAL PROCEDURES TO BE VALIDATED ..................... 9310.2 TYPICAL VALIDATION PARAMETERS FOR CHEMICAL TESTS ................. 9310.2.1 FULL VALIDATION FOR IN-HOUSE METHODS ...................................... 9310.2.2 PARTIAL VALIDATION FOR COMPENDIAL/ PHARMACOPOEIALMETHODS ................................................................................................. 9510.3 TYPICAL VALIDATION CHARACTERISTICS FOR MICROBIOLOGICALTESTS ............................................................................................................. 9611. GUIDELINE FOR THE SUBMISSION OF PRODUCT SAMPLES FORLABORATORY TESTING ............................................................................... 9711.1 GENERAL REQUIREMENTS .......................................................................... 9711.2 SPECIFIC REQUIREMENTS .......................................................................... 9811.2.1 NATURAL PRODUCTS ......................................................................... 9811.2.2 PHARMACEUTICAL PRODUCTS ......................................................... 9811.3 APPEAL FOR RETESTING ............................................................................. 99SECTION D: INSPECTION AND LICENSING12. INSPECTION ................................................................................................. 10013. LICENSING ................................................................................................... 10113.1 TYPES OF LICENSES .................................................................................. 10113.2 LICENSE APPLICATION FORM ................................................................... 10213.3 ADDITIONAL LIST OF LICENSE FOR REGISTERED PRODUCTS ............. 10213.4 GMP CERTIFICATE ...................................................................................... 103National Pharmaceutical Control BureauFirst Edition, January 201321

Drug Registration Guidance Document (DRGD)SECTION E: POST-REGISTRATION PROCESS14. MAINTENANCE OF REGISTRATION .......................................................... 10415. WITHDRAWAL OF PRODUCT REGISTRATION ......................................... 10416. AMENDMENTS TO PARTICULARS OF A REGISTERED PRODUCT ........ 10516.1 VARIATION ................................................................................................... 10516.1.1 MODE OF SUBMISSION ........................................................................ 10816.1.2 RESPONSIBILITY OF APPLICANT ......................................................... 10916.1.3 OTHER INFORMATION .......................................................................... 10916.2 CHANGE OF MANUFACTURING SITE ........................................................ 11016.2.1 CONDITIONS ON APPLICATION FOR COS: ......................................... 11016.2.2 CONDITIONS ON GOOD MANUFACTURING PRACTICE (GMP): ........ 11116.2.3 TYPES OF MANUFACTURING SITE CHANGES (COS) ........................ 11116.2.4 MODE OF SUBMISSION ......................................................................... 11316.2.5 OTHER INFORMATION .......................................................................... 11316.3 CHANGE OF PRODUCT REGISTRATION HOLDER ................................... 11416.4 NEW/ ADDITIONAL INDICATION ................................................................. 11416.4.1 FULL EVALUATION PROCESS .............................................................. 11416.4.2 VERIFICATION PROCESS ..................................................................... 11416.5 APPLICATION FOR A CONVENIENT PACK ................................................ 11517. POST-MARKETING ACTIVITIES.................................................................. 11717.1 PHARMACOVIGILANCE ............................................................................... 11717.1.1 ADVERSE DRUG REACTION REPORTING AND SAFETY UPDATES . 11717.2 POST-MARKET SURVEILLANCE ................................................................. 11817.2.1 PRODUCT COMPLAINTS ....................................................................... 11817.2.2 PRODUCT RECALLS.............................................................................. 11817.3 PUNITIVE ACTION FROM THE AUTHORITY .............................................. 11917.3.1 ADULTERATION ..................................................................................... 119National Pharmaceutical Control BureauFirst Edition, January 201322

Drug Registration Guidance Document (DRGD)APPENDICES ............................................................................................................. 120APPENDIX 1: FEES .................................................................................................... 121APPENDIX 2: REQUIREMENTS FOR PRODUCT REGISTRATION ......................... 126APPENDIX 3: GUIDELINES ON REGISTRATION OF BIOLOGICS ........................... 145APPENDIX 4: GUIDELINE ON REGISTRATION OF HEALTH SUPPLEMENTS ....... 168APPENDIX 5: GUIDELINE ON REGISTRATION OF NATURAL PRODUCTS ........... 230APPENDIX 6: GUIDELINE ON REGULATORY CONTROL OF ACTIVEPHARMACEUTICAL INGREDIENTS (API).......................................... 303APPENDIX 7: SPECIAL CONDITIONS FOR REGISTRATION FOR A PARTICULARPRODUCT OR GROUP OF PRODUCTS ............................................ 320APPENDIX 8: LIST OF PERMITTED, PROHIBITED AND RESTRICTEDSUBSTANCES ..................................................................................... 323APPENDIX 9: LABELLING REQUIREMENTS ............................................................ 337APPENDIX 10: GUIDELINE ON PATIENT DISPENSING PACK FORPHARMACEUTICAL PRODUCTS IN MALAYSIA ............................. 417APPENDIX 11: GUIDELINE ON FILLING THE ONLINE APPLICATION FORM FORPRODUCT REGISTRATION VIA QUEST SYSTEM ......................... 425APPENDIX 12: CONDITIONS AND SUPPORTING DOCUMENTS REQUIRED FOR ANAPPLICATION OF VARIATION ......................................................... 447APPENDIX 13: SUPPORTING DOCUMENTS REQUIRED FOR CHANGE OFMANUFACTURING SITE (COS) APPLICATION ............................... 471LIST OF UPDATES…………………………………………………………………………474National Pharmaceutical Control BureauFirst Edition, January 201323

Drug Registration Guidance Document (DRGD)SECTION A: GENERAL OVERVIEW1. INTRODUCTIONThe Control of Drugs and Cosmetics Regulations (CDCR) 1984 were promulgatedunder the Sale of Drugs Act 1952. The Authority (known as Drug Control Authority,DCA) established under these Regulations, is tasked with ensuring the quality, safetyand efficacy of medicinal products through the registration, including quality control,inspection & licensing and post-registration activities. The National PharmaceuticalControl Bureau (NPCB) acts as the secretariat to the Authority.Under the CDCR 1984, Regulation 7(1): Except as otherwise provided in theseRegulations, no person shall manufacture, sell, supply, import, possess or administerany product unless:(a) the product is a registered product; and(b) the person holds the appropriate licence required and issued under theseRegulations.The phases of implementation for product registration are as shown in Figure 1 below:* 1 st July 2012:All manufacturers shall be certified for GMP as directed via Directive Arahan di Bawah Peraturan29, Peraturan-peraturan Kawalan Dadah dan Kosmetik 1984 Bil. 1 Tahun 2012Reference: Circulars Bil (25) dlm BPFK/PPP/01/03 Jld 1 and Bil (96)dlm.BPFK/PPP/01/03 Jld. 2** Voluntary registration of API commenced in April 2011, started with New Drug Products (NDP),followed by mandatory registration of API for NDP which were implemented in January 2012. Asfor Generics, the mandatory registration of API will be announced at a later date.National Pharmaceutical Control BureauFirst Edition, January 201324

Drug Registration Guidance Document (DRGD)Registration process includes quality control, inspection & licensing as well as postregistrationprocess of medicinal products is illustrated in Figure 2 below:Pre-Submission of RegistrationApplicationSubmission of RegistrationApplication and Screening Process* GMP Inspectionand CertificationData Evaluation** Sample testingMeeting of the Drug Evaluation CommitteeMeeting of the AuthorityRegulatory OutcomeApproval Rejection Appeal*** LicensingPost-Registration Process* Good Manufacturing Practice (GMP) Certification** For natural products only*** Application for Import and/or Wholesale LicenseNational Pharmaceutical Control BureauFirst Edition, January 201325

Drug Registration Guidance Document (DRGD)1.1 REGISTRATION OF PRODUCTSUnder the CDCR 1984, Regulation 2: “Product” means:(a) a drug 1 in a dosage unit or otherwise, for use wholly or mainly by beingadministered to one or more human beings or animals for a medicinal purpose 2 ; or(b) a drug 1 to be used as an ingredient of a preparation for a medicinal purpose 2 .Under Sales of Drug Act 1952, Section 2:1“drug” includes any substance, product or article intended to be used or capable, orpurported or claimed to be capable, of being used on humans or any animal, whetherinternally or externally, for a medicinal purpose.2 “medicinal purpose” means any of the following purposes:(a) alleviating, treating , curing or preventing a disease or a pathological condition orsymptoms of a disease;(b) diagnosing a disease or ascertaining the existence, degree or extent of aphysiological or pathological condition;(c) contraception;(d) inducing anaesthesia;(e) maintaining, modifying, preventing, restoring, or interfering with, the normaloperation of a physiological function;(f) controlling body weight;(g) general maintenance or promotion of health or wellbeing.Note:In this DRGD, the term “medicinal product” refers to the term “product” as stipulatedin the Regulation 2, CDCR 1984.National Pharmaceutical Control BureauFirst Edition, January 201326

Drug Registration Guidance Document (DRGD)1.1.1 REGISTRABLE PRODUCTSAny product as defined in 1.1 shall be registered with the Authority.The products include, but not limited to the following:a) Pharmaceutical products containing scheduled poisonsb) Pharmaceutical products containing non-scheduled poisons(For examples: Medicated plaster with medicine, antiseptic/ disinfectants for useon the human body, diagnostic agents for human use (in-vivo) and healthsupplement such as probiotics and chitosan)c) Natural productsIncludes herbal and traditional products1.1.2 NON-REGISTRABLE PRODUCTSi) Diagnostic agents and test kits for laboratory/ in-vitro useDiagnostic agents/ test kits for laboratory use must be labeled „FORLABORATORY USE ONLY‟.Note:Products which are not labelled as such shall be deemed to be for human oranimal use and need to be registered with the Authority.ii)Medical Devices“Medical device” means any instrument, apparatus, implement, machine,appliance, implant, in vitro reagent or calibrator, software, material or othersimilar or related article intended by the manufacturer to be used, alone or incombination, for human beings for the purpose of:National Pharmaceutical Control BureauFirst Edition, January 201327

Drug Registration Guidance Document (DRGD)(i) diagnosis, prevention, monitoring, treatment or alleviation of disease;(ii) diagnosis, monitoring, treatment, alleviation of or compensation for an injury;(iii) investigation, replacement or modification, or support of the anatomy or of aphysiological process;(iv) support or sustaining life;(v) control of conception;(vi) disinfection of medical device; or(vii) providing information for medical or diagnostic purpose by means of in vitroexamination of specimens derived from the human body,These products do not achieve its primary intended action in or on the humanbody by pharmacological, immunological or metabolic means, but that may beassisted in its intended function by such means.This includes but is not limited to the following:- Non-medicated bandages, plaster- Surgical dressings, wound care/ dressing materials containing hydrogel,collagen, calcium alginate- Visco-elastic products for mechanical or physical protection of tissues duringor after surgical procedures- Instruments, apparatus, syringes, needles, sutures, catheters- Disinfectants for equipments/ devices- Lubricants for gloves, condoms and endoscopes- Contact lens care products- Copper IUDs- Bone cement, tissue adhesives- Dental fillings- Blood bags containing anti-coagulants- Non-medicated medical and contraceptive devicesFor more information, please refer Medical Device Bureau.National Pharmaceutical Control BureauFirst Edition, January 201328

Drug Registration Guidance Document (DRGD)iii)FoodAs defined under the Food Act 1983 and Food Regulations 1985, includes everyarticle manufactured, sold or represented for use as food or drink for humanconsumption or which enters into or is used in the composition, preparation, andpreservation, of any food or drink and includes confectionery, chewingsubstances and any ingredient of such food, drink, confectionery or chewingsubstances. This includes food for special dietary use for persons with a specificdisease, disorder or medical condition, and food which contain quantities ofadded nutrients allowable under the Food Act 1983 and Regulations.For more information, please refer Food Safety & Quality Division, Ministry ofHealth Malaysia.iv)Sports Nutrition, such as body-building products containing protein/ whey/ soyabeanv) Raw herbs used in extemporaneous preparations, including those that are dried& cut into pieces, without dosage instructions and indicationsvi)Insect repellants, insecticides, pesticides and parasiticidesProducts containing pesticides as listed under First Schedule of Pesticide Act1974 for external use only shall be controlled by the Pesticide Board.For more information, please refer http://www.doa.gov.myvii)Detergents/ disinfectants for domestic useNational Pharmaceutical Control BureauFirst Edition, January 201329

Drug Registration Guidance Document (DRGD)1.1.3 EXEMPTIONS FOR PRODUCTS USED IN CLINICAL TRIALS ANDMANUFACTURING SAMPLES FOR REGISTRATIONa) Clinical Trial Import License (CTIL)Products which are not registered with the Authority and are intended to beimported for the purpose of clinical trial shall have a Clinical Trial Import License.This is in accordance to the Regulation 12(1)(c), CDCR 1984: “The Director ofPharmaceutical Services may, subject to the provisions of these Regulations,issue the following license subject to such conditions as he may impose, aclinical trial import license in Form 4 in the Schedule, authorizing the licensee toimport any product for purposes of clinical trials, notwithstanding that the productis not a registered product”.b) Clinical Trial Exemption (CTX) & Exemption for Manufacturing Sample forRegistrationi) Products which are not registered with the Authority and are intended to bemanufactured locally for the purpose of clinical trial shall require ClinicalTrial Exemption (CTX) from the Director of Pharmaceutical Services; andii)Any person who wishes to manufacture any product solely for the purposeof producing a sample for registration should apply for an exemption formanufacture of sample. (Applies to locally manufactured products only).This is in accordance to the Regulation 15(5), CDCR 1984: “Any person whowishes to manufacture any product solely for the purpose of producing samplesfor clinical trials, for registration or issuance of notification note under theseRegulation may on application be exempted by the Director of PharmaceuticalServices from the provisions of regulation 7 (1) or regulation 18A”.For more information, please refer Regulation 15, CDCR 1984: Exemptions &Saving; and Guidelines on Clinical Trial.National Pharmaceutical Control BureauFirst Edition, January 201330

Drug Registration Guidance Document (DRGD)1.2 CATEGORIES OF PRODUCTNote:Before submission of application for a product registration, applicants mayverify via Classification Form if unsure for the product category.Medicinal products for registration are classified under the following categories:1.2.1 NEW DRUG PRODUCTSNew Drug Products (NDP) is defined as any pharmaceutical products that havenot been previously registered in accordance with the provisions of the CDCR1984.An NDP may be classified according to the following categories:a) New Chemical Entity (NCE)/ Radiopharmaceutical SubstanceA new pharmaceutical product containing any of the following:i. New Chemical Entity (NCE)Defined as an active moiety that has not been registered in anypharmaceutical product.ii. Radiopharmaceutical substanceDefined as a radionucleotide, ligand or the coupling mechanism tolink the molecule and the radionucleotide that has not beenregistered in any pharmaceutical product.b) New Combination ProductA new pharmaceutical product containing two or more drugs that arephysically, chemically or otherwise combined or mixed and producedNational Pharmaceutical Control BureauFirst Edition, January 201331

Drug Registration Guidance Document (DRGD)1.2.2 BIOLOGICSThe term „biopharmaceutical‟ was coined in the 80‟s to define proteins thatwere made by recombinant DNA technology [which includes hybridomatechnology for monoclonal antibody (mAb) production].Biologic/ Biological product refers to a product whose active substance ismade by or derived from a living organism (plant, human, animal ormicroorganism) and may be produced by biotechnology methods and othercutting-edge technologies. This product imitates natural biologicalsubstances in our bodies such as hormones, enzymes or antibodies.Biological substance is defined as a substance that is produced by orextracted from a biological source and that needs, for its characterization andthe determination of its quality, a combination of physicochemical-biologicaltesting together with the production process and its controls.Biopharmaceuticals/ Biologics/ Biological products can also be defined as:“a protein (including antibodies) or nucleic acid-based pharmaceuticals usedfor therapeutic, which is produced by means other than direct extraction froma native (non-engineered) biological source”. This corresponds to the newbiotechnology view (that is, by elimination, it is largely restricted torecombinant/ genetically engineered and mAb-based products).The term „Biotechnology product‟ and „Biological product‟ are used to broadlyrefer to all biopharmaceuticals (by the broad biotechnology view).Note:Today, biologics have become inextricably intertwined with biopharmaceuticals,to the point where they are synonymous. The general consensus is that the term„Biologic‟ and „Biopharmaceutical‟ are interchangeable.Biologics include a wide range of products such as:Vaccines;Blood products;Monoclonal antibodies (therapeutics);National Pharmaceutical Control BureauFirst Edition, January 201333

Drug Registration Guidance Document (DRGD)Recombinant proteins:- Insulins- Hormones- Erythropoetins and other hematopoietic factors- Cytokines: Interferons, interleukins, colony-stimulating factors, tumournecrosis factors.But does not include:Metabolites from microorganisms; e.g. antibiotics and some hormones;Macromolecules produced by chemical synthesis; e.g. peptides/ oligonucleotidesproduced by chemical synthesis;Whole blood or cellular blood components.Note:This document is not intended to apply on the control of geneticallymodified live organisms designed to be used directly in humans, e.g. livevaccinesFor details, please refer Appendix 3: Guideline on Registration of Biologicsand Guideline on Registration for Biosimilars in Malaysia1.2.3 GENERICSA generic product is a product that is essentially similar to a currentlyregistered product in Malaysia. However, the term generic is not applicable toBiologics.Generics may be further classified into two groups:1. Scheduled Poison(Known as Controlled Medicine/ Controlled Poison)Products containing poisons as listed in the First Schedule underPoisons Act 1952.National Pharmaceutical Control BureauFirst Edition, January 201334

Drug Registration Guidance Document (DRGD)2. Non-scheduled Poison(Known as Non-Poison or “Over-the-Counter”, OTC)Products containing active ingredients which are not listed in theFirst Schedule under Poisons Act 1952; and is excluding activeingredient which is categorized under health supplements or naturalproducts or cosmetics.1.2.4 HEALTH SUPPLEMENTSA Health Supplement (HS) means any product that is used to supplement a dietand to maintain, enhance and improve the health function of human body. It ispresented in small unit dosage forms (to be administered) such as capsules,tablets, powder, liquids and shall not include any sterile preparations (i.e.injectables, eyedrops). It may contain one or more, or the following combination:i) Vitamins, minerals, amino acids, fatty acids, enzymes, probiotics, andother bioactive substances;ii) Substances derived from *natural sources, including animal, mineral andbotanical materials in the forms of extracts, isolates, concentrates,metabolite;iii) Synthetic sources of ingredients mentioned in (i) and (ii) may only be usedwhere the safety of these has been proven.For details, please refer to Appendix 4: Guidelines for Registration of HealthSupplements1.2.5 NATURAL PRODUCTSa) Traditional medicine (as defined under the Control of Drugs and CosmeticsRegulations 1984):Any product used in the practice of indigenous medicine, in which the drugconsist solely of one or more naturally occurring substances of a plant, animalNational Pharmaceutical Control BureauFirst Edition, January 201335

Drug Registration Guidance Document (DRGD)or mineral, of parts thereof, in the unextracted or crude extract form, and ahomeopathic medicine. It shall not include any sterile preparation, vaccines,any substance derived human parts, any isolated and characterized chemicalsubstances.b) Finished Herbal ProductFinished herbal products consist of herbal preparations made from one ormore herbs. If more than one herb is used, the term “mixture herbal product”can also be used. Finished herbal products and mixture herbal products maycontain excipients in addition to the active ingredients. However, finishedproducts or mixture herbal products to which chemically defined activesubstance have been added, including synthetic compounds and/ isolatedconstituents from herbal materials, are not considered to be herbal.c) Herbal RemedyAny drug consisting of a substance or a mixture of substances produced bydrying, crushing or comminuting, but without subjecting to any other process,a natural substance or substances of plant, animal or mineral origin, or anypart of such substance or substances.d) Homeopathic MedicineAny pharmaceutical dosage form used in the homeopathic therapeutic systemin which diseases are treated by the use of minute amounts as of suchsubstances which are capable of producing in healthy persons symptomssimilar to those of the disease being treated.For details, please refer to Appendix 5: Guidelines for Registration of NaturalProductsNational Pharmaceutical Control BureauFirst Edition, January 201336

Drug Registration Guidance Document (DRGD)1.3 FOOD - DRUG - INTERFACE PRODUCTSThis guide serves to assist in determining if a product is to be regulated by the NationalPharmaceutical Control Bureau (NPCB) or the Food Safety and Quality Division (FSQD)of the Ministry of Health Malaysia.1.3.1 INTRODUCTIONMalaysians are now more health conscious and there is generally greater awareness ofthe importance of the nutrition to overall well-being. In recent years, many consumersalso rely on a variety of “dietary supplements” to improve their health. These diverseproducts are freely available through a myriad of outlets. A variety of products areavailable in the market, supposedly for the maintenance, prevention and even treatmentof chronic diseases. These products may range from foods modified to have specialproperties or pure forms of vitamins and minerals to extract of various botanical oranimal products.It is important to monitor and regulate the marketing and sale of these products so as toprotect the interest of the consumer. Some of these products are not clearly marketedas “food” or “drugs”. These have been termed as “food-drug interface (FDI) products”and include a variety of so-called health products.Previously, it had been difficult to determine which authority within the Ministry of HealthMalaysia should regulate the marketing and sale of such products, either FSQD orNPCB. This has caused difficulty to the companies intending to market such products. Itis also not beneficial to the consumer as the products could be in the market and notregulated by either of the authorities.To overcome these problems and to enable a decision to be made as to which authorityshould regulate a particular product, the Committee for the Classification of Food-DrugInterface Products has been formed since year 2000. The main terms of reference ofthe Committee is to assist the FSQD and NPCB in classifying, in a consistent manner,an application from the industry which is not clearly defined as a food or drug productthat is a FDI product. Other duties include advising the two divisions of the Ministry ofHealth in strengthening and updating the relevant regulations as well as to providescientific input on these products.National Pharmaceutical Control BureauFirst Edition, January 201337

Drug Registration Guidance Document (DRGD)1.3.2 CLASSIFICATION OF FDI PRODUCTSThe Committee for the Classification of Food-Drug Interface Products, comprising ofmembers from FSQD and NPCB has established a system for the classification of FDIproducts.This classification is based on multiple criteria, as outlined below:a) Main criteriaThe ingredients of the product are the main criteria of this classification process:i) If the product content close to 100% of active ingredients, e.g. amino acids &peptides, collagen, coral calcium, dietary fibre, enzymes, fatty acids, livemicroorganism, minerals, plant stanol/ sterol & esters, vitamins, etc, the producthas to be regulated by NPCB.ii) Substances or ingredients used for therapeutic purposes shall not be added tofood. For examples: gypsum fibrosum, pearl powder and gamat (stichopus spp.).iii) # A product content close to 100% of a herb or a mixture of herbs that are nottraditionally used as food and possess medicinal values if shall be regulated byNPCB. Examples of such products are aloe vera, alfafa, barleygrass, dukunganak, gamat extract, kacip fatimah, manjakani, mas cotek, misai kucing, noniextract, royal jelly, spirulina, tongkat ali, tunjuk langit, wheatgrass, psyllium husk,pegaga tablet, and rooibos tea.iv) # Herbs and spices that are traditionally used in food preparation shall beregulated by FSQD e.g. black cumin (habbatus sauda), garlic, ginger, pegaga,traditional chinese raw herbs, turmeric.v) Products containing a mixture of food ingredients with active ingredients and/orherbs identified in point marked with # above shall be classified according to the80:20 ratio general rule below, unless otherwise specified.- If a product contains more than 20% of the active ingredients or naturalingredients with pharmacological and/or therapeutic properties, such aproduct shall be regulated by NPCB.National Pharmaceutical Control BureauFirst Edition, January 201338

Drug Registration Guidance Document (DRGD)- If a product contains equal to or less than 20% of active ingredients ornatural ingredients with pharmacological and/or therapeutic properties, theproduct shall be regulated by FSQD.- Notwithstanding this general rule, if a product contains specific activeingredients which possess high pharmacological or therapeutic potencies,the product may be regulated by NPCB even if these active ingredients arepresent in less than 20%.vi) When there is greater uncertainty regarding the safety of a product, it shall beregulated by NPCB. This is to enable closer monitoring of such products, so as tosafeguard the interest of the consumer.vii) Notwithstanding the above points, the following ingredients do not follow the80:20 ratio general rule mentioned above and shall be regulated by NPCB:- Plant sterols/ stanols and esters that are consumed ≥ 3.5g/day- Psyllium husk that are consumed ≥ 3.5g/dayb) Other criteriaThe following may be used as additional criteria to assist in the classification of FDIproducts:i) Intended use and claims made by the productEventually, if a product has been decided to be regulated by FSQD, no claimsshould be made, other than those permitted by the Food Regulations.ii) Dosage form- Any foods or combination of foods that are regulated under FSQD shall notbe in the form of soft gel, capsule or tablet that is to be directly swallowed.National Pharmaceutical Control BureauFirst Edition, January 201339

Drug Registration Guidance Document (DRGD)- Any product to be regulated under NPCB shall not be in the conventional foodform such as cake, muffins, biscuits, gummy, jelly, chocolate, premixbeverages etc.iii) Unusual application- Products with unusual application for example spray may not be accepted byFSQD.- Products of coffee/ tea (coffea species/ camellia sinensis) containing herbsand a mixture of creamer and sugar are not allowed to be registered undercategory of natural product by NPCB.iv) Oils in pharmaceutical dosage formOils that are not traditionally used as food or are in combination with edible oil forexample evening primrose oil, garlic oil, fish oil, flaxseed oil and grapeseed oil incapsule or soft gel shall be regulated by NPCB.Notes:Applicant shall verify on FDI product classification with NPCB in order to determinewhether the product shall be registered by the Authority or otherwise.Reference: Circular (97)dlm.BPFK/PPP/01/03 Jld. 2National Pharmaceutical Control BureauFirst Edition, January 201340

Drug Registration Guidance Document (DRGD)1.3.3 PICTORIAL GUIDE TO CLASSIFICATION OF FOOD-DRUG INTERFACE PRODUCTSFigure 3:ProductIngredient 1Legend:Regulated by FSQDRegulated by NPCBContent close to100% activeingredients (singly orin combination)Substances oringredients that areused for therapeuticpurposes shall notbe added to foodContent close to100% herbs (singlyor in combination)that are nottraditionally used asfood and havemedicinal propertyHerbs & spices thatare traditionally usedin food preparationsMixtures of foodingredients withactive ingredientsand/or herbsFor example:Amino Acids &PeptidesCollagenCoral calciumDietary Fibre 2EnzymesFatty AcidsLive microorganism 3, 4MineralsPlant Stanol/Sterol & Esters(≥3.5g/day)VitaminsFor example:GypsumfibrosumPearl PowderGamatFor example:AlfalfaAloe veraBarleygrassDukung AnakKacip FatimahManjakaniMas CotekMisai KucingNoni ExtractRoyal JellySpirulinaTongkat AliTunjuk LangitWheatgrassPsylliumHusk(≥3.5g/day)For example:Black cumin(Habbatussauda)GarlicGingerPegagaTraditionalChinese RawHerbsTurmeric> 20% activeingredients withpharmacological/therapeuticproperties, singly orin combination.≤ 20% of activeingredients or naturalingredients withpharmacological and/ortherapeutic properties.However, if a productcontains specific activeingredients whichpossess highpharmacological ortherapeutic potencies,the product may beregulated by NPCBeven if these activeingredients are presentin less than 20%National Pharmaceutical Control BureauFirst Edition, January 201341

Drug Registration Guidance Document (DRGD)Notes:1234Substances listed in the prohibited ingredient list of the Drug Registration Guidance Document (DRGD) and SchedulePoison shall not be permitted for use in any product.Dietary fibre includes inulin, fructooligosacharrides, galactooligosacharrides, polydextrose, acacia gum, oat solublefibre, resistant dextrose and resistant maltodextrine.Permitted live microorganism when present by itself singly or in combination in pharmaceutical dosage form shall beregulated under NPCB and shall contain minimum of 10 6 cell/g of the viable cells for each strain.Permitted live microorganism when present in foods shall be treated as food ingredient and shall contain minimum of10 6 viable cells/g of the viable cells, depending on the strains.National Pharmaceutical Control BureauFirst Edition, January 201342

Drug Registration Guidance Document (DRGD)1.3.4 ADDITIONAL GUIDANCE NOTES FOR FOOD PRODUCTSa) FoodsUnder Section 2, Food Act 1983:"Food" includes every article manufactured, sold or represented for use as food or drinkfor human consumption or which enters into or is used in the composition, preparation,preservation, of any food or drink and includes confectionery, chewing substances andany ingredient of such food, drink, confectionery or chewing substances.All food products must comply with the Food Act 1983 and Food Regulations 1985.b) List of Food Products that may contain Herbs or Botanical Plants under FoodRegulations 1985- Meat extract or meat essence- Botanical Beverage Mix (regulation 356)- Mixed Food Products- Food standards that contain words: “may contain other food”c) Permitted Added Nutrients in Food ProductsFor details, please refer to Food Regulations 1985, Table 1 under the Twelfth Schedule.d) Maximum Amounts of Vitamins and Minerals permitted in Food, as shown in Table Ibelow:Added NutrientVitamin AThiamineRiboflavinPyridoxineMaximum amount in recommended daily serving5,000 I.U.2.2 milligram3.2 milligram4 milligramsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 43

Drug Registration Guidance Document (DRGD)Added NutrientBiotinPantothenic acidNiacinAscorbic acidVitamin DVitamin ECalciumIodineIronPhosphorusFolic acidVitamin B 12Maximum amount in recommended daily serving400 micrograms14 milligrams22 milligrams100 milligrams800 I.U.50 I.U.1.4 grams200 micrograms20 milligrams1.4 grams400 micrograms4 microgramse) Permitted Bifido Bacteria in Food, as shown in Table II below:PERMITTED BIFIDO BACTERIA IN FOODNameMinimum viable cells/gBifido bacterium lactis (L-form) 10 6Bifido bacterium longum (L-form) 10 6National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 44

Drug Registration Guidance Document (DRGD)1.4 MEDICAL DEVICE - DRUG - COSMETIC INTERFACEPRODUCTS1.4.1 INTRODUCTIONThe Committee for the Classification of Medical Device-Drug-Cosmetic Interface (MDDCI)Products, comprising of members from Medical Device Authority and NPCB, hasestablished a system for the classification of MDDCI products.Registration of drug products/ notification of cosmetics that has been classified must followthe requirements that have been set forth as follows:a) Drugs & Cosmetics – The registration/ notification regulated by the NPCB is inaccordance with the requirements set forth in the Poisons Act 1952 and itsRegulations, Sales of Drugs Act 1952 and the Control of Drugs and CosmeticsRegulations 1984;b) Medical Device – The registration regulated by Medical Device Authority is inaccordance with the requirements set forth in the Medical Devices Act 2012 (Act737).For Drug-Device Combination Product, it will be regulated according to the classificationthat has been made and by the relevant agencies.1.4.2 CLASSIFICATION CRITERIAThe following may be used as criteria to assist in the classification of products:a) The primary intended purpose of the product;b) The primary mode of action/ the principal mechanism of action by which the claimedeffect or purpose of the product is achieved;i) Medical device is based on function by physical means, e.g. mechanicalaction, creation of a physical barrier or replacement or support of organ orbody function;ii) Drug is based on pharmacological, immunological or metabolic action in/onthe body.c) Active ingredient, indication and pharmaceutical dosage form (these are the maincriteria for classification of the drugs);National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 45

Drug Registration Guidance Document (DRGD)d) Classification of the products in reference countries.For classification of MDDCI products as decided by the committee, please referTable III and it shall be used as guidance for classification only.Table III: Summary of Product Classification DecisionNO. PRODUCT INTENDED PURPOSE OR INDICATION CATEGORY1 Eye Lubricant A sterile substance used to provide supplementallubrication/ hydration to the natural eye to treat dry,tired, and/or strained eyes resulting from dry eyesyndrome, ageing/ hormone changes(menopause), or environmental factors (e.g.pollution and air conditioning).2 Irrigation solutions For mechanical cleansing and rinsing includingthose used in the eye such as for cleansing of theeye, body tissues, body cavities, wounds orirrigation of a special tube called a catheter whichis used to drain the bladder.3 Medical gases To be used in anaesthesia and inhalation therapy,including their primary containers.4 Medical gases For in-vivo diagnostic purposes including lungfunction tests.MEDICAL DEVICEMEDICAL DEVICE(If it containspharmacologically activesubstance, it will be classifiedas DRUG)DRUGDRUG5 In vivo diagnosticagents6 Hyaluranon basedproducts used as;For diagnostic purposes, carrier solutions tostabilize micro bubbles for ultrasound imaging.DRUGa) Synthetic-fluidtissuereconstructivematerialb) Synovial jointreplacement fluid(Joint lubricant)To correct cutaneous contour deformities of theskin (e.g. wrinkles, folds, scars), particularly incases of ageing or degenerative lesions, or as asubmucosal implant in the urinary tract for urinaryincontinence or vesicoureteral reflux. It may alsobe injected into the vocal cords to treat the effectsof paralysis, atrophy, or scarring.To help cushion the joint, especially in cases ofendogenous synovial fluid reduced viscosity fromdegenerative disease.MEDICAL DEVICEMEDICAL DEVICENational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 46

Drug Registration Guidance Document (DRGD)c) Aqueous/vitreous humourreplacementmedium7 Peritoneal dialysisdialysate8 HaemodialysisdialysateIt is used to assist in performing during ophthalmicsurgery, e.g. to maintain the shape of the eyeballduring the intervention, preserve tissue integrity,protect from surgical trauma, or to function as atamponade during retinal reattachment.It is used for the exchange of solutes across theperitoneum of the patient (in this case, used as asemi-permeable membrane)It is used for the exchange of solutes with bloodthrough a semi-permeable membrane in thedialyser of a haemodialysis system.MEDICAL DEVICEDRUGMEDICAL DEVICE9 Fluoride dentalpreparationsa) Oral care product To maintain oral hygiene.COSMETIC(If concentration of fluoride isless than or equal to1500ppm)To maintain oral hygiene and prevent oraldiseases.DRUG(If concentration of fluoridemore than 1500ppm)b) Fluoride dentalpreparations witha typical devicemode of action.10 Wound treatmentproducta) comprising amatrixb) comprising amatrixTo provide filling to the cavity and provide layer fordiseases prevention.To administer medicinal product.To provide protective layer/ barrier to preventmicrobial penetration and create healingenvironment.MEDICAL DEVICEDRUGMEDICAL DEVICEc) providing a matrix,typically of livingcells (fibroblasts)and/or structuralproteinsTo facilitate the infiltration of native skin elements(e.g., fibroblasts, leukocytes, blood vessels) forskin regeneration.MEDICAL DEVICEd) topical applicationto a skin wound(e.g. abrasion,laceration, cut,ulcer)To facilitate local haemostasis primarily throughhaemoglobin binding. It is available in variousforms (e.g. gel, spray, powder, ointment, plaster/gauze pad) that can be applied directly to thewound where it forms a seal of transparent layer.MEDICAL DEVICENational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 47

Drug Registration Guidance Document (DRGD)e) topical applicationto a skin woundTo provide and maintain a moist internalenvironment for wounds to assist the healingprocess.MEDICAL DEVICE11 Medicated healthpatch - To relieve fatigue, body aches, joint pains; or- To regulate hormone imbalanceDRUG12 Personal IntimateHygiene Product(Rinse off)For the female intimate hygiene.COSMETIC13 Personal IntimateLubricantTo use as vaginal lubricants during the climaterium(pre-menopause, menopause, post-menopause)and to treat irritations in vaginal epithelium in casesof physiological decrease of lubrication andconsequent increase in vaginal dryness.MEDICAL DEVICE14 Root canal fillingincorporatingantibioticTo use for symptomatic relief of vaginal irritation bylowering the pH value.To seal the canal and disinfecting the dentinalwalls by diffusing through dentine. The antibioticprovides ancillary actions as bactericidal antibioticand anti-inflammatory agent to assist in reducingpain and in maintaining a bacteria-freeenvironment within the root canal.DRUGDrug-device combinationproduct regulated asMEDICAL DEVICE15 Synthetic-fluid tissuereconstructivematerial(Soft tissue fillerincorporating localanaesthetic)It is used for correction of moderate to severe facialwrinkles and folds (such as nasolabial folds) andlocal anaesthetic is an ancillary medicinalsubstance to provide patients with a morecomfortable injection experience during procedure.Drug-device combinationproduct regulated asMEDICAL DEVICENational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 48

Drug Registration Guidance Document (DRGD)16 General PurposeSurgical DrapeA sterile protectivecovering made ofnatural or syntheticmaterials, or bothTo isolate a site of surgical incision or a surgicalfield from contamination (e.g., microbial,substance) in various clinical settings (e.g. in anoperating room or catheterization laboratory). Thedevice may also be used to protect a patient fromheat/ flame during a surgical procedure. This is areusable or single use device.MEDICAL DEVICE(If the product/ device did notcontain Iodine or containedIodine < 2%)DRUG(If the product/ devicecontained Iodine ≥ 2%)17 Wart Cryogenic KitA refrigerant madefrom dimethyl etherand propane.To freeze superficial skin lesions (e.g. warts) fortheir destruction and removal.MEDICAL DEVICE18 Pressure-ulcerTopical DressingA solution or emulsiondesigned to be appliedto dermal pressuresores.To prevent and treat pressure/ decubitus ulcersand lower extremity ulcers. It is intended primarilyto create a barrier between the skin lesion(s) andthe external environment to promote protection andhealing.MEDICAL DEVICE19 Hand Sanitizer For general hand hygiene COSMETICNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 49

Drug Registration Guidance Document (DRGD)2. DATA EXCLUSIVITYData exclusivity refers to protection of undisclosed, unpublished and non-public domainpharmaceutical test data, the origination of which involves a considerable effort, submittedas required to the Director of Pharmaceutical Services for the purpose of scientificassessment in consideration of the:a) Quality, safety and efficacy of any new drug product containing a New Chemical Entityb) Safety and efficacy for a second indication of a registered drug product as a conditionfor registration of any new drug product containing a New Chemical Entity; or approvalfor a Second Indication of a registered drug product.For information pertaining to Register of Data Exclusivity Granted in Malaysia, please refer:Register of Data Exclusivity Granted in Malaysia (New Drug) and Register of DataExclusivity Granted in Malaysia (Second Indication)2.1 HOW TO APPLYAn application for Data Exclusivity (DE) can be made via a Letter of Intent (LOI) inconjunction with the:a) Application for registration of a new drug product containing a New Chemical Entity; orb) Application for a Second Indication of a registered drug product.The LOI shall be addressed and submitted manually to the Director of NPCB.The application must comply with all terms and conditions stated in the directive ArahanBagi Melaksanakan Data Eksklusiviti Di Malaysia, Bilangan 2 Tahun 2011.The following details are extracted from the Directive on Data Exclusivity (DE) issued bythe Director of Pharmaceutical Services under Regulation 29 of the Control of Drugs andCosmetics Regulations 1984, Bil (11) dlm BPFK/PPP/01/03 Jld 1, 28 February 2011.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 50

Drug Registration Guidance Document (DRGD)2.2 APPLICABILITY AND DATE OF COMING INTO FORCEThe directive is applicable to:i) New drug product containing a new chemical entity; andii) Second indication of a registered drug product.New drug product containing any new chemical entity means a product that containsan 1 active moiety that has not been registered in accordance with the provisions ofthe CDCR 1984.1 An active moiety is defined as the molecule or ion, excluding those appendedportions of the molecule that cause the drug to be an ester, salt (including a salt withhydrogen or coordination bonds) or other non-covalent derivative (such as acomplex, chelate or clathrate) of the molecule, responsible for the physiological orpharmacological action of the drug substance.Second indication for a registered drug product means a single or cluster oftherapeutic indications applied subsequent to the first indication(s) approved at thepoint of registration of the product. The application for approval of the secondindication contains reports of new clinical investigations other than bioavailabilitystudies.The directive shall come into force on 1 st March 2011.2.3 GRANT OF DATA EXCLUSIVITYAny person may apply for Data Exclusivity. Such application shall be made uponsubmission of documents to the Director of Pharmaceutical Services for the:a) Registration of a new drug product containing a new chemical entity; orb) Approval for second indication of a registered drug product.An application for Data Exclusivity shall only be considered if the application inMalaysia for:a) New drug product containing a new chemical entity is made within eighteen (18)months from the date the product is first registered or granted marketingauthorization; ANDNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 51

Drug Registration Guidance Document (DRGD)Granted Data Exclusivity/ Test Data Protection in the country of origin or in anycountry, recognized and deem appropriate by the Director of PharmaceuticalServices.b) Second indication of a registered drug product is made within twelve (12) monthsfrom the date the second indication is approved; ANDGranted Data Exclusivity/ Test Data Protection in the country of origin or in anycountry, recognized and deemed appropriate by the Director of PharmaceuticalServices.Before the Data Exclusivity is granted:a) The applicant of a new drug product containing a new chemical entity shallprovide to the Director of Pharmaceutical Services the undisclosed, unpublishedand non-public domain pharmaceutical test data, the origination, of whichinvolves a considerable effort; ORb) The applicant for a second indication of a registered drug product shall provide tothe Director of Pharmaceutical Services, the reports of new clinical investigationsother than bioavailability studies, conducted in relation to the second indicationand the origination of which has involved considerable effort.The Director of Pharmaceutical Services shall decide on whether the application willbe granted the Data Exclusivity. The period of the Data Exclusivity granted shall bemade on a case to case basis.The period of the Data Exclusivity shall not be more than:a) Five (5) years for a new drug product containing a new chemical entity; andb) Three (3) years for a second indication of a registered drug product. The periodof Data Exclusivity is for the data concerning the second indication only.Calculation of the period of Data Exclusivity:a) For a new drug product containing a new chemical entity, the period of DataExclusivity shall be calculated from the date the product is first registered orgranted marketing authorization AND granted Data Exclusivity/ Test DataProtection in the country of origin or in any country recognized and deemedappropriate by the Director of Pharmaceutical Services.b) For a second indication of a registered drug product, the period of DataExclusivity shall be calculated from the date the second indication is firstNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 52

Drug Registration Guidance Document (DRGD)approved AND granted Data Exclusivity/ Test Data Protection in the country oforigin or in any country recognized and deemed appropriate by the Director ofPharmaceutical Services.2.4 CONSIDERATION OF OTHER APPLICATIONS UPON THEGRANT OF DATA EXCLUSIVITYFor a registered new drug product containing a new chemical entity, registration ofany other drug product where the active moiety is in all respect the same as theactive moiety in the registered drug product which has been granted Data Exclusivityin Malaysia can be considered if:a) The applicant provides undisclosed, unpublished and non-public domainpharmaceutical test data, the origination of which involves a considerable effortto demonstrate the quality, safety and efficacy if the drug product submitted forregistration; ORb) The applicant has obtained consent in writing for right of reference or use of thetest data from a person authorised by the owner of the registered new drugproduct containing a new chemical entity.2.5 NON-APPLICATION OF DATA EXCLUSIVITYNothing in the Data Exclusivity shall:a) Apply to situations where compulsory licences have been issued or theimplementation of any other measures consistent with the need to protect publichealth and ensure access to medicines for all; orb) Prevent the Government from taking any necessary action to protect publichealth, national security, non-commercial public use, national emergency, publichealth crisis or other extremenly urgent circumstances declared by theGovernement.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 53

Drug Registration Guidance Document (DRGD)2.6 APPEALAny person aggrieved by the decisions of the Director of Pharmaceutical Servicesmay make a written appeal to the Minister within fourteen (14) days from the datethe decision is made known to him and any decision of the Minister made on anappeal shall be final.A person making an appeal may submit any supporting data or documents to theDirector of Pharmaceutical Services not later than:a) 120 days for application of new drug products containing any new chemicalentity; orb) 90 days for the application for second indication of a registered drug product.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 54

Drug Registration Guidance Document (DRGD)3. APPLICATION FORMALITIES3.1 WHO CAN APPLY FOR PRODUCT REGISTRATIONThe applicant for product registration shall be known as the Product RegistrationHolder (PRH) and must be a locally incorporated company, corporate or legal entityin the field of pharmaceuticals, with permanent address and registered with eitherCompanies Commission of Malaysia (with the scope of business related to thehealth/ pharmaceutical product as it appears in the `Memorandum and Article ofAssociation‟ of the company).The name of the PRH, including product manufacturer shall not reflect the following:a) Name of a government agency;b) Name of a research/ institute of higher education;c) A name that reflects the quality of pharmaceutical producte.g. “Amalan Perkilangan Baik (APB)”, Good Manufacturing Practice (GMP);d) Name of a disease;e) Name of an organ.e.g. Heart, Brain, Kidney etc.The PRH (if the company is not the product owner) should be authorized in writingby the product owner to be holder of the product registration certificate and beresponsible for all matters pertaining to quality, safety and efficacy of the product.This shall include updating any information relevant to the product/ application.3.2 RESPONSIBILITY OF APPLICANTa) To ensure that all transactions with NPCB shall be done by their appointedperson(s);b) Responsible for all information pertaining to quality, safety and efficacy in supportof the product registration application; and shall inform the Authority in a timelymanner any change in product information during course of evaluation;National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 55

Drug Registration Guidance Document (DRGD)Under the CDCR 1984, Regulation 8(9): Any person who knowingly supplies anyfalse or misleading information to the Authority with his application for theregistration of a product commits an offence.c) Responsible for all matters pertaining to quality, safety and efficacy of theregistered product, including:i. Data updates on product quality, safety and efficacy or current GoodManufacturing Practice (cGMP) compliance of the manufacturers (andrepackers, where applicable).Under the CDCR 1984, Regulation 8(5): Any change in any document,item, sample, particulars or information which shall be notified in writing bythe applicant to the Authority within fourteen (14) days from the date ofsuch change.ii. Any decision to withdraw the registration of the product with reasons.d) To notify the Authority of any change in correspondence details, including thename, address, contact person, telephone number, fax number and email;e) To notify the Authority immediately upon cessation of the applicant as theproduct registration holder;3.3 HOW TO APPLYFor registration of products, only web-based online submissions via QUEST athttp://www.bpfk.gov.my shall be accepted.To conduct transactions via QUEST system, the applicant must first register amembership for QUEST system with NPCB and purchase a USB Token thatcontains a User Digital Certificate, from Digicert Sdn. Bhd., which shall be installedto the applicant‟s computer.For details, please refer to Frequently Asked Questions on QUEST System.For charges regarding QUEST USB token, please refer to Appendix 1: Fees.The applicant shall be responsible for any act of fraudulence or misuse pertaining toits authorized QUEST USB token(s).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 56

Drug Registration Guidance Document (DRGD)The NPCB reserves the rights to approve or reject any application for the QUESTmembership.4. FEESUnder the CDCR 1984, Regulation 8(3): The Authority may charge any applicantsuch costs as it may incur for the purpose of carrying out any evaluation orinvestigation prior to the registration of any product.Any payment made shall NOT be REFUNDABLE once the application has beensubmitted and payment confirmed.Applications without the correct fees will not be processed.4.1 FEES IMPOSEDPlease refer to Appendix 1: Fees for fees imposed, which include:a) Charges for USB Token of QUEST Membership;b) Processing and Analysis Fee for Product Registration;c) Charges for Application of Licence;d) Charges for Amendments to Particulars of a Registered Product; ande) Fee for Certificates.4.2 MODE OF PAYMENTThe processing fee and any other charges shall be paid in the form of bank draft/banker‟s cheque/ money order/ postal order made payable to “Biro PengawalanFarmaseutikal Kebangsaan”.A separate bank draft/ banker‟s cheque/ money order/ postal order are required foreach application.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 57

Drug Registration Guidance Document (DRGD)5. TYPES OF APPLICATION5.1 REGISTRATION OF PRODUCTS5.1.1 APPLICATION FOR PRODUCT REGISTRATION FOR THEFOLLOWING CATEGORIES:a) New Drug Products;b) Biologics;c) Generic;d) Health supplements; ande) Natural Products.For details, please refer to Section A, 1.2 Categories of Product and SectionB: Product Registration Process.5.1.2 REGISTRATION OF COMBINATION PACK (COMBO PACK)a) Refers to products which are packed together in combination for atherapeutic regimen such as for the treatment of Helicobacter Pylori,Hepatitis C, etc.).b) Shall be registered as a single product.c) Must consist of registered products only:i. Where a combination pack consists of registered and unregisteredproducts, the unregistered product needs to be registered first, priorto submission of the application;ii.Where a combination pack consists of registered products fromdifferent product owners/ PRH, letters of authorization whichinclude product name and product registration number from eachproduct owner shall be submitted.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 58

Drug Registration Guidance Document (DRGD)d) A product which is packed together with diluent(s)/ adjuvant(s) is NOTconsidered as a combination pack.e) Labelling requirement specifically for combination pack is shown inTable IV:No. Outer Label Immediate Label1. Name of combination packIndividual name for each productsOR name of combination pack2.3.4.5.Registration number for thecombination packName and address ofmanufacturer and productregistration holderBatch number of thecombination pack productExpiry date(according to the shortestexpiry date from the individualproducts)Individual registration number foreach products OR registrationnumber for combination packName and address ofmanufacturer and productregistration holderIndividual batch number for eachproductsIndividual expiry date for eachproductsNote:These labeling requirements for a combo pack shall as well be subjectedto other labelling requirements as stated in Appendix 9.1: Label (mock-up)for Immediate Container, Outer Carton and Proposed Package Insert)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 59

Drug Registration Guidance Document (DRGD)5.1.3 REGISTRATION OF PRODUCT FOR EXPORT ONLY (FEO)a) Refers to locally manufactured products for export only which are notmarketed locally with a different formulation (e.g. colour or strength ofingredients) or shape compared to a registered product;b) For products containing ingredients/ formulations which are not allowedby the Authority for local use, applicant shall submit a confirmation inwriting from the competent authority of the importing country that there isno objection to the importation and sale of the said ingredients/formulations. Evidence of registration of the said formulation with thecompetent authority in importing country may be submitted as supportingdata;c) Upon application, a Certificate of Pharmaceutical Product (CPP) will beissued to the applicant for the registered FEO products;d) For a registered product which is marketed locally and intended to beexported, new registration for export only is NOT necessary if there is nochange in the formulation or appearance of the registered product. In thiscase, a CPP will be issued to the applicant for the registered product,together with an explanation/ declaration letter of any difference(s) to theimporting country (e.g. a product exported with a different product name),upon application.5.2 AMENDMENTS TO PARTICULARS OF A REGISTEREDPRODUCT5.2.1 VARIATIONVariation refers to change of particulars of a registered product. No change ofany particulars of a registered product shall be made without prior approvalfrom NPCB. The registration of a product shall be reviewed for suspension orcancellation if changes are made without prior approval of the Authority.There are two types of variation, which are Variation Type I and VariationType II.For details, please refer to Section E: 16.1 Variation.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 60

Drug Registration Guidance Document (DRGD)5.2.2 CHANGE IN MANUFACTURING SITEChange of Manufacturing Site (COS) refers to change of manufacturing sitefor certain part or all of the manufacturing process of a product, but it does notcover changes related to a new site, where only:a) batch release takes place ORb) to a new packager (secondary packaging or labelling), as these changesare covered under applications for amendments to the particulars of aregistered product (variation).However, a change of manufacturing site for biologics shall require a newproduct application only if the change is extensive that will have an impact onthe quality, safety and efficacy profile of the final product.For details, please refer to Section E: 16.2 Change of Manufacturing Site.5.2.3 CHANGE IN PRODUCT REGISTRATION HOLDERIt refers to a transfer of marketing authorization from the existing productregistration holder (PRH) to another proposed new holder. This applicationallows the same registration number of the registered product to bemaintained.For details, please refer to Section E: 16.3 Change of Product RegistrationHolder.5.2.4 NEW/ ADDITIONAL INDICATIONIt is defined as an indication which was not initially approved for a registeredpharmaceutical product. This shall include new therapeutic indication orindication for a new age group, such as usage in children and shall notinclude changing/ rephrasing of sentences.There are two (2) types of evaluation process available for a new/ additionalindication application, i.e. full evaluation process and verification process.For details, please refer to Section E: 16.4 New/ Additional Indication.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 61

Drug Registration Guidance Document (DRGD)5.2.5 APPLICATION FOR A CONVENIENT PACKa) Refers to products which are packed together in a single packaging unitfor convenience of the consumers, such as a Confinement Set or SetJamu Bersalin.b) Shall consist of registered products only.c) Applicable to health supplements and natural products only.d) Application for a convenient pack shall be made via the variation process.For details, please refer to Section E: 16.1 Variation and Section E: 16.5Application for a Convenient Pack.5.3 RENEWAL OF PRODUCT REGISTRATIONThe registration shall be valid for five (5) years or such a period as specified in theregistration certificate (unless sooner suspended or cancelled by the Authority);The renewal of product registration should be done not later than 6 month prior to expirytogether with appropriate fee.Please refer also at Section E: 14 Maintenance of Registration.5.4 CERTIFICATES5.4.1 CERTIFICATE OF PHARMACEUTICAL PRODUCT (CPP)A CPP which follows the format recommended by WHO shall be issued to locallymanufactured products that are to be exported. For application of CPP, applicantshall fill in form BPFK 412.2: Permohonan Perakuan Keluaran Farmaseutikal.A fee, as stated in Appendix 1: Fees, is payable on the issue of such certification.Upon receipt of complete application, the certificate shall be issued within fifteen (15)working days.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 62

Drug Registration Guidance Document (DRGD)5.4.2 GOOD MANUFACTURING PRACTICE (GMP) CERTIFICATEAccording to the CDCR 1984, compliance to Good Manufacturing Practice (GMP) isprerequisite to application of a manufacturing license, as well as product registration/cosmetic notification.GMP is a standard which shall be followed by the manufacturers to ensure that theproducts manufactured are safe, efficacious and of quality.Upon complete application, a GMP certificate will be issued and a fee, as stated inAppendix 1: Fees, is payable on the issue of such certification.If a manufacturer who wishes to build a new manufacturing premise, themanufacturer may submit a proposed premise layout plan to the Centre forCompliance and Licensing, NPCB for evaluation.For more information, please refer Section D: 13.4 GMP Certificate and/or NPCBwebsite.5.5 LICENSESNote:In addition to the relevant laws and regulations as stated in this DRGD,manufacturers are required to comply with the principles of Good ManufacturingPractice (GMP) and Good Distribution Practice (GDP). Meanwhile, Importers andWholesalers are required to comply with the principles of Good Distribution Practice(GDP).According to the CDCR 1984, any company who wishes to manufacture, import and/orwholesale any registered products needs to have Manufacturer‟s Licence, Import Licenceand/or Wholesaler‟s License.For more information pertaining application of appropriate licences, please refer Section D:13. Licensing or contact Licensing Unit, Centre for Compliance and Licensing (CCL), NPCBor NPCB website.As for processing fee for these applications, please refer to Appendix 1: FeesNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 63

Drug Registration Guidance Document (DRGD)5.6 CLINICAL TRIAL IMPORT LICENCE (CTIL)/ CLINICALTRIAL EXEMPTION (CTX)For more information pertaining to any matters of clinical trial, please refer to NPCBwebsite.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 64

Drug Registration Guidance Document (DRGD)6. GENERAL CONDITIONS FOR REGISTRATION OFDRUG PRODUCTS UNDER THE CONTROL OFDRUGS AND COSMETICS REGULATIONS 19846.1 REGISTRATION NUMBERThe product registered with the Registration Number as stated in the RegistrationCertificate shall have the name, composition, characteristics, specifications andorigin as specified in the registration documents.6.2 PRODUCT PARTICULARThe holder of the registration certificate shall supply such documents, items,samples, particulars or information as the Authority may require in relation to theregistered product.No change in name, composition, characteristics, origin, specifications,manufacturer, packing, indications, labeling, package insert, product literature or anyrelevant particulars of the registered product shall be made without prior approval ofthe Authority.6.3 LABELLINGThe registered product shall be labeled with the Registration Number. The labels forthe registered product shall comply with all other labeling requirements specified bythe Authority.6.4 PRODUCT AUTHENTICATIONThe registered product shall be affixed with the security device approved by theAuthority. The said security device (hologram), which is serialized, shall be used toauthenticate and verify that the product is registered with the Authority, and will beaffixed to each unit pack of the product, whether locally manufactured or imported.The security device shall be affixed onto the outer packaging of the product, (or,where there is no outer packaging, on the immediate packaging), on the front panelNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 65

Drug Registration Guidance Document (DRGD)of the product label. None of the product particulars on the label shall be coveredover by the security device.Please refer to:a) Appendix 9: Labelling Requirements where the security device may be affixed onthe product label;b) FAQ no. 20 on hologram, for details; andc) Circulars pertaining to hologram and the latest directive Hologram Meditag III.6.5 INDICATIONS, SPECIAL CONDITIONSThe registered product shall only be indicated for use as approved by the Authority.The importation, manufacture, sale and supply of the registered product shall complywith all other specific conditions imposed by the Authority.6.6 ADVERSE REACTIONS, COMPLAINTSThe product registration holder or any person who possesses any registered productshall inform the Senior Director of Pharmaceutical Services immediately of anyadverse reactions arising from the use of the registered product.6.7 HOLDER OF REGISTRATION CERTIFICATEThe holder of the registration certificate shall inform the Authority of any change inhis name or address.6.8 WITHDRAWAL FROM REGISTRATIONThe holder of the registration certificate shall notify the Authority with regards to anydecision to withdraw registration of a product and shall state reasons for thedecision.The holder shall also notify the Authority when he is no longer authorized to be theholder of the registration certificate.Upon withdrawal, the registration certificate is no longer valid.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 66

Drug Registration Guidance Document (DRGD)6.9 CANCELLATION, SUSPENSION, AMENDMENT BYTHE AUTHORITYThe Authority may, at any time and without assigning any reason suspend or cancelthe registration of any product, and may amend the conditions of registration. Theholder of the registration certificate shall immediately surrender to the Authority theregistration certificate upon cancellation or suspension of the registration of theproduct.The Authority may, at any time and without assigning any reason suspend or cancelthe registration of any product, and may amend the conditions of registration, uponwhich the registration certificate is no longer valid.6.10 DIRECTIVESThe Senior Director of Pharmaceutical Services may issue written directives orguidelines to any person or a group of persons as he think necessary for the bettercarrying out of the provisions of these Regulations and which in particular relate to:a) Product quality, safety and efficacy;b) Labeling;c) Change of particulars of a product;d) Transfer of licenses;e) Manufacturing;f) Storage includes requirements as to containers;g) Retailing;h) Promotion of sale including product information;i) Product recall;j) Product disposal;k) The cost of product recall or product disposal;l) Clinical trials; orm) Records and statistics pertaining to manufacture, sale, supply, import or export ofany products.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 67

Drug Registration Guidance Document (DRGD)7. USE OF HALAL LOGOHalal logo may be used voluntarily on registered product label for the following categories,for both local and export market, provided that such products have been certified andapproved halal by the Malaysia Department of Islamic Development (Jabatan KemajuanIslam Malaysia, JAKIM):a) Non-scheduled poison, excluding parenteral dosage form and veterinary products;Reference: Circular (95)dlm.BPFK/PPP/01/03 Jld. 2b) Health supplements;c) Natural products; andd) Cosmetics.However, the logo is NOT allowed to be used on label of registered products other than thecategories as listed above.Only halal logo issued by JAKIM or any Islamic Body which is recognized by JAKIM shallbe accepted.Consideration by the Authority for use of halal logo on product label of such products shallbe based on application as it is not a mandatory requirement.Applicant shall submit application for variation type II to NPCB for approval to affix halallogo on product label of a registered product of which a halal certification has been granted.A copy of the halal certificate must be submitted as a supporting document.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 68

Drug Registration Guidance Document (DRGD)SECTION B: PRODUCT REGISTRATION PROCESSThe process of product registration ensures that pharmaceutical products are evaluated forits safety, efficacy and quality, whereas natural products are evaluated for its safety andquality, prior to being registered by the Authority and finally released into the market.8. FLOW OF REGISTRATION PROCESSFigure 4:Process of Product RegistrationApplicationRejectedNon-SatisfactorySubmission ofApplicationScreening ofApplicationSatisfactoryEvaluation ofApplicationRegulatoryOutcomeApprovedPost-RegistrationProcessRejectedAppealNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 69

Drug Registration Guidance Document (DRGD)8.1 PRE-SUBMISSION OF APPLICATIONPrior to submission of an application for product registration, applicant shall determine/understand:a) The category of the product (different product category requires different data);b) Method of evaluation;c) General and specific requirements;d) Conditions applied;e) Multiple applications;f) Variants; andg) Language.A product shall only be registered if it fulfills regulatory requirements imposed by theAuthority, especially with respect to quality, efficacy and safety of the product andtaking into consideration on the following criteria:a) Necessity of the product;b) Potential for abuse; andc) Therapeutic advantages.8.1.1 CATEGORY OF PRODUCTApplicant shall determine on the category of a product, as described under Section A -General Overview.If the product category is uncertain, applicant may submit a Classification Form to Sectionof Regulatory Coordination, Centre for Product Registration, NPCB for verification.8.1.2 METHOD OF EVALUATIONMethod of evaluation for registration of a product is divided into two (2) types, which are:a) Full Evaluation; andb) Abridged Evaluation.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 70

Drug Registration Guidance Document (DRGD)Table V: Method of Evaluation According to Product CategoriesMethod of EvaluationNo.Product CategoryFullEvaluationAbridged Evaluation1. New Drug Products √ Not Applicable2. Biologics √ Not Applicable3.Generics(Scheduled Poison)√Not Applicable4.Generics(Non-ScheduledPoison)[or known as OTC]* All productsfrom thiscategory,unless statedin AbridgedEvaluationIncludes, but not limited to the following:Antiseptics/ skin disinfectants;Locally-acting lozenges/ pastilles;Topical analgesic/ counter-irritants;Topical nasal decongestants;Emollient/ demulcent/ skin protectants;Keratolytics;Anti-dandruff;Oral care;Anti-acne;Medicated plasters/ patch/ pad; andTopical antibacterial.5.Health Supplementsa) General orNutritional Claimsb) FunctionalClaims (Medium)c) Disease RiskReduction Claims(High)Not ApplicableNot Applicable√√√Not Applicable6. Natural Products Not Applicable √National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 71

Drug Registration Guidance Document (DRGD)* Table VI:Products containing Glucosamine, Chondroitin and Methylsulphonylmethane (MSM)No.ProductProductCategoryRoute ofEvaluationConditionon ProductIndicationRemark1.ProductscontainingGlucosamineAs singleactiveingredientAscombinationwithChondroitinand/or MSMOTCOTCFullevaluationFullevaluationAs adjuvanttherapy forosteoarthritisAs adjuvanttherapy forosteoarthritisAs combinationwith othersupplementingredients areNOT allowed tobe registeredAs singleingredient2.ProductscontainingChondroitinORIncombinationwith othersupplementingredientsHealthsupplementAbridgedEvaluationNotherapeuticclaims areallowed-As singleingredient3.ProductscontainingMSMORIncombinationwith othersupplementingredientsHealthsupplementAbridgedEvaluationNotherapeuticclaims areallowed-AscombinationwithChondroitinHealthsupplementAbridgedEvaluationNotherapeuticclaims areallowed-Reference: Circular Bil (66) dlm BPFK/02/5/1.3National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 72

Drug Registration Guidance Document (DRGD)8.1.3 REQUIREMENTS FOR PRODUCT REGISTRATIONApplicant shall submit the following requirements to support an application for productregistration, applicable according to different category of product:a) General requirements (either for full or abridged evaluation);i) Full Evaluation;(In accordance to ASEAN ACTD/ ACTR or ICH guidelines)OR• Part I - Administrative data and product information;• Part II - Data to support product quality (Quality Document);• Part III - Data to support product safety (Nonclinical Document); and• Part IV - Data to support product safety and efficacy (Clinical Document).ii) Abridged Evaluation.For details, please refer Appendix 2: Requirements for Product Registrationb) Specific requirements according to category of product (biologics, health supplementsand natural products).- Biologics : Refer Appendix 3: Guideline on Registration of Biologics- Healthsupplements- Naturalproducts: Refer Appendix 4: Guideline on Registration of HealthSupplements: Refer Appendix 5: Guideline on Registration of NaturalProductsFor regulatory control of active pharmaceutical ingredient (API), it is applicable to allpharmaceutical products either locally manufactured or imported, excluding biologics,health supplements and natural products.The implementation has begun with voluntary submission for New Drug Product (NDP) inApril 2011 and followed by;Phase 1 - New Drug Products (NDP) (mandatory in Jan 2012)Phase 2 - Generics (Scheduled Poison) (to be determined)Phase 3 - Generics (Non-scheduled Poison) (to be determined)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 73

Drug Registration Guidance Document (DRGD)No separate application for registration of the API is required. However, the requiredtechnical documentation pertaining to each API at Part 2.S ACTD (Part II Quality: DrugSubstance) shall be submitted as part of the application for product registration.For details pertaining to regulatory control of API, please refer Appendix 6: Guideline onRegulatory Control of Active Pharmaceutical Ingredients (API).8.1.4 CONDITIONS APPLIED ON PRODUCT REGISTRATIONApplicant shall comply with the following conditions applied on product registration. Failureto do so shall results in rejection of the application by the Authority.a) Applicant shall comply with all requirements as specified in the following appendicesand directions from the Authority:i) Appendix 7:Special Conditions for Registration for a Particular Product or Group of Products;ii) Appendix 8:List of Permitted, Prohibited and Restricted Substances;iii) Appendix 9:Labelling Requirements;iv) Appendix 10:Guideline on Patient Dispensing Pack for Pharmaceutical Products in Malaysia(Applicable to pharmaceutical products only).b) Applicant shall provide supplementary data/ information, documentation or samples, ifrequested by the Authority;c) Applicant shall respond and provide feedback for the requested supplementary data/information, documentation or samples by the Authority within the specified timeframe.If the applicant is unable to submit the requirements within the specified timeframe, awritten request for an extension shall be submitted to NPCB;d) Application shall be rejected if the applicant fails to submit required supplementary data/information, documentation or samples within six (6) months from the firstcorrespondence date;(Reference: Circular Bil (08) dlm. BPFK/PPP/01/03)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 74

Drug Registration Guidance Document (DRGD)e) Applicant shall submit sample of natural product for laboratory testing to the Centre forQuality Control, NPCB within fourteen (14) days from date of confirmed payment.Failure to do so within thirty (30) days from the date of the payment shall result inrejection of the application;8.1.5 MULTIPLE APPLICATIONSSeparate application for product registration shall be required for each product for thefollowing conditions:a) Products containing the same ingredients but made to different specifications, in termsof strength/ content of ingredient(s), dosage form, description, etc.; orb) Different manufacturer.However, different packings (materials) or pack sizes (quantity/ volume) of a product madeby the same manufacturer to the same specifications, formulation and dosage form(including parenteral preparations, peritoneal dialysis fluids and haemofiltration solutionswhich are introduced into human bodies) shall require only one application for productregistration. The product registration shall be for the packings and pack sizes stated in theregistration documents only.Note:Registration of same product in all aspects but with different product name by the samePRH is not allowed by the Authority.8.1.6 SECOND OR THIRD SOURCEIt is defined as product which is the same as the product from first source in all aspects,except for the site of manufacture.An application for a second source may be considered by the Authority but only withjustification.For biologics, a third source may be considered if justified.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 75

Drug Registration Guidance Document (DRGD)8.1.7 VARIANTSVariants refer to products with differences in terms of fragrance/ flavour or consequentlycolour.When variants are registered:a) The variants should only differ in terms of fragrance/ flavour and colour.b) Product name of the variants shall remain the same, with the addition of an identifyingvariant name.c) Each variant shall be registered as one (1) product with a different registration number.A maximum of five (5) variants to the registered product may be considered for thefollowing dosage forms:a) Products Containing Scheduled PoisonONLY for pediatric oral liquid preparationsb) Products Containing Non-Scheduled Poisoni) Lozenges;ii) Chewable tablets;iii) Effervescent powders/ tablets;iv) Powder;v) Granule;vi) Oral liquid;vii) Dental preparations (rinses, dentifrices);viii)Medicated soaps (bar, liquid); andix) Vaginal creams and douches.8.1.8 LANGUAGEAll data and information including supporting documents for product registration such ascertificates, letters and product labels shall be in English or Bahasa Malaysia.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 76

Drug Registration Guidance Document (DRGD)8.2 SUBMISSION OF APPLICATIONApplication of product registration shall be submitted via the online QUEST system atwww.bpfk.gov.my.Applicant shall ensure all data requirements needed to support the application is fulfilledbefore submission.Upon submission, the application shall be given a call number for reference, which isspecific to a particular product. Applicant shall refer to this call number during allcorrespondence pertaining to the registration of the product.Applicants are advised to read the explanatory notes as stated in Appendix 11: Guidelineon Filling the Online Application Form for Product Registration via Quest System, and alsorelevant ASEAN or ICH guidelines and checklists, for full information on requirement forproduct registration.8.3 SCREENING OF APPLICATIONAfter an online submission of the product registration application has been done, theapplication shall be undergone an initial evaluation (or known as screening process) whichshall ensure the required data/ information of the submitted application are complete.Further evaluation shall be done after payment for the application has been made.8.3.1 SATISFACTORYOnly complete application shall be accepted and approved for payment.Upon approval from the screening process, applicant shall print three (3) copies of paymentvoucher and submit two (2) copies of payment voucher together with correct fees toFinance Department, NPCB for payment confirmation. Applicant shall keep a copy of thepayment voucher for future reference. A product reference number shall be given to theapplication upon payment confirmation.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 77

Drug Registration Guidance Document (DRGD)Applicant shall make payment within thirty (30) days from the date of approval for payment.The application form shall be deleted from the system if payment has not been made withinthe specified timeframe.8.3.2 NON-SATISFACTORYIf the application is found incomplete during the screening process, the application shall berejected and the applicant shall be notified via the system.Note:If there is any decision made by the applicant/ required by the Authority in certain casesto withdraw a submitted application for registration of a product, at any stage ofevaluation prior to its approval, the applicant shall notify the Authority and shall state thereasons for the decision.8.4 EVALUATION OF APPLICATION8.4.1 INITIATION OF REVIEWUpon confirmation of payment, the application with the submitted data shall be evaluated.Review of applications shall follow a queue system. There shall be separate queues for thedifferent categories of products and/or according to level of claims i.e. general, medium orhigh claim.Priority review may be granted for product which is intended for treatment of a serious orlife-threatening disease, where the likelihood of death is high unless the course of thedisease is interrupted.8.4.2 CORRESPONDENCECorrespondence via the system shall be sent to the applicant if there is any clarification andfurther supplementary data/ information, documentation or samples pertaining to theapplication, if deemed necessary by the Authority.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 78

Drug Registration Guidance Document (DRGD)Application shall be rejected if the applicant fails to respond to the correspondence fromNPCB to submit the required supplementary data/ information, documentation or sampleswithin six (6) months from the first correspondence date. (Reference: Circular Bil (08) dlm.BPFK/PPP/01/03)8.4.3 STOP CLOCKUnder review.8.4.4 TIMELINE FOR PRODUCT REGISTRATIONTable VII:No.(A)Full EvaluationProduct Category* Duration(Inclusive screening process)1. New Drug Products 245 working days2. Biologics 245 working days3. Generics (Scheduled Poison) 210 working days4. Generics (Non-Scheduled Poison) 210 working days(B)Abridged Evaluation*Duration(Inclusive screening process)5.Generics (Non-Scheduled Poison)(Product categories as stated in Table V above)80 working days6.Natural Productsa) Single active ingredientb) Two (2) or more active ingredientsa) 116 working daysb) 136 working daysNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 79

Drug Registration Guidance Document (DRGD)(B)Abridged Evaluation*Duration(Inclusive screening process)7. Health Supplementsa) ** Single active ingredientb) ** Two (2) or more active ingredientsa) 116 working daysb) 136 working days** Applicable for:i) General or Nutritional Claims; andii) Functional Claims (Medium Claims)c) Disease Risk Reduction Claims(High Claims)c) 245 working days* Upon receipt of complete application.8.5 REGULATORY OUTCOME8.5.1 DECISIONS OF THE AUTHORITYA regulatory decision shall be made based on the outcome of the evaluation of thesubmitted documentation, and samples (if applicable). An application may beapproved or rejected by the Authority, and the Authority decision will be sent viaemail/ official letter to the product registration holder.As stipulated under the CDCR 1984, Regulation 11(1), the Authority may, at anytime reject, as well as cancel or suspend the registration of any product if there aredeficiencies in safety, quality or efficacy of the product or failure to comply withconditions of registration.8.5.2 PRODUCT REGISTRATION NUMBERAs stipulated in Regulation 8(8), CDCR 1984, upon registration of a product by theAuthority, the product registration holder shall be notified by the Authority and aNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 80

Drug Registration Guidance Document (DRGD)product registration number (i.e. MAL number) shall be assigned to the registeredproduct via the system.The registration number is specific for the product registered with the name, identity,composition, characteristics, origin (manufacturer) and product registration holder,as specified in the registration documents. It shall NOT be used for any otherproduct.8.5.3 CERTIFICATE OF REGISTRATIONForm 1 (Certificate of Registration) for a product with the provisions, conditions,limitations and etc. of the registration, as stipulated in Regulation 8(8) of CDCR1984, has been deleted from the regulation in year 2006 via amendment of PU(A)336/06. Therefore, the certificate will no longer be issued by the Authority.Applicant shall refer to the product registration approval notification sent by theAuthority or the Approved Product Registration List in NPCB website.Reference: Circular (100)dlm.BPFK/PPP/01/03 Jld. 28.6 POST-REGISTRATION PROCESSRegistration status of a product shall be valid for five (5) years or such period as specifiedin the registration certificate (unless the registration is suspended or cancelled by theAuthority).Upon approval for product registration by the Authority, applicants shall fulfill allcommitments and conditions imposed during approval of the product registration and shallbe responsible for the maintenance of the product in terms of quality, safety and efficacythroughout the validity period of registration. Failure to do so may result in rejection ofapplication for renewal of product registration.The Authority shall be notified of any changes to the product‟s efficacy, quality and safety,as described in detail at Section E: Post-Registration Process.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 81

Drug Registration Guidance Document (DRGD)8.7 REJECTED APPLICATIONAs stipulated in Regulation 18, CDCR 1984:a) Any person aggrieved by the decision of the Authority or the Director of PharmaceuticalServices, a written appeal may be made to the Minister of Health Malaysia;b) All notice of appeals shall be made within fourteen (14) days from the date ofnotification from the Authority;- A period of 180 days from the date of notice of appeal is given for submission of anyadditional information/ supplementary data/ documents for New Drug Products andBiologics.- A period of 90 days is allowed for other categories of product.- The appeal shall not be considered if all the required information is not submittedwithin the specified timeframe given. Any request for extension of this periodshall not be considered too.c) Any decision of the Minister made on an appeal shall be final.Re-submission for product registration of a rejected application due to reason of safety andefficacy shall not be accepted within two (2) years after the rejection. However, if theproduct is registered in the reference countries, submission of application can be madeearlier.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 82

Drug Registration Guidance Document (DRGD)8.7.1 PROCESS OF APPEAL FOR QUEST 2 PRODUCTFigure 5:* Applicants may confirm toappeal for rejected application ofany product within 14 daysfrom the date of notificationfrom the Authority, via theQUEST systemApplicant shall print a copy ofappeal letter generated by theQUEST system on thecompany‟s letterhead* Note:For suspended/ cancelled registration of aproduct, applicant may confirm to appealmanually by sending an appeal letter to NPCBwithin fourteen (14) days from the receipt ofnotification letter from the Authority, and itshall be subjected to the same process ofappeal.Applicant shall send the signedappeal letter to NPCB as peraddress stated in the letter** Applicant shall submitrequired additional information/supplementary data/ documentswithin 90 or 180 days from thedate of appeal confirmationEvaluation by the AuthorityMemorandum of appealprepared by the Authority andsent to the Minister of Healtha) ** 90 Days is a timeframe given to applicantapplicable for rejected application of theseproduct categories: generic (scheduled poison& non-scheduled poison), health supplementand natural product. Additional information/supplementary data/ documents shall besubmitted via QUEST system.b) ** 180 Days is a timeframe given to applicantapplicable for rejected application of new drugproduct and biologics; and cancelledregistration of an adulterated product.Additional information/ supplementary data/documents shall be submitted manually toSection of Regulatory Coordination, Centre forProduct Registration, NPCB.Regulatory outcomeRejectedAppeal rejectedApprovedPost-Registration ProcessNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 83

Drug Registration Guidance Document (DRGD)8.7.2 PROCESS OF APPEAL FOR QUEST 3 PRODUCTFigure 6:# Applicants may confirm toappeal for rejected application ofany product within 14 daysfrom the date of notificationfrom the Authority# Note:The same process of appeal is applicable toregistration of a product which has beensuspended/ cancelled by the Authority.Applicant shall submit appealletter to NPCB as per addressstated in the template appealletter*** Applicant shall submitrequired additional information/supplementary data/ documentswithin 90 or 180 days from thedate of appeal confirmationEvaluation by the AuthorityMemorandum of appealprepared by the Authority andsent to the Minister of Health*** Note:a) 90 Days is a timeframe given to applicantapplicable for rejected application of theseproduct categories: generic (scheduled poison &non-scheduled poison), health supplement andnatural product. Additional information/supplementary data/ documents shall besubmitted manually to Section of RegulatoryCoordination, Centre for Product Registration,NPCB.b) 180 Days is a timeframe given to applicantapplicable for rejected application of biologicsand new drug product; and cancelledregistration of an adulterated product. Additionalinformation/ supplementary data/ documentsshall be submitted manually to Section ofRegulatory Coordination, Centre for ProductRegistration, NPCB.c)Regulatory outcomeRejectedAppeal rejectedApprovedPost-Registration ProcessNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 84

Drug Registration Guidance Document (DRGD)8.7.3 TEMPLATE FOR AN APPEAL LETTERLETTERHEAD SYARIKAT PEMEGANG PENDAFTARAN PRODUKNama dan alamat pemegangTarikh:Y. B. Menteri Kesihatan Malaysiad/a Biro Pengawalan Farmaseutikal KebangsaanKementerian Kesihatan MalaysiaJalan Universiti, Peti Surat 319,46730 Petaling Jaya(u.p. Setiausaha PBKD)Y. B.,PERATURAN 18 – RAYUAN TERHADAP PENOLAKAN PERMOHONANPENDAFTARANNAMA PRODUK : Sila nyatakan nama produk (Please state the product name)NO. RUJUKAN : Sila nyatakan nombor pendaftaran produk(Please state reference number of the product)Dengan segala hormatnya, pihak kami ingin membuat rayuan terhadap penolakanpermohonan produk seperti di atas.2. Alasan – alasan rayuan serta data tambahan/ maklumat akan dihantar kepadapihak Y.B. dalam tempoh *90 hari / 180 hari dari tarikh surat ini dikeluarkan.Sekian, terima kasih.Yang benar,Tandatangan Wakil Pemegang(NAMA WAKIL PEMEGANG)Jawatan Wakil Pemegang* Potong mana-mana yang tidak berkaitan.(Please cross out words that do not apply.)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 85

Drug Registration Guidance Document (DRGD)SECTION C: QUALITY CONTROLThe requirement for the submission of the protocol of analysis (POA), analyticalmethod validation (AMV) and product samples for laboratory testing are presented inthis section.The submission of POA and AMV to the Centre for Quality Control shall be done viathe online system (Quest system) and also using hardcopies, once payment for theregistration has been confirmed. Documents to be submitted are listed below:Documents to be submitted via online Quest system1. E9 : Complete protocol of analysis for finished product includingpreservatives and diluents (if any).2. E10 : Summary of AMV which includes all the relevant validationcharacteristics, its acceptance criteria and results.3. E11 : Certificate of analysis for active drug substance (1 batch) andrecent batches of finished product (3 different batches).Documents to be submitted as hardcopy:1. Certificate of analysis for active drug substance (1 batch) and recent batches offinished product (3 different batches)2. Complete protocol of analysis for active drug substances and finished product(including preservatives and diluents, if any)3. Complete testing method for the AMV.4. Complete results for the AMV with all relevant validation parameters, includingacceptance criteria and supporting raw data (e.g. chromatograms, spectrums etc.)Note:1. A cover letter consisting of the following information should be enclosed with everyhard copy document submission:i) Name of product;ii) Reference Number/ Protocol Number;iii) Contact person (name/ email address/ telephone no.);iv) Name and address of company.2. Documents submitted should be well organized and indexed.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 86

Drug Registration Guidance Document (DRGD)9. GUIDELINE FOR THE SUBMISSION OF PROTOCOL OFANALYSIS (POA)This guideline consists of general and specific requirements for the POA submission.The general requirements are referred to POA content whilst details of the testmethods are illustrated in the specific requirements9.1 GENERAL REQUIREMENTSa) The POA shall be written in Bahasa Malaysia or English only.b) The POA shall contain the following information:i) Name of product;ii) Name and address of manufacturer;iii) Name, signature and designation of authorized person;iv) Effective date and Review date.c) The POA shall comply with the following requirements :i) To provide updated testing methods, shelf-life specifications and certificate ofanalysis for the intended product to be registered.ii) References used must be clearly stated.iii) The latest version of British Pharmacopoeia (BP) and United StatePharmacopeia (USP) shall be used as the main references.iv) All tests and its specification listed in BP and/or USP shall be the minimumrequirement. However, a specific testing method for quantitative analysis shallbe accepted.v) All test specifications set by the manufacturer shall be in line or more stringentthan official pharmacopoeias (BP and USP).d) Details of test methods shall include the following items:i) List of equipment and apparatus;ii) List of chemical, reagents and media;iii) Preparation of solutions such as sample, standard, mobile phase, medium etc.;iv) Setting up of analytical instrumentation;v) System suitability tests (resolution, percentage of Relative Standard Deviation(%RSD), tailing factor and theoretical plate for High Performance LiquidChromatography (HPLC) and Gas Chromatography (GC) methods);vi) Complete formula for calculation and interpretation of results;National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 87

Drug Registration Guidance Document (DRGD)vii) Specification or acceptance criteria.e) Photocopies or methods directly copied from pharmacopoeias shall not beaccepted. In cases where test methods are adopted from official pharmacopeia,details of specifics requirements should be submitted.f) All relevant data collected during chemical and microbiological testing such aschromatograms HPLC/ GC, test reports and formulae used for calculating shouldalso be submitted.g) All documents should be arranged and labeled accordingly.9.2 SPECIFIC REQUIREMENTSThe specific requirements for test methods are based on type of tests and dosageforms of product as stated in Table VIII below:Categories Type of Tests Specific RequirementsPhysical &PerformanceTestsPhysical test (friability,uniformity of weight,pH, etc)Disintegration testDissolution testSpecific method for the intended analysisSpecific method for related dosage formsa. Dissolution parameters should include:i) type of apparatusii) type and volume of dissolutionmediumiii) rotation rateiv) temperature of solutionv) sampling timeb. Complete formula for calculationespecially for extended and delayedrelease products.c. Method of analysis for example HPLC,UV, etc.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 88

Drug Registration Guidance Document (DRGD)Categories Type of Tests Specific RequirementsIdentification testsuch as color test,Fourier TransformInfrared (FTIR), ThinLayer Chromatography(TLC) etc.Impurities/degradation/ purity testAssay and uniformityof contentSpecific method for the intended analysisa. Analysis method should include:-i) Placebo solution (if any)ii) Relative retention times of impuritiesor degradation productb. Complete formula for calculationc. Method of analysis for example HPLC,TLC, etc.Specific method for the intended analysisQuality TestBiological Assay ofAntibioticsa. Procedure for preparation of followingsolutions/ substances:-i) Culture mediumii) Buffer solutionsiii) Diluentsiv) Microorganisms used in assayb. Detailed test method (diffusion orturbidimetric method), which includes:i) Preparation of standard solutions(including steps to counteract theantimicrobial properties of anypreservatives, etc present in thesample)ii) Preparation of test solutions(including any steps to neutralize theantimicrobial properties of anypreservatives, etc present in thesample)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 89

Drug Registration Guidance Document (DRGD)Categories Type of Tests Specific Requirementsiii) Test for Media Sterility and GrowthPromotion Testiv) Dilution schemes for test andstandard solutions.Application of test & standardsolutions (volume, use of latinsquares, etc.)Incubation temperature & timeInterpretation of resultDetailed calculation for the testincluding ANOVA table and otherdata showing validity of testresults.Safety testsPyrogen TestBacterial EndotoxinsTest (BET) or LimulusAmebocyte Lysate(LAL) Testa. List of depyrogenated or pyrogen-freeapparatus, glassware and reagentsb. Temperature recording systemc. Retaining conditions of the animalsd. Selection of animals for teste. Preliminary test/ Sham test proceduref. Detailed test procedureg. Volume and dose of injectionh. Interpretation of test resultsa. Certificate of analysis for endotoxin andLAL (limulus amebocyte lysate) reagentb. List of depyrogenated or pyrogen-freeapparatus, glassware and reagentc. Preparation of standard solutions, LALreagent/ substrate, sampled. Detailed calculation for determination ofmaximum valid dilution (MVD)e. The product's endotoxin limitconcentration (ELC) and source ofNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 90

Drug Registration Guidance Document (DRGD)Categories Type of Tests Specific Requirementsinformationf. Detailed calculation for determination ofendotoxin limit concentration if the ELCis not in BP, USP, JP or EPg. Detailed test procedureh. Calculation and interpretation of testresultSterility Test* MicrobialContamination Testa. List of media and reagenti) Culture mediaii) List of rinsing solution, buffersolution and diluentiii) Neutralizing agent (if any)b. Preparation of media & Composition ofRinsing Bufferc. Test for Media Sterility and GrowthPromotion Testd. Preparation of test sample (includingsteps to eliminate antimicrobial activitydue to antibiotic samples or sampleswhich contain preservatives).e. Detailed test procedure for sterility testi) Quantity of sample / Volume ofsampleii) Membrane filtration / Directinoculationiii) Open System or Closed System (ifuses Membrane filtration method)iv) Volume of rinsing fluida. Preparation of mediab. Test for Growth Promoting, Inhibitoryand Indicative Properties of Mediac. Preparation of test sample (includingneutralizing of preservatives forNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 91

Drug Registration Guidance Document (DRGD)Categories Type of Tests Specific Requirementssamples that contain preservatives)d. Total Viable Aerobic CountDetailed test procedure for TotalAerobic Microbial Count TAMC) andTotal Yeasts and Moulds Count(TYMC) by Plate Count, MembraneFiltration or Most-Probable Number(MPN) method.e. Test for Specified MicroorganismsDetailed test procedure for eachspecific microorganism tested(including identification andconfirmation test)Specification and acceptancecriteriaFor details, please refer circular Bil(4) dlm. BPFK/PKK/12/05Mycrocystin test For a product containingAphanizomenonflosaquae, applicantswould have to provide certificates ofanalysis showing that the microcystin-LR ortotal microcystins content of the rawmaterial does not exceed 1μg/g and thefinished product has been tested formicrocystin-LR using an acceptablemethod* Note:Manufacturer shall ensure that products manufactured locally or overseas are free fromany contamination of Burkholderia Cepacia. Please refer to these circulars for details:Pekeliling Ujian Burkholderia cepacia.pdfPekeliling Ujian Kontaminasi Burkholderia cepaciaNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 92

Drug Registration Guidance Document (DRGD)10. GUIDELINE FOR THE SUBMISSION OF ANALYTICALMETHOD VALIDATION (AMV) DOCUMENTS10.1 TYPES OF ANALYTICAL PROCEDURES TO BE VALIDATEDa) Identification testsb) Quantitative tests for impurities' contentc) Limit tests for control of impuritiesd) Quantitative tests of the active ingredient in the sample (assay and dissolution)e) Pyrogen or Bacterial endotoxin testf) Sterility testg) Microbial Contamination Testh) Biological Assay of Antibiotics10.2 TYPICAL VALIDATION PARAMETERS FOR CHEMICAL TESTS10.2.1 FULL VALIDATION FOR IN-HOUSE METHODSPlease refer to Table IX on next page.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 93

Drug Registration Guidance Document (DRGD)TABLE IX:Type of Analytical MethodCharacteristicsIdentificationTesting for ImpuritiesQuantitationLimitAssay:- dissolution(measurement only)- content/ potencyAccuracy √ √PrecisionRepeatabilityInterm. Precision√√ (1)√√ (1)Specificity (2)Detection LimitQuantitation Limit√ √ √ √(3) √√LinearityRange√√√√National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 94

Drug Registration Guidance Document (DRGD)10.2.2 PARTIAL VALIDATION FOR COMPENDIAL/ PHARMACOPOEIALMETHODSTABLE X:CharacteristicsIdentificationType of Analytical MethodTesting for ImpuritiesQuantitationLimitAssay:- dissolution(measurement only)- content/ potencyPrecisionInterm. Precision √ (1)Specificity (2) √ √ √ √Detection Limit (3) √Quantitation Limit√Note:√signifies that this characteristic is normally evaluated.(1) In cases where reproducibility has been performed, intermediate precision is notneeded.(2) Lack of specificity of one analytical procedure could be compensated by othersupporting analytical procedure(s).(3) May be needed in some cases.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 95

Drug Registration Guidance Document (DRGD)10.3 TYPICAL VALIDATION CHARACTERISTICS FORMICROBIOLOGICAL TESTS:Table XI:Microbiological testsBacterial Endotoxin TestSterility TestMicrobial ContaminationTestMicrobiological Assay ofAntibioticsValidation characteristicsa. Test for Confirmation of Labelled LysateSensitivity(Verification of criteria for standard curve)b. Test for Interfering Factors (Inhibition/ Enhancementtests)Validation (Bacteriostasis or Fungistasis) TestQuantity of Sample/ Volume of SampleMembrane filtration/ Direct inoculationOpen System or Closed System (if uses Membranefiltration method)Volume of rinsing fluida. Validation of total viable aerobic count (suitability of thecounting method in the presence of product)b. Validation of test for specified microorganism (suitabilityof the test method)Linearity of the dose response relationshipNote:1. All the analytical validation done by the industry should be in accordance to ASEANGuidelines for Analytical Procedures, ICH Technical Requirements for Registration ofPharmaceuticals for Human Use under Validation of Analytical Procedures: Text andMethodology Q2 (R1), British Pharmacopoeia (BP) or United State Pharmacopeia(USP).2. The applicants should ensure all documents available in the online Quest system are ofthe latest versions. All correspondence on the protocol of analysis and analyticalmethod validation should comply with any relevant circulars regarding the registrationprocess. Failure to do so may cause cancellation or rejection of product registration(Reference: Circular Bil (08) dlm. BPFK/PPP/01/03)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 96

Drug Registration Guidance Document (DRGD)11. GUIDELINE FOR THE SUBMISSION OF PRODUCTSAMPLES FOR LABORATORY TESTINGThe submission of sample for laboratory testing is as part of the registration process. Thisguideline consists of the general and specific requirements for the submission of samplesto the Centre for Quality Control for laboratory testing. The general requirements define thecondition of the samples to be submitted whereas the specific requirements illustrate theadditional details needed according to the category of product.The sample shall be submitted to the Centre for Quality Control within 14 days after thepayment has been confirmed. Application for product registration shall be rejected by theAuthority if the sample is not submitted within 30 days from the date of confirmed payment.The applicants shall comply with these requirements and failure to meet any of theserequirements may cause rejection of the samples.11.1 GENERAL REQUIREMENTSa) After the registration payment has been approved, applicants must makeappointment with the Laboratory Services Unit for the submission of registrationsamples for laboratory testing.b) Requirements for samples:i) Samples submitted must be in their original packaging & labeling.ii)iii)Samples submitted must be from the same manufacturing premise as statedin the application for registration.Samples submitted must have an expiry date of least one (1) year from thedate of submission.c) For imported products, applicants are required to submit the original import permittogether with the samples for laboratory testing. The import permit will be issued bythe Centre for Registration and Centre for Quality Control for natural product andpharmaceutical products, respectively. The applicant should ensure that the importpermit is endorsed by the enforcement officer at the entry point.d) The payment voucher and approved payment application status should also besubmitted together with the samples.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 97

Drug Registration Guidance Document (DRGD)11.2 SPECIFIC REQUIREMENTS11.2.1 NATURAL PRODUCTSQuantity of samples submitted must be:a) a minimum of 6 separate containers of all dosage forms with total contents ofnot less than 200 g or 200 mL; ORb) a minimum of 60 pieces of plasters or patches with total of not less than 200g.11.2.2 PHARMACEUTICAL PRODUCTS(Upon request from NPCB)a) An official certificate of analysis and the recent shelf-life specification from themanufacturer for the same batch of sample must be submitted with the sample.b) Quantity of samples submitted must be in accordance with the quantityrequested.c) Other materials such as HPLC columns, reagents, etc must be submitted whenrequested.d) Reference standards are required to be submitted along with thepharmaceutical products. Requirements for these reference standards are asfollows:i) The type & quantity of reference standards submitted must be inaccordance with the type & quantity requested;ii) Reference standards submitted must have an expiry date of least one (1)year from the date of submission. In special situations, an expiry date ofnot less than six (6) months can be accepted;iii)iv)All reference standards must be accompanied by an official certificate ofanalysis for the same batch with the stated purity (as is, dried, anhydrousetc.) and all other relevant information (water content, loss on dryingetc.);All reference standards must be properly labeled with name, batchnumber, purity and expiry date;v) All reference standards must be submitted in small sealed air-tight amberglass containers.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 98

Drug Registration Guidance Document (DRGD)11.3 APPEAL FOR RETESTINGa) Applicants are allowed only one (1) appeal for any sample that fails laboratorytesting (except if found to be adulterated) the Centre for Quality Controlsubjected to approval by the Deputy Director, Centre for Quality Control.b) Appeal for retesting must be submitted through the on-line registration systemwithin 30 days from the date of result being released.c) If no appeal within 30 days or appeals received after 30 days or the appeal isrejected, the original test result is final and the sample will be considered asfailed laboratory testing.d) Upon approval of appeal for retesting, an applicant needs to submit newsample, reference standards (if required), and other relevant materials (ifrequired) as requested earlier. They should also submit the payment voucherand approval letter for the appeal. This sample shall be treated as a newregistration sample and the applicant will be endured all the cost on the sampleanalysis.(Reference: Circular Bil (67) dlm BPFK/02/5/1.3)e) The result of the re-tested sample is final and there is no provision for a secondappeal.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 99

Drug Registration Guidance Document (DRGD)SECTION D: INSPECTION & LICENSINGInspection and licensing of manufacturing premises or facilities, importers and wholesalersof registered products or notified cosmetics on the basis of compliance with GoodManufacturing Practice (GMP) as well as Good Distribution Practice (GDP) are vitalelement of drug control. Compliance to GMP is a prerequisite for the application of amanufacturing license as well as product registration or cosmetic notification whereascompliance to GDP is a prerequisite for the application of a wholesale license or importlicense.12. INSPECTIONInspection of GMP and GDP are conducted to ensure manufacturers‟, importers‟ andwholesalers‟ compliance towards the current GMP and GDP requirements besidesensuring the registered products and notified cosmetics that are put in the market are safe,efficacious and of quality.The related GMP and GDP guidelines referred are as below in Table XII:GuidelinesPIC/S Guide to Good ManufacturingPractice for Medicinal Products *GMP Guideline for Traditional Medicinesand Health Supplements, 1 st Edition, 2008Guidelines on Good Manufacturing Practice(GMP) for Cosmetic (Annex 1, Part 9)Supplementary Guidelines on GMP forVeterinary Premixes, Supplements andHerbal/ Natural Preparations, 1 st Edition, 1January 2012Guidelines on Good Distribution Practice(GDP); 1st Edition 2011Product Type/ CategoryPharmaceuticals(Poison and Non-Poison)Veterinary ProductsTraditional ProductsHealth SupplementsCosmeticsVeterinary ProductsFor activities related to the storage anddistribution by manufacturers, importersand wholesalers (where applicable)* Refer to Pharmaceutical Inspection Co-operation Scheme (PIC/S) website at www.picscheme.orgNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 100

Drug Registration Guidance Document (DRGD)12.1 FOREIGN GMP INSPECTIONPRH must provide acceptable evidence to show that the manufacturer of the productfollows an internationally accepted standard of Good Manufacturing Practice (GMP) andrecognized by the Authority in Malaysia.The Control of Drugs and Cosmetics Regulations 1984 (CDCR) requires that the standardof manufacture and quality control of medicinal products manufactured outside Malaysia istaken into consideration before the products are registered with the Authority. NPCB as thesecretariat to the DCA is responsible to ensure all manufacturers of registered products inMalaysia are able to provide acceptable evidence that the manufacturing premises conformto current GMP requirements. Hence, foreign manufacturers are also subjected to GMPconformity assessments through acceptable GMP evidence or GMP inspection.For details and forms, please refer Guidance Document on Foreign GMP Inspection.13. LICENSINGAccording to the Controls of Drugs and Cosmetics Regulations 1984, any company thatwant to manufacture, import or wholesale any registered products need to have a validManufacturer‟s License, Import License or Wholesale License.13.1 TYPES OF LICENSESTable XIII:Type of LicensesManufacturer‟s LicenseImport LicenseWholesaler‟s LicenseActivityLicensed Premises is allowed to:Manufacture registered products and to sell by wholesaleor supply their productsLicensed Premises is allowed to:Import and sell by wholesale or supply registered productsLicensed Premises is allowed to:Sell by wholesale or supply registered productsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 101

Drug Registration Guidance Document (DRGD)13.2 LICENSE APPLICATION FORM1. The license application for registered products (Manufacturer‟s License, Import Licenseand Wholesaler‟s License) shall be submitted by filling Borang BPFK-413 Application forLicense for Registered Product.2. Application form must be submitted with the following supporting documents.a) Company‟s Organization Chartb) Location Map of Premisec) Layout Plan of Premised) List of Storage Equipmentse) Details of other products (Non-medicinal) stored at the same premisef) A copy of Business License (Local Authority) for business premise or store (if any)g) A copy of Applicant‟s/License Holder‟s Identity Cardh) A copy of Annual Retention Certificate and/or Type A License (This document isnecessary if products manufactured/ imported/ wholesale are Scheduled Poison Aproducts or any other products that require a Pharmacist)i) A copy of previous license (For renewal application)3. An application shall only be processed if it is complete and payment has beenapproved.4. The processing fee shall not be refundable. The processing fee of an application for aManufacturer‟s License is RM 1,000.00 and RM 500.00 for an Import License or aWholesaler‟s License.5. Each license is valid for one (1) year.13.3 ADDITIONAL LIST OF LICENSE FOR REGISTERED PRODUCTS1. Additional list of License are issued based on the application submitted when theproducts are newly registered, changing of manufacturer or importer or any registeredleft out products from the products list of Manufacturer‟s License and Import License.2. When submitting the application form for Additional List of License for RegisteredProducts the documents that shall be attached together are a copy of Manufacturer‟sNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 102

Drug Registration Guidance Document (DRGD)License/ Import License and a copy of approval letter from the Authority (The Authority‟smeeting result).3. The application of additional list shall be submitted by filling Borang BPFK-413TApplication for (Additional) Product List of License for Registered Product.13.4 GMP CERTIFICATE1. GMP certificates are issued for the purpose of exportation of locally manufacturedregistered products. It endorses that the local manufacturer complies with the currentGMP requirements. These certificates are required by the overseas regulatory agenciesfor products registration in their countries. Thus, when filling in the GMP certificateapplication form, the correct address of the overseas regulatory agencies given by thecompany is crucial.2. The application of GMP Certificate shall be submitted by filling Borang BPFK-420Permohonan Sijil Amalan Perkilangan Baik (APB).3. A fee of RM50.00 is payable on the issue of such certification.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 103

Drug Registration Guidance Document (DRGD)SECTION E: POST-REGISTRATION PROCESS14. MAINTENANCE OF REGISTRATIONRegistration of a product shall be valid for five (5) years or such period as specifiedin the registration certificate (unless the registration is suspended or cancelled by theAuthority).Application for renewal of product registration of a product shall be done within six(6) months prior to the expiry of the validity period of a product registration. Afterthe expiry date, status of product registration shall change to status of expired, andapplication for renewal of the product registration can‟t be submitted.In order to maintain registration of an imported product, starting on 1 st January 2014,applicant shall comply with GMP requirement as stated in the directive issued bythe Director of Pharmaceutical Services under Regulation 29, CDCR 1984 ArahanBil. 1 Tahun 2012 Syarat Pendaftaran Produk Farmaseutikal Dari Luar NegaraBerkaitan Keperluan Amalan Perkilangan Baik (APB) (Reference: Circulars Bil (25)dlm BPFK/PPP/01/03 Jld 1 and Bil (96)dlm.BPFK/PPP/01/03 Jld. 2). The Authorityshall not consider any renewal application that fails to comply with the stipulatedrequirement.15. WITHDRAWAL OF PRODUCT REGISTRATIONThe Product Registration Holder shall inform the Authority pertaining to decision towithdraw the registration of a product before the end of the validity of suchregistration and shall state the reasons for the decision. The onus is on the holder toinform the manufacturer/ contract manufacturer.The registration of a product, once withdrawn, shall not be reinstated and certificateof registration of the withdrawn product shall be invalid.A new application shall be submitted if the product registration is required again at alater date.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 104

Drug Registration Guidance Document (DRGD)16. AMENDMENTS TO PARTICULARS OF A REGISTEREDPRODUCTThroughout the life cycle of a registered product, changes to improve the product‟sefficacy, quality and safety are likely to occur. Therefore, applicant shall inform theAuthority pertaining to any changes or amendment to particulars of a registeredproduct via applications.Starting on 1 st January 2014, applicant who wishes to apply for any application forimported products of which GMP requirement shall be considered, such as changeof manufacturing site and variation, shall comply with the requirement, as stated indirective issued by the Director of Pharmaceutical Services under Regulation 29,CDCR 1984 Arahan Bil. 1 Tahun 2012 Syarat Pendaftaran Produk FarmaseutikalDari Luar Negara Berkaitan Keperluan Amalan Perkilangan Baik (APB) (Reference:Circulars Bil (25) dlm BPFK/PPP/01/03 Jld 1 and Bil (96)dlm.BPFK/PPP/01/03 Jld.2). The Authority shall not consider any application in which the requirement is failedto comply with.16.1 VARIATIONVariation refers to change of particulars of a registered product. No change of anyparticulars of a registered product shall be made without prior approval from NPCB.The registration of a product shall be reviewed for suspension or cancellation ifchanges are made without prior approval of the Authority.There are two types of variation, which are Variation Type I and Variation Type II:Table XIV:No.1.Type I: Minor changeChange in name of manufacturerand/or other manufacturers withoutany change in address of siteVariationType II: Major changeChange of product nameNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 105

Drug Registration Guidance Document (DRGD)No.2.Type I: Minor changeReplacement, addition or deletionof company logo on the packagingcomponents (without any changeson graphic or label content)3. Change in product owner4. Change in importer/ store address5.6.7.8.Change or addition of imprints,bossing or other markings (exceptscoring/ break lines) on tablets orprinting on capsules, includingreplacement, or addition of inksused for product markingChange in shape or dimensions ofthe container or closure without anyother changesChange in pack size of the drugproduct (Finished product), withoutchange in primary packagingmaterial; or change in the numberor units (e.g. tablets, ampoules) in apack; or change in volume of nonsterile preparationsTightening of specification limits ofdrug product (finished product)and/or drug substance (activeingredient)VariationType II: Major changeChange in content of leaflet orprescribing information/ PatientInformation Leaflet (PIL)/ Summaryof Product Characteristics (SPC)Change in content of label inclusiveof change in graphics/ artworkChange in manufacturing process ofthe finished productChange in overage of activeingredient or excipientReplacement of an excipient with acomparable excipient and/or changein content of excipientChange in batch sizeChange in hard capsule shell (color,size or source)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 106

Drug Registration Guidance Document (DRGD)No.9.10.11.12.Type I: Minor changeChange in particular ofmanufacturer of drug substance(active ingredient ) without anychange in specification:- Change in manufacturer ofdrug substance- Addition of manufacturer ofdrug substance- Change in name and/orrephrasing of address of amanufacturer of drugsubstanceChange in secondary packagingmaterial (or change in any part ofthe primary packaging material thatis not in contact with the finishedproduct (e.g. color of flip off caps,color code rings on ampoules,change of needle shields i.e.different plastic used)Change in testing procedure of anexcipient.VariationType II: Major changeChange in finished product or activeingredient specification (includesaddition of a new test parameter)Change to in-process tests or limitsapplied during manufacture of theproductChange or addition in primarypackaging materialChange in shelf life of finishedproduct:- As packaged for sale- After first opening- After dilution/ reconstitution13. Change in storage conditions14.15.16.Appointment, deletion or change ofother manufacturersAddition or deletion of scoring/ breakline on tabletChange in test procedure oranalytical protocols of finishedproductNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 107

Drug Registration Guidance Document (DRGD)No.17.Type I: Minor changeVariationType II: Major changeChange or addition of fill volumeand/or change of shape or dimensionof container or closure for a sterilesolid and liquid drug productAll supporting documents in accordance to the specified conditions laid down foreach type of variations should be submitted. For further information pertaining toconditions and supporting documents required for an application of variation, pleaserefer to Appendix 12: Conditions and Supporting Documents Required forApplication of Variation Type I & Type II.If deemed necessary, NPCB reserves the right to request for additional supportingdocuments and variation approval letters from other regulatory bodies for allcategories of product.For variations which are not covered in this guidance document, please referASEAN Variation Guideline for Pharmaceutical Product 2012.16.1.1 MODE OF SUBMISSIONTable XV:No. Variation QUEST 2 Product QUEST 3 Product1. Type IApplicant shall submit application forVariation Type I via both manual andonline QUEST 2 system.For manual submission, applicantcan download Form BPFK 416.2from NPCB‟s websitewww.bpfk.gov.my, and shall submitto the Variation Section, Centre ofPost Registration, NPCB.Applicant shall submitapplication for VariationType I and/or Type IImanually to the VariationSection, Centre of PostRegistration, until furthernotice pertaining to onlinesubmission.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 108

Drug Registration Guidance Document (DRGD)No. Variation QUEST 2 Product QUEST 3 Product2. Type IIApplicant shall submit application forVariation Type II via online QUEST 2system.16.1.2 RESPONSIBILITY OF APPLICANTa) The applicant shall provide to NPCB the reason for variation applied. For everyvariation being made, reason for variation/ remarks, should be clearly written andexplained. Other supporting documents can be attached at E12 (or F12) wheresuch documents are necessary.b) The applicant is responsible for ensuring that all the necessary validation hasbeen conducted to demonstrate that the change does not reduce the quality,safety or efficacy of the product as per ASEAN Guideline on Submission ofManufacturing Process Validation Data for Drug Registration. Process validationreport may be requested when deemed necessary.16.1.3 Other Informationa) In the event that a variation application is complex, consultation with relevantofficer is encouraged, prior to submission of the application into the onlineQUEST 2 system.b) The online QUEST 2 variation module is an overwrite-system. For data alreadyapproved in the system which is intended to be retained, it shall be submittedtogether under “proposed change data”. For instance, whereby existing approvedpackaging is “HDPE bottle” while the proposed variation is to include “blisterpack”, stability data for both packaging (combined into a single file) is required tobe submitted during application for variation.c) No correspondence with the applicant for Quest 2 variation module can be made.For any rejection made for a certain field, only the main field will be rejected (i.e.the supportive documents will be kept until the main field is resubmitted).However, if the main field is not resubmitted without any reason for a certainNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 109

Drug Registration Guidance Document (DRGD)period of time, the supportive documents will be rejected and a new applicationshall be submitted.16.2 CHANGE OF MANUFACTURING SITEChange of Manufacturing Site (COS) refers to change of manufacturing site forcertain part or all of the manufacturing process of a product, but it does not coverchanges related to a new site, where only:c) batch release takes place ORd) to a new packager (secondary packaging or labelling), as these changes arecovered under applications for amendments to the particulars of a registeredproduct (variation). Please refer to paragraph Section E: 16.1 Variation.However, a change of manufacturing site for biologics shall require a new productapplication only if the change is extensive that will have an impact on the quality,safety and efficacy profile of the final product.Upon receipt of complete application, the application shall be processed within fortyfive(45) working days.16.2.1 CONDITIONS ON APPLICATION FOR COS:Change in Manufacturing Site is only applicable in the following situations:a) a change in manufacturing site for the same company, including rationalization inthe event of mergers; andb) a company which previously contracts out the manufacture of its product(s),transfers the manufacture of the product to its own premises.A change in manufacturing site between contract manufacturers is not routinelyallowed but may be considered in a crisis situation (refer Type V COS: CrisisSituation)Validity of registration for a product which has been approved for change ofmanufacturing site remains unchanged, without any extension of the validity.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 110

Drug Registration Guidance Document (DRGD)16.2.2 CONDITIONS ON GOOD MANUFACTURING PRACTICE (GMP):a) The new manufacturing site shall comply with current Good ManufacturingPractice (cGMP);b) Local manufacturing sites are subjected to pre-licensing inspections by theNPCB inspectors;c) For manufacturing sites outside Malaysia, certification on GMP by the competentauthority is acceptable.d) The Authority reserves the right to conduct an inspection on any manufacturingsite.e) For further information pertaining to the requirements on GMP, please refer tothese circulars and directive.i) Bil (35) dlm. BPFK/PPP/01/03ii) Bil (40) dlm. BPFK/PPP/01/03iii) Bil (25) dlm BPFK/PPP/01/03 Jld 1iv) Bil (96)dlm.BPFK/PPP/01/03 Jld. 216.2.3 TYPES OF MANUFACTURING SITE CHANGES (COS)Table XVI:No. Types of COS Description1. Type I2. Type IIChange ofmanufacturingsite withinMalaysiaChange ofmanufacturingsite fromforeign countryto MalaysiaChange in the location of the site of manufacturewithin Malaysia only. This change may be due toupgrading of facilities, and/or expansion ofmanufacturing activities or moving to a newlyconstructed plant.Change in location of the site of manufacture fromoutside of Malaysia to a location in Malaysia. Thischange may be due to the ability of the localcounterpart to manufacture the product.3. Type IIIChange ofmanufacturingsite locatedoutsideMalaysiaChange of location of the site of manufacture tomanufacturing facilities located outside Malaysia. Thismay be due to a merger or rationalization ofmanufacturing sites in line with multinationals‟manufacturing strategies.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 111

Drug Registration Guidance Document (DRGD)No. Types of COS Descriptioni) Transfer of manufacturing of an asepticallyprocessed sterile product to a:a) newly constructed or refurbished asepticprocessing facility or area;4. Type IV5. Type VChange ofmanufacturingsite for sterileproductsChange ofmanufacturingsite in crisissituationb) an existing processing facility or area that doesnot manufacture similar approved products.(For example, transferring the manufacture of alyophilized product to an existing asepticprocess area where there is no approvedlyophilized product is manufactured).ii) Transfer of a finished product sterilized by terminalprocesses to a newly constructed facility at adifferent manufacturing site.Once this change has been approved, subsequentsite changes to the facility for similar types ofproduct and processes will not be categorized as aType IV COS.i) Change of location of the site of manufacture thatis deemed necessary due to certain circumstancessuch as natural disasters, closure or suspension ofpremise (revocation of manufacturing license) andmatters related to breach of product quality, safetyand efficacy ONLY.ii) Prior to submission of Type V COS, approval letterissued by the secretariat of the Authority shall beobtained.iii) Application for Type V COS must be made withinthree (3) months from the date of the crisis.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 112

Drug Registration Guidance Document (DRGD)16.2.4 MODE OF SUBMISSIONa) Complete application for COS with supporting documents shall be submittedmanually to Variation Section, Centre of Post-Registration, NPCB.b) For submission of COS Type II to Type V, applicant can download Form BPFK415.3 from NPCB‟s website www.bpfk.gov.my under Industry - Forms.Submission of completed application form with supporting documents shall bemade together with processing fees, according to category of product, asstipulated in the form.16.2.5 OTHER INFORMATIONa) Application for COS will be rejected if applicant failed to submit required datawithin six (6) months from the first correspondence date;b) All supporting documents in accordance to the specified conditions laid down foreach type of COS should be submitted. For details, please refer to Appendix 13:Supporting Documents Required for Change of Manufacturing Site Application.c) If deemed necessary, NPCB reserves the right to request for additionalsupporting documents.d) For further information pertaining to COS, please refer these circulars.i) Bil (59) BPFK/17/VF/9.2ii) Bil (22) dlm. BPFK/PPP/01/03iii) Bil (31) dlm. BPFK/PPP/01/03iv) Bil (39) dlm. BPFK/PPP/01/03v) Bil (10) dlm BPFK/PPP/01/03 Jld 1National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 113

Drug Registration Guidance Document (DRGD)16.3 CHANGE OF PRODUCT REGISTRATION HOLDERProcedure is under revision.16.4 NEW/ ADDITIONAL INDICATIONNew/ additional indication is defined as an indication which is not initially approvedfor a registered pharmaceutical product. This shall include new therapeutic indicationor indication for new age group, such as usage in children, and shall not includechanging/ rephrasing of sentences.There are two (2) types of evaluation process available for a new/ additionalindication application:16.4.1 FULL EVALUATION PROCESSFor new indication which has been registered in any one of the Authority‟s eight (8)reference countries (United Kingdom, Sweden, France, United States of America,Australia, Canada, Japan and Switzerland).This application will require specialists‟ comments.16.4.2 VERIFICATION PROCESSFor new indication which has been registered in European Countries (UnitedKingdom, Sweden and/or France) and one of the other Authority‟s referencecountries (United States of America, Australia, Canada, Japan and Switzerland).Note:The approved new indication in these countries should be the same as that of theproposed new indication.Other supporting documents that are deemed necessary shall be submitted uponrequest to support the efficacy and safety of the proposed additional indication.The supporting documents may include but not limited to the following:National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 114

Drug Registration Guidance Document (DRGD)a) Approval of Additional Indication(s) in country of origin;b) Approval status in reference countries, its corresponding approval letter andapproved Package Insert;c) Approval Indication status in ASEAN Member States and its approvedcorresponding package insert;d) Revised Package Insert;e) World Wide Approval status;f) Patient Information Leaflet (PIL);g) Clinical Expert Reports;h) Synopsis of Individual Studies;i) Clinical Studies Report/ In-House Clinical Trials;j) Published Clinical Papers;k) Current Periodic Safety Update Report (PSUR).16.5 APPLICATION FOR A CONVENIENT PACKa) This type of application is referring to registered products which are packedtogether in a single packaging unit for convenience of the consumers, such asa Confinement Set or Set Jamu Bersalin.b) Individual registered products are allowed to be packed together andmarketed as a convenient pack, provided that the application is justifiedsatisfactorily.c) Shall consist of registered products from the category of natural productand/or health supplement only.d) Application for a convenient pack shall be made via the process of variationType II.The holder has to submit the convenient pack label and also the individuallabel via application for variation under Part D2 (outer label). The convenientpack label shall contain the same information as in the primary label.For details of variation, please refer to Section E: 16.1 Variation.e) Individual registered products involved in the convenient pack can be soldindividually or as a pack.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 115

Drug Registration Guidance Document (DRGD)f) Conditions for application:i) Individual registered products proposed to be packed together as aconvenient pack shall be sourced from the same product owner/ PRH;ii) Submission of the application shall be made by the same PRH.iii) The manufacturing site for the convenient pack shall be a GMP certifiedfacility.g) Approved indication of each individual registered product in the convenientpack remains unchanged. There is no common specific indication for theconvenient pack.h) Labelling requirement specifically for convenient pack:Table XVII:Outer LabelContents in the labelling of eachindividual registered product have tobe included in the outer label of theconvenient pack.Immediate LabelAs per labelling requirements forregistered products.Note:For the purpose of application submission, if the individual registered productis also marketed independently, outer label of the packaging soldindependently and outer label of the convenient pack shall be submittedtogether.i) Additional information on differentiation from Combination Pack(Combo Pack):Table XVIII:No.ParticularsConvenientPackCombinationPack(Combo Pack)1.New registration number(MAL No.) to be assignedupon approvalNoYesNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 116

Drug Registration Guidance Document (DRGD)No.ParticularsConvenientPack2. Mode of application Variation Type IICombinationPack(Combo Pack)Application forregistration as anew product3. Purpose of productFor convenienceof the consumerFor therapeuticregimen4. New indication No Yes5. Sale of product6. ExampleCan be soldindividually or asa packConfinement Setor Set JamuBersalinOnly to be soldas a packKlacid HP7(for treatment ofpeptic ulcerdiseasesassociated withH. pyloriinfection)17. POST-MARKETING ACTIVITIES17.1 PHARMACOVIGILANCE17.1.1 ADVERSE DRUG REACTION REPORTING AND SAFETY UPDATESIn accordance with Regulation 28 : Reporting adverse reaction under Control ofDrugs and Cosmetics Regulations 1984, Sale of Drugs Act 1952 (amendment 2006),the product registration holders or any person who possesses any registeredproduct shall inform immediately the Director of Pharmaceutical Services of anyadverse reaction arising from the use of the registered product.All product registration holders must ensure that a pharmacovigilance system is inplace by the company and appropriate action is taken, when necessary.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 117

Drug Registration Guidance Document (DRGD)Product registration holders are required to monitor and report any product safetyissues that arises locally or internationally to the NPCB and comply with all safetyrelateddirectives issued by the Authority.The product registration may be cancelled if the product registration holder fails toinform the Authority of any serious adverse reactions upon receipt of such reports.The WHO encourages reporting of ALL adverse drug reactions.For further information, please refer Malaysian Guidelines for the Reporting &Monitoring.17.2 POST-MARKET SURVEILLANCEa) Samples of products registered by the Authority may be taken and tested forcompliance with official or pharmacopoeia standards or specifications agreed by themanufacturer;b) If a sample fails to meet adequate specifications, the product registration holder willbe issued a warning. Unless the failure is serious enough to justify recall of theproduct, the product registration holder has up to thirty (30) days to identify thesource/ cause of quality defect and actions to be taken to improve quality.17.2.1 PRODUCT COMPLAINTSa) The product registration holder should notify the Director of PharmaceuticalServices of any product quality related problems (with registered products) thatthe holder is aware of;b) It is also the responsibility of the prescribers, the pharmacists, as well as all otherhealth professionals who come into contact with the drug to report.17.2.2 PRODUCT RECALLSa) Recalls of defective or unsafe products are instituted by the Authority, supportedby the Pharmaceutical Services Division, Ministry of Health Malaysia;National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 118

Drug Registration Guidance Document (DRGD)b) The product registration holder is responsible for conducting recalls of defectiveor unsafe products. No recall should take place without first consulting/ informingthe Director of Pharmaceutical Services.17.3 PUNITIVE ACTION FROM THE AUTHORITY17.3.1 ADULTERATIONAs stated in circular Bil (30) BPFK/PPP/01/03, 13 th May 2009, punitive action shall be takenagainst companies who are involved in adulteration.Any registered products found to have been adulterated, the following action shall be takenby the Director of Pharmaceutical Services:a) The registration of the related product shall be cancelled and recall of all batches ofthe product shall be done immediately;b) The manufacturer‟s license of the related manufacturer shall be revoked for six (6)months for the first offence and one (1) year for the subsequent offence, from the dateof revocation letter;c) All transactions (including application for product registration, application for change ofproduct registration holder, application for change of manufacturing site) for theadulterated product registration holder shall be frozen for six (6) months for the firstoffence and one (1) year for the subsequent offence, from the date of cancellationletter from the Authority.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 119

Drug Registration Guidance Document (DRGD)APPENDICESAppendix 1Appendix 2Appendix 3Appendix 4Appendix 5Appendix 6Appendix 7Appendix 8Appendix 9Appendix 10Appendix 11Appendix 12Appendix 13FeesRequirements for Product RegistrationGuidelines on Registration of BiologicsGuideline on Registration of Health SupplementsGuideline on Registration of Natural ProductsGuideline on Regulatory Control of Active PharmaceuticalIngredients (API)Special Conditions for Registration for a Particular Product orGroup of ProductsList of Permitted, Prohibited and Restricted SubstancesLabelling RequirementsGuideline on Patient Dispensing Pack for PharmaceuticalProducts in MalaysiaGuideline on Filling the Online Application Form for ProductRegistration via Quest SystemConditions and Supporting Documents Required forApplication of Variation Type I & Type IISupporting Documents Required for Change of ManufacturingSite (COS) ApplicationNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 120

Drug Registration Guidance Document (DRGD)APPENDIX 1:FEESOutline:1.1 Charges for USB Token of QUEST Membership;1.2 Processing and Analysis Fee for Product Registration;1.3 Charges for Application of Licence;1.4 Charges for Amendments to Particulars of a Registered Product; and1.5 Fee for Certificates.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 121

Drug Registration Guidance Document (DRGD)1.1 CHARGES FOR USB TOKEN OF QUEST MEMBERSHIPApplicationcategoryFirst-time UserSupplementaryUserRenewal of USBtokenChargesPackage A(USB Token of 2-years validity + Guide Manual) : COST RM335Package B(USB Token of 1-year validity + Guide Manual) : COST RM320Package A(USB Token of 2-years validity + Guide Manual) : COST RM335Package B(USB Token of 1-year validity + Guide Manual) : COST RM320Package C1(New USB Token of 2-years validity) : COST RM280Package C2(Utilized old USB Token of 2-years validity) : COST RM100National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 122

Drug Registration Guidance Document (DRGD)1.2 PROCESSING AND ANALYSIS FEE FOR PRODUCT REGISTRATIONEvery application for registration shall be accompanied with a processing andanalysis fee, as specified below (effective 1 st January 2007):No.Category ofProduct* ProcessingFeesAnalysis FeesTotal FeesPharmaceuticalSingle active ingredient :RM 3,000.00RM 4,000.001.a) New DrugProductsRM 1,000.00b) BiologicsTwo or more active ingredients :RM 4,000.00RM 5,000.00Pharmaceuticala) Generic(ScheduledPoison)Single active ingredient :RM 1,200.00RM 2,200.002.b) Generic(Non-ScheduledPoison)c) HealthsupplementRM 1,000.00Two or more active ingredients:RM 2,000.00RM 3,000.003. Natural Product RM 500.00 RM 700.00 RM 1,200.00* As stipulated in the CDCR 1984, Regulation 8.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 123

Drug Registration Guidance Document (DRGD)1.3 CHARGES FOR APPLICATION OF LICENSES1.3.1 Before a product is registered, the applicant shall apply for a manufacturerlicense. The processing fee is as specified below:License Processing fee Timeline Validity1. Manufacturer RM 1,000.00 Not more than 1 month 1 year1.3.2 After a product is registered, the applicant shall apply for an import/ wholesalelicense. The processing fees are as specified below:License Processing fee Timeline Validity1. Import RM 500.00 Not more than 1 month 1 year2. Wholesale RM 500.00 Not more than 1 month 1 year1.4 CHARGES FOR AMENDMENTS TO PARTICULARS OF AREGISTERED PRODUCTTypes of AmendmentPharmaceuticalProcessing feeNatural Product1. Change of Manufacturing Site(Type II, III, IV, V)RM 1,000.00 RM 500.002. Change of Product Registration Holder RM 1,000.00 RM 500.00National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 124

Drug Registration Guidance Document (DRGD)1.5 FEE FOR CERTIFICATESUnder the CDCR 1984, Regulation 16: “The Director of Pharmaceutical Services may issuesuch certification on any matter relating to any product where such certification is requiredby any country importing such a product.”Certificates Fee ValidityIssuance of one (1) Certificate ofPharmaceutical ProductRM 50.002 yearsIssuance of one (1) Certificate of GoodManufacturing Practice (GMP)RM 50.002 yearsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 125

Drug Registration Guidance Document (DRGD)APPENDIX 2:REQUIREMENTS FOR PRODUCT REGISTRATIONIMPORTANT NOTES:1. This appendix is for reference purpose only, where applicable, and it may notfollow the sequence as in the online product registration application forms (inQUEST system).2. Online application forms are available for different product categories.3. Applicant shall follow and comply with all requirements in the online applicationforms as well as any supplementary documentation requested by the Authority,whichever it may deems fit.This appendix comprises of two (2) parts which are:2.1 General requirements for:2.1.1 Full Evaluation;(In accordance to ASEAN ACTD/ ACTR or ICH guidelines)• Part - I Administrative data and product information• Part - II Data to support product quality (Quality Document)• Part - III Data to support product safety (Nonclinical Document)• Part - IV Data to support product safety and efficacy (ClinicalDocument)2.1.2 Abridged Evaluation.2.1.3 Additional Information on Requirement of:• Bioavailability (BA) Study• Bioequivalent (BE) Study2.2 Product Specific RequirementsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 126

Drug Registration Guidance Document (DRGD)2.1 GENERAL REQUIREMENTSData to be submitted as general requirement to support an application for productregistration is based on the product category as shown below:(A)FULL EVALUATION (based on ACTD/ ACTR)No. Product Category Part I Part II Part III Part IV1. New Drug Products √ √ √ √2. Biologics √ √ √ √3.Generics(Scheduled Poison)√√NotApplicableNotApplicable4.Generics(Non-Scheduled Poison)√√NotApplicableNotApplicable5.(B)No.1.Health Supplements:Disease Risk ReductionClaims (High)ABRIDGED EVALUATIONProduct Category* Generics(Non-Scheduled Poison)√ √ √ √2.Health Supplements:a) General or Nutritional Claimsb) Functional Claims (Medium)3. Natural Products* Generics (non-scheduled poison) which are evaluated under abridged evaluation include,but not limited, to the following:a) Antiseptics/ skin disinfectants;National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 127

Drug Registration Guidance Document (DRGD)b) Locally-acting lozenges/ pastilles;c) Topical analgesic/ counter-irritants;d) Topical nasal decongestants;e) Emollient/ demulcent/ skin protectants;f) Keratolytics;g) Anti-dandruff;h) Oral care;i) Anti-acne;j) Medicated plasters/ patch/ pad; andk) Topical antibacterial.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 128

Drug Registration Guidance Document (DRGD)2.1.1 GENERAL REQUIREMENTS FOR FULL EVALUATIONNo.1.Step I: Product ValidationIs your product has a brand name? (Yes/ No)(If yes, please provide brand name and product name)2. Dosage Form3.4.5.Active Ingredient(s)a) Active Ingredient Nameb) Strength of Active Ingredient (Quantity unit/ dose)c) Source of Active Ingredient (Animal – e.g. Bovine, Porcine, Ovine orOthers/ Plant/ Others)d) Form of Active Ingrediente) Remarks (if any)Excipient(s)a) Excipient nameb) Strength of Excipient (Quantity unit/ dose)c) Function of excipient (e.g. absorbent, diluents, bulking agent, coatingagent, anti-caking agent etc.)d) Source of excipiente) Remarks (if any)Is there any source of ingredients derived from animal origin, including activeingredient? (Yes/ No)6. Manufacturer (Name and Address)7. Is the selected manufacturer a contract manufacturer? (Yes/ No)8.9.Is the product from second source? (Yes/ No)If yes, please provide:a) Letter of declaration stating that this product is a second source productb) Registration number and product name of the first sourceIs this product containing any premix? (Yes/ No)a) State your premix formb) Manufacturer namec) Manufacturer addressd) Certificate of Good Manufacturing Practice (GMP)e) Formulationf) Manufacturing Processg) Specification of Analysish) Certificate of Analysis (CoA)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 129

Drug Registration Guidance Document (DRGD)No.10.11.Step I: Product ValidationIs this a replacement product? (Yes/ No)If yes, please provide:a) Letter of Declaration stating that this product is a replacement productb) Registration number and product name of the replaced productIs there any other manufacturer (repacker)? (Yes/ No)a) Manufacturer (repacker) nameb) Manufacturer (repacker) addressc) Certificate of Good Manufacturing Practice (GMP)d) Packaging Process12. Is this an imported product? (Yes/ No)Step II:Part I: Administrative Data And Product InformationNo.Section A: Product Particulars1. Product Name2. Name & Strength of Active Substance and Excipient3. Dosage Form4. Product Description5. Pharmacodynamics6. Pharmacokinetics7. Indication8. Recommended Dose9. Route of Administration10. Contraindication11. Warning and Precautions12. Interaction of Other Medicaments13. Pregnancy and Lactation14. Side Effects15. Symptoms and Treatment of OverdoseNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 130

Drug Registration Guidance Document (DRGD)Step II:16. Storage Condition17. Shelf Life18. Therapeutic Code/ ATC CodeNo.Section B: Product Formula1. Batch Manufacturing Formula2. Attachment of Batch Manufacturing Formula DocumentationNo.Section C: Particulars of Packing- Please refer Appendix 10: Guide for Implementation of Patient DispensingPack for Pharmaceutical Products in Malaysia1.2.Pack Size(Fill details by weight/ volume/ quantity)Immediate Container Type(Container Type and Description)e.g. Aluminium/ Glass/ Metal/ Paper/ Plastic/ Others3. Barcode/ Serial No. (Optional)4. Recommended Distributor‟s Price (RM) (Optional)5. Recommended Retail‟s Price (RM) (Optional)No.Section D: Label (Mock-up) For Immediate Container, Outer Carton,Proposed Package Insert- Please refer Appendix 9: Labelling Requirements1. Proposed Label Mock-up for Immediate Container2. Proposed Label Mock-up for Outer Carton3. Proposed Package InsertNo.Section E: Supplementary Documentation1. Product Owner2. Letter of Authorization from Product Owner3.Letter of Appointment of Contract Manufacturer from Product Owner (ifapplicable)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 131

Drug Registration Guidance Document (DRGD)Step II:4.5.Letter of Acceptance from Contract Manufacturer(if applicable)Is the active ingredient(s) patented in Malaysia?(Yes/ No)(If yes, please attach the related document)6. Certificate of Pharmaceutical Product (CPP)7. CPP Issuing Body8.Is this product licensed to be placed on the market for use in the exportingcountry? (Yes/ No)(If no, please state the reason)9.Is the product on the market in the exporting country? (Yes/ No)(If no, please state the reason)10. Date of Issue of CPP11. Date of Expiry of CPP12. Certificate of Free Sale (CFS)13. CFS Issuing Body14. Date of Issue of CFS15. Date of Expiry of CFS16. Certificate of Good Manufacturing Practice (GMP)17. Certificate of GMP Issuing Body18. Date of Issue of Certificate of GMP19. Date of Expiry of Certificate of GMP20.Summary of Product Characteristics(Product Data Sheet)21. Patient Information Leaflet (PIL)22. *Attachment of Protocol Analysis23. *Attachment of Analytical Validation24. *Certificate of Analysis (CoA)25. Other Supporting Document (if any)26. Manufacturer (Name and address)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 132

Drug Registration Guidance Document (DRGD)Step II:27. Importer (if any)28.Other manufacturer(s) involved, e.g. repacker (if any)(Please attach Certificate of GMP, if yes)29. Store AddressPART II: QUALITY OF PRODUCTNo.Section P: Drug Product (Finished Product)1. Description and Composition2. Pharmaceutical Developmenta) Information on Development Studiesb) Components of the Drug Productc) Finished Productsd) Manufacturing Process Developmente) Container Closure Systemf) Microbiological Attributesg) Compatibility3. Manufacturera) Batch Manufacturing Formulab) Manufacturing Process and Process Controlsc) Manufacturing Process Flowchartd) Control of Critical Steps & Intermediatese) Process Validation and/or Evaluation4. Control of Excipientsa) Specificationsb) Analytical Proceduresc) Validation of Analytical Proceduresd) Justification of Specificationse) Excipient of Human or Animal OriginNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 133

Drug Registration Guidance Document (DRGD)Step II:f) Novel Excipients5. Control of Finished Productsa) Specificationsb) Analytical Proceduresc) Validation of Analytical Proceduresd) Batch Analysese) Characterization of impuritiesf) Justification of Specifications6. Reference Standards or Materials7. Container Closure System8. Stability9.No.Product Interchangeability/ Equivalent Evidence (Bioavailability/Bioequivalence, BA/BE)- Please refer 2.1.3 Additional information on requirements of BA andBE.Section S: Drug Substance1. General Informationa) Nomenclatureb) Structure and Attachment for Structure of Drug Substancec) General Properties2. Manufacturera) Manufacturer Name and Addressb) Description of Manufacturing Process and Process Controlsc) Controls of Materialsd) Controls of Critical Steps and Intermediatese) Process Validation and/or Evaluationf) Manufacturing Process DevelopmentNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 134

Drug Registration Guidance Document (DRGD)Step II:3. Characterisationa) Elucidation of Structure and Characteristicsb) Impurities4. Control of Drug Substancesa) Specificationsb) Analytical Proceduresc) Validation of Analytical Proceduresd) Batch Analysise) Justification of Specifications5. Reference Standards or Materials6. Container Closure System7. StabilityPART III: NONCLINICAL DOCUMENTSection A: Table of ContentsNo. Section B: Nonclinical Overview1. Overview of the Nonclinical Testing Strategy2. Pharmacology3. Pharmacokinetics4. Toxicology5. Integrated Overview & Conclusions6. List of Literature CitationsSection C: Nonclinical Written and Tabulated SummariesSection D: Nonclinical Study ReportsSection E: List of Key Literature ReferencesNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 135

Drug Registration Guidance Document (DRGD)PART IV: CLINICAL DOCUMENTNo.Section A: Table of ContentsSection B: Clinical Overview1. Product Development Rationale2. Overview of Biopharmaceutics3. Overview of Clinical Pharmacology4. Overview of Efficacy5. Overview of Safety6. Benefits & Risks ConclusionsNo.Section C: Clinical Summary1. Summary of Biopharmaceutics Studies and Associated Analytical Methods2. Summary of Clinical Pharmacology Studies3. Summary of Clinical Efficacy4. Summary of Clinical Safety5. Synopses of Individual StudiesSection D: Tabular Listing of all Clinical StudiesSection E: Clinical Study ReportsSection F: List of Key Literature References, Published Clinical Papersand Latest Periodic Safety Update Report (PSUR)Notes:* Evaluated by Centre for Quality Control. For details, please refer to Section C:Quality Control in the main DRGD.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 136

Drug Registration Guidance Document (DRGD)2.1.2 GENERAL REQUIREMENTS FOR ABRIDGED EVALUATIONNo.Step I: Product Validation1. Product Name2. Dosage Form3.4.Active Ingredient(s)a) Active Ingredient nameb) Strength of Active Ingredient (Quantity unit per dose)c) Source of Active Ingredient (Animal – e.g. Bovine, Porcine, Ovine orOthers/ Plant/ Others)d) Form of Active Ingrediente) Remarks (if any)Excipient(s)a) Excipient nameb) Strength of Excipient (Quantity unit per dose)c) Function of excipient (e.g. absorbent, diluents, bulking agent, coatingagent, anti-caking agent etc.)d) Source of excipiente) Remarks (if any)5.Is there any source of ingredients derived from animal origin, includingactive ingredient? (Yes/ No)6. Manufacturer (Name and Address)7. Is the selected manufacturer a contract manufacturer? (Yes/ No)8.9.Is the product from second source? (Yes/ No)If yes, please provide:a) Letter of declaration stating that this product is a second sourceproductb) Registration number and product name of the first sourceIs this product containing any premix? (Yes/ No)a) State your premix formb) Manufacturer namec) Manufacturer addressd) Certificate of Good Manufacturing Practice (GMP)e) Formulationf) Manufacturing Processg) Specification of Analysish) Certificate of Analysis (CoA)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 137

Drug Registration Guidance Document (DRGD)No.10.11.Step I: Product ValidationIs this a replacement product? (Yes/ No)If yes, please provide:a) Letter of Declaration stating that this product is a replacement productb) Registration number and product name of the replaced productIs there any other manufacturer (repacker)? (Yes/ No)a) Manufacturer (repacker) nameb) Manufacturer (repacker) addressc) Certificate of Good Manufacturing Practice (GMP)d) Packaging Process12. Is this an imported product? (Yes/ No)Step II:No.Section A: Product Particulars1. Product Name2. Product Description3. Dosage Forma) Source of Capsule Shellb) Certificate to verify the source of the capsule shellc) Coloring agent used in capsule shell(Please attach COA of the capsule shell)4. Product Indication/ Usage5. Dose/ Use Instruction6. Contraindication7. Warning and Precautions8. Drug Interaction9. Side Effects/ Adverse reaction10. Signs and Symptoms of Overdose and Treatment11. Storage Condition12. Shelf LifeNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 138

Drug Registration Guidance Document (DRGD)Step II:13. Therapeutic Code/ ATC CodeNo.1.2.3.Section B: Product FormulaBatch Manufacturing Formulaa) Batch Sizeb) UnitActive Ingredientsa) Active Ingredients Nameb) Quantityc) Sourced) Form of Substancee) Overage (%)f) RemarksExcipientsa) Active Ingredients Nameb) Quantityc) Functiond) Sourcee) Overage (%)f) Remarks4. Attachment of Batch Manufacturing Formula Documentation5. Manufacturing Process6. Attachment of Manufacturing Process Documentation7. In-Process Quality Control8. Attachment of Finished Product Specification Documentation9.No.1.Attachment of Stability Data Documentation(For two batches) - Compulsory for imported productSection C: Particulars of Packing- Please refer Appendix 10: Guide for Implementation of Patient DispensingPack for Pharmaceutical Products in MalaysiaPack Size(Fill details by weight/ volume/ quantity)Measurement TypeNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 139

Drug Registration Guidance Document (DRGD)Step II:2.Immediate Container Type(Container Type and Description)e.g. Aluminium/ Glass/ Metal/ Paper/ Plastic/ Others3. Barcode/ Serial No. (Optional)4. Recommended Distributor‟s Price (RM) (Optional)5. Recommended Retail‟s Price (RM) (Optional)6. Other Related Attachment (if any)No.Section D: Label (Mock-up) For Immediate Container, Outer Carton,Proposed Package Insert- Please refer Appendix 9: Labelling Requirements1. Proposed Label Mock-up for Immediate Container2. Proposed Label Mock-up for Outer Carton3. Proposed Package InsertNo.Section E: Particulars of Product Owner, Manufacturer, Importer andOther Manufacturer(s) Involved and Store address1. Product Owner2. Manufacturer3.Other Manufacturer(s) involved (if any)a) Manufacturer Name and Addressb) Processing Steps Involvedc) Certificate of Good Manufacturing Practice (GMP)4. Store Name and Address5. ImporterNo.Section F: Supplementary Documentation1. Letter of Authorization from Product Owner2.3.4.Letter of Appointment of Contract Manufacturer from Product Owner (ifapplicable)Letter of Acceptance from Contract Manufacturer(if applicable)Is the active ingredient(s) patented in Malaysia?(If yes, please attach the related document)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 140

Drug Registration Guidance Document (DRGD)Step II:5. Certificate of Pharmaceutical Product (CPP)6. CPP Issuing Body7.Is this product licensed to be placed on the market for use in the exportingcountry?(If no, please state the reason)8.Is the product on the market in the exporting country?(If no, please state the reason)9. Date of Issue of CPP10. Date of Expiry of CPP11. Certificate of Free Sale (CFS) (if any)12. CFS Issuing Body13. Date of issue of CFS14. Date of expiry of CFS15. Certificate of Good Manufacturing Practice (GMP)16. Certificate of GMP Issuing Body17. Date of issue of Certificate of GMP18. Date of expiry of Certificate of GMP19.Summary of Product Characteristics(Product Data Sheet)20. Patient Information Leaflet (PIL)21. Attachment of Protocol Analysis22.Attachment of Certificate of Analysis (CoA)(For two batches)* Compulsory for imported products23. Attachment of Specifications and Certificate of Analysis of Active Ingredient24. Other Supporting Documents (if any)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 141

Drug Registration Guidance Document (DRGD)2.1.3 ADDITIONAL INFORMATION ON:A) BIOAVAILABILITY (BA) STUDYFor modified-release products, dosage recommendations and regime must be supportedby bioavailability studies.Studies comparing availability or establishing equivalence of similar products would beuseful.B) BIOEQUIVALENCE (BE) STUDYNote: This requirement is applicable to generics (scheduled poison) only.With the increasing availability of generic products, a mechanism is required to ensure thatsuch products are therapeutically equivalent to the innovators‟ products and are clinicallyinterchangeable.In practice, demonstration of bioequivalence (BE) is generally the most appropriate methodof substantiating therapeutic equivalence between medicinal products. A list of drugsubstances, which, when formulated in oral solid dosage forms, require BE data as aprerequisite for registration, has been established by the authority (please refer to BPFKwebsite at http://www.bpfk.gov.my). This list is updated based on the requirements.Bioequivalence (BE) Study Requirements for Generic Product in Immediate Release,Oral Solid Dosage Form Submitted as a Second Source ApplicationIn general, for a second source application of a generic product (immediate release, oralsolid dosage form), BE study report from the actual manufacturing site must be submittedduring the submission of application for registration. The base of this requirement is due tothe difference in manufacturing site from the first source that may change the characteristicand specifications of a second source product.However, biowaiver can be considered, provided that Comparative Dissolution Profile(CPD) report against the registered first source product is submitted as a surrogate tobioequivalence study conducted for the second source product and all the followingconditions shall be fulfilled.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 142

Drug Registration Guidance Document (DRGD)a) Bioequivalence study conducted using the registered first source product has beenevaluated by the NPCB and found satisfactory.b) The second source product is the same as registered first source product used in thebioequivalence study in terms of:i) Product formulation;ii) Equipment used in the manufacturing process;iii) Source and supplier of raw material;iv) Quality control and specifications of raw material;v) Manufacturing process of product and standard operating procedures;vi) Environmental conditions during the manufacturing process of product;vii) Quality control and specifications of finished product.c) Comparative Dissolution Profile must be conducted in accordance to ASEANGuidelines for the Conduct of Bioavailability and Bioequivalence Studies including thecalculation of similarity factor (f2) to prove the similarity of these two products.d) Process validation has been conducted on 3 pilot or commercial batches of thesecond source product and found satisfactory by the NPCB.This exemption is not applicable for any new submission of application for registration of afirst source product. BE study must be conducted for this product which ismanufactured at the actual manufacturing site submitted for registration.(Reference: Circular Bil.(10)dlm.BPFK/PPP/07/18Jld.1 , 2 Jun 2011)Starting on 1 st of January 2012, bioequivalence (BE) study is required for all application ofregistrations for generic products containing scheduled poison in the form of immediaterelease, oral, solid dosage form whereas renewal of registered products, the effective dateis on 1 st January 2013.(Directive Arahan di Bawah Peraturan 29, Peraturan-peraturan Kawalan Dadah danKosmetik 1984 Bil. 1 Tahun 2011, 2 March 2011 Bil (10) dlm BPFK/PPP/01/03 Jld 1)Sponsors or BE study centers are compulsory to notify the Authority pertaining to all BEstudies which do not require Clinical Trial Import Licence (CTIL) or Clinical TrialExemptions (CTX) and are going to be done at either local or overseas BE study centersfor registered products or products to be registered in Malaysia (Directive Arahan di BawahPeraturan 29, Peraturan-peraturan Kawalan Dadah dan Kosmetik 1984 Bil. 13 Tahun 2011,14 October 2011, Bil (23) dlm BPFK/PPP/01/03 Jld 1).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 143

Drug Registration Guidance Document (DRGD)Effective 1 st March 2013, biowaiver may be granted to generic immediate release oral soliddosage form products containing BCS Class I active ingredients listed in the Guidance OnBiopharmaceuticals Classification System (BCS) – Based Biowaiver document. BCS Basedbiowaivers takes the three major factors that govern the rate and extent of drug absorptionfrom immediate-release solid dosage forms into accounts i.e. solubility and permeability ofthe drug substance/ API, and dissolution characteristics of the dosage form. This BCSapproach provides an opportunity to waive in vivo pharmacokinetic bioequivalence testingfor certain categories of immediate-release drug products.(Directive Arahan di Bawah Peraturan 29, Peraturan-peraturan Kawalan Dadah danKosmetik 1984 Bil. 1 Tahun 2013, 14 October 2011, 28 February 2013, Bil(101)dlm.BPFK/PPP/01/03 Jld 2).For more information on BE, please refer Bioequivalence (BE).2.2 SPECIFIC REQUIREMENTSFor biologics, health supplements and natural products, please refer guidelines for therespective product category at:a) Appendix 3: Guidelines on Registration of Biologicsb) Appendix 4: Guideline on Registration of Health Supplementsc) Appendix 5: Guideline on Registration of Natural ProductsPlease refer as well on Appendix 11: Guideline on Filling the Online Application Form forProduct Registration via Quest System before submission of an application for productregistration.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 144

Drug Registration Guidance Document (DRGD)APPENDIX 3:GUIDELINES ON REGISTRATION OF BIOLOGICSIMPORTANT NOTES:1. This document shall be read in conjunction with the relevant sections of the mainguidance document: Drug Registration Guidance Document (DRGD), which is inaccordance to the legal requirements of the Sale of Drugs Act 1952 and theControl of Drugs and Cosmetics Regulations 1984.2. The National Pharmaceutical Control Bureau‟s (NPCB) requirements for registration ofbiologics/ biopharmaceuticals products are aligned with the scientific guidelines andrecommendations for quality, clinical efficacy and safety and non-clinical of the WorldHealth Organization (WHO), European Medicines Agency (EMA) and InternationalConference of Harmonization (ICH).3. Where appropriate, the relevant WHO, EMA and ICH guidelines on biologics/biopharmaceuticals shall be consulted.WHO (http://www.who.int/boodproducts/en/index.html)EMA (http://www.ema.europa.eu)ICH (http://www.ich.org)4. Every biologic is regulated as a new product and also considered „high risk‟, itmust comply to Good Manufacturing Practice strictly. Adoption of GMP as an essentialtool of Quality Assurance System.5. The requirements for registration of biologics/ biopharmaceuticals shall be inaccordance to the ASEAN Common Technical Dossier (ACTD) format and inadherence to the general regulatory requirement as described in sections of the mainDRGD. It covers:Administrative informationProduct quality dataProduct safety dataClinical data, demonstrating clinical efficacy and capacity to meet therapeuticclaims, through clinical studies.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 145

Drug Registration Guidance Document (DRGD)6. Animal derived materials/ products are commonly used in the manufacture of biologics/biopharmaceuticals. Please provide detail information regarding the rationale for use ofsuch material, the source etc., as per Checklist A and Checklist B; and also provide aconfirmation on the presence/ absence of the animal materials in the final product.7. Since biosimilars are follow-on products of the original biopharmaceutical products(well-characterised recombinant proteins), this document also is applicable tobiosimilars. Additionally, a separate Guideline for Registration of Biosimilars isavailable.8. This document is intended to provide guidance for the registration of biologics.However, the document will serve as a living document that will be updated/ revisedfurther in the line with the progress in scientific knowledge and experience.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 146

Drug Registration Guidance Document (DRGD)Outline:3.1 General Information3.1.1 Definitions3.1.2 Introduction3.2 Specific Requirements for Registration of Biologics3.2.1 Requirements for Registration of Biologics(Vaccines and Biotechnology Products)a) Vaccinesi) Definition of Vaccineii) Requirements for Registration of Vaccines(Chemistry, Manufacturing And Controls, CMC)b) Biotechnology Productsi) Definition of Biotechnology Productii) Additional Requirements for Registration of BiotechnologyProductsc) References3.2.2 Requirements for Registration of Blood Productsa) Definition of Blood Productb) Requirements for Registration of Blood Productsc) Checklist of Plasma Master File for Blood Productsd) References3.3 Checklists of Registration for Products Containing Materials ofAnimal Origin:3.3.1 Checklist A: Products Containing Animal-Derived Materials witha valid TSE risk evaluation Certificate of Suitability(CEP)3.3.2 Checklist B: Products Containing Animal-Derived Materialswithout a valid TSE risk evaluation Certificate ofSuitability (CEP)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 147

Drug Registration Guidance Document (DRGD)3.1 GENERAL INFORMATION3.1.1 DEFINITIONS:i) Biopharmaceutical/ Biotechnology Productii) Biologic/ Biological ProductThe term „biopharmaceutical‟ was coined in the 80‟s to define proteins that weremade by recombinant DNA technology [which includes hybridoma technology formonoclonal antibody (mAb) production].Biologic/ Biological product refers to a product whose active substance is madeby or derived from a living organism (plant, human, animal or microorganism)and may be produced by biotechnology methods and other cutting-edgetechnologies. This product imitates natural biological substances in our bodiessuch as hormones, enzymes or antibodies.Biopharmaceuticals/ Biologics/ Biological products can also be defined as:“a protein (including antibodies) or nucleic acid-based pharmaceuticals used fortherapeutic, which is produced by means other than direct extraction from anative (non- engineered) biological source”. This corresponds to the newbiotechnology view (that is, by elimination, it is largely restricted to recombinant/genetically engineered and mAb-based products).The term „Biotechnology product‟ and „Biological product‟ are used to broadlyrefer to all biopharmaceuticals (by the broad biotechnology view).Note: Today, biologics have become inextricably intertwined withbiopharmaceuticals, to the point where they are synonymous. The generalconsensus is that a „Biologic‟ and „Biopharmaceutical‟ are interchangeableterminology, but a biologic might incorporate some other products (e.g. allergenics,somatic cells etc.).Biologics include a wide range of products such as:Vaccines;Blood products;Monoclonal antibodies (therapeutics);Recombinant proteins:- Insulins- Hormones- Erythropoetins and other hematopoietic factors- Cytokines: interferons, interleukins, colony-stimulating factors, tumournecrosis factors.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 148

Drug Registration Guidance Document (DRGD)But does not include:Metabolites from microorganisms; e.g antibiotics and some hormones.Macromolecules produced by chemical synthesis; e.g peptides/oligo-nucleotidesproduced by chemical synthesis.Whole blood or cellular blood components.Note: This document is not intended to apply to the control of genetically-modifiedlive organisms designed to be used directly in humans, e.g. live vaccines.3.1.2 INTRODUCTIONIt is acknowledged that biological substances used in the practice of medicinesmake a vital contribution to health care. Nevertheless, because of their nature,biologicals demand special attention with regard to their regulations to assurequality, efficacy and safety.Biologicals are inherently variable due to their biological nature, produced frombiological materials, and often tested in biological test systems, themselves variable,a feature that has important consequences for the safety and efficacy of the resultingproduct. Each product must be evaluated on its own merits. A prerequisite for theuse of biological is therefore to assure the consistency of quality and safety from lotto-lot.Today, the biological field is one of enormous expansion and increasing diversity,most especially in the area of new biotechnologies. The revolution of DNA-basedand other cell technologies has opened up a new and exciting vista, and in manyinstances, traditional products are being replaced by equivalents derived byrecombinant DNA technologies or other cutting-edge technologies.It is important to note that the demonstration that a product consistently possesses adesired characteristics of safety and efficacy will depend on a multifaceted approachon the part of manufacturer and the regulatory authority - drawing on thoroughcharacterization of starting materials, demonstration of consistency of production,and appropriate selection of lot release tests - all under the stringent anddocumented controls imposed by good manufacturing practices - as well as rigorouspost marketing surveillance activities.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 149

Drug Registration Guidance Document (DRGD)3.2 SPECIFIC REQUIREMENTS FOR REGISTRATION OF BIOLOGICSSpecific requirements for registration of biologic/ biopharmaceutical are described asfollows:- Requirements for Registration of Biologics (Vaccines and Biotechnology products);- Requirements for Registration of Blood Products.3.2.1 REQUIREMENTS FOR REGISTRATION OF BIOLOGICS (VACCINES ANDBIOTECHNOLOGY PRODUCTS)a) VACCINES:i) DEFINITION OF VACCINEA vaccine contains an active component (the antigen). A vaccine is an immunogen,the administration of which is intended to stimulate the immune system to result inthe prevention, amelioration or therapy of any disease or infection.Vaccines for human use include one or more of the following:a) microorganisms inactivated by chemical/ physical means that retain appropriateimmunogenic properties;b) living microrganisms that have been selected for their attenuation whilst retainingimmunogenic properties;c) antigen extracted from microorganisms, secreted by them or produced byrecombinant DNA technology; ord) antigen produced by chemical synthesis in vitro.The antigens may be in their native state, truncated or modified followingintroduction of mutations, detoxified by chemical or physical means and/oraggregated, polymerized or conjugated to a carrier to increase immunogenicity.Antigens may be presented plain or in conjunction with an adjuvant, or incombination with other antigens, additives and other excipients.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 150

Drug Registration Guidance Document (DRGD)ii) REQUIREMENTS FOR REGISTRATION OF VACCINES(CHEMISTRY, MANUFACTURING AND CONTROLS, CMC)A. DESCRIPTION• Description - Information on the source materials: source materials include anycomponent/ unformulated active substance used in the manufacture of theproduct (e.g microorganisms, cells/ cell subtrate, immunogen) including theirspecifications and the tests used to demonstrate compliance with thespecifications. For combination vaccines, each active substance, which will bepooled, combined with other antigens and formulated, shall be described.• Any chemical modification or conjugation of the drug substance shall bedescribed in detail.• List of inactive substances, which may be present in the drug substance.B. METHOD OF MANUFACTURE/ PRODUCTION1. Manufacturing Formula:• List of all materials (culture media, buffers, resins for peptide synthesis,chemicals, columns etc.) and their tests and specifications, or reference topharmacopoeia.• Complete formula inclusive of any adjuvants, diluents, preservatives, additives,stabilisers etc.• Production of each antigen in the vaccine (i.e. fermenter or culture volumes foreach bulk batch size as applicable and typical bulk volumes per production run).• Batch formula for each batch size and final formulated bulk product.• Lot numbering system for intermediates and final product.2. Manufacturing Process:Flow Charts/ Diagrams be Accompanied by a Descriptive Narrative:• Detailed description of manufacturing process and characterization of theproduct. Include complete history and characterization/ characteristics of eachspecies, strain, cell banking systems - Master Cell bank (MCB) and Working CellBank (WCB), cell/ seed lot system, cell substrate system, animal sources(including fertilized avian eggs), virus source or cellular sources.Ref: WHO TRS 878 (1998) Annex 1: Requirements for the use of animal cellsas in vitro substrates for the production of biologicals.• The flow chart should show the steps in production and a complete list of the in-National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 151

Drug Registration Guidance Document (DRGD)process controls and tests performed on the product at each step.• In-process holding steps, with time and temperature limits indicated.• Description of the manufacturing processes (flow diagram) in detail to supportthe consistency of manufacture of drug substance - cell growth and harvesting.• Identification of any processes or tests performed by contract manufacturers ortesters.• Animal cells: Cells of animal origin may harbour adventitious agents andconsequently pose a potentially greater risk to humans. Description of measurestaken to remove, inactivate, or prevent contamination of the product from anyadventitous agent present.• Information on measures to prevent any catastrophic events that could renderthe cell banks unusable and to ensure continuous production of vaccines iscrucial.For recombinant vaccines: description of the construction and characterization ofthe recombinant vector as well as source of master cell bank/ constructs.3. Process Validation Program:• Describe general policy for process validation and provide process validationactivities performed.4. Handling, Storage and Packaging:• All arrangements for the handling of starting materials, packaging materials, bulkand finished products, including sampling, quarantine, release and storage.C. QUALITY CONTROL1. Starting Materials:• List of all control tests performed on raw materials, with appropriatecharacterisation on starting materials.• List of raw materials meeting compendia specifications.• List of raw materials meeting in-house specifications including the testsperformed and specifications• Biological starting materials (human or animal origin) with information on therequirements to avoid risk of transmissible spongiform encephlopathies (TSEs)and human diseases (HIV, hepatitis,etc) in the final product including Certificateof Suitability (CEP). Please refer Checklist A & BRef: WHO Guidelines on Transmissible Spongiform Encephalopathies in relation toBiological and Pharmaceutical products (2010).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 152

Drug Registration Guidance Document (DRGD)2. Intermediate Products (as appropriate):• List the routine tests performed and specifications for intermediates.3. Finished Products (including diluents):• List routine tests performed and specifications for final product.• Description of the method and retest criteria.4. Analytical Validation Activities Performed:• Include complete description of the protocol used for each bioassay, the controlstandards, the validation of inherent variability of test and the establishment ofacceptance limits for each assay.D. STABILITY(http://www.who.int/biologicals/publications/trs/areas/vaccines/stability/en/ )• Information on stability of intermediates and final product, quality control methodsand rationale for the choice of tests for determining stability.• Information on the dates of manufacture of the lots, the lot numbers, the vial anddose size, and the scale of production.• Describe the policy for assigning the date of manufacture of each component aswell as the final product (e.g combination vaccine) and diluents, as appropriate.• In addition to final product stability data at the recommended storagetemperature, the accelerated stability data at elevated temperatures should besufficient to justify the choice of Vaccine Vial Monitor (VVM) for use with theproduct [Vaccine Vial Monitor WHO/PQS/E06/IN05.1]E. LOT SUMMARY PROTOCOL AND LOT RELEASE FOR VACCINE• Lot Summary Protocol - a document which describes the key steps and criticaltest results at each step of the production process must be submitted.• Lot release is a basic principle in the control of vaccine. The aim of lot release isthe confirmation of consistency of production as each lot of vaccine is unique.• Submit Lot/ Batch Release Certificate issued by the competent authority.Ref: Guidelines for Independent Lot Release of Vaccines by Regulatory AuthoritiesWorld Health Organization 2010F. NONCLINICAL STUDIES FOR VACCINE• Vaccines are a diverse class of biological products and their nonclinical testingprograms will depend on product-specific features and clinical indications.• Preclinical testing is a prerequisite to moving a candidate vaccine from thelaboratory to the clinic and includes all aspects of testing, productcharaterization, proof of concept/ immunogenicity studies and safety testing inanimals conducted prior to clinical testing in humans.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 153

Drug Registration Guidance Document (DRGD)• Some live attenuated vaccines must be tested for safety in animals before theyare used in humans.Ref: WHO TRS 927 (2005) Annex 1: WHO guidelines on nonclinical evaluation ofvaccinesG. CLINICAL STUDIES FOR VACCINE• Clinical studies designed and conducted to meet WHO and international GCPprinciples.• Tabulated summary of the clinical development program of the vaccine, in whichcritical parameters that may have changed during the clinical development.• Copies of publications about these trials should accompany the submission.• Clinical summary: Provide detailed summary and intepretation of the safety andefficacy data obtained from clinical studies that supports the current prescribinginformation.• Clinical Expert Report: Provide an independent clinical expert report on theclinical studies (evidence of expertise and independence should be provided)Ref:- WHO TRS 924 (2004) Annex 1: WHO guidelines on clinical evaluation ofvaccines:Regulatory expectations.- WHO TRS 850 (1995) Annex 3: Guidelines for good clinical practice (GCP) for trialson pharmaceutical products.H. POST MARKETING SURVEILLANCE FOR VACCINES• Provide an outline of the post marketing pharmacovigilance plan for the vaccine.• Periodic safety update report (PSUR) in accordance to ICH Guideline E2C(R1)Clinical Safety Data Management: Periodic Safety Update Reports for MarketedDrugs.• In the case of vaccines that have recently been registered/ licensed, provideinformation on any ongoing phase IV studies or on any active monitoring of thesafety profile that is taking place including adverse events followingimmunization(AEFI).• Risk management plan.Please also refer to: NPCB‟s Guidelines for Pharmacovigilance on Safety ofVaccines in Malaysia (January 2010) ISBN 978-967-5570-05-6National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 154

Drug Registration Guidance Document (DRGD)b) BIOTECHNOLOGY PRODUCTSi) DEFINITIONBiotechnological products includes the use of the new genetic tools of recombinantDNA to make new genetically modified organisms or genetic engineering products.Products of recombinant technology are produced by genetic modification in whichDNA coding for the required product is introduced, usually by means of a plasmid orviral vector into a suitable microorganism or cell line, in which DNA is expressed andtranslated into protein. The desired product is then recovered by extraction andpurification.ii) ADDITIONAL REQUIREMENTS FOR REGISTRATION OF BIOTECHNOLOGYPRODUCTS:I. PRODUCTION PROCESSES• The production system shall be well defined and documented.• The effectiveness of the overall purification process for active substance shall bedemonstrated.• Validation of procedures for removing contaminating cellular DNA, viruses andimpurities.J. HOST CELL AND GENE CONSTRUCT• Source of host cells, characterisation, stability, purity and selection.• Information on gene construct, amino acid sequence, vector information andgenetic markers for characterisation of production cells.• Cloning process to form the final gene construct and mapping of sited used inconstructions of final recombinant gene construct.• Method of gene construct amplication and selection of recombinant cell.K. SPECIFICATIONS• Drug substances should include assays for identity, purity, potency,physiochemical and stability.• Identity and quantity of impurities along with analytical data which supportsimpurities profile• Acceptable limits of impurities and should be included in the specifications ifpresent in finished products.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 155

Drug Registration Guidance Document (DRGD)L. CHARACTERISATION• Analytical testing performed to characterise the drug substance with respect toidentity, purity, potency, and stability.• Characterisation of drug substance include physiochemical characterisation,immunological properties and biological activity.• Sufficient sequence information to characterise the product should be obtained.• Post translational modifications should be identified and adequetly characterised,especially when such modifications are likely to differ from those found in naturalcounterpart and may influence biological, pharmacological and immunologicalproperties of the product.M. NONCLINICAL STUDIES• Preclinical testing is a prerequisite to moving a candidate biotechnology productsfrom the laboratory to the clinic and includes all aspects of testing, productcharaterization, proof of concept/ immunogenicity studies and safety testing inanimals conducted prior to clinical testing in humans.• The primary goals of nonclinical studies/preclinical safety evaluation are toidentify an initial safe dose and subsequent dose escalation schemes in humans,potential target organs for toxicity (whether such toxicity is reversible) and safetyparameters for clinical monitoringRef: ICH Topic S6 Preclinical Safety Evaluation of Biotechnology-DerivedPharmaceuticals.N. CLINICAL STUDIES• Clinical studies designed and conducted to meet WHO and international GCPprinciples.• Overall approach to the clinical developement of a medicinal product.• Overview of the clinical findings and provide an evaluation of benefits and risksbased upon the conclusions of the relevant clinical studies.• Interpretation of how the efficacy and safety findings support the proposed doseand target indication.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 156

Drug Registration Guidance Document (DRGD)O. POST MARKETING SURVEILLANCE FOR BIOTECHNOLOGY PRODUCT• Provide an outline of the post marketing pharmacovigilance plan.• Periodic safety update report (PSUR) in accordance to ICH Guideline E2C(R1)Clinical Safety Data Management: Periodic Safety Update Reports for MarketedDrugs.• All relevant clinical and nonclinical safety data should cover the period of thereport with exception of updates of regulatory authority or marketingauthorisation holder (MAH) actions taken for safety reasons, as well as data onserious, unlisted adverse drug reactions (ADRs), which should be cumulative.• Risk management planc) REFERENCES FOR VACCINES AND BIOTECHNOLOGY PRODUCTS:i) Vaccines:WHO (http://www.who.int/biologicals/vaccines)i) WHO Technical Report Series: Vaccinesii) Biotechnology Products:WHOi) WHO Technical Report Series 1991 No. 814, Annex 3. Guidelines for assuring thequality of pharmaceutical and biological products prepared by recombinant DNAtechnology. (under revision)ii) WHO Technical Report Series 1991 No 822, Annex 3. Guidelines for assuring thequality of monoclonal antibodies for use in humans.iii) WHO Technical Report Series No 878, Annex 1 and Addendum. Requirements forthe use of animal cells as in vitro substrates for the production of biologicals.iv) WHO Technical Report Series No.786, Annex 3.Requirements for human interferonsprepared from lymphoblastoid cells (Requirements for biological substances N0.42)v) WHO Technical Report Series No.771, Annex 7 Requirements for human interferonsmade by recombinant DNA techniques (Requirement for biological substance No.41)EMAi) CHMP/BWP/157653/07. Production and Quality Control of Monoclonal Antibodiesand Related Substances.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 157

Drug Registration Guidance Document (DRGD)ii) CPMP/BWP/328/99. Development Pharmaceutics for Biotechnological andBiological Products - Annex to Note for Guidance on Development Pharmaceutics.iii) CHMP/BWP/157653/2007. Guideline on Development, Production, Characterisationand Specifications for Monoclonal Antibodies and Related Products.iv) EMEA/410/01 Rev. 3 Minimising the Risk of Transmitting Animal SpongiformEncephalopathy Agents via Human and Veterinary Medicinal Products.ICHi) ICH Topic Q5A Viral Safety Evaluation Of Biotechnology Products Derived FromCell Lines Of Human Or Animal Origin.ii) ICH Topic Q5B Quality of Biotechnological Products: Analysis of the ExpressionConstruct in Cell Lines used for Production of r-DNA derived Protein Products.iii) ICH Topic Q5D Quality of Biotechnological Products: Derivation andCharacterisation of Cell Substrates used for Production of Biotechnological/Biological Products.iv) ICH Topic Q5C Quality of Biotechnological products: Stability Testing ofBiotechnological/ Biological Products.v) ICH Topic Q5D Derivation and Characterisation of Cell Substrates Used forProduction of Biotechnological/ Biological Products.vi) ICH Topic Q5E Comparability of Biotechnological/ Biological Products Subject ToChanges in Their Manufacturing Process.vii) ICH Topic Q6B Specifications: Test Procedures and Acceptance Criteria forBiotechnological/ Biological Products.viii)ICH Topic Q2 Validation of Analytical Procedures: Text and Methodology.ix) ICH Topic Q8 Pharmaceutical Development.x) ICH Topic Q11 Development and Manufacture of Drug Substances (ChemicalEntities and Biotechnological/ Biological Entities).xi) ICH Topic S6 Preclinical Safety Evaluation of Biotechnology-DerivedPharmaceuticals.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 158

Drug Registration Guidance Document (DRGD)3.2.2 REQUIREMENTS FOR REGISTRATION OF BLOOD PRODUCTSNote: This document is applicable to all plasma-derived products containing an active andinactive ingredient that is derived from human blood.a) DEFINITION OF BLOOD PRODUCTAny therapeutic product derived from human blood or plasma and produced by amanufacturing process that pools multiple units.Plasma-derived therapies and their recombinant analogs are unique amongpharmaceuticals and biologics. Their production begins with a biological starting material,human plasma. Each therapy has a unique biochemical profile as a result of differences inproduction and processing methods that can lead to differing clinical responses andefficacy among patients.Hence, from the starting material, through manufacturing and final distribution to patients,the complexities of producing blood products places it in a unique class of biologics.Blood products are regulated as medicinal product. Blood products are inherently variabledue to their biological nature, and the biological methods to test them. They are subjectedto comprehensive assessment of the quality, efficacy and safety.Four (4) principal complementary approaches are adopted:• Starting material: Assurance of the quality and safety of the plasma forfractionation.• Manufacturing technique: Control of the fractionation and subsequentmanufacturing procedures for isolation, purification, viral inactivation and/or removalsteps.• Good manufacturing practice (GMP): Strict adherence to GMP. Adoption of GMPas an essential tool of Quality Assurance System.• Product Compliance: Standardization of biological methods needed incharacterisation of in-process and finished products.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 159

Drug Registration Guidance Document (DRGD)Plasma for fractionation and blood products that are regulated by National PharmaceuticalControl Bureau (NPCB) includes:• Plasma products derived from plasma collected and fractionated in Malaysia for usein Malaysia;• Plasma products derived from plasma collected and fractionated overseas for use inMalaysia; and• Plasma products derived from overseas-sourced plasma fractionated in Malaysia foruse overseas.b) REQUIREMENTS FOR REGISTRATION OF BLOOD PRODUCTS1. QUALITY OF PLASMA SOURCE MATERIALPlasma Master File (PMF). It can also be a stand-alone document. Documentpertaining to the collection and controls of source materials. Key elements of PMFare:• Requirements for a formal contract governing purchase and supply of plasma.• Source plasma.• GMP status of the blood establishments/ collection centers.• Description of the quality assurance system applying to plasma supply anduse.• Arrangements for donor selection, selection/exclusion criteria.• Data on population epidemiology and blood-borne infections.• Requirements for testing of samples of donations and pools. Mandatoryserology on all plasma donations. Each unit of source material tested forHBsAg, anti-HIV and anti-HCV• Plasma bags, plasma quality and plasma specifications.• Arrangement for communication and review of post-donation information.• Plasma inventory hold.• Traceability from donor to end product and vice versa.Ref: CHMP/BWP/3794/03 Rev. 1 Scientific data Requirements for Plasma MasterFile (PMF) and also the checklist.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 160

Drug Registration Guidance Document (DRGD)2. MANUFACTURING PROCESS AND CONTROLDocuments that verify each batch of source material intended for manufacture hasbeen serological tested for hepatitis B (HBV), hepatitis C (HCV) and HIV. Eachbatch of source material must also be tested for HCV RNA by Nucleic Acid Testing(NAT) and (increasingly for other viruses including HIV, HBV, B19, and HAV) andexclusion of reactive donations.Characterization: Physicochemical and biological characterization: Specific teststhat will provide information regarding identity, purity, potency, stability andconsistency of manufacture for the drug substance.Manufacture and Controls:i) Formula:• Include a list of all starting materials, reagents, monoclonal antibodies,intermediate products and auxiliary materials (buffers, sera, antibiotics etc.)with specifications or statement of quality for each.• Excipients: List of excipients.• For non-compendial excipients: Describe tests and specifications.• For novel excipients: Include description for preparation, characterisation andcontrols.• When used as excipient in the product, the expiry date of the plasma-derivedproduct should not be earlier than that of the finished product.ii) Manufacturing:• Detailed description of manufacturing process and controls to demonstrateproper quality control or prevention of possible contamination with adventitiousagents.• In-process and final controls.Viral inactivation and/ or removal processesViral validation studies and reportPathogen safety document inclusive of Transmissible SpongiformEncephalopathies (TSEs) risk assessmentInformation or certification supporting the freedom of reagents, inactiveingredients of human or animal origin from adventitious agents.Process consistencyAnalytical validation studiesProcess validation studies (purification, sterility etc.)Batch record and batch release specificationsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 161

Drug Registration Guidance Document (DRGD)3. THE FINAL PRODUCT• Finished product testing and quality control• Stability study program and expiration date• Product history• Container closure system, storage and handling• Package insert and labels• Lot/ batch release protocols• Certificate of batch review and release from a competent authority4. CLINICAL STUDIES• Demonstrating product‟s efficacy5. POST MARKETING SURVEILLANCE – mandatory follow-up• Periodic Safety Update Report (PSUR)• Risk Management PlansNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 162

Drug Registration Guidance Document (DRGD)c) Checklist of Plasma Master File for Blood ProductsSection Documents Yes/No1. General Information1.1 Plasma Derived Products‟ List1.21.3Overall Safety StrategyCollection of plasmaTestingStorageGeneral LogisticsFlowchart of supply chain of plasma2. Technical Information on Starting Materials/Plasma2.1Plasma OriginInformation on Collection CentersInformation on Testing CentersSelection/ Exclusion Criteria for DonorsTraceability2.22.3Plasma Quality and SafetyCompliance with Ph. Eur. Monographs or relevantmonographsScreening Tests for Markers of InfectionTechnical Characteristics of Bags and Bottles for Bloodand Plasma Collection, Including Information onAnticoagulant Solutions UsedStorage and TransportProcedures for any Inventory Hold PeriodCharacterisation of the Fractionation PoolContract Between Manufacturer and Blood CollectionEstablishment(s)System in place between the manufacturer and/orplasma fractionators/ processor on one hand, and bloodcollection establishments on the other hand whichdefines the conditions of their interaction and theiragreed specificationsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 163

Drug Registration Guidance Document (DRGD)d) REFERENCES FOR BLOOD PRODUCTS:The National Pharmaceutical Control Bureau‟s requirements for registration of bloodproducts are aligned with the scientific guidelines and recommendations for quality, clinicalefficacy and safety and non-clinical of the World Health Organization (WHO), EuropeanMedicines Agency and International Conference of Harmonization (ICH).Where appropriate, the relevant WHO, EMA and ICH guidelines on blood productsshall be consulted in particular the followings:WHO (http://www.who.int/boodproducts/en/index.html)i) WHO Technical report Series 941, Annex 4, Recommendations for production,control and regulation of human plasma for fractionation.ii) WHO Technical report Series 924, Annex 4, Guidelines on viral inactivation andremoval procedures intended to assure the viral safety of human plasma products.iii) WHO Guidelines on tissue infectivity distribution in Transmissible SpongiformEncephalopathies.EMA (http://www.ema.europa.eu)i) EMA/CHMP/BWP/706271/2010 Committee for medicinal products for human use(CHMP) Guideline on plasma-derived medicinal productsii) CHMP/BWP/3794/03 Rev. 1 Scientific data Requirements for Plasma Master File(PMF)iii) CPMP/BWP/268/953AB8A Virus Validation Studies: The Design, Contribution andInterpretation of Studies validating the Inactivation and Removal of Virusesiv) EMEA/410/01 Rev. 3 Minimising the Risk of Transmitting Animal SpongiformEncephalopathy Agents via Human and Veterinary Medicinal Productsv) Guideline on the clinical investigation of recombinant and human plasma-derivedfactor VIII products, European Medicines Agency, EMA/CHMP/BPWP/144533/2009.vi) Note for Guidance on the Clinical Investigation of Human Plasma Derived Factor VIIIand IX products, European Medicines Agency, CPMP/BPWG/198/95REV.1.vii) Guideline on the Clinical Investigation of Human Normal Immunoglobulin forIntravenous Administration (IVIg), European Medicines Agency,EMA/VHMP/BPWP/94033/2007 REV.2.ICH (http://www.ich.org)i) ICH Topic 5QC Quality of Biotechnological products: Stability Testing ofBiotechnological/ Biological Products.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 164

Drug Registration Guidance Document (DRGD)3.3 CHECKLISTS3.3.1 Checklist A:Products Containing Animal-Derived Materials WITH a valid TSE risk evaluationCertificate of Suitability (CEP)No. Documents Yes/ No1. TSE Risk Evaluation Certificate of Suitability (CEP)2. Basic information providing a brief description of the following:3. Rationale for using animal-derived materials4.5.6.7.8.9.Source of AnimalsDeclaration of materials of porcine originDeclaration of materials of other animal originDeclaration of the nature of the animal tissue/ parts of animalused.Description of the tissue/ organ-collection procedures andmeasures in place to avoid cross-contamination.Nature and quantity of each animal-derived material used:As a drug substance.As an excipient or adjuvant.As a starting material used in the manufacture of a drugsubstance.As a starting material used in the manufacture ofexcipient.As a reagent or culture media component used inmanufacture.As a reagent or culture media component used inestablishing master cell banks.As a reagent or culture media component used inestablishing working cell banks.Others, please provide detailsDeclaration that the final product does not contain any animalcontainingmaterials with the relevant evidence (if applicable)Other supporting documents e.g. Halal Certification of the animalderived ingredient from a competent Halal Certification Authority.10. Labelling of the animal derived materials.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 165

Drug Registration Guidance Document (DRGD)3.3.2 Checklist B:Products Containing Animal-Derived Materials WITHOUT a valid TSE risk evaluationCertificate of Suitability (CEP)Section Documents Yes/ No1.Detailed Assessment Report for the risk of TSE.The scope of this assessment report should include thefollowing:2. Rationale for using animal-derived materials3.Source of AnimalsDeclaration of materials of porcine originDeclaration of materials of other animal origin4. Declaration of the nature of the animal tissue/ parts used.5.6.7.8.Description of the tissue/ organ-collection procedures andmeasure in place to avoid cross-contamination.Detail of the risk factors associated with the route ofadministration and maximum therapeutic dosage of the product.Nature and quantity of each animal-derived material used:As a drug substanceAs an excipient or adjuvantAs a starting material used in the manufacture of a drugsubstance.As a starting material used in the manufacture ofexcipient.As a reagent or culture media component used inmanufacture.As a reagent or culture media component used inestablishing master cell banks.As a reagent or culture media component used inestablishing working cell banks.Others, please provide details.Relevant information to support the claim that the manufacturingprocess is capable of inactivating TSE agents.9. Certificates of analysis for each animal-derived materials used.10.Declaration that the final product does not contain any animalcontainingmaterials with the relevant evidence (if applicable)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 166

Drug Registration Guidance Document (DRGD)Section Documents Yes/ No11.Other supporting documents eg. Halal Certification of the animalderived ingredient from a competent Halal Certification Authority.12. Labelling of the animal derived materials.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 167

Drug Registration Guidance Document (DRGD)APPENDIX 4:GUIDELINE ON REGISTRATION OF HEALTH SUPPLEMENTSIMPORTANT NOTES:This guideline will serve as an additional reference guide for the registration ofhealth supplement products which consist of pharmaceutical active ingredients forhuman use as well as ingredients derived from natural sources.Applicants are advised to refer to Drug Registration Guidance Document for thecommon requirements for the preparation of a well-structured dossier applicationto be submitted for product registration.Outline:4.1 Definition4.1.1 Health Supplement (HS)4.1.2 Indication4.1.3 Route of Administration4.1.4 Exclusion as Health Supplement4.1.5 Exemption4.2 Active Ingredients4.3 Maximum Daily Levels of Vitamins and Minerals for Adults Allowed inHealth Supplements4.4 Health Supplement Claim4.4.1 Conditions4.4.2 Types and Evidence of Claims4.4.3 Claims Substantiation4.4.4 Illustrative Substantiation Evidence4.5 Specific Dossier Requirement for Registration of Health SupplementsAttachment 1:Attachment 2:AcknowledgementsChecklist of Dossier Requirement for Health SupplementsTable 20: Allowable Claims for Specific Active Ingredients inHealth SupplementsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 168

Drug Registration Guidance Document (DRGD)4.1 DEFINITION4.1.1 HEALTH SUPPLEMENT (HS)A Health Supplement (HS) means any product that is used to supplement a diet and tomaintain, enhance and improve the health function of human body. It is presented in smallunit dosage forms (to be administered) such as capsules, tablets, powder, liquids and shallnot include any sterile preparations (i.e. injectable, eyedrops). It may contain one or more,or the following combination:i) Vitamins, minerals, amino acids, fatty acids, enzymes, probiotics, and otherbioactive substances;ii) Substances derived from *natural sources, including animal, mineral and botanicalmaterials in the forms of extracts, isolates, concentrates, metabolite;iii) Synthetic sources of ingredients mentioned in (i) and (ii) may only be used where thesafety of these has been proven.4.1.2 INDICATIONi) Used as a Health Supplement;ii) Vitamin and mineral supplements for pregnant and lactating women.4.1.3 ROUTE OF ADMINISTRATIONOral4.1.4 EXCLUSION AS HEALTH SUPPLEMENTS:Health Supplements shall NOT include:i) Any product as a sole item of a meal;ii) Any injectable and sterile preparation;iii) Any human part or substance derived from any part of the human body;iv) Any substance listed in the Schedule of the Poison Act;v) Any other route of administration other than the oral route.4.1.5 EXEMPTIONExtemporaneous preparations that have been prepared and given directly to the patient bya healthcare practitioner during the course of treatment.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 169

Drug Registration Guidance Document (DRGD)4.2 ACTIVE INGREDIENTSListed active ingredients can be checked trough http://www.bpfk.gov.my of product search.4.3 MAXIMUM DAILY LEVELS OF VITAMINS AND MINERALS FORADULTS ALLOWED IN HEALTH SUPPLEMENTSNO. VITAMINS & MINERALS UPPER DAILY LIMIT1. Vitamin A 5000 IU2. Vitamin D 1000 IU3. Vitamin E 800 IU4. Vitamin K (K1 and K2) 1 0.12mg5. Vitamin B1 (Thiamine) 100 mg6. Vitamin B2 (Riboflavine) 40 mg7. Vitamin B5 (Panthothenic Acid) 200 mg8. Vitamin B6 (Pyridoxine) 100 mg9. Vitamin B12 (Cyanocobalamin) 0.6 mg10. Vitamin C (Ascorbic Acid) 1000 mg11. Folic Acid 0.9 mg12. Nicotinic Acid 15 mg13. Niacinamide (Nicotinamide) 450 mg14. Biotin 0.9 mg15. Boron 6.4 mg16. Calcium 1200 mg17. Chromium 0.5 mg18. Copper 2 mg19. Iodine 0.3 mg20. Iron 2 20 mg21. Magnesium 350 mgNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 170

Drug Registration Guidance Document (DRGD)NO. VITAMINS & MINERALS UPPER DAILY LIMIT22. Manganese 3.5 mg23. Molybdenum 0.36 mg24. Phosphorus 800 mg25. Selenium 0.2 mg26. Zinc 15 mgNote:1. Vitamin K (K1 and K2) is restricted only for combination with other vitamins andminerals in oral preparations. Vitamin K (K1 and K2) as a single ingredient in anoral preparation is not allowed.2. For pre and antenatal use, as part of a multivitamin and mineral preparation,levels higher than the 20mg limit established for adults may be permitted at thediscretion of the Authority.3. Any form of fluoride as an ingredient is not permitted in formulation of healthsupplement products.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 171

Drug Registration Guidance Document (DRGD)4.4 HEALTH SUPPLEMENT CLAIM4.4.1 CONDITIONSAll claims made for HS shall:i) be consistent with the definition of HS;ii) enable consumers to make an informed choice regarding products;iii) not be misleading or false;iv) support the safe, beneficial and appropriate use of the product;v) maintain the level of scientific evidence which is proportional to the type ofclaims;vi) be for health maintenance and promotion purpose only;vii) not be medicinal or therapeutic in nature, such as implied for treatment, cure orprevention of disease.4.4.2 TYPES AND EVIDENCE OF CLAIMSi) A health supplement claim refers to the beneficial effects of consuming HS topromote good health and well-being (physical and mental) by providing nutrition,enhancing body structure/ function, relieving physiological discomfort and/orreducing the risk of health related conditions or diseases.ii) Types of HS claims are:o General or Nutritional Claims;o Functional Claims (medium);o Disease Risk Reduction Claims (high).iii) For a HS product making a General or Functional Claim on vitamin(s) and/ormineral(s), it must contain minimum of 15% of the Codex Nutrient Reference Value(NRV) per daily dose of the vitamin(s) and/or mineral(s). Other ingredients must besubstantiated by the evidences to which it has been supported.For example, if vitamin is less than 15% NRV, then the specific claim for this vitaminis not allowed unless there is evidence to support effect below this value.iv) For a HS product making Disease Risk Reduction Claim, it must be substantiated bythe evidences to which it has been supported.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 172

Drug Registration Guidance Document (DRGD)(i) Table 1: General or Nutritional ClaimsLevel ofclaimDefinitionExamples/Wording ofclaimCriteriaEvidence tosubstantiate HSclaimsGeneralorNutritionalClaims• General HealthMaintenance• Benefits derivedfromsupplementationbeyond normaldietary intake• Supportshealthygrowth anddevelopment• Nourishesthe body• Relievesgeneraltiredness,weakness• Helps tomaintaingood health• For energyand vitality• Is in line withestablished nutritionknowledge inreference texts• Is related to generalwell-being in linewith scientificknowledge• Claim does not referto the structureand/or function ofthe human body• In accordance to HSprinciples andpractice in Malaysia1 or more of thefollowingevidences:i) Standard referencee.g. referencetextbooks,pharmacopoeia,monographsii) Recommendationson usage fromreferenceregulatoryauthorities orreferenceorganisations• Forstrengtheningthe bodyPlease refer to Illustrative Substantiation Evidence List for the list of acceptable references,organisations and authorities.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 173

Drug Registration Guidance Document (DRGD)(ii) Table 2: Functional Claims (medium)Claims must be adequately substantiated through ingredient-based evidence and whennecessary through product-based evidence.Types ofHS claimFunctionalClaims(medium)Definition• Maintains orenhances thestructure orfunction ofthe humanbody,excludingdiseaserelatedclaimsExamples/Wording ofclaimsAcceptableclaims basedon the singleingrediente.g.• Vitamin Ahelps tomaintaingrowth, visionand tissuedevelopment• Vitamin Dhelps innormaldevelopmentandmaintenanceof bones andteeth.• Chondroitinhelps topromotehealthy jointsCriteriaFor claims onestablishednutrients andingredients suchas vitamins &minerals withdailyrecommendedvalues• Meet theconditions fornutrient functionclaims as setby the Authority• Claims haveconsistentscientificsupportaccording toscientific reviewand evaluation• In accordanceto HS principlesand practice inMalaysiaEvidence to substantiateHS Claims1 or more of the followingevidence:i) Standard reference e.g.reference textbooks,pharmacopoeia,monographsii) Recommendations onusage from referenceregulatory authorities orreference organisationsiii) Good quality scientificevidence from humanobservational studies(refer to ASEANGuidelines on efficacydata requirement) (only inthe event that humanexperimental study isnot ethical, animalstudies will be acceptedtogether withepidemiological studiesor other scientificliterature anddocumented traditionaluse)iv) Peer-reviewed scientificdata or meta-analysisPlease refer to Illustrative Substantiation Evidence List for the list of acceptable references,organisations and authorities.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 174

Drug Registration Guidance Document (DRGD)(iii) Table 3: Disease risk reduction (high)Types ofHS claimDiseaseriskreductionDefinition• Significantlyaltering orreducing arisk factor ofa disease orhealth relatedcondition.Examples/Wording ofclaims• Helps toreduce risk ofosteoporosisbystrengtheningbone• Helps toreduce the riskofdyslipidaemiaCriteria• The relationshipbetween the HSingredient or productand disease riskreduction issupported byconsistent scientificevidence• Documented inauthoritativereference texts• Recognised by theAuthority referenceor internationalorganisations orregulatoryauthorities• Adheres to the keyprinciples of HSclaimsEvidence tosubstantiate HS ClaimsCompulsory evidence:i) Scientific evidencefrom humanintervention study oningredient and/orproductii) Toxicological study(chronic)iii) PharmacologicalstudyAt least 1 additionalevidence:i) Standard referencee.g. referencetextbooks,pharmacopoeia,monographs etc.ii) Recommendationson usage fromreference regulatoryauthorities orreferenceorganisationsiii) Evidence frompublished scientificreviews or metaanalysisiv) Report prepared byexpert committees/expert opinion(subject to theAuthority approval)Please refer to Illustrative Substantiation Evidence List for the list of acceptable references,organisations and authorities.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 175

Drug Registration Guidance Document (DRGD)4.4.3 CLAIMS SUBSTANTIATIONClaims must be in line with the respective HS principles and supported by adequate evidence. To reflect the totalavailable usage evidence (including relevant scientific evidence), the evidence shall be summarized as part of thesubstantiation document for the claim as in the Table 4 below.Indication/claimProduct/IngredientstudiedDosage andadministrationrouteDurationoftreatmentType ofevidence(scientificevidence)StudydesignStudypopulationSummary offindingsLimitations ofthe studySource of evidencei) Authorii) Titleiii) Publicationdetailsiv) Yearv) Type (text,…)Note: Evidence not summarised as in the above format will not be further evaluated.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 176

Drug Registration Guidance Document (DRGD)4.4.4 ILLUSTRATIVE SUSBSTANTIATION EVIDENCEi) Reference textsa. Martindale, latest edition. The Complete Drug. Pharmaceutical Press, 2009.b. The ABC Clinical Guide to Herbs. American Botanical Councilc. WHO Monographs on Selected Medicinal Plantsd. British Pharmacopoeiae. United States Pharmacopoeiaf. Indian Pharmacopoeiag. Chinese Pharmacopoeiah. Natural Standards (www.naturalstandard.com)i. Office of Dietary Supplements, National Institutes of Health - Dietary SupplementFact Sheets(http://ods.od.nih.gov/Health_Information/Information_About_Individual_Dietary_Supplements.aspx)ii) Organisationsa. American Botanical Council (www.herbalgram.org).b. American Nutraceutical Association (www.ana-jana.org)c. CODEX Alimentariusd. Global Information Hub for Integrated Medicine (http://www.globinmed.com)e. National Centre for Complementary and Alternative Medicine (http://nccam.nih.gov/)f. Office of Dietary Supplements, National Institutes of Health (USA)(http://ods.od.nih.gov)iii) Reference regulatory authoritiesa. Australia TGAb. Chinese Health Authority on Chinese medicinal herbsc. European Commissiond. Health Canadae. United States FDANotes:1. This list is not meant to be exhaustive and will be reviewed from time to time.2. The Authority will nonetheless conduct a detailed evaluation of the evidence included in thereport to ensure that the health claim is substantiated.3. The Authority will be willing to consider review other than the listed above, if the standards ofevidence are consistent with those of the Authority.4. All references must be current.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 177

Drug Registration Guidance Document (DRGD)4.5 SPECIFIC DOSSIER REQUIREMENT FOR REGISTRATION OFHEALTH SUPPLEMENTSPRODUCT VALIDATION1. PRODUCT NAMEMay include product name, dosage form and strength (e.g. XYZ Capsule 500mg)Dosage form and strength of product would need to be entered as part of productname to allow for multiple dosage forms (e.g. tablet, capsule) and strengths (e.g.200mg and 400mg) for any particular named (proprietary or generic) product.In any event if found that registered product name is similar to another registeredproduct, NPCB reserve the rights to request for the change in the product name.Product with more than 1 active ingredient could not include strength of activeingredients in the product name.Product name may be included together with the brand name or trademark name, ifapplicable.Table 5: List of Non-Permissible Product Name for Health Supplement ProductsNo. Issue Example1. Prohibited use of disease names as statedin the Medicines (Advertisement and Sale)Act 1956 (revised 1983)2. Prohibited use of a single active ingredientas a product name in products containingmore than one active ingredient unlessproduct name contains words such as„Plus, Compound, Complex, HerbanikaDiabetes, Asthma, CancerIf the product contain Vitamin C,Vitamin E and Fish OilProduct name: “Vitamin C” is notallowed but product name:“Vitamin C Plus” is allowed.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 178

Drug Registration Guidance Document (DRGD)No. Issue Example3. Prohibited use of superlativeNames which indicates superiority inefficacy4. Prohibited use of spelling of words whichmay cause confusioni)Words which involve names of/partthereof:20 disease names prohibited in the Medicines(Advertisement and Sale) Act 1956 (Revised1983)ii) Other diseases without scientific proofiii) Prohibited indication5. Prohibited use of names which may causeambiguityAmbiguous product name6. Prohibited use of names which may beoffensive or indecentPower, Superior, Pure, Mustajab,Safe, Healthy, Penawar, VIP,Good, World Number 1Go Out = GOUT (label)UtixB For Energy?SENXBIG=SEnXBIG(label)Sexy, Enjoy, Paradise, Heavenly,Blue boy, Casanova, Desire7. Product name which is not congruent withthe active ingredient.The active ingredient is EveningPrimrose oil (EPO) and theproduct name: “Marine tablet” isnot allowed.8. Prohibited use of product names which haselements of ludicrous beliefStatements referring to ancientbelieve/negative spirits/supernatural powerWords such as miracle, magic,magical, miraculous, saintly,heavenlyNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 179

Drug Registration Guidance Document (DRGD)No. Issue Example9. Prohibited use of product names similar tothe existing approved product namesProduct name similar to the spelling andpronunciation of words of an existing productnames10. Prohibited use of product names whichmay cause ambiguity in the nature ofproduct (drug/ food/ beverage)Product name similar to a food/ beveragename11. Prohibited use of product names whichrepresents professional advice or opinionElegen vs L-gen vs L-jen Fortevs FortJuice, Health drink, Beverage,KookyDr Sunny, Professor12. Product name that symbolize a claim Vigour, Youthful, High, Hi13. Product name that uses strength butformulation contains more than one activeingredient.If the product containsmultivitamins and minerals.Product name:“XXX multivitamins and minerals500mg” is not allowed.14. Other prohibited product names Minda, IQ, Smart, Unique, UltraMega, Detox15. Names of organs and brain Heart, kidney, skin, liverNote:1. This list is not meant to be exhaustive and will be reviewed from time to time.2. The Authority reserves the right to disallow any other words, phrases or graphics for productlabel which in its opinion is misleading, improper or not factual.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 180

Drug Registration Guidance Document (DRGD)2. DOSAGE FORMDosage forms allowed:a) Tablets- Caplet, Lozenge, Chewable tablet, Dispersible tablet,Effervescence tablet, uncoated tablet, enteric coated tablet, Sugarcoated tablet, Film coated tablet, extended release tablet;b) Capsules- Soft capsule, Hard capsule, Enteric coated capsule, Chewable softcapsule, Extended released capsule;c) Powder/ Granules;d) Liquid- Emulsion, syrup, spray, suspension.Products in the shape of animal dosage forms are not allowed.Supporting data from established reference (e.g. Standard Pharmacopeia) shall berequired for new dosage form.The form that correctly describes it in terms of its product quality controlspecifications and performance shall be selected.A separate application for registration is required for each dosage form.The following documents will have to be provided during submission of productdossier for Sustained-release/ Extended-release/ Timed-release dosage formi) Protocol of analysis;ii) In-Process Quality Control (IPQC);iii) Finished Product Specification (FPQC);iv) Certificate of Analysis (COA).3. ACTIVE INGREDIENTName of Active Ingredient:Please select active ingredient from the search database. If substance is not listed,please select the „Not Listed Ingredient‟ button. Automatic e-mail will be send toNPCB for notification.Approved names, pharmacopoeia names of ingredients shall be used wheneverpossible.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 181

Drug Registration Guidance Document (DRGD)Strength of active ingredient :To enter the content of active ingredients (numerical) and then select the weightsand measures from the given list.Content of ingredients shall be expressed as appropriate in the following manner:a. quantity per dose unit (e.g. for unit dose formulations - tablet, capsule, lozenge,etc.)b. percentage composition - %w/w, %w/v, %v/v, etc.c. weight per ml. (e.g. for solutions,suspension etc.)d. quantity (percentage or amount) per measured dose (e.g. oral liquids, drops,etc.)Metric weights and measures shall be used.Source of Active ingredient:To specify the source such as animal, plant, synthetic or others (to specify)Remarks on active ingredient (if any):To specify the equivalent/providing amount of active component from the rawmaterial (e.g: Sodium ascorbate 520 mg providing.... Vitamin C)Declaration of species name from natural source (plant, animal or others)Table 6: Additional data to support a new health supplement active ingredients:No. Types of documents Checklist1.2.Standard/ establishedreferencesInformation from thecompetent authorities ofreference countriesMartindale, Pharmacopeias, Monographetc.Information shall be provided from thecompetent authorities of referencecountries (Refer to 9.6.5)Example of supporting documents:‣ Registration status and maximumregistered dosage as healthsupplement‣ established monograph‣ GRAS statusNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 182

Drug Registration Guidance Document (DRGD)No. Types of documents Checklist3.4.5.Clinical studies or scientificevidencesNon-clinical studies to supportlong term-useToxicology studies with thedetermination of NOAEL (Noobserved adverse effect level)Full published articlesUnpublished data may be consideredMandatory for high claim6. Pharmacological study7.Justification for the use of newactive ingredient as healthsupplement8. Registration status worldwide Registered and Marketed DateNote: The documentation must support the safety use and dose of new active ingredientsas a health supplement.4. ANY ANIMAL ORIGINAny source from animal origin must be declared and to specify the type of animal.5. MANUFACTURERManufacturer is defined as “A company that carries out at least one step ofproduction as well as the final release of the finished product”.The requirements for Good Manufacturing Practice (GMP) of the premises are in Table 7as followed:National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 183

Drug Registration Guidance Document (DRGD)Level of claimsRequirements for GMPGeneral/ Functionala) Malaysia Guidelines on Good Manufacturing Practice forTraditional Medicine and Health Supplement latest edition.Orb) The accepted standards for GMP will be determined bythe category the product is classified in the country oforigin.For example, if the product is classified as food in thecountry of origin, GMP certificate of food standard issuedby relevant country authority will be accepted on conditionthat the standards are similar to those practices inMalaysia.Orc) If the product is not regulated in the country of origin anddoes not require GMP certification, the manufacturer willhave to produce a GMP certificate issued by anindependent body recognised by the Authority. Informationincluding the standard/ regulations/ legislation to which theinspection was based upon must be mentioned.Disease RiskReductiona) Malaysia Guidelines on Good Manufacturing Practice forTraditional Medicine and Health Supplement latest editionOrb) The Pharmaceutical Inspection Convention andPharmaceutical Inspection Co-operation Scheme (PIC/S)Standards.Orc) GMP certificates issued by relevant country authority willbe accepted on condition that the standards are similar toPIC/S StandardsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 184

Drug Registration Guidance Document (DRGD)6. CONTRACT MANUFACTURERContract manufacturer is aplicable when product owner is not the product manufacturer7. SECOND SOURCE INFORMATIONAn application for a second source may be considered where deemed necessary. Thissecond source product shall be the same as the first product in all respects except for thesite of manufacture.8. PRODUCT CONTAINING PREMIXPremixed active ingredient(s) is a combination of two or more active ingredients that arepreviously manufactured by a different manufacturer.Certificate of GMP for manufacturer/ supplier is required for the premixed ingredient(s) informulation. The requirements for GMP are same as in Field 5 as above.9. REPLACEMENT PRODUCTA product registration holder is not allowed to register/ hold two or more products withsimilar formulation (same active ingredient of raw material, strength and dosage form) atany one time unless product variant.Letter of justification for replacement by product holder is required.10. OTHER MANUFACTURERAny manufacturer involved in Assembly, Fill & Finish, Active Ingredients, Packing, Labelingetc.11. IMPORTED PRODUCTSImported product needs to be declared.SECTION A: PRODUCT PARTICULARSProduct Description:State, briefly, visual and physical characteristics of the product, including as in thefollowing Table 8 (where applicable):National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 185

Drug Registration Guidance Document (DRGD)No. Dosage Form Description1. Tablet2. Capsule3. LiquidShape, size, colour, odour, taste, marking, emboss, type oftablet (e.g. coated, uncoated, film, sugar etc.)Shape, size, colour, odour, taste, marking, emboss, coating,content of capsule, type of capsule (e.g.: soft, hard, chewableetc.)Clarity, type (e.g. solution/ suspension/ emulsion etc.), taste,odour, colour.4. Powder Colour, odour, taste etc.5. Pill Colour, odour, taste, size etc.6. Granules Colour, odour, taste, size etc.Indication/ UsageState briefly recommended use(s) of product. The following indications are allowed:‣ Used as a Health Supplement; or‣ Vitamins and mineral supplements for pregnant and lactating women.Recommended Dose (Dose/ Use Instruction) & Route of administrationState the dose (normal dose, dose range) and dosage schedule (frequency, duration ifapplicable). Dosage for adults and children (where appropriate) shall be stated.ContraindicationState conditions for which or under which the product shall not be used.Note 1:Indicate clearly which conditions are:- absolutely contraindicated,- contraindicated but may be used under special circumstances and whatprecautions to be taken in such cases.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 186

Drug Registration Guidance Document (DRGD)Warnings and PrecautionsState briefly precautions and warnings necessary to ensure safe use of the product e.g.caution against giving to children and elderly; use in pregnancy and lactation; in infants;etc.Drug InteractionsState only interactions which are observed and/or for which there is potential clinicalsignificance. Interactions may occur with- other medicinal products used;- other herbs/ substance;- meals, or specific types of food.Side Effects/ Adverse ReactionsState in order of severity and frequency, the side effects, adverse reactions, toxiceffects, etc. (i.e. reactions, toxic effects, other than those desired therapeutically)including reactions such as allergy, hypersensitivity, dependence, addiction,carcinogenicity, tolerance, liver/ kidney toxicity etc.Indicate also symptoms and sites of effects/reactions.Note 1: Reactions, whether minor or serious, shall be stated.Note 2 : Severity, reversible, frequency of occurrence shall be indicated whereverpossible.Note 3 :Clinical tests for detection of „sensitive‟ patients, measure for management ofadverse reactions developed shall be described wherever possible.Pregnancy and LactationPlease state any effect on pregnancy and lactation if applicable.Signs and Symptoms of Overdose and TreatmentState briefly symptoms of overdose/ poisoning, and where possible, recommendedtreatment and antidotes for overdose/ poisoning.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 187

Drug Registration Guidance Document (DRGD)Storage ConditionsState the recommended storage conditions (specific temperature eg: 30 o C, humidity,light etc.).Information shall also include storage condition before first opening, after reconstitutionand/or after opening and for all the listed pack types where applicable. Stability data tosupport such storage condition shall be available.Shelf LifeThe shelf life for all the listed pack types shall be supported by stability data.Information shall also include shelf life before first opening, after reconstitution and/orafter opening where applicable. Stability data to support such shelf life shall beavailable.Evidence is required to demonstrate that the product is stable (meets the finishedproduct shelf life specifications throughout its proposed shelf-life).Therapeutic Code (If any)Please select “Health Supplement”SECTION B: PRODUCT FORMULAChange of formulation whether for active ingredient or excipient is not allowedduring product evaluation.Batch Manufacturing FormulaState the batch size and actual batch manufacturing master formula. Data fromvalidation step will be captured in terms of substance name, type (active ingredient orexcipient), function and quantity per unit dose. Other information will need to beentered.An attachment of the Batch Manufacturing Formula documentation must be provided.The documents must be verified by authorized personel.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 188

Drug Registration Guidance Document (DRGD)Example of BMF documentation:ABC Sdn. BHD.Batch Manufacturing FormulaProduct Name:Batch Quantity: 1,000,000 capsulesNameFunctionQuantityper capsuleBatchquantityOveragePyridoxine HCl Active _ mg _ kg _ %Cholecalciferol Active _ mg _ kg _ %Glycerin Excipient _ mg _ kg NoneGelatin Excipient _ mg _ kg NonePurified water Excipient 0 mg * _ kg NoneTotal: _ mg* evaporated, does not exist in final formulation(Signature)Post of authorized personName of authorized personDate:Total: _ kgManufacturing processState a brief description of the manufacturing process. Essential points of each stage ofmanufacturing process and a description of the assembling of the product into finalcontainers shall be covered. If the product is repacked/assembled by anothermanufacturer, details of repacking/assembly and quality control must be supplied.An attachment of the manufacturing process, in the form of a flow chart can be made.In Process Quality Control (IPQC)To provide a summary of the tests performed, stages at which they are done, and thefrequency of sampling and number of samples taken each time. Specifications forquality assurance of the product shall be supplied.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 189

Drug Registration Guidance Document (DRGD)Example of In Process Quality Control:Company Name/ Address:Applicant/ Client Name/ Address:Date:In-Process Quality Control: Test performed during manufacturing processNo.Test Done(example)Stage Done(example)Frequencyof testing(example)Quantitysampletaken(example)Specifications(example)Method(example)1. AppearanceBeforeweight, afterencapsulation2 10 gramBlue likeorangeOrganoleptictest2. DisintegrationAftercompression2 10 tabletNMT 30minutesEquipmentetc3.Uniformity ofweightAftertableting,Packaging4 20 Tablets 1 gram/tab4. Microbiology Final Stage 15. Heavy metal Final stage 1* Declaration (if any)Signature (authorized personnel)Name:Designation:* The above parameters are only as an example; other test may be required for specificproduct.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 190

Drug Registration Guidance Document (DRGD)Finished Product Quality SpecificationProvide details of quality control specifications including a list of tests for both releaseand shelf life specifications (if they are different) and state the limits of acceptance.Example of Finished Product Quality SpecificationFinished Product Quality Control (FPQC) - Finished product Specification/Specification SheetCompany name/Address:Product Name:Batch no.Dosage form:Packaging:Date of manufacture:Date of expiry:No. Test Method Specification Reference1.2.Appearance/Organoleptic:OdourColourAssay:List the active ingredientsEx:Macroscopic/MicroscopicHPLC/ GC/MS/ UVTo describethecharacteristicTo specifyIn-house/pharmacopoeia(e.g. BP/USP etc)To specify3. Disintegration/Dissolution To specify DRGD DRGD4. Uniformity of weight To specify5. Water content To specify6.7.8. Etc:Microbial contaminationTAMC, TYMC, specifiedmicroorganismHeavy MetalContamination:Lead, Arsenic, Cadmium,MercuryTo specify DRGD DRGDTo specify DRGD DRGDSignature:Name:Designation: (At least by Quality Assurance Manager or equivalent)Date of signature:* The above parameters are only as an example; other test may be required forspecific product.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 191

Drug Registration Guidance Document (DRGD)Stability DataTable 9:No. Stability Study Shelf Life1. i) 2 batches of complete real-time stabilitystudy at 30 ± 2 ºC / RH 75± 5% for theclaimed shelf-life.ORii) 2 batches of on-going real timestability study ( at least 6 months) at 30 ± 2 ºC/ RH 75 ± 5% + Letter of commitment(LOC) to submit complete real time stabilitydata when study is complete/ whenrequested.AND- Shelf life will be basedon data stability at 30 o Cof not more than 5 years.- 3 years2 batches of 6 months accelerated stabilitystudy at 40ºC.2. i) 2 batches of complete real time stabilitystudy at a temperature and relative humidity(RH) different from the Zone IVB for at least 2years + LOC to conduct real time stabilitystudy at Zone IVB and submit when the studyis complete/ when requestedORii) 2 batches of on-going real time andaccelerated stability study (at least 6 months)at a temperature/ relative humidity (RH)different from Zone IVB + LOC to conduct realtime stability study at Zone IVB and submitwhen the study is complete/ when requested.3. 2 batches of complete real-time stability studyat temperature and RH other than zone IVB forvery unstable active ingredient(s)/ product(must be substantiated).- Shelf life will be basedon data stability atspecified temperature.- 2 years at specifiedtemperature in thestability study.- Shelf life will be basedon data stability atspecified temperature.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 192

Drug Registration Guidance Document (DRGD)Storage Conditions with Type of Container Closure System/ Stability StudyTable 10:No. Type of Container Closure System/ Study Storage Condition1.2.Products in primary containers permeableto water vapourProducts in primary containers impermeableto water vapour30°C + 2°C/75% RH +5%RH30°C + 2°C3. Accelerated studies40°C + 2°C/75% RH +5%RHReports of stability studies shall provide details of:the batches placed under study (a minimum of 2 batches are required).containers/ packaging type.conditions of storage during study (temperature, humidity, etc).duration of study and frequency (interval) of the tests/ observations.the tests performed and acceptance limits.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 193

Drug Registration Guidance Document (DRGD)Example of Stability DataSTABLITY DATAPRODUCT NAME: TABLET ABC 500MG BATCH NO.:MANUFACTURING DATE: dd/mm/yy TEMPERATURE: 30 °C ± 2 °CEXPIRY DATE: dd/mm/yy RELATIVE HUMIDITY: 75 % ± 5%TestsProduct descriptionDisintegration testAssaysMicrobialContamination test:Total AerobicMicrobial CountSpecificationFilm-coated tablet,brownish in colourNMT 30 minuteseg: 90% -120% (ref….)NMT 2 x 10 4Frequency of Testing0 3 6 9 12 15 18 21 24Total Yeasts &Moulds CountTest for SpecifiedMicroorganismsNMT 2 x 10 2‣ NMT 2 x 10 2 CFU ofbile-tolerant gramnegativebacteria in1g or 1ml‣ Absence ofSalmonella in 10g or10ml‣ Absence ofEscherichia coli in1g or 1mlHeavy metal test:LeadArsenicMercuryCadmium‣ Absence ofStaphylococcus≤10.0 mg/kg (≤ 10ppm)≤5.0 mg/kg (≤ 5ppm)≤0.5 mg/kg (≤ 0.5ppm)≤0.3 mg/kg (≤ 0.3ppm)Conclusion ------------------------------------------------------------Analyst name: (signature) Verified by: (signature)Name:Name:DesignationDesignationDate:Date:National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 194

Drug Registration Guidance Document (DRGD)Stability study data checklists are as in Table 11 below:Data RequiredCompany nameProduct nameDosage formPackagingparticularsStorageconditionFrequency oftestingList of relevanttestsSpecificationsResults for eachtestApproval byauthorizedpersonRemarks- From product holder/ manufacturer/ third party lab- To be same with other documentation- To be same with A3- Material and pack size must be stated- To be same with C1- Temperature and humidity must be stated- Shall comply with ASEAN Zone IV requirement(30±2°C/75±5%RH)- If different storage condition (e.g. 25°C, 2-8°C), must providejustification/ supporting data.For example:- 0, 3, 6, 9, 12, 18, 24 months and annually for the proposedshelf life- All tests required for each dosage form shall be conducted,for example:o Physical appearance changeso Disintegration test (if applicable)o Chemical Assays for active ingredients (if applicable)o Microbial tests- Acceptance limit for each test must be stated- To be supported by established references (e.g. USP, BP) ifavailable- Must meet the specifications- Must have the name, post and signature of authorized personNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 195

Appearance/organoleptic(odor, color, taste)AssayHardness/friabilityDisintegration ordissolution rateMoisturecontentViscositypHMicrobial contentGranules/ ParticleSize variationRe-suspendabilityDrug Registration Guidance Document (DRGD)Testing Parameters of Stability Study for each type of dosage forms are shown inTable 12 below:Testing ParametersDosageFormOral powder √ √ √ √Hard capsule √ √ √ √ √Soft capsule √ √ √ √Coated and UncoatedTablet√√√(uncoated)√ √ √Coated and UncoatedPill/ Pellet√ √ √ √ √Suspension √ √ √ √ √ √ √Solution √ √ √ √ √Emulsion √ √ √ √ √Granules √ √ √ √ √*Notes:1. The list of tests for each product is not intended to be exhaustive, nor is it expected thatevery listed test to be included in the design of the stability study protocol for a particularfinished product.* Assay to determine the stability of a single active ingredient or a single marker/surrogateindicator that is susceptible to change during storage and is likely to influence quality shallbe sufficient to infer the overall stability of the TM/HS product irrespective of whether thefinished product contains single or multiple active ingredients.2. Justification must be given if one of the tests is not conducted for relevant dosage form.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 196

Drug Registration Guidance Document (DRGD)SECTION C: PARTICULARS OF PACKINGPackaging‣ Maximum pack size allowed for tablets, pills, capsules is based on dailydosing for a quantity not exceeding six (6) months usage.‣ Maximum pack size allowed with disease risk reduction claim for 1 monthsupply of products unless justified.‣ Product with dosage form of softgel with tail (twist and squeeze) shall comewith children proof cap.Packing particulars to the listing of packing as follows ;- C1: pack size and fill details by weight, or volume or quantity;- C2 : container type- C3 : Barcode/ serial No (optional);- C4 : recommended distributor‟s price (optional);- C5 : recommended retail price (optional);National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 197

Drug Registration Guidance Document (DRGD)SECTION D: LABELLING REQUIREMENTSLabel (mock-up) for immediate container, outer cartonOuter Unit Carton, Immediate & Blister/ Strips LabelsThe following information in Table 13 shall be present on the label of theproduct:No. ParametersOuter Carton(Unit Carton)ImmediateLabelsBlister/Strips1. Product Name 2. Dosage Form * NA3. Name of Active Substance(s) **4. Strength of Active Substance(s) **5. Batch Number 6. Manufacturing Date * NA7. Expiry Date 8. Route of Administration NA9. Storage Condition * NA10. Country‟s Registration Number * NA11.12.13.Name & Address of ProductRegistration Holder (PRH)Name & Address ofManufacturerWarnings and/or SpecificLabelling(if applicable) *At least nameof town/ cityand country ofmanufacturer*At least nameof town/ cityand countryofmanufacturerName/ LogoofManufacturer/ProductOwnerNA * NANational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 198

Drug Registration Guidance Document (DRGD)No. ParametersOuter Carton(Unit Carton)ImmediateLabelsBlister/Strips14. Pack Sizes (unit/ volume) NA15.16.17.18.19.20.Name & content ofpreservative(s) where presentName & content of alcohol,where presentTo declare source ofingredients derived from animalorigin, including gelatin (active,excipient, and/or capsule shell)Recommended daily allowance(RDA) for vitamins/multivitamins/ mineralpreparations used as dietarysupplementsThe words “Keep medicine outof reach of children” or wordsbearing similar meaning in bothBahasa Malaysia & EnglishOther country specific labellingrequirements(if applicable) NA NA NA NA * NA * NA21. Security Label (Hologram) * NANotes:NA - Not applicable** For multi-vitamins and minerals preparations it is suggested to label as multivitaminsand mineralsIf the product is without an outer carton, the inner label shall bear all the informationthat is requiredInformation on the Product Name and Name and Strength of active ingredient(s)must be printed repeatedly.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 199

Drug Registration Guidance Document (DRGD)Package inserts (Optional)The following information is required to be included in a package insert:(i)(ii)(iii)(iv)(v)(vi)(vii)(viii)(ix)(x)(xi)(xii)(xiii)(xiv)(xv)Brand or Product NameName and Strength of Active Substance(s)Product DescriptionIndicationDose/ Use InstructionContraindicationsWarnings and PrecautionsInteractions with Other MedicationsStatement on usage during pregnancy and lactationAdverse Effects/ Undesirable EffectsOverdose and TreatmentStorage Conditions (may be omitted if the information is stated on thelabel or outer carton labels)Dosage Forms and packaging availableName and Address of manufacturer/ product registration holderDate of Revision of Package InsertNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 200

Drug Registration Guidance Document (DRGD)Standard Labelling for Health SupplementsName and Strength ofactive substances, RDAPreservative(s) (wherepresent)Alcohol (where present)IndicationDose / Use InstructionFunctional ClaimWarnings (If applicable)Name & address ofMarketingAuthorization HolderName & address ofManufacturerName & address ofRepacker (ifapplicable)Sources (animalorigin)Storage ConditionKeep out of reachof children / Jauhi darikanak-kanakPack SizeDosage FormBatch NumberManufacturing DateExpiry DateMAL ……………………...Note:Product label shall follow the standard labelling for Health SupplementInformation stated in the left and right panel is interchangeable.All information on the label must be truthful and not misleading to the consumers.Batch number, manufacturing date, expiration date: can be stated on label, on top of cap orbottom of bottleNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 201

Drug Registration Guidance Document (DRGD)Additional Requirements for Labelling‣ Product with dosage form of soft gel with tail (twist and squeeze) shallinclude the statement „Under parent supervision‟ in the label.‣ For products containing animal origin(s), please add this statement: Thisproduct contains substance(s) from animal origin.‣ For products containing porcine, please add this statement: This productcontains animal part(s) (porcine/pig).Health supplement products with disease risk reduction claims (high) areencouraged to be dispensed under the supervision of pharmacists or medicalpractitioners. At such, the label and package insert of health supplementproducts with disease risk reduction claims (high) shall have the followingstatement:“Please consult a healthcare professional before taking this product”.The front panel must contain the information as specified in DRGD. However,the information on the side panels is interchangeable. Additional cautionarylabelling relating to the safety of the product may be imposed.Specific Labelling Requirement (Label & Package Insert)1. ALFALFAThe following boxed warning shall be included on the labels of productscontaining Alfalfa (Medico sativa):This product contains Alfalfa (Medico sativa).Individual with a predisposition to systemic lupuserythematosus shall consult their phycisian beforeconsuming this product.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 202

Drug Registration Guidance Document (DRGD)2. ARGININEThe following statement shall be included on the labels and in the packageinsert of oral preparations containing Arginine for health supplements:WARNING:Arginine is not recommended for patients following a heart attack.3. ASPARTAMEThe following statement shall be included on the labels and in the packageinsert of products containing Aspartame:WARNING:Unsuitable for phenylketonurics4. BEE POLLENThe following statement shall be included on the labels and in the packageinsert of product containing bee pollen:This product contains Bee Pollen and may cause severe allergicreactions, including fatal anaphylactic reactions in susceptible individuals.Asthma and allergy sufferers may be at greater risks.5. CHITOSANThe following statement shall be included on the labels and in the packageinsert of products containing chitosan.“DERIVED FROM SEAFOOD”6. GINKGO BILOBA/ GINKGO EXTRACTThe following statements shall be included on the labels and in the packageinsert of products containing Ginkgo Biloba/ Ginkgo Extract:National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 203

Drug Registration Guidance Document (DRGD)As the use of Ginkgo may increase the tendency of bleeding, please consultyour physician/ pharmacist if you are on or intend to start using any othermedicines and before you undergo any surgical/ dental procedure.(Memandangkan Ginkgo boleh meningkatkan kemungkinan pendarahan, silarujuk kepada doktor/ ahli farmasi sekiranya anda sedang atau/ akanmenggunakan ubat lain dan sebelum prosedur pembedahan/ dentaldijalankan).7. GINSENGThe following statements shall be included on the labels and in the packageinsert of products containing Ginseng (including all Panax genus):Contraindicated in pregnant women.Safe use in lactating women and children has not been established.Do not exceed the stated dose.Safety on long term use has not been established.8. INGREDIENTS DERIVED FROM SEAFOODThe following statement shall be included on the labels and in the packageinsert of products.“DERIVED FROM SEAFOOD”9. ROYAL JELLYThis product contains royal jelly and may cause severe allergic reactionsincluding fatal anaphylactic reactions in susceptible individuals.Asthma and allergy sufferers may be at the greater risk.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 204

Drug Registration Guidance Document (DRGD)10. SODIUM METABISULPHITE (Excipient)The following statement shall be included in the package insert of productscontaining Sodium metabisulphite:WARNING:This preparation contains Sodium metabisulphite that may cause seriousallergic type reactions in certain susceptible patients. Do not use if known tobe hypersensitive to bisulphites.Prohibited Visual/ Graphics on Label, as shown in Table 14 below:No. Issue Example Note1.Marketing strategyExample:“Money back guarantee”“Buy 1 free 1”“Backed by RM5 millionproduct Liability Insurance”Such statementsare prohibited onlabels, as perMedicines(Advertisementand Sale) Act1956 requirements2.Usage guide whichpromotes use ofother product(s)Example:“After consumption of thisproduct (Product A), forbetter results, it isrecommended to takeProduct B”Prohibited onproduct label3. Consumer testimonialProhibited onproduct labelNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 205

Drug Registration Guidance Document (DRGD)No. Issue Example Note4.Clinical Trial results orany information onclinical trial done onproductExample :“Clinically Tested”“Randomized Double BlindPlacebo Control ClinicalStudy”Such statementsare prohibited onlabels (as perMedicines(Advertisementand Sale) Act1956Requirement5.Reference to Hadith/ Al-Quran/ Bible/ ReligiousbooksProhibited onproduct label6.Opinion of prominentfigure(s) onproduct or its activeingredient/contentExample:Opinion ofproduct/formulation inventorProhibited onproduct label7.Label design (graphicand color) similar tolabels from anothercompanyProhibited onproduct label8.Statement on activeingredient originExample:Source from the Mountainsof AlpsAllowed if proventrue9.Introduction of founder/ManufacturerProhibited onproduct label10. Logo with certificationExample:SIRIM/ ISO / GMP/ HACCPProhibited onproduct labelbecausecertificationrenewal is on ayearly basisNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 206

Drug Registration Guidance Document (DRGD)No. Issue Example Note11.Name/ Statement/Logo/ registeredtrademark which doesnot satisfy thespecificationsExample:“Dr.ABC‟s Formula”“Nothing like it”Prohibited onproduct label12.Patency claim/ Patencynumber/ Specialtechnique used/superiority iningredients (Example:capsule coat)Example:Patented techniqueAllowed if proventrue13.Nutritional claims withanalysis certificateattachedExample:Calorie, Fat, Protein andothersProhibited onproduct label14.Graphics or picture ofinternal organsExample:Kidney, Heart, Nerves.Prohibited onproduct label15.Sex symbol(male or female)(♀ and/or ♂)Prohibited onproduct label16.Indecent photographs/pornographyProhibited onproduct label17.Graphics which areincoherent withthe indicationExample:- Noted indication is forconstipation, but graphicson label shows a slimlookinglady whichdenotes indication forweight loss- Indication for urination butlabel graphics containspicture of a water hose.Prohibited onproduct labelNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 207

Drug Registration Guidance Document (DRGD)No. Issue Example Note18.Highlightingunnecessary body partsExample:Indication is for generalhealth but graphics on labelhighlights male and femalesexual organ partsProhibited onproduct label19.Graphics of plants oranimal whichmay cause confusionExample:Radix Ginseng which isimprovised as a malesexual partProhibited onproduct label20. Other statementsExample:- This product is blendedwith premium quality- Certified chemical residuefreeProhibited onproduct labelNotes:1. This list is not meant to be exhaustive and will be reviewed from time to time2. The Authority reserves the right to disallow any other words, phrases or graphics forproduct label which in its opinion is misleading, improper or not factualNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 208

Drug Registration Guidance Document (DRGD)SECTION E: PARTICULAR OF PRODUCT OWNER, MANUFACTURER,IMPORTER AND OTHER MANUFACTURERPlease select whether the product owner is the product holder, manufacturer orboth product holder and the manufacturer.If the product owner is neither product holder nor the manufacturer, pleaseselect name and address of the product owner (applicable for imported productonly).Other details such as Section E1: Product Owner, Section E2: Manufacturer,Section E3: Repacker, Section E4: Other manufacturer involved in themanufacturing process, Section E5: Store address and Section E6 Importer (Ifany) have to filled. It is mandatory for the Repacker to acquire GMP certificate.SECTION F: SUPPLEMENTARY DOCUMENTSLetter of authorization of product ownerThis is applicable for imported product in which the product owner appoints theproduct holder (in Malaysia) as their product holder in MalaysiaLetter of appointment of contract manufacturer and/ or repackerApplicable if the product is contract manufactured by a manufacturer who is not theproduct holder.Letter of acceptance as contract manufacturer and/ or repackerApplicable if the product is contract manufactured by a manufacturer who is not theproduct holder.Certificate Of Pharmaceutical Product (CPP), Free Sale Certificate (CFS) andGood Manufacturing Practice (GMP)CPP can be attached as a replacement of CFS and GMP certificate if the product isclassified as pharmaceutical product in the country of origin:National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 209

Drug Registration Guidance Document (DRGD)GMP/ CFS TemplateAuthority name, address, countryType of certificateCompany name (product owner/ manufacturer)Product nameProduct formulation if availableDosage formStatement of freely sold (similar meaning) if for CFS certificateStandard of GMP and compliance status if for GMP certificateDuration of certificationName, signature and designation of authorized personnelDate of signatureNote: The certificate must be in English or translated into English(certified true by issuance or embassy or notary public)Attachment of Protocol AnalysisProtocol analysis is attached here.Finished Product Quality Control (FPQC)‣ The certificate must be complete with the product specification and result.The list of tests and specifications must be same with finished productspecification document.‣ Quality Control Test For Health Supplement Product are as follows:1. Limit Test for Heavy Metalsa) Lead : NMT 10.0 mg/kg or 10.0 mg/litre (10.0ppm)b) Arsenic : NMT 5.0 mg/kg or 5.0 mg/litre (5.0ppm)c) Mercury : NMT 0.5 mg/kg or 0.5 mg/litre (0.5ppm)d) Cadmium : NMT 0.3 mg/kg or 0.3 mg/litre (0.3ppm)* Required for products with ingredients from natural sources.The test shall be conducted either on the raw material or finished product.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 210

Drug Registration Guidance Document (DRGD)2. Disintegration Test (for tablets, capsules and pills)Disintegration time:a) Uncoated tablets : NMT 30 minutesb) Film-coated tablets : NMT 30 minutesc) Sugar-coated tablets : NMT 60 minutesd) Enteric-coated tablets : Does not disintegrate for 120 minutes inacid solution but to disintegrate within 60minutes in buffer solutione) Capsules : NMT 30 minutesf) Pills : NMT 120 minutes3. Test for Uniformity of Weight (tablets and capsules only)i) Tablet- For tablet with average weight of 130mg or less: Not more than 2tablets differ from the average weight by more than 10% AND notablets differ from the average weight by more than 20%- For tablet with average weight between 130-324mg: Not more than 2tablets differ from the average weight by more than 7.5% AND notablet differs from the average weights by more than 15%- For tablets with average weight more than 324mg: Not more than 2tablets differ from the average weight by more than 5% AND no tabletdiffers from the average weight by more than 10%ii) CapsuleIndividual weight of the capsule to be within the limit of 90-110% of theaverage weight.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 211

Drug Registration Guidance Document (DRGD)4. Tests for Microbial Contamination, as shown in Table 15 below:Route of AdministrationNon-aqueous preparations for oraluseTAMC(CFU/g or CFU/ml)TYMC(CFU/g or CFU/ml)Specified micro-organisms10 3 10 2 Absence of Escherichia coli (1 g or 1 ml)10 2 10 1Aqueous preparations for oral use 10 2 10 1 Absence of Escherichia coli (1 g or 1 ml)Absence of Burkholderia cepacia (1 g or 1 ml)Oromucosal useml)Absence of Pseudomonas aeruginosa (1 g orAbsence of Staphylococcus aureus (1 g or 11 ml)Absence of Burkholderia cepacia (1 g or 1 ml)Special Ph. Eur. provision for oraldosage forms containing rawmaterials of natural (animal,vegetal or mineral) origin for whichantimicrobial pretreatment is notfeasible and for which thecompetent authority acceptsTAMC of the raw materialexceeding 10 3 CFU per gram orper millilitre10 4 10 2 Not more than 10 2 CFU of bile-tolerant gramnegativebacteria (1 g or 1 ml)Absence of Salmonella (10 g or 10 ml)Absence of Staphylococcus aureus (1 g or 1ml)Absence of Burkholderia cepacia (1 g or 1 ml)– for aqueous preparation onlySpecial Ph. Eur provision forherbal medicinal productsconsisting solely of one or moreherbal drugs (whole, reduced andpowdered):- herbal medicinal products towhich boiling water is addedbefore use- herbal medicinal products towhich boiling water is not addedbefore useNot more than 10 2 CFU of Escherichia coli (110 710 5g or 1 ml)Not more than 10 3 CFU of bile-tolerant gramnegativebacteria (1 g or 1 ml)Absence of Escherichia coli (1 g or 1 ml)Absence of Salmonella (10 g or 10 ml)Notes:- Abbreviation:TAMC : Total Aerobic Microbial CountTYMC : Total Yeasts & Moulds CountNMT : Not more than- Interpretation of the results as follows:10 1 CFU : maximum acceptable count = 20;10 2 CFU : maximum acceptable count = 200;10 3 CFU : maximum acceptable count = 2000, and so forth.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 212

Drug Registration Guidance Document (DRGD)Specifications and Certificate of Analysis of Active IngredientCertificate of analysis for each active ingredient (raw material) is required preregistration.The certificate must consist of specifications and results of analyses.Other Supporting documents‣ For the submission of other supporting documents.‣ Additional requirement for safety and quality of active ingredient/ product (e.g.;dose for children, pregnant etc.)‣ Quality testing for specific ingredient:- For product containing Aphanizomenon flos-aquae, applicants wouldhave to provide certificates of analysis showing that the microcystin-LR ortotal microcystins content of the raw material does not exceed 1μg/g andthe finished product has been tested for microcystin-LR using anacceptable method‣ Quality testing for specific product:- Certificate of Analysis for Dioxin level is required for product containingingredient(s) derived from seafood- Certificate of Analysis for proof of hormone-free is required for productcontaining placentaNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 213

ATTACHMENT 1Drug Registration Guidance Document (DRGD)CHECKLIST OF DOSSIER REQUIREMENT FOR HEALTH SUPPLEMENTSDepending on the level of claims, submission may follows the route as outlined:i) General/ Nutritional and Medium Claims - Abridge evaluationii) Disease Risk Reduction Claims - Full evaluationTable 16: Checklist for General/ Nutritional and Medium ClaimNo.FieldGeneral orNutritionalClaimsFunctionalClaimsA1A2A3Product NameBrand name and product nameProduct Description- Describe visual and physical characteristics ofthe product including shape, size, superficialmarkings, colour, odour, taste, type ofcoating, type of capsule etc where applicable- Animal shape is only allowed for „For ExportOnly‟ (FEO) ProductsDosage Form- COA capsule shell is required- Source of capsule shell- BSE/ TSE free certificate if capsule fromanimal source from competent authority- Letter to rectify the source of gelatine from theproduct manufacturer- Colouring agent used in capsuleA4 Product indication/ Usage √ √A5Dose/ Use Instruction- Quantity and frequency- Dosing schedule must be stated(e.g. take before/ after/ with meal)A6 Contraindication, if applicable √ √A7 Warning/ Precautions, if applicable √ √√√√√√√√√National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 214

Drug Registration Guidance Document (DRGD)No.FieldGeneral orNutritionalClaimsFunctionalClaimsA8 Drug Interaction, if applicable √ √A9 Side Effects/ Adverse Reactions, if applicable √ √A10Signs and Symptoms of overdose andtreatment, if applicable√√A11Storage Condition- According to stability data√√Shelf lifeA12- Must be supported by stability study- Please refer to B5√√A13Therapeutic Code- As a health supplement√√B1.1 Batch Manufacturing Formula √ √B1.2List of Active ingredient(s)- BSE/ TSE free certificate if active ingredientfrom animal sourceB1.3 List of excipient(s) √ √B1.4Attachment of Batch Manufacturing Formula- Shall be on the product owner‟s/manufacturer‟s original letterhead, productdetails, date and signature & designation ofauthorized personnelB2.1 Manufacturing Process √ √√√√√B2.2Attachment of Manufacturing ProcessDocument or Manufacturing Flow Diagram√√B3In-Process Quality Control (IPQC)√*LOC to submitdata during postregistration√National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 215

Drug Registration Guidance Document (DRGD)No.FieldGeneral orNutritionalClaimsFunctionalClaimsB4Finished Product Specification (FPQC)√* LOC to submitdata during postregistration√B5 Stability Data (Please refer page 24) √ √D1 Label for immediate container √ √D2 Label for outer carton (if applicable) √ √D3Proposed package insert / Product informationleaflet (if applicable)√√E1 Company name and address of product owner √ √E2Company name and address ofmanufacturer(s)√√E3Company name and address of repacker(if applicable)√√E4Company name and address of othermanufacturer (if applicable)√√E5 Store address(s) √ √E6 Importer(s) √ √F1Letter of authorization from product owner tomarketing authorization holder (if applicable)√√F2Letter of Appointment of ContractManufacturer/ Repacker from Product Owner(if applicable)√√F3Letter of Acceptance from ContractManufacturer/ Repacker (if applicable)√√F4Certificate of Pharmaceutical Product (CPP)- Applicable to imported products, must beissued by the competent authority in thecountry of origin. CPP issued by referencecountry may be considered.√√National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 216

Drug Registration Guidance Document (DRGD)No.FieldGeneral orNutritionalClaimsFunctionalClaimsF5Certificate of Free Sale (CFS)- Applicable if CPP is not available, must beissued by the competent authority in thecountry of origin/ products owner country.√√F6Certificate of Good Manufacturing Practice(GMP)- Applicable if CPP is not available, must beissued by the competent authority in themanufacturing country.√√F9Attachment of protocol analysis√- dosage formextendedrelease* LOC to submitduring post forother types ofdosage form√- dosage formextendedrelease- validation ofanalyticalmethod fornew actives ornewcombinationdosageF10Attachment of Certificate of finished product(COA of finished product)√* LOC to submitduring postregistration√F11Attachment of Specifications and Certificate ofAnalysis (COA) of Active Ingredient√√Examples of supporting documentsDioxin level test results (for product containingingredients derived from seafood)F12Certificate of Good Manufacturing Practice(GMP) for premixed active ingredientsHormone free test results(for placenta products)√√Declaration letter from product manufacturer onthe hormone - free status for product containingplacentaNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 217

Drug Registration Guidance Document (DRGD)No.FieldGeneral orNutritionalClaimsFunctionalClaimsManufacturing process validation report ifapplicableLetter of commitment if applicableEtc.* Complete stability study conducted at 30 ± 2 ºC / RH 75 ± 5%, IPQC, FPQC, protocol analysisand COA of finished product are required to be submitted 2 years after product registration withSAMPLE of the products. Failure on submission will cause the product be suspended until thecomplete documents are submitted, the registration of the product will be terminated if thecomplete documents still cannot be produced upon renewal of product registration.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 218

Drug Registration Guidance Document (DRGD)Dossier Requirement for Disease risk reduction as in Table 16 above andTable 17 below:Table 17: Additional Quality Data Checklist for Disease Risk Reduction ClaimNo. Field Disease Risk Reduction ClaimPARTPP. HEALTH SUPPLEMENT PRODUCTP1. Description and CompositionP2. Pharmaceutical DevelopmentP2.1 Information on DevelopmentStudiesP2.2 Components of the HealthSupplement ProductP2.3 Finished ProductP2.4 Manufacturing ProcessDevelopmentP2.5 Container Closure SystemP2.6 Microbiological AttributesP2.7 CompatibilityP3. ManufacturerP3.1 Batch Manufacturing FormulaP3.2 Manufacturing Process &Process ControlP3.2.1 Manufacturing ProcessFlowchartP3.3 Control of Critical Steps &IntermediatesP3.4 Process Validation andEvaluationP4. Control of ExcipientsP4.1 SpecificationsP4.2 Analytical ProcedureP4.3 Validation of AnalyticalProceduresP4.4 Justification of SpecificationP4.5 Excipient of Human or AnimalOriginP4.6 Novel ExcipientsP5. Control of Finished ProductP5.1 SpecificationP5.2 AnalyticalProceduresP5.3 Validation of Analytical√National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 219

Drug Registration Guidance Document (DRGD)No. Field Disease Risk Reduction ClaimProceduresP5.4 Batch AnalysesP5.5 Characterization of impuritiesP5.6 Justification of SpecificationP6. Reference Standards or MaterialsP7. Container Closure SystemP8. StabilityP9. Product Interchangeability/EquivalentevidencePARTSS. HEALTH SUPPLEMENTSUBSTANCES1. General InformationS1.1 NomenclatureS1.2 StructureS1.3 General PropertiesS2. ManufactureS3. CharacterisationS4. Control of Health SupplementSubstanceS4.1 SpecificationS4.2 Analytical ProceduresS4.3 Validation of AnalyticalProcedureS4.4 Batch AnalysisS4.5 Justification of SpecificationS5. Reference Standards or MaterialsS6. Container Closure SystemS7. Stability√National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 220

PART III: NON-CLINICAL DATADrug Registration Guidance Document (DRGD)- Applicable to disease risk reduction claims(For new active ingredient, new combination of active ingredients and new dose)Table 18:No. Field Disease Risk Reduction Claims1.2.3.4.Overview of non-clinical testing strategy- nomenclature- structure- general propertiesPharmacology- related information (including academicliterature) of pharmacology studies on thedeclared efficacyPharmacokinetics- related information (including academicliterature) of pharmacokinetics studies on thedeclared efficacyToxicology- related information (including academicliterature) of toxicology studies5. Integrated overview and conclusions √6. Other toxicity studies if available √7.References- List of references used√√√√√- All information must be provided in the following format/ table:StudyTitleTypeofStudyProduct(formulation)Study Summary- Study Design (e.g. casecontrol, randomisedplacebo controlled, invitro data, cohort study)- Dosage- Subject- Study Duration- Outcome parametersSummary findings(Includes scientific details such asstrength of evidence [e.g. p-values], conclusions, anyshortcomings, etc.For traditional evidence includeenough information todemonstrate relevance)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 221

PART IV: CLINICAL DOCUMENTSDrug Registration Guidance Document (DRGD)- Applicable to disease risk reduction claims (for new active ingredient, newcombination of active ingredients and new dose).Table 19:No. Field Disease Risk Reduction Claims1. Clinical overview √2. Production Development Rational √3.4.5.6.7.Overview of Bio-pharmaceutics- To include associated analytical methodsOverview of Clinical Pharmacology- Summary of clinical pharmacology studiesOverview of Efficiency- Summary of clinical efficacyOverview of Safety- Summary of clinical safetyReferences- List of all clinical studies- List of key literature references- Published clinical papers√√√√√National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 222

- All information must be provided in the following format/table:Drug Registration Guidance Document (DRGD)Forms ofstudySample sizeDurationRandomisationof groupsEndpointStatistical analysis ofdataRandomised,controlled,andpreferablyblindedinterventionstudiesMust bejustified andmust involvesufficientlylarge number ofsubjects toestimateincidence andnature ofpotentialadversereactionsMust bejustified andmust be ofsufficientduration toensure nosafetyconcernswith respectto long termuseAll groups shallhavecomparablebaselinevalues,particularly forthose factorsthat are knownto be, or maybe,confounders orrisk factorsAs adecreaseincidence ofthe diseaseor areduction ofa factor, or asurrogatethereof, ofthe manythatcontribute tothedevelopmentof a diseaseMethods to calculatethe sample size,setting the powerand the significancelevel at conventional80% and p

ATTACHMENT 2Drug Registration Guidance Document (DRGD)Table 20: Allowable claims for specific active ingredients in HS productsIngredientsVitamin AVitamin CVitamin DVitamin EGeneralMaintenanceof good healthMaintenanceof good healthMaintenanceof good healthClaimsFunctionalHelps to maintaingrowth, vision andtissuedevelopmentAids inmaintaining thehealth of the skinand mucousmembraneFor healthybones,(cartilage), teeth,gums as well asgeneral make-upof the bodyHelps in normaldevelopment andmaintenance ofbones and teethHelps the bodyutilize calciumand phosphorusClaim for specificpopulationsubgroups:Elderly peoplewho are confinedindoorsReduced RiskReduction ClaimNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 224

Drug Registration Guidance Document (DRGD)IngredientsBeta CaroteneVitamin B1 (Thiamine)Riboflavin (Vitamin B2)Niacin (Vitamin B3)GeneralMaintenanceof good healthHelps tomaintain goodhealthA factor inmaintenanceof good healthA factor inmaintenanceof good healthClaimsFunctionalHelps inmaintenance ofgrowth, vision andtissuedifferentiationHelps inmaintenance ofgrowth, vision andtissuedifferentiationHelps the body toutilize energyfrom food/metabolizeprotein, fats andcarbohydratesClaim for specificpopulationsubgroups:-Additionalamounts ofRiboflavin arerequired duringpregnancy andbreast feedingwhen diet doesnot provide asufficient dailyintakeHelps normalgrowth anddevelopmentHelps the body inutilization ofenergy from foodReduced RiskReduction ClaimNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 225

Drug Registration Guidance Document (DRGD)IngredientsGeneralClaimsFunctionalReduced RiskReduction ClaimPyridoxine (Vitamin B6)A factor inmaintenanceof good healthHelps the body tometabolizeproteins, fats andcarbohydratesCyanocobalamine(Vitamin B12)Helps inmaintenanceof good healthHelps in theformation of redblood cellFolic AcidHelps in formationof red blood cellHelps preventneural tubedefects forwomen who areplanning apregnancy beforeconception andduring 12 weeksof pregnancy at adose of 400 mcgdailyBiotinHelps inmaintenanceof good healthHelps tometabolize fatsandcarbohydratesPanthothenic AcidHelps inmaintenanceof good healthHelps tometabolize fatsandcarbohydratesNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 226

Drug Registration Guidance Document (DRGD)IngredientsClaimsGeneralFunctionalReduced RiskReduction ClaimCalciumHelps inmaintenanceof good healthHelps in theformation andmaintenance ofbones and teethClaim for specificsubgroup:- Additionalcalcium isrequired forpregnant andlactatingwomen, whendiet does notprovide asufficient dailyintake to helpin proper boneformation indevelopingbabyPhosphorusHelps inmaintenanceof good healthHelps in theformation andmaintenance ofbones and teethMagnesiumHelps inmaintenanceof good healthHelps the body tometabolizecarbohydrateIronHelps inmaintenanceof good healthHelps in theformation of redblood cellHelps to preventiron anemiaHelps to preventanemia due toiron deficiencyIodineHelps inmaintenanceof good healthHelps in thefunction of thethyroid glandsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 227

Drug Registration Guidance Document (DRGD)IngredientsGeneralClaimsFunctionalReduced RiskReduction ClaimZincA factor inmaintenanceof good healthHelps tometabolizecarbohydrates,fats and proteinCopperA factor inmaintenanceof good healthHelps in theformation of redblood cellManganeseA factor inmaintenanceof good healthHelps tometabolizecarbohydratesand proteinsProbioticsHelps to improvea beneficialintestinalmicrofloraNotes:1. This list is not meant to be exhaustive and will be reviewed from time to time.2. The Authority will nonetheless conduct a detailed evaluation of the evidence included inthe report to ensure that the health claim is substantiated.3. The Authority will be willing to consider review other than the listed above, if thestandards of evidence are consistent with those of the Authority.4. All references must be current.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 228

Drug Registration Guidance Document (DRGD)ACKNOWLEDGEMENTSThe National Pharmaceutical Control Bureau acknowledges its indebtedness to themembers from the industries, government agencies and universities as statedbelow, who provided comments and advices during the preparation of theseguidelines.Government agencies:i) Bahagian Keselamatan dan Kualiti Makanan (BKKM), KKMii) Bahagian Perubatan Tradisional & Komplementari, KKMiii) Institut Penyelidikan dan Perubatan (IMR), KKMiv) Kementerian Pertanian & Industri Asas Tani Malaysiav) Unit Perancang Ekonomi, Jabatan Perdana MenteriUniversities:i) Jabatan Pemakanan dan Dietetik, Fakulti Perubatan & Sains Kesihatan,Universiti Putra Malaysiaii) Jabatan Pemakanan dan Dietetik, Fakulti Sains Kesihatan Bersekutu,Universiti Kebangsaan Malaysiaiii) Pejabat Dietetik, Pusat Perubatan Universiti Malayaiv) Program Sains Makanan, Fakulti Sains dan Teknologi, Universiti KebangsaanMalaysiaIndustries/ Associations:i) Biotropic Malaysia Berhadii) Direct Selling Association of Malaysia (DSAM)iii) Federation of Chinese Physician and Medicine-Dealers Association ofMalaysia (FCPMDAM)iv) Malaysian Biotechnology Corporation (BiotechCorp)v) Malaysian Dietary Supplement Association (MADSA)vi) Malaysian Direct Distribution Association (MDDA)vii) Persatuan Industri Farmaseutikal Malaysia (MOPI)viii)Persatuan Pengeluar-pengeluar Ubat Tradisional Melayu Malaysia(PURBATAMA)ix) Perubatan Traditional India Malaysia (PEPTIM)x) Pharmaceutical Association of Malaysia (PhAMA)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 229

APPENDIX 5:Drug Registration Guidance Document (DRGD)GUIDELINE ON REGISTRATION OF NATURAL PRODUCTSIMPORTANT NOTES:1. This document shall be read in conjunction with the relevant sections of themain DRGD.2. Natural products will be evaluated based on the criteria for safety and qualityof the product and where appropriate efficacy/ claimed benefits.3. This document is intended to provide guidance for the registration of naturalproducts. However, the document will serve as a living document that will beupdated/ revised further in the line with the progress in scientific knowledgeand experience.4. The following lists are by no means exhaustive. It may be reviewed as andwhen it is deemed necessary.Outline:1. General Information1.1 Definitions1.1.1 Traditional Medicines1.1.2 Finished Herbal Product1.1.3 Herbal Remedy1.1.4 Homeopathic Medicine1.2 Exemption from Product Registration1.3 Preparations which are not allowed to be registered1.4 Classification for Specific Active Ingredients1.4.1 Products Containing Cassia/ Senna1.4.2 Products Containing Psyllium Husk/ Plantago OvataNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 230

Drug Registration Guidance Document (DRGD)2. General Requirements for Registration of Natural Products2.1 Ingredients2.1.1 Active Ingredients2.1.2 Premix2.1.3 Prohibited/ Banned Ingredients2.1.4 Use of Protected/ Endangered Ingredients2.2 Excipients2.3 Indications2.3.1 Indications Acceptable for Natural Products2.3.2 Non-Permissible Indications2.4 Product Name2.5 Quality Control2.5.1 Sample for Testing2.5.2 Appeal for Sample Retesting2.5.3 Quality Testing for Specific Ingredient2.5.4 Limit Test for Heavy Metals2.5.5 Disintegration Test2.5.6 Test for Uniformity of Weight (For Tablets and Capsules Only)2.5.7 Tests for Microbial Contamination2.6 Stability Data2.7 Labelling Requirement2.7.1 Statements to be stated on Product Label2.7.2 Specific Labelling Statements/ Warning & Precautions2.7.3 Cautionary Statement for Products Specially Used in Women2.7.4 Prohibited Visual/ Graphics/ Statement on Label of Natural Products inWomen3. Product Specific Requirements:3.1 Foot Patch3.2 Herbal Tea3.3 Homeopathic ProductsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 231

1. GENERAL INFORMATIONSDrug Registration Guidance Document (DRGD)1.1 DEFINITIONS1.1.1 Traditional medicineAs defined under the CDCR 1984, traditional medicine refers to any productused in the practice of indigenous medicine, in which the drug consist solelyof one or more naturally occurring substances of a plant, animal or mineral, ofparts thereof, in the unextracted or crude extract form, and a homeopathicmedicine. It shall not include any sterile preparation, vaccines, any substancederived human parts, any isolated and characterized chemical substances.1.1.2 Finished Herbal ProductFinished herbal products consist of herbal preparations made from one ormore herbs. If more than one herb is used, the term “mixture herbal product”can also be used. Finished herbal products and mixture herbal products maycontain excipients in addition to the active ingredients. However, finishedproducts or mixture herbal products to which chemically defined activesubstance have been added, including synthetic compounds and/ isolatedconstituents from herbal materials, are not considered to be herbal.1.1.3 Herbal RemedyAny drug consisting of a substance or a mixture of substances produced bydrying, crushing or comminuting, but without subjecting to any other process,a natural substance or substances of plant, animal or mineral origin, or anypart of such substance or substances.1.1.4 Homeopathic MedicineAny pharmaceutical dosage form used in the homeopathic therapeutic systemin which diseases are treated by the use of minute amounts as of suchsubstances which are capable of producing in healthy persons symptomssimilar to those of the disease being treated.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 232

1.2 EXEMPTION FROM PRODUCT REGISTRATIONDrug Registration Guidance Document (DRGD)The following preparations do not require registration with the Authority:a) Extemporaneous preparation that has been prepared and given directly to thepatient by any traditional practitioner during the course of treatment;b) Traditional preparation containing plants, animal parts or mineral substanceor a mixture of these substances of natural origin that is produced onlythrough drying, without any treatment/process involved. For example, rawherbs;c) Traditional preparation containing plants, animal parts, mineral substance/extracts or a mixture of these substances of natural origin traditionally usedas food, spices or flavouring of food which do not have any medicinal claim;d) Traditional preparation that is used for cosmetic purposes such as to whitenor improve the appearance of skin, hair, teeth, etc has to be registered ascosmetic product.1.3 PREPARATIONS WHICH ARE NOT ALLOWED TO BE REGISTEREDa) Traditional preparation with the indication as listed in “List of Non PermissibleIndications for Natural Product”(Reference: Medicine Advertisement and Sale Act 1956)b) Traditional preparation containing herbal ingredients as listed under PoisonAct 1952 except for those exempted for homeopathic preparation.Please refer to Section 4 - General guidelines for the registration ofhomeopathic products.c) Traditional preparation containing ingredient known or reported to cause anyadverse effect on humans. Please refer to List of Botanicals (& botanicalingredients) which are banned due to reported adverse event.d) Traditional preparation containing combination of plants, animal parts ormineral substance of natural origin with chemical/ synthetic substance withtherapeutic effect.e) Traditional preparation containing combination of plants, animal parts ormineral substance of natural origin with vitamins and amino acids.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 233

Drug Registration Guidance Document (DRGD)f) Traditional products are prohibited from containing ingredients derived fromhuman origin. For examples:i) CRINIS CARBONISATUS = Carbonised human hair(Reference: Pharmacopoeia Of The People‟s Republic Of China: EnglishEdition 1992)ii) HUMAN PLACENTA1.4 CLASSIFICATION FOR SPECIFIC ACTIVE INGREDIENTS1.4.1 PRODUCTS CONTAINING CASSIA/ SENNA:Products containing less than 0.5g of the crude drug or 20 mg sennoside(standardized preparation) are allowed make claims for general health only.(Reference: Micromedex)1.4.3 PRODUCTS CONTAINING PSYLLIUM HUSK/ PLANTAGO OVATAFinished products containing less than 3.5g of this active ingredient in asingle formulation and not in a pharmaceutical dosage form with specificdosage instructions will be classified as a non-drug. However quantitiesabove this amount and up to 6.9 g will require this product to be classified asa traditional product and will require registration before it can be marketed.(Reference: Circular on 14 May 2010 - Bil (24) dlm.BPFK/PPP/07/11Jld 5)2. GENERAL REQUIREMENTS FOR REGISTRATION OF NATURALPRODUCTS2.1 INGREDIENTS2.1.1 ACTIVE INGREDIENTSa) Active ingredients are those substances that have a therapeutic role in theformulation. Substances that are included in the formulation as activeingredients must make a contribution to the proposed indications for theproduct. Where a claim links the presence of an ingredient to the productNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 234

Drug Registration Guidance Document (DRGD)indication, that ingredient must contribute to that indication. The evidencemay be scientific and or traditional.b) Overages of active ingredientOverages may be used during manufacture. An overage is where the amountof an ingredient added during manufacturing that is greater than thenominated on the product label. Details of the overage used must beavailablec) Listed active ingredients can be checked through http://www.bpfk.gov.my ofproduct search. Ingredients not listed will require safety and/or efficacy dataevaluation prior to addition to this list.d) For new active ingredients or new combination products, the followinginformation shall be required:‣ Product containing new single ingredient:i) Extract form- Information on the taxonomy of the ingredient;- Techniques and methods in preparing/ processing the extract andsubsequently the product;- Information on the use and safety of the ingredient and the productQuality standard.ii) Powder/ Granules- Information on the taxonomy of the ingredient;- Techniques and methods in preparing/ processing the extract andsubsequently the product;- Information on the use and safety of the ingredient and the product.‣ Product containing multiple ingredients (contains ingredients which areknown to be used traditionally):- The source of the product formulation;e.g. Chinese Pharmacopoeia- Proof or evidence of the use, traditionally.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 235

Drug Registration Guidance Document (DRGD)‣ Product containing multiple ingredients (contains ingredients which are notknown to be used traditionally):- Information on the use and safety of every new ingredient;- Safety data on the new formulation;- Regulatory status in other countries.2.1.2 PREMIXEffective from 1 December 2007, premixed ingredient(s) shall not be used ina traditional product formulation, as directed in circular Bil (71) dlmBPFK/02/5/1.3, 1 Jun 20072.1.3 PROHIBITED/ BANNED INGREDIENTSThe following lists are prohibited/ banned ingredients which are not allowed inthe formulation of natural products registered by the Authority:a) Botanicals (and botanical ingredients) containing scheduled poisons aslisted under the Poisons Act 1952;b) Botanicals (& botanical ingredients) which are banned due to reportedadverse event;c) Ingredients (botanicals and substance derived from animals) which arebanned due to safety reasons.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 236

Drug Registration Guidance Document (DRGD)a) Table 1: Botanicals (and botanical ingredients) containing scheduledpoisons as listed under the Poisons Act 1952Part of plantprohibitedGenusSpeciesCommon/Local Name(whole plantunlessotherwisespecified)Constituent(s) ofconcernAconitum All species AconiteAsidospermaquebrachoWhitequebrachoAsidospermine,yohimbineAtropabelladonnaDeadlynightshadeAtropine,hyoscine(scopolamine),hyoscyamineBerberineBerberisAll species* Also present inHydrastiscanadensis(Goldenseal) andCoptic chinensis(Golden thread)Cabola albarrane Squill GlycosidePeriwinkleMadagascar,Old Maid,Vinca rosea,MyrtleCatharanthusroseusSyn: Vincabalcanica,Vincadifformis,Vinca heracea,Vinca major,Vinca minor,Vincae minorisherbaVinca, Vincristine,VinblastineNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 237

Drug Registration Guidance Document (DRGD)Part of plantprohibitedGenusSpeciesCommon/Local Name(whole plantunlessotherwisespecified)Constituent(s) ofconcernChondodendrontomentosumCurare, Velvetleaf, Ice Vine,TubocurarineClaviceps purpurea Ergot ErgometrineColchicumautumnaleAutumnCrocus/MeadowSaffron/ NakedLady)ColchicineDaturametelDevil‟sTrumpet,Metel, JCaliforniaJimson WeedAtropine,ScopolamineSyn.: DaturawrightiiDaturastramoniumJimson Weed/GypsumWeed,LocoWeedAtropine,Hyoscyamine,ScopolamineDelphiniumstaphysagriaLice bane,StavesacreDelphinineDigitalispurpureaCommonFoxglove,PurpleFoxglove,KecubungLeafGlycosideSquillDrimiamaritimaSyn.:Urgineamaritima, ScillamaritimaGlycosideNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 238

Drug Registration Guidance Document (DRGD)Part of plantprohibitedGenusSpeciesCommon/Local Name(whole plantunlessotherwisespecified)Constituent(s) ofconcernRelatedsubstance:Urginea indica,Urgineapancreatium,Urginea scillaEphedra All species Ma HuangEphedrine,PseudoephedrineGelsemiumsempervirensYellowJessamine,EveningTrumpet,Carolina JessamineGelsemineHyoscyamusmuticusEgyptianhenbaneHyoscyamineHyoscyamus niger Black henbaneHyoscyamineatropineLobeliainflataLobelia,pokeweed,Indian tobacco,gagroot,asthma weed,vomitwort,bladderpod,rapuntiuminflatum.LobelineLobelia nicotianifolia Wild Tobacco LobelineMitragyna speciosa Daun Ketum MitrogynineNicotianatabacumCommontobaccoNicotineNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 239

Drug Registration Guidance Document (DRGD)Part of plantprohibitedGenusSpeciesCommon/Local Name(whole plantunlessotherwisespecified)Constituent(s) ofconcernPapaver somniferum Opium poppyMorphine,codeine,hydrocodone,meperidine,methadone,papaverineYohimbe,JohimbePausinystaliayohimbeSyn.Corynanthejohimbi,Corynanthe yohimbiYohimbinePhysostigma venenosum Calabar bean PhysostigminePilocarpusmicrophyllusPilocarpusjaborandi,jaborandiPilocarpinePunica granatum Pomegranate Bark Iso-PellatrierineRauwolfiaserpentinaIndiansnakeroot,SerpentinerootReserpineRauwolfiavomitoriaAfricanserpentwoodReserpineSchoenocaulonofficinaleVeratrumofficinaleSabadilla,VeratrineScillaebulbusSea onion,SquillSolanumnigrumBlacknightshadeSolanineNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 240

Drug Registration Guidance Document (DRGD)Part of plantprohibitedGenusSpeciesCommon/Local Name(whole plantunlessotherwisespecified)Constituent(s) ofconcernStrychnosnux-vomicaPoison nut,Quaker button,strychninetree, ma qianzi/maqianziStrychnineValerianAll speciesAll partsexcept forroot partValepotriatesVeratrumAll speciesVincaAll speciesIncludingCatharanthusroseusVinca, Vincristine,Vinblastine,VinpocetinNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 241

Drug Registration Guidance Document (DRGD)b) Table 2: Botanicals (& botanical ingredients) which are banned due toreported adverse eventGenusSpeciesCommon/ LocalNamePart ofplantprohibitedReason forprohibitionAristolochiaAll speciesContain AristolochicAcid reported tocause kidney toxicity(**Please refer tofootnote below)DrybalanopsaromaticaBorneo/Malay/SumatraCamphor, PokokKapurWhole herbContain camphor- notallowed for oralpreparationBorneolum syntheticum Bingpian,borneolContain borneol- notallowed for oralpreparationLarreatridenatamexicanaChapparalReported to causeliver toxicityHydrastiscanadensisGoldenseal,EyeBalm, IndianDyeReported to causedisturbance of thenervous systemMagnoliaStephaniaofficinalistetrandraHoupu,MagnoliaReported to causekidney toxicityPipermethysticumKava-kavaofficinaleSymphytumasperumx. uplandicumComfreyReported to causeliver toxicityNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 242

Drug Registration Guidance Document (DRGD)GenusSpeciesCommon/ LocalNamePart ofplantprohibitedReason forprohibitionaureusLife rootjacobaeaTansy ragwort,TansyButterweedbicolornemorensisSilver ragwortAlpane ragwort,Wood ragwortReported to causeliver toxicitySeneciovulgarisCommongroundsel,Groundsel, Oldman-inthespringlongilobus-syn .withdouglasii,filifoliusThreadleafgroundsel,ThreadleafragwortScandensBuch.-HamGerman/African/Cape Ivy,ClimbingGroundsel** To identify the Botanicals which may contain Aristolochic Acid besidesthe Aristolochia genus, please refer the following lists on the nextpage:a. List A - Botanicals Known or Suspected to contain Aristolochic Acidb. List B - Botanicals which may be Adulterated with Aristolochic AcidNotes:Products containing any of the listed herbs (EXCEPT for Aristolochia spp. whichis totally banned) will have to be sent to any governmental doping centre fortesting and the result shall be attached with the registration form.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 243

Drug Registration Guidance Document (DRGD)(Source for Lists A and B)U. S. Food and Drug AdministrationCenter for Food Safety and Applied NutritionOffice of Nutritional Products, Labeling, andHealth Supplements[Revised April 9, 2001]List A: Botanicals Known or Suspected to Contain Aristolochic AcidTable 3:Asarum canadense Linn.Botanical Name*Syn. Asarum acuminatum (Ashe) E.P. BicknellSyn. Asarum ambiguum (E.P. Bicknell) DanielsSyn. Asarum canadense var. ambiguum (E.P.Bicknell) Farw.Syn. Asarum canadense var. reflexum (E.P. Bicknell)B.L.Rob.Syn. Asarum furcatum Raf.Syn. Asarum medium Raf.Syn. Asarum parvifolium Raf.Syn. Asarum reflexum E.P. BicknellSyn. Asarum rubrocinctum PeattieAsarum himalaicum Hook. f. & Thomson ex KlotzschorAsarum himalaycum Hook. f. & Thomson exKlotzschAsarum splendens (F. Maek.) C.Y. Cheng & C.S.YangCommon or Other NamesWild gingerIndian gingerCanadasnakerootFalse coltsfootColic rootHeart snakerootVermontsnakerootSouthernsnakerootTanyou-saishin(Japanese)Do-saishin(Japanese)Bragantia wallichii R.Br.Specimen exists at New York Botanical Gardens.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 244

Drug Registration Guidance Document (DRGD)Botanical Name*Common or Other NamesTropicosdoes not list this species as a synonym for anyThotteaspecies. Kew Gardens Herbarium does notrecognize thegenera Bragantia. Until additional information isobtained wewill use the name as cited in J. Nat. Products45:657-666(1982)List B: Botanicals which may be Adulterated with Aristolochic AcidTable 4:Botanical Name*Common or Other NamesAkebia spp.Akebia quinata (Houtt.) Decne.Syn. Rajania quinata Houtt.AkebiaMu tongKu mu tongZi mutongBai mu tongMokutsu (Japanese)Mokt'ong (KoreanChocolate vineFiveleaf akebiaMu tongYu zhi ziMokutsu (Japanese)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 245

Drug Registration Guidance Document (DRGD)Botanical Name*Akebia trifoliata (Thunb.) Koidz.Asarum forbesii Maxim.Asarum heterotropoides F. SchmidtSyn. Asarum heterotropoides F. SchmidtSyn. Asiasarum heterotropoides (F. Schmidt) F.Maek.Asarum sieboldii Miq.Syn. Asarum sieboldii fo. seoulense (Nakai) C.Y.Cheng &C.S. YangSyn. Asarum sieboldii var. seoulensis NakaiSyn. Asiasarum heterotropoides var. seoulense(Nakai) F.Maek.Syn. Asiasarum sieboldii (Miq.) F. Maek.Clematis spp.Common or Other NamesMu tongThree leaf akebiaYu zhi ziBatei-saishin(Japanese)Keirin-saishin(Japanese)Chinese wild gingerManchurian wildgingerBei xi xinXin xinUsuba-saishin(Japanese)Chinese wild gingerXi XinHua Xi XinManchurian wildgingerSiebold's wild gingerClematisMufangjiClematidisIreisen (Japanese)Wojoksum (Korean)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 246

Drug Registration Guidance Document (DRGD)Clematis armandii Franch.Botanical Name*Syn. Clematis armandii fo. farquhariana (W.T.Wang)Rehder & E.H. WilsonSyn. Clematis armandii var. biondiana (Pavol.)RehderSyn. Clematis biondiana Pavol.Syn. Clematis ornithopus Ulbr.Clematis chinensis Osbeck.Common or Other NamesArmand's clematisChuan mu tong(stem)Xiao mu tongArmand's virginbowerChinese clematisWei ling xian (root)Clematis hexapetala Pall.Clematis montana Buch.-Ham. ex DC.Syn. Clematis insulari-alpina HayataClematis uncinata Champ. ex Benth.Syn. Clematis alsomitrifolia HayataSyn. Clematis chinensis var. uncinata (Champ. exBenth.) KuntzeSyn. Clematis drakeana H. Lév. & VaniotSyn. Clematis floribunda (Hayata) Yamam.Syn. Clematis gagnepainiana H. Lév. & VaniotSyn. Clematis leiocarpa Oliv.Syn. Clematis ovatifolia T. Ito ex Maxim.Syn. Clematis uncinata var. biternata W.T. WangSyn. Clematis uncinata var. coriacea Pamp.Syn. Clematis uncinata var. floribunda HayataSyn. Clematis uncinata var. ovatifolia (T. Ito exMaxim.)Ohwi ex TamuraSyn. Clematis uncinata var. taitongensis Y.C. Liu &C.H. OuNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 247

Drug Registration Guidance Document (DRGD)Botanical Name*Common or Other NamesCocculus spp.CocculusCocculus carolinus (L.) DC.Syn. Cebatha carolina BrittonSyn. Epibaterium carolinum (L.) BrittonSyn. Menispermum carolinum L.Cocculus diversifolius DC.Syn. Cocculus madagascariensis DielsCocculus hirsutus (L.) DielsSyn. Cocculus villosus DC.Syn. Menispermum hirsutum L.Cocculus indicus RoyleSyn. Anamirta paniculata Colebr.Indian cockleCocculus laurifolius DC.Syn. Cinnamomum esquirolii H. Lév.Cocculus leaebe DC.Cocculus madagascariensis DielsSyn. Cocculus diversifolius DC.Cocculus orbiculatus DC.Syn. Cissampelos pareira Linn.Cocculus orbiculatus (L.) DC.Syn. Cocculus cuneatus Benth.Syn. Cocculus sarmentosus (Lour.) DielsSyn. Cocculus sarmentosus var. linearis Yamam.Syn. Cocculus sarmentosus var. pauciflorus Y.C. WuSyn. Cocculus sarmentosus var. stenophyllus Merr.Syn. Cocculus thunbergii DC.Moku-boui(Japanese)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 248

Drug Registration Guidance Document (DRGD)Botanical Name*Common or Other NamesSyn. Cocculus trilobus (Thunb.) DC.Syn. Menispermum orbiculatus L.Syn. Menispermum trilobum Thunb.Syn. Nephroia sarmentosa Lour.Cocculus palmatus (Lam.) DC.ColumbaColumboCocculus pendulus DielsSyn. Cebatha pendula (J.R. & C. Forst.) KuntzeSyn. Epibaterium pendulus Forst. f.Syn. Cocculus Epibaterium DC.Cocculus pendulus (Forst. & Forst.) DielsCocculus palmatus Hook.Syn. Jateorhiza Miersii OliverColomboCocculus thunbergii DC.Diploclisia affinis (Oliv.) DielsSyn. Diploclisia chinensis Merr.Syn. Cocculus affinis Oliv.Diploclisia chinensis MerrillXiangfangchiMenispernum dauricumSaussurea lappa (Decne.) Sch. Bip. / AucklandiaLappaMokkou (Japanese)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 249

Drug Registration Guidance Document (DRGD)Botanical Name*Sinomenium acutum (Thunb.) Rehder & E.H. WilsonSyn. Cocculus diversifolius var. cinereus DielsSyn. Cocculus heterophyllus Hemsl. & E.H. WilsonSyn. Menispermum acutum Thunb.Syn. Sinomenium acutum (Thunb.) Rehder & E.H.Wilsonvar. cinereum (Diels) Rehder & E.H. WilsonSyn. Sinomenium diversifolium (Diels) DielsStephania spp.Stephania tetrandra S. MooreVladimiria souliei (Franch.) LingCommon or Other NamesOrientvineXunfengtengDafengtengDaqingmuxinagZhuigusanDa ye qingshenerMufangjiHanfangjiTutengZhuigufengMaofangjiStephaniaFen fang ji , fang jiFang ji (root)Han fang jiKanboi (Japanese)Hanbanggi (Korean)Fun-boui (Japanese)Sen-mokkouNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 250

Drug Registration Guidance Document (DRGD)c) Ingredients (Botanicals and Substance Derived from Animals) which arebanned due to safety reasons:Table 5:GenusSpeciesPart ofPlant/AnimalProhibited(whole plant/animalunlessotherwisespecified)Constituent ofConcern Reasonsfor ProhibitionReasons for ProhibitionAbrus precatorius SeedAbrin, Agrus,Agglutinin- Potent inhibitor of proteinand DNA synthesis- Severe diarrhea- Severe stomach cramp- Severe gastroenteritisAdonis vernalis AdonitoxinUncontrolled dose candamage heart and causedeathAnimal parts containing hormones (All species)Antiaris toxicaria Latex, sapCardiac glycoside(antiarin),Cardenolides &alkaloids withcardiac arrestingpotential- Latex is highly poisonous- Paralyze heart muscle andcause deathAristolochia All species Aristolochic acidReported to cause kidneytoxicity, interstitialnephropathyCalotropisgiganteanproceraLatexCardiac glycosides,calotropinSevere mucous membraneirritation characterized byvomiting, diarrhea,bradycardia, convulsion anddeathNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 251

Drug Registration Guidance Document (DRGD)GenusSpeciesPart ofPlant/AnimalProhibited(whole plant/animalunlessotherwisespecified)Constituent ofConcern Reasonsfor ProhibitionReasons for ProhibitionCannabissativaindicaCannabinoids- Potential abuse- Psychoactive on CNS- Prolonged heavy use maylead to tolerance andpsychological dependenceCatharanthus roseus Vinca alkaloidsBone marrow depression,central and peripheral(including autonomic)neurotoxicitymanghasSeedDigitoxynglycoside,Cerberine,Cerberoside,thevetin- Drastic purgative and emetic- Burning in the stomachsensation, vertigo, nausea,violent purgation and colic- Heart failureCerbera- Gastro intestinal symptoms- cardiac toxicityodollamSeedCerberine,Cerberoside,odollin, odolotoxin,thevetin andcerapain- Nausea, severe retching,vomiting, abdominal pain,blurring of vision- Arterial block and nodalrhtym, hyperkalaemia- Irregular respiration, collapseand death from heart failure- Resistance of malarial vectorCinchonaAll speciesQuinine andderivatives- Use of bark iscontraindicated in pregnancyand ulcers, intestinal orgastric, and if takenconcommitantly withanticoagulants can increasedNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 252

Drug Registration Guidance Document (DRGD)GenusSpeciesPart ofPlant/AnimalProhibited(whole plant/animalunlessotherwisespecified)Constituent ofConcern Reasonsfor ProhibitionReasons for Prohibitiontheir effects- Can elicit thrombocytopeniawith purpura- Cinchona alkaloids are toxic.Can cause symptoms suchas blindness, deafness,convulsions and paralysisCitrullus Colocynthis Seed, fructus Curcubitacin- Carcinogenic effects, induceinfertility in both sexes- Enterohepatonephro-toxicityDryopteris filix-mas Rhizome Filicin, aspidinol Hepatotoxic and blindnessEuphorbiaantiquorumtrigonaLatexApha euphorbol,Beta amyrincycloartenol EupholInflammation of thegastrointestinal mucousmembrane, irritate skin,difficult respiration, eyespupil dilatedExcoecaria agallocha LatexExcoecariaphorbol- Highly irritant to skin- Cause blindness if it entersthe eye- BiocidalGarciniaacuminatehanburyimorellaGum resinCambogic acid, β-guttiferin, α-1guttiferinVomiting, hypercarthasis,sympathetic irritation ofsympathetic nervous system,caused death by gastroenteritisGelsemiumelegansRoot, leaf,rhizomeGelsemine &gelseminine(Gelsemium indolealkaloid)Paralysis, shortness ofbreath, musclestiffeningcoma, hypocyclosisNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 253

Drug Registration Guidance Document (DRGD)GenusSpeciesPart ofPlant/AnimalProhibited(whole plant/animalunlessotherwisespecified)Constituent ofConcern Reasonsfor ProhibitionReasons for ProhibitionHyoscyamusmuticusHyoscyamine,atropine, hyoscineDifficulty in swallowing andtalking, transient bradycardiafollowed by tachycardia withpalpitation and arrhythmias,CNS depression, comaJatropha multifida Fruit, seedPhytotoxin(toxalbumin -CurcinNausea, vomiting, seriouspurgative actionLantanacamaraLantadene,LancamaronCause toxicity in buffalo,cattle, sheep and goat.Symptoms includephotosensitive dermatitis,jaundice and yellowing ofmucous membrane and lossof appetite with a decrease inruminal motilityLobeliachinensisLobeline- Stimulant and has peripheraland central effects- Excessive use can causenausea, vomiting anddizzinesstupa- Stimulant and has peripheraland central effects- Caused arrhythmiasLyttavesicatoriaWhole body,tinctureCantharidin- Excessive salivation,abdominal pain, swelling ofkidney and urogenitalsystem, headache, vomitingand diarrhea accompaniedby bleeding- Burning of the mouth,dysphagia, nausea,hematemesis, grosshematuria and dysuriaNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 254

Drug Registration Guidance Document (DRGD)GenusSpeciesPart ofPlant/AnimalProhibited(whole plant/animalunlessotherwisespecified)Constituent ofConcern Reasonsfor ProhibitionReasons for Prohibition- Renal dysfunction andrelated to acute tubularnecrosis and glomerulardestructionMelaleuca alternifolia Tea tree oilSkin irritation, respiratorydistress, vomiting, diarrheaand cytotoxic for oraladministration.* Banned in oral preparation- Potential abusePapaverAll speciesMorphine andderivatives,codeine- Dependence, palpitation,hallucination, euphoricactivities, CNS depression- Nervous system toxicity- Possible death fromcirculatory and respiratoryfailurePilocarpuspinnatifoliusjaborandiBarkPilocarpineBronchospasm, ocularproblem, miosis, blurredvisionPodophyllumemodiipeltatumRoot, leafPodophyllin resin- Serious systemic toxicity withexcessive amounts(persistent nausea andvomiting, tachypnea, fever,stupor, coma, tachycardia,neuropathy and death)- Renal failure andhepatotoxicitySolanumdulcamaraLeaf,floweringtopsSolanaceousalkaloidsTypical antimuscarinic effecte.g. dry mouth, mydriasisNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 255

Drug Registration Guidance Document (DRGD)GenusSpeciesPart ofPlant/AnimalProhibited(whole plant/animalunlessotherwisespecified)Constituent ofConcern Reasonsfor ProhibitionReasons for ProhibitionStrophantusAll speciesStrophantusalkaloidsCardiac effect similar todigoxinSymphytumpregrinumPyrrolizidinealkaloidReported to cause livertoxicity2.1.4 USE OF PROTECTED/ ENDANGERED INGREDIENTSa) PROTECTED/ ENDANGERED WILDLIFE SPECIESIt is the responsibility of the applicant to ensure that the ingredient(s)derived from wildlife species its parts and derivatives used in theformulation COMPLIES with the Wildlife Conservation Act 2010 (Act716) and International Trade in Endangered Species Act 2008 (Act686). Both guidelines can be downloaded through this linkhttp://www.wildlife.gov.my.The applicant shall contact the following department to obtain thenecessary permit/ license. A copy of the permit/ license shall beattached together with the application form for product registration.Department of Wildlife and National Parks, Peninsular MalaysiaKm. 10, Jalan Cheras,56100 Kuala Lumpur,Tel: +603-90866800, Fax: +603-90753873b) ENDANGERED BOTANICAL SPECIESIt is the responsibility of the applicant to declare the source of thebotanical ingredient if it is listed under the International Trade inNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 256

Drug Registration Guidance Document (DRGD)Endangered Species Act 2008 (Act 686). If the ingredient is from alocal source, a special permit/ license shall be obtained from the:Division of Protection and Quarantine of Plants,Department of Agriculture,Tingkat 1-3, Wisma Tani,Jalan Sultan Salahuddin,50632 Kuala Lumpur.Tel: +603 - 20301400, Fax: +603 - 26913550.2.2 EXCIPIENTSa) Excipients are substances used to assist in the manufacture of activesubstance into dosage forms suitable for administration to consumers. Eachexcipient ingredient included in a formulation must have a justifiable excipientrole and shall be controlled by specifications. The intended use of anexcipient shall be appropriate.b) New excipient will require safety and/or other additional data to support thefunction in the product prior to addition into the Quest 3 database.2.3 INDICATIONS2.3.1 INDICATIONS ACCEPTABLE FOR NATURAL PRODUCTSa) General Health Maintenance/ Kesihatan Am“Traditionally used…./ “Digunakan secara tradisional….“Digunakan secara homeopati untuk.../ “Homeopathically used....1. For general health/ for health/ untuk kesihatan.2. General health maintenance/ for general well being.3. For health and strengthening the body/ untuk kesihatan danmenguatkan badan.4. For relief of body heatiness/ untuk melegakan panas badan.5. For general debility, weakness after illness or childbirth/ untuk letihlesu/ kelesuan badan selepas sakit atau selepas bersalin.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 257

Drug Registration Guidance Document (DRGD)6. For loss of appetite/ untuk kurang selera makan.7. For difficulty in sleep/ bagi melegakan kesukaran untuk tidur.8. For relief of fatigue/ untuk melegakan kepenatan.9. As an aid to overcome fatigue during physical exertion/ membantumelegakan kepenatan fizikal.10. To expel wind and invigorate vital energy/ untuk membuang angin danmenambah tenaga.11. To improve appetite/ untuk menambah selera makan.12. For relieving waist ache and body weakness/ untuk melegakan sakitpinggang dan lemah anggota badan.13. For relieving dizziness, sweating, and difficulty in sleep/ untukmelegakan pening, berpeluh berlebihan dan sukar untuk tidur.14. For reducing body odour/ untuk mengurangkan bau badan.15. For reducing toothache/ untuk mengurangkan sakit gigi.16. To relieve tired eyes/ untuk melegakan kepenatan mata.17. For healthy eyes/ untuk kesihatan mata.b) Blood & Body Fluid/ Darah & Cecair Badan“Traditionally used…./ “Digunakan secara tradisional….1. For improving blood circulation/ untuk melancarkan perjalanan darah.2. To improve urination/ untuk melawaskan kencing/ buang air kecil.3. For improving bowel movement/ untuk melawaskan buang air besar.4. For relieving mild vomiting/ untuk melegakan muntah ringan.5. For reducing minor swelling/ untuk melegakan bengkak-bengkakringan.c) Bone, Muscle & Joint/ Tulang, Otot & Sendi“Traditionally used…./ “Digunakan secara tradisional….1. For strengthening muscle and bone/ untuk menguatkan otot dantulang.2. For relieving muscular ache/ untuk melegakan sakit otot.3. For relieving waist ache and backache/ untuk melegakan sakitpinggang dan sakit belakang.4. For relief of joints and muscular pain/ untuk melegakan sakit sendi danotot.5. For relieving muscles sprain/ untuk melegakan terseliuh/ terkehel.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 258

Drug Registration Guidance Document (DRGD)d) Pain & Fever/ Sakit Am & Demam“Traditionally used…./ “Digunakan secara tradisional….1. To relieve/ alleviate pain/ untuk melegakan kesakitan.2. For relieving fever/ untuk melegakan demam.3. For relieving headache/ untuk melegakan sakit kepala.4. For relieving pain and itchiness related to piles/ untuk melegakankesakitan dan rasa gatal akibat buasir.5. For symptomatic relief of body heatiness/ body heat / untuk melegakanpanas badan.e) Cough & Cold/ Batuk & Selsema“Traditionally used……/ “Digunakan secara tradisional…..1. For relief of fever, cough and cold/ untuk melegakan demam, batukdan selsema.2. For relief of sore throat/ untuk melegakan sakit tekak.3. For reducing phlegm and relief of cough, sore throat and bodyheatiness/ untuk mengurangkan kahak dan melegakan batuk, sakittekak dan panas badan.4. For relief of throat irritations and cough/ untuk melegakan sakit tekakdan batuk.5. For relief of nasal congestion/ untuk melegakan hidung tersumbat.6. For relief of sore throat and cough/ untuk melegakan sakit tekak danbatuk.7. For relief of mouth ulcers due to heatiness/ untuk melegakan sakitmulut akibat panas badan.8. To relieve sinusitis/ untuk melegakan resdung.f) Digestive System/ Sistem Pencernaan“Traditionally used…./ “Digunakan secara tradisional….1. For relief of stomach ache, mild diarrhoea/ untuk melegakan sakitperut, cirit-birit ringan.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 259

Drug Registration Guidance Document (DRGD)2. For relief of flatulence, stomach ache, mild diarrhoea, and loss ofappetite/ untuk melegakan kembung perut, sakit perut, cirit-birit ringandan kurang selera makan.3. For relief of mild diarrhoea, vomiting and improve appetite/ untukmelegakan cirit-birit, muntah ringan dan menambah selera makan.4. For relief of mild constipation/ untuk melegakan sembelit ringan.5. To improve appetite and digestion/ untuk menambah selera makandan pencernaan.6. For relieving abdominal pain and flatulence/ untuk melegakan sakitperut dan kembung perut.7. For relief of stomach ache, constipation, mild vomiting and indigestion/untuk melegakan sakit perut, sembelit, muntah ringan dan makanantidak hadzam.8. Aid in digestion/ untuk membantu penghadzaman.g) Women‟s Health/ Kesihatan Wanita“Traditionally used…../ “Digunakan secara tradisional….1. To relieve menstrual pain, headache and to regulate menstruation/untuk melegakan senggugut, sakit kepala dan melancarkan perjalananhaid.2. To reduce body weight/ untuk mengurangkan berat badan.3. For relief of vaginal discharge/ untuk melegakan keputihan.4. For women after childbirth/ untuk wanita lepas bersalin.5. For general wellbeing and strengthen the body after childbirth/ untukkesihatan dan menguatkan badan wanita selepas bersalin.6. For women after childbirth to reduce body weight/ untuk ibu-ibuselepas bersalin untuk mengurangkan berat badan.7. For symptomatic relief of vaginal discharge and mild itch/ untukmelegakan keputihan dan gatal-gatal ringan.8. To improve menstrual flow, for relief of menstrual pain, vaginaldischarge and flatulence/ untuk melancarkan haid, melegakansenggugut, keputihan dan kenbung perut.9. For strengthening body muscle and reducing body weight/ untukmengencangkan otot-otot tubuh dan mengurangkan berat badan.10. For general health of women after childbirth/ untuk menyihatkan rahimselepas melahirkan anak.11. To relieve symptoms of menopause/ untuk melegakan simptommenopause. [Note: For specific active ingredient only, examples: redclover (trifolium pratense) and black cohosh (cimicifuga racemosa)]National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 260

Drug Registration Guidance Document (DRGD)h) Men‟s Health/ Kesihatan Lelaki“Traditonally used…./ “Digunakan secara tradisional….1. For energy and men‟s health/ for vitality/ untuk memulihkan tenaga dankesihatan lelaki.i) Skin And External Usage/ Kulit Dan Kegunaan Luar“Traditionally used…../ “Digunakan secara tradisional…1. For symptomatic relief of pain and itch associated with insect bites/untuk melegakan sakit dan gatal-gatal digigit serangga.2. For relief of minor burns/ untuk melegakan melecur ringan.3. For relief minor cuts/ untuk melegakan luka-luka ringan.4. For relief of minor bruises/ untuk melegakan lebam yang ringan.5. For reducing pimples/ untuk mengurangkan jerawat.6. To help maintaining healthy skin, nail and hair/ untuk kesihatan kulit,kuku dan rambut.7. For reducing pimples and mild itch/ untuk melegakan jerawat dangatal-gatal ringan.2.3.2 NON-PERMISSIBLE INDICATIONSTable 6:NO.NON-PERMISSIBLE INDICATIONS1. Penyakit atau kecacatan ginjal / Disease or defects of the kidney2. Penyakit atau kecacatan jantung / Disease or defects of the heart3. Kencing manis / Diabetes4. Epilepsi atau sawan / Epilepsy or fits5. Kelumpuhan / ParalysisNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 261

Drug Registration Guidance Document (DRGD)NO.NON-PERMISSIBLE INDICATIONS6. Tibi / Tuberculosis7. Asma / Asthma8. Kusta / Leprosy9. Kanser / Cancer10. Kepekakan / Deafness11. Ketagihan dadah / Drug addiction12. Hernia atau pecah / Hernia or rupture13. Penyakit mata / Disease of the eye14. Hipertensi (Darah Tinggi) / Hypertension15. Sakit otak / Mental disorder16. Kemandulan / Infertility17. Kaku / Frigidity18.Lemah fungsi seks atau impoten / Impairment of sexual function orimpotency19. Penyakit venerus / Venereal disease20.Lemah urat saraf atau aduan atau kelemahan lain timbul daripadaatau perhubungan dengan perhubungan seks / Nervous debility orpother complaint of infirmity arising from or relating to sexualintercourse.2.4 PRODUCT NAMEa) If the product owner wishes to use the formulary name, any amendments madeto the product formulation such as the addition of active ingredients, removal ofactive ingredients or change in strength of active ingredients is not permitted.b) A brand name in front of the formulary name shall be requested to be added, inorder to differentiate and identify their product from products with the sameformulary name.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 262

Drug Registration Guidance Document (DRGD)c) Product names which are not permitted to be registered are as specified inTable 7 below:No. Non-Permissible Product Names Example1.2.3.4.5.Prohibited use of disease names asstated in the Medicines (Advertisementand Sale) Act 1956 (Revised 1983)Prohibited use of a single activeingredient as a product name inproducts containing more than oneactive ingredient unless product namecontains words such as „Plus,Compound, Complex, HerbanikaProhibited use of superlative - Nameswhich indicates superiority inefficacyProhibited use of spelling of wordswhich may cause confusionWords which involve names of/partthereof:i) 20 disease names prohibited in theMedicines (Advertisement and Sale)Act 1956 (Revised 1983)ii) Other diseases without scientific proofiii) Prohibited indicationProhibited use of names which maycause ambiguityAmbiguous product nameExample :Diabetes, Asthma, CancerExample :Tongkat Ali Capsule ----But product contains tongkat ali,ginseng, ect.Example :Power/ Kuasa, Superior, Pure,Mustajab, Safe, Healthy/ Sihat,Penawar/ Shifa, VIP, Good, Heal/Sembuh, Premium, Mustajab,Men/ Women/ Children Complete,Men/ Women/ Children Enriched,Paradise/ Syurga, MenawanExample :a) Go Out = GOUT (label)b) UTixExample:B For Energy?National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 263

Drug Registration Guidance Document (DRGD)No. Non-Permissible Product Names Example6.7.8.9.10.11.12.Prohibited use of names which may beoffensive or indecentProhibited use of product names whichare incoherent with the approvedindicationName containing a product claim whereasproduct is indicated for more than theapproved indicationProhibited use of product names whichhas elements of ludicrous beliefStatements referring to ancient believe/negative spirits/ supernatural powerProhibited use of product names similarto the existing approved product namesProduct names similar to the spelling andpronunciation of words of the existingproduct namesProhibited use of product names whichmay cause ambiguity in the nature ofproduct (drug/ food/ beverage)Product names similar to a food/ beverageproductProhibited use of product names whichrepresents professional advice oropinion or referring to the professionProhibited use of product names whichrepresent weight loss/ slimmingpropertiesExample:SENXBIG=SEnXBIG(label)Sexy, Enjoy, Paradise,Heavenly, Blue boy, Casanova,Desire(Dezire),Sensual(Xenxual),Asmara,SyokExample:Cough Syrup X= Approvedindication for cough, dizziness, fluand itchExample:Words such as miracle, magic,magical, miraculous, saintly,heavenlyExample:Tenormin vs Tenormine vsTenormyRe-Liv vs Re-LifExample:Juice, Health drink, Beverage,KookyExample:Dr Sunny, Dr Noortier RooiboseTea, Professor, Herbalist, DoctorExample:Slim, Langsing, Trim, Trimnfit,Sleen, Kurus, Susut perutNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 264

Drug Registration Guidance Document (DRGD)No. Non-Permissible Product Names Example13.Prohibited use of product namesreferring to any religious contentExample:Maksum, Mahmudah, Arifbillah14. Other prohibited product namesExample:Minda, IQ, Smart, Genius, UltraMega, DetoxNote:The Authority reserves the right to disallow any other words or phrases for productnames which in its opinion is misleading, improper or not factual.2.5 QUALITY CONTROL2.5.1 SAMPLE FOR TESTINGSample for testing shall be submitted to the Drug Analysis Division, NPCBwithin 14 days of payment confirmation by the NPCB.For further information, please refer Section C: Guideline for Submissionof Product Samples for Laboratory Testing in the main DRGD.2.5.2 APPEAL FOR SAMPLE RETESTINGAppeal for retesting must be submitted through on-line registration systemwithin 30 days from the date the results are sent to the applicant. Samplessubmitted after the 30 days grace period will not be entertained. Theapplication will then be tabled to the Authority for rejection.2.5.3 QUALITY TESTING FOR SPECIFIC INGREDIENTi) For product containing Aphanizomenon flosaquae, applicants would haveto provide certificates of analysis showing that the microcystin-LR or totalmicrocystins content of the raw material does not exceed 1μg/g and theNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 265

Drug Registration Guidance Document (DRGD)finished product has been tested for microcystin-LR using an acceptablemethod;ii) For products containing Red Yeast Rice (Monascus purpureus),applicants shall provide certificates of analysis (for both raw material andfinished product) showing the Monacolin-K content. The Monacolin-Kconsumed shall not exceed 10 mg per day.2.5.4 LIMIT TEST FOR HEAVY METALSLimit for heavy metals:i) Lead : NMT 10.0 mg/kg or 10.0 mg/litre (10.0ppm)ii) Arsenic : NMT 5.0 mg/kg or 5.0 mg/litre (5.0ppm)iii) Mercury : NMT 0.5 mg/kg or 0.5 mg/litre (0.5ppm)iv) Cadmium : NMT 0.3 mg/kg or 0.3 mg/litre (0.3ppm)2.5.5 DISINTEGRATION TESTDisintegration time for tablets, capsules and pillsi) Uncoated tablets : NMT30 minutesii) Film-coated tablets : NMT 30 minutesiii) Sugar-coated tablets : NMT 60 minutesiv)Enteric-coatedtablets: Does not disintegrate for 120 minutes in acidsolution but to disintegrate within 60 minutes inbuffer solutionv) Capsules : NMT 30 minutesvi) Pills : NMT 120 minutesNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 266

Drug Registration Guidance Document (DRGD)2.5.6 TEST FOR UNIFORMITY OF WEIGHT (FOR TABLETS ANDCAPSULES ONLY)i) Tablet- For tablet with average weight of 130mg or less: Not more than 2tablets differ from the average weight by more than 10% AND notablets differ from the average weight by more than 20%- For tablet with average weight between 130-324mg: Not more than 2tablets differ from the average weight by more than 7.5% AND notablet differs from the average weights by more than 15%- For tablets with average weight more than 324mg: Not more than 2tablets differ from the average weight by more than 5% AND no tabletdiffers from the average weight by more than 10%ii) CapsuleIndividual weight of the capsule to be within the limit of 90 - 110% ofthe average weight.2.5.7 TESTS FOR MICROBIAL CONTAMINATIONTABLE 8:Route of AdministrationTAMC(CFU/g or CFU/ml)TYMC(CFU/g or CFU/ml)Test for SpecifiedMicroorganismsRectal Use NMT 2 x 10 3 NMT 2 x 10 2Oromucosal UseGingival UseCutaneous UseNasal UseAuricular UseNMT 2 x 10 2 NMT 2 x 10 1 - Absence of Staphylococcusaureus in 1g or 1ml- Absence of Pseudomonasaeruginosa in 1g or 1mlNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 267

Route of AdministrationTAMC(CFU/g or CFU/ml)Drug Registration Guidance Document (DRGD)TYMC(CFU/g or CFU/ml)Test for SpecifiedMicroorganismsVaginal Use NMT 2 x 10 2 NMT 2 x 10 1 - Absence of Staphylococcusaureus in 1g or 1ml- Absence of Pseudomonasaeruginosa in 1g or 1ml- Absence of Candida albicansin 1g or 1mlTransdermal Patches(limits for one patchincluding adhesive layerand backing)Inhalation Use (SpecialRequirement apply toliquid preparations fornebulisation)Special Ph. Eur. provisionfor oral dosage formscontaining raw materialsof natural (animal,vegetal or mineral) originfor which antimicrobialpretreatment is notfeasible and for which thecompetent authorityaccepts TAMC of the rawmaterial exceeding 10 3CFU per gram or milliliterNMT 2 x 10 2 NMT 2 x 10 1 - Absence of Staphylococcusaureus in 1 patch- Absence of Pseudomonasaeruginosa in 1 patchNMT 2 x 10 2 NMT 2 x 10 1 - Absence of Staphylococcusaureus in 1g or 1ml- Absence of Pseudomonasaeruginosa in 1g or 1ml- Absence of bile-tolerantgram-negative bacteria in 1gor 1mlNMT 2 x 10 4 NMT 2 x 10 2 - NMT 2 x 10 2 CFU of biletolerantgram- negativebacteria in 1g or 1ml- Absence of Salmonella in10g or 10ml- Absence of Escherichia coliin 1g or 1ml- Absence of Staphylococcusaureus in 1g or 1mlSpecial Ph. Eur. provisionfor herbal medicinalproducts consisting solelyof one or more herbaldrugs (whole, reduced orpowdered):National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 268

Drug Registration Guidance Document (DRGD)Route of AdministrationTAMC(CFU/g or CFU/ml)TYMC(CFU/g or CFU/ml)Test for SpecifiedMicroorganisms- Herbal medicinalproducts to whichboiling water is addedbefore use- Herbal medicinalproducts to whichboiling water is notadded before useNMT 2 x 10 7 NMT 2 x 10 5NMT 2 x 10 5 NMT 2 x 10 4- NMT 2 x 10 2 CFU ofEscherichia coli in 1g or 1ml- NMT 2 x 10 3 CFU of biletolerantgram- negativebacteria in 1g or 1ml- Absence of Escherichia coliin 1g or 1ml- Absence of Salmonella in10g or 10mlNotes:TAMC : Total Aerobic Microbial CountTYMC : Total Yeasts & Moulds CountNMT : Not more than(Reference: British Pharmacopoeia 2009)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 269

Drug Registration Guidance Document (DRGD)2.6 STABILITY DATAStability data as shown in the following example shall be submitted for evaluation.EXAMPLE:STABILITY DATAPRODUCT NAME : TABLET ABC 500MG BATCH NO. :DOSAGE FORM : STRENGTH/ VOLUME :CONTAINER/ PACKAGING : DATE OF REPORT :MANUFACTURING DATE : dd/mm/yy TEMPERATURE : 30 °C ± 2 °CEXPIRY DATE : dd/mm/yy RELATIVE HUMIDITY : 75 % ± 5%PERIOD OF STUDY:TestsProductdescriptionAcceptance Criteria/SpecificationFilm-coated tablet,brownish in colourFrequency of Test, in month (Kekerapan Ujian, bulan)0 3 6 9 12 15 18 21 24Disintegration testNMT 30 minutesNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 270

Drug Registration Guidance Document (DRGD)TestsMicrobialContaminationTest:- Total AerobicMicrobial Count- Total Yeasts &Moulds Count- Test for SpecifiedMicroorganismsAcceptance Criteria/SpecificationNMT 2 x 10 4NMT 2 x 10 2‣ NMT 2 x 10 2 CFU ofbile-tolerant gramnegativebacteria in1g or 1ml‣ Absence ofSalmonella in 10g or10ml‣ Absence ofEscherichia coli in 1gor 1ml‣ Absence ofStaphylococcusFrequency of Test, in month (Kekerapan Ujian, bulan)0 3 6 9 12 15 18 21 24National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 271

Drug Registration Guidance Document (DRGD)TestsAcceptance Criteria/SpecificationFrequency of Test, in month (Kekerapan Ujian, bulan)0 3 6 9 12 15 18 21 24Heavy Metal Test:- Lead- Arsenic- Mercury- Cadmium≤10.0 mg/kg (≤ 10ppm)≤5.0 mg/kg (≤ 5ppm)≤0.5 mg/kg (≤ 0.5ppm)≤0.3 mg/kg (≤ 0.3ppm)Conclusion ------------------------------------------------------------Prepared by: (signature) Checked by: (signature)Name:Name:Designation:Designation:Date:Date:Approved by:Name:Designation:Date:(signature)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 272

Drug Registration Guidance Document (DRGD)2.7 LABELLING REQUIREMENTa) The following information as shown in Table 9 shall be included in the productlabel. Please refer example of label for natural products approved by theAuthority, as shown below.No.ItemsImmediateLabelOuter LabelPackageInsertBlisterPack1. Product name2. Dosage Form √ √ √ √3.4.Name of active ingredients,including part of plant usedStrength of active ingredientin weight5. Indication6. Batch number7. Manufacturing date8. Expiry date9. Dosage/ Use instruction10.Storage condition(s)- state temperature used inthe stability study- state “Protect from lightand moisture” (If productis not packed in moistureresistant container)11. Registration number (MAL)12.Name and address ofproduct registration holder(Example: ProductRegistration Holder: XXXXX)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 273

Drug Registration Guidance Document (DRGD)No.ItemsImmediateLabelOuter LabelPackageInsertBlisterPack13.Name and address ofmanufacturer(Example: Manufacturer:XXXXX)At least nameof town/ cityand countryofmanufacturerAt least nameof town/ cityand countryofmanufacturer14.Warning label (if applicable)a. Ginsengb. Bee pollenc. Senna leaf (Cassia) andRhubarb/ radix orRhizoma Rheid. Camphore. Chelidonium majusf. Alfalfa (Medicago sativa)g. St. John‟s Worth. Black cohoshi. Propolisj. Royal jellyk. Ginkgo biloba / Ginkgoextractl. Pelargonium sidoidesm. Benzyl Alcohol /Phenylmethanol(preservative)n. Red Yeast Riceo. Substance from seafood15. Pack size (unit/ volume)16.17.Name and strength ofpreservativeName and content ofalcohol,where present18.To declare source ofingredients (active, excipient,and / or capsule shell) -derived from animal originNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 274

Drug Registration Guidance Document (DRGD)No.ItemsImmediateLabelOuter LabelPackageInsertBlisterPack19.Additional statement(if applicable)20.Contraindication/ Precaution(if any)21. Security Label (Hologram)b) All labels and package inserts must be in Bahasa Malaysia or English. Inadditional to this, translation to another language will be allowed.c) Please ensure all requirements as specified below are stated on the labelsand package inserts:State the weight per dosage formState the quantity/ content of active ingredients per dosage formFor products in liquid form (syrup), content of active ingredients shall bestated as follows:“Each ____ml (per dosage) product contains extract of the followingingredients”Herb X = ___mgHerb Y = ___mgCheck and correct all spelling/ grammar and translations.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 275

d) Example of label approved by the Authority:Drug Registration Guidance Document (DRGD)This is a traditional medicinePlease consult your pharmacist/doctor before taking this productJauhkan daripada kanak-kanakKeep out of reach of childrenIndication: Traditionally used forwomen‟s healthWarning: Pregnancy andbreastfeeding: Insufficient reliabledataKeep below 30 ° celciusProtect from light and moistureManufacturing date:Expiry date:Batch No.:KAPSUL PQR500MGMALXXXXXXXXT50 CAPSULEHologramEach Capsule (Vegetable capsule)contains :Folium XXFructus QY200mg300mgDosage : 2 capsule taken twice aday after foodMarketing authorization holder:Syarikat XYZ Sdn Bhd18, Jalan Utama47000 Sungai BulohSelangorManufactured by:Syarikat ABC Sdn Bhd3, Jalan Universiti46730 Petaling JayaSelangorManufacturing date :Expiry date:Batch No. :2.7.1 STATEMENTS TO BE STATED ON PRODUCT LABELThe following statements shall also be stated on the product label, whereapplicable:For product with an indication “For general health/ well being” or“Untuk kesihatan umum”, please state:- “Please consult your pharmacist / doctor before taking this product orSila merujuk kepada ahli farmasi/ doktor sebelum mengambilproduk ini.”For product with an indication “To relieve symptoms for…. (anyillness)” or “untuk mengurangkan tanda-tanda/ simptom….”, pleasestate:- “Please consult your pharmacist/ doctor if symptoms persist/ worsenor Sila merujuk kepada ahli farmasi/ doktor jika simptom berlarutan/bertambah teruk.”National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 276

Drug Registration Guidance Document (DRGD)“This is a traditional medicine/Ini adalah ubat tradisional.” OR “This is ahomeopathy medicine/Ini adalah ubat homeopati.”Unless otherwise supported, all herbal/ traditional products label shallstate the following general cautionary statement, EXCEPT for productwith indication for men‟s health or product for children use only:“Pregnancy and breastfeeding: Insufficient reliable data”For product with an indication to be taken/ used specially for women,please refer 2.6.3 Cautionary Statement for Products SpeciallyUsed in Women.“Keep out of reach of children & Jauhi dari kanak-kanak” (in bothBahasa Malaysia and English).“Protect from light and moisture.”Please state the storage condition according to the temperature statedin stability data.For products containing ingredients as specified below, please add therequired statements:i) Animal part(s):“This product contains animal part(s).”ii) Animal origin(s):“This product contains substance(s) from animal origin.”iii) Porcine:“This product contains animal part(s) (porcine/ pig).”iv) Alcohol:- “This product contains alcohol.”- Please declare the percentage of alcohol contained in theproduct.For the following dosage forms, please add this statement:i) Topical preparations: “For external use only.”ii) Liquids and suspensions: “Shake well before use”National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 277

Drug Registration Guidance Document (DRGD)2.7.2 SPECIFIC LABELLING STATEMENTS/ WARNING &PRECAUTIONSFor products containing the following active ingredients, specific cautionarystatement(s) as specified shall be included:For product containing Alfalfa (Medicago sativa), please state:This product contains Alfalfa (Medicago sativa).Individuals with a predisposition to systemic lupus erythematosus shallconsult their physician before consuming this product.For product containing „Anti-diarrhoea‟, please state:“Contraindicated in children below 1 year old.”For product containing Aspartame, please state:WARNING:“Unsuitable for phenylketonurics”For products containing BEE POLLEN, please state:- This product contains Bee Pollen and may cause severe allergicreactions, including fatal anaphylactic reactions in susceptible individuals.- Asthma and allergy sufferers may be at greater risks.For product containing Benzyl Alcohol/ Phenylmethanol (as preservative),please state:As this preparation contains benzyl alcohol, its use shall beavoided in children under 2 years of age. Not to be used inneonates.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 278

Drug Registration Guidance Document (DRGD)For product containing Black Cohosh (Cimicifuga racemosa), please state:Warning:- Stop taking this product if signs and symptoms suggestive ofliver injury develop such as tiredness, loss of appetite, yellowingof the skin and eyes or severe upper stomach pain with nauseaand vomiting or dark urine and consult your doctor immediately.- Patients using herbal medicinal products shall tell their doctorabout it.For products containing Camphor:i) The following warning shall be stated on the label:WARNING:CAN CAUSE CONVULSIONCONTRAINDICATED IN INFANTS BELOW 2 YEARS OF AGE.CAUTION MUST BE EXERCISED WHEN OLDER CHILDREN ARETREATED.AVOID DIRECT APPLICATION INTO NOSTRILSPRECAUTION:It is dangerous to place any camphor – containing product into the nostrilof children. A small amount applied this way may cause immediatecollapse.- Avoid contact with the eyes.- Do not apply to wounds or damaged skin.ii) The following warning and precaution shall be stated on product leaflet:WARNING: “This product is contraindicated in infants under 2years of age. Caution must be exercised when older children aretreated”PRECAUTION: “It is dangerous to place any camphor containingproduct into the nostrils of children. A small amount applied thisway may cause immediate collapse”National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 279

Drug Registration Guidance Document (DRGD)For product containing Chelidonium Majus, please state (in BahasaMalaysia & English):- Warning: This Product may cause adverse reaction to the liver.- Amaran: Produk ini mungkin boleh menyebabkan kesansampingan pada hepar (hati).For products containing GAMAT/ STICHOPUS spp. for ORAL USE ONLY,please state:“Please consult your pharmacist, doctor, or other healthcare providersabout any other supplements/ medications you are taking and otherhealth care problems. There may be a potential for interactions or sideeffects.”For product contraining Ginkgo biloba/ Ginkgo extract, please state:“As the use of Ginkgo may increase the tendency of bleeding, pleaseconsult your physician/ pharmacist if you are on or intend to startusing any other medicines and before you undergo any surgical/dental procedure.”(Memandangkan Ginkgo boleh meningkatkan kemungkinanpendarahan, sila rujuk kepada doktor/ ahli farmasi sekiranya andasedang atau sedang akan menggunakan ubat lain dan sebelumprosedur pembedahan/ dental dijalankan.)For products containing GINSENG (including all PANAX genus), please state:- “Contraindicated in pregnant women.”- “Safe use in lactating women and children has not beenestablished.”- “Do not exceed the stated dose.”- “Safety on long term use has not been established.”National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 280

Drug Registration Guidance Document (DRGD)For product containing Momordica Charantia, please state:- “Shall not be used in pregnant and breast-feeding women.”- “Be sure to tell your pharmacist, doctor, or other healthcareproviders about any other supplements you are taking. There maybe a potential for interactions or side effects.”For product containing Pelargonium sidoides, please state:In very rare cases, pelargonium sidoides may causehypersensitivity reactionsFor product containing Propolis (topical preparation), please state:“Propolis may cause allergic skin reaction.”For product containing Propolis (for oral use), please state:- “This product contains propolis and may cause severe allergicreactions including fatal anaphylactic reaction in susceptibleindividuals.”- “Asthma and allergy sufferers may be at a greater risk.”For product containing Royal Jelly (for oral use), please state:- “This product contains royal jelly and may cause severe allergicreactions including fatal anaphylactic reaction in susceptibleindividuals.”- “Asthma and allergy sufferers may be at a greater risk.”For product containing naturally occurring SALICYLIC ACID (e.g. WillowSalix spp.), please state:- “People allergic to aspirin/ other NSAID should avoid thisproduct.”National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 281

Drug Registration Guidance Document (DRGD)For product containing Senna Leaf (Cassia) and Rhubarb/ Radix etRhizoma Rhei, please state:- “Do not use when abdominal pain, nausea or vomiting ispresent.”- “Frequent or prolonged used of this preparation may result independence towards the product and „imbalanced electrolytes‟.”For product containing St. John‟s Wort, please state:The product may interact with other medicines. Pleaseconsult a doctor/ pharmacist before using it.For product containing substance from seafood, please state:“Derived from seafood.”For product with indication “To regulate menstruation/ To improvemenstrual flow”, please state:“Contraindicated in pregnant women.”For product with indication „To reduce body weight‟, please state thesestatements, (unless proven otherwise):- “Balanced diet and regular exercise are essential.”- “Safety on long term use has not been established.”National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 282

For product containing Red Yeast Rice, please state:Drug Registration Guidance Document (DRGD)“This product contains naturally occurring lovastatin. Please consultyour doctor/ pharmacist before using this product.”“Do not take this product if you are already on statin products(lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin,rosuvastatin,etc).”“If you experience any allergic reactions or side effects such aslethargy, body and muscle aches, please stop using this product.”“Concurrent use of fibrates may cause severe myositis andmyoglobinuria.”2.7.3 CAUTIONARY STATEMENT FOR PRODUCTS SPECIALLY USEDIN WOMENSpecial precaution shall be given to ingredients taken during pregnancy. TheAuthority urges pregnant women to consult their medical/ traditional healthcare provider prior to taking any herbal or traditional products.Unless otherwise supported, all herbal/ traditional products label shall statethe following general cautionary statement:“Pregnancy and breastfeeding: Insufficient reliable data”However, for products containing any ingredients as listed in the followinglists, i.e. List of Prohibited Ingredients in Pregnancy and List of RestrictedIngredients in Pregnancy, the following cautionary statement shall be statedin the product label:i) Prohibited Ingredients in Pregnancy:“Contraindicated in pregnant women.”ii) Restricted Ingredients in Pregnancy:“To be used with caution in pregnancy.”The list of herbs contraindicated in pregnancy is rarely in agreement as mostherbal products are used in combination. The following list has been compiledNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 283

Drug Registration Guidance Document (DRGD)based on well documented information as an aid to the industry to complywith the labelling requirement for products used during pregnancy.Table 10: List of Prohibited Ingredients in PregnancyLatin Compendium NameCommon/ ChineseNameA Acorus Calamus CalamusRemarksAchillea MillefoliumAngelica ArchangelicaYarrowAngelicaAngelica sinensis Dong Quai When taken orallyArtemisia VulgarisArctostaphylos Uva UrsiArtemisia AbsinthiumAstragalus gummiferMugwortUva UrsiWormwoodTragacanthB Bryonia Alba White BryonyBupleurum chinense,Bupleurum falcatumBupleurumC Calendula Officinalis CalendulaCapsella Bursa-PastorisCassia MarilandicaShepherd‟s PurseSennaCaulophyllum Thalictroides Blue Cohosh When taken orallyChamaemelum nobile(Anthemis nobilis)ChenopodiumAmbrosioidesCichorium intybusRoman ChamomileEpazoteChicoryWhen taken orallyCimicifuga Racemosa Black Cohosh When taken orallyCnicus BenedictusConium maculatumConvalaria MajalisCortex CinnamomiBlessed ThistleHemlockLily of the ValleyRou GuiNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 284

Drug Registration Guidance Document (DRGD)Latin Compendium NameCortex MoutanCrocus SativusCommon/ ChineseNameMu Dan PiSaffronRemarksE Equisetum arvense L. HorsetailF Flos Carthami Hong HuaFlos GenkwaFolium SennaeFructus AurantiiFructus Aurantii ImmaturusYuan HuaFan Xie YeZhi KeZhi ShiG Gentiana lutea GentianGinkgo BilobaGinkgoH Helleborus spp. HelleboreI Iris Versicolor Blue FlagIpecac IpecachuanaIpecacJ Juglans Canadensis ButternutJuglans nigraJuniper (Juniperuscommunis)Black WalnutJuniper BerriesL Leonurus Cardiaca MotherwortM Marrubium Vulgare HorehoundMentha PulegiumPennyroyalMonarda didymaBee BalmWhen used orallyor topicallyMylabris / Radix SacchariArundinaceiBan MaoN Natrii Sulfas Mang XiaoNepeta catariaCatnipO Oenothera biennis L. Evening PrimrosePPanax Ginseng, PanaxQuinquefoliusGinsengPassiflora incarnata L. Passion Flower When taken orallyNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 285

Drug Registration Guidance Document (DRGD)Latin Compendium NamePetroselinum CrispumPodophyllum PeltatumPolygala SenegaCommon/ ChineseNameParsleyAmerican MandrakeSenega SnakerootRemarksRRadix EuphorbiaePekinensisRadix et Rhizoma RheiRadix Kansui/ RadixEuphorbiae KansuiRadix PhytolaccaeRhizoma SparganiiResina Toxicodendri/Resina Rhois PraeparataRhizome et Radix VeratriRadix AchyranthisBidentataeRhizome ChuanxiongRhizome CurcumaeLongaeRhamnus PurshianaRhamnus FrangulaRheum PalmatumRuta GraveolensRheum AustraleJing Da JiDa HuangGan SuiShang LuSan LengGan QiLi LuNiu XiChuan XiongJiang HuangCascara SagradaBuckthornRhubarb RootRueTurkey RhubarbS Sanguinaria Canadensis BloodrootSemen PharbitidisSemen StrychniSemen PersicaeQian Niu ZiMa Qian ZiTao RenSerenoa repens Saw Palmetto When taken orallyT Tabebuia impetiginosa Pay D‟ Arco When taken orallyTanacetum partheniumFeverfewNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 286

Drug Registration Guidance Document (DRGD)Latin Compendium NameTanacetum VulgareThuja OccidentalisTurnera DiffusaTrigonella foenumgraecumTrillium ErectumTussilago FarfaraCommon/ ChineseNameTansyArbor VitaeDamianaFenugreekBethrootColtsfootRemarksV Venenum Bufonis Chan SuViscum AlbumEuropean MistletoeX Xanthoxylum Americanum Prickley AshTable 11: Restricted in PregnancyNo.Latin Compendium Name1. Zingiber Officinalis GingerCommon/Chinese NameRemarks> 1g dryweight/dayNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 287

Drug Registration Guidance Document (DRGD)2.7.4 PROHIBITED VISUAL/ GRAPHICS/ STATEMENT ON PACKAGING MATERIAL (LABEL, BOX, PACKAGEINSERT OR PATIENT INFORMATION LEAFLET)General requirement:The graphics printed on outer and inner label has to be standardized to avoid confusion to the customers.Table 12:No. Subject Matter Example(s) Notes1. Marketing strategy Example:“Money back guarantee”“Buy 1 free 1”“ Backed by RM5 millionproduct Liability Insurance”Such statements are prohibited onlabels, as per Medicines (Advertisementand Sale) Act 1956 requirements2. Usage guide which promotes use ofother product(s)Example:“After consumption of thisproduct (Product A), for betterresults, it is recommended totake Product B”Not allowed3. Consumer testimonial Prohibited on product labelNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 288

Drug Registration Guidance Document (DRGD)No. Subject Matter Example(s) Notes4. Clinical Trial results or anyinformation on clinical trial done onproductExample:“Clinically Tested”“Randomized Double BlindPlacebo Control Clinical Study”Such statements are prohibited onlabels, as per Medicines (Advertisementand Sale) Act 1956 requirement5. Photograph of product pioneer Not allowed6. Reference to Hadith/ Al-Quran/Bible/Prohibited on product labelReligious books7. Opinion of prominent figure(s) onproduct or its active ingredient/content8. Label design (graphic and color)similar to labels from anothercompanyExample:Opinion of product/formulation inventorProhibited on product labelProhibited on product label9. Statement on herbal origin Example:Source from theMountains of AlpsAllowed if proven trueNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 289

Drug Registration Guidance Document (DRGD)No. Subject Matter Example(s) Notes10. Introduction of founder/manufacturer11. Logo with certification Example:SIRIM/ ISO / GMP /HACCPProhibited on product labelProhibited on product label becausecertification renewal is on a yearly basis12. Name/ Statement / Logo/ registeredtrademark which does not satisfythe specifications of the TraditionalUnit13. Patency claim/ Patency number/Special technique used/ superiorityin ingredients(Example: capsule coat)14. Nutritional claims with analysiscertificate attached15. Graphics or picture of internalorgansExample:“Dr.ABC‟s Formula”“Nothing like it”Example:Patented techniqueExample:Calorie, Fat, Protein andothersExample:Kidney, Heart, Nerves.Prohibited on product labelAllowed if proven trueProhibited on product labelThis is not a food supplement.Prohibited on product label16. Photograph of celebrities Example: Prohibited on product labelNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 290

Drug Registration Guidance Document (DRGD)No. Subject Matter Example(s) NotesArtiste, Sports person(s),Politician17. Sex symbol (male or female) (♀ and / or ♂) Prohibited on product label18. Indecent photographs/ pornography Prohibited on product label19. Graphics which are incoherent withthe indicationExample:- Noted indication is forconstipation, but graphics onlabel shows a slim-lookinglady which denotes indicationfor weight loss- Indication for urination butlabel graphics containspicture of a water hose.Prohibited on product label20. Highlighting unnecessary bodypartsExample:Indication is for general healthbut graphics on label highlightsmale and female sexual organpartsProhibited on product label21. Graphics of plants or animal which Example: Prohibited on product labelNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 291

Drug Registration Guidance Document (DRGD)No. Subject Matter Example(s) Notesmay cause confusion Radix Ginseng which isimprovised as a male sexualorgan22. Statement on sugars in traditionalproductsExample:- This product contains no sugar-This product contains no addedsugarAllowable on product label provided theproduct contains no fructose, glucose,sucrose or other kind of sugars with apotential to affect diabetics are notincluded in the formulation23. Other statements Example:- This product is blended withpremium quality- Certified chemical residue freeProhibited on product labelNotes:The Authority reserves the right to disallow any other words, phrases or graphics for product label which in its opinion ismisleading, improper or not factual.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 292

Drug Registration Guidance Document (DRGD)3. PRODUCT SPECIFIC REQUIREMENTS3.1 FOOT PATCHESA foot patch which contains herbs with a health claim needs to be registered with theAuthority.Summary of registration for foot patches is described below:a) Product Indication- Traditionally used fora) General health;b) Promoting blood circulation;c) Relieve fatigue.- If there are other indications other than those mentioned above, applicant isrequired to submit clinical study data to support the proposed indication.b) Active ingredient/ Excipient- May only contain active ingredient which are classified under the category ofNatural Products (Traditional).- Pharmaceutical ingredients which have dual-function as an active ingredientand excipient, e.g. Vitamin C can be used as excipient.- However the maximum allowable amount for the excipient in the traditionalproduct has to follow the pharmacopoeia limits established. If for example inthis case the amount of Vitamin C is more than 0.1%, the product shall beclassified as an OTC product. The product will then have to fulfill therequirement for the registration of an OTC product.c) Certificate of Analysis for Finished Product- It is required with at least one batch data for registration.d) Certificate For Free Sale- CFS from the regulatory authority of the country of origin of the productdepending on the product classification of that product in that countryNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 293

Drug Registration Guidance Document (DRGD)e) Good Manufacturing Practice- GMP from the governmental issuing body declaring manufacturer adherenceto GMP/ ISO or other standards depending on the classification of the productin the country of origin.(Reference: Circular Bil.(3)dlm.BPFK/PPP/01/03Jld.1)1.2 HERBAL TEAa) Raw or crude herbs that contain more than 20% of active ingredients and has atherapeutic or pharmacological effect will be controlled under NPCB;b) Raw or crude herbs that are less than 20% of total active ingredient and arenormally consumed as food will be controlled under the Food Service Division,Ministry of Health;c) Active ingredients in extract forms will have to be registered irrespective of theamount present in the finished product.(Reference: Circular (92)dlm.BPFK/PPP/01/03 Jilid 2)3.3 HOMEOPATHIC PRODUCTSThe following guidance notes are published as First Edition in October 2010 and thelatest revision is on October 2012.This guidance notes serve as an additional reference on the requirements for theregistration of homeopathic products. Other aspects of registration requirements arecovered in the Drug Registration Guidance Document. Applicants for productregistration are also requested to refer to the latest edition on the Guidelines of GoodManufacturing Practices (GMP) for Traditional Medicines.2 nd RevisionAcknowledgementsThe National Pharmaceutical Control Bureau acknowledges its indebtedness to theMalaysia Homeopathic Medical Council and the Traditional & ComplementaryMedicine Division, Ministry of Health who provided comments and advice during thepreparation of these guidelines.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 294

Drug Registration Guidance Document (DRGD)Outline:1. Introduction2. Exemptions3. Preparations not considered by the Authority for registration4. Ingredients5. Quality6. Good Manufacturing Practice7. Labelling8. Indications for useAttachments:• Attachment 1: List of exempted Single Homeopathic Potentised Dilutions• Attachment 2: Negative List• Attachment 3: List of acceptable references• Attachment 4: List of endangered animal species/ protected wildlifeNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 295

Drug Registration Guidance Document (DRGD)1. INTRODUCTIONRegulation 7(1)(a) of the Control of Drugs and Cosmetics Regulations (CDCR) 1984requires all products to be registered with the Authority prior to being manufactured,sold, supplied, imported or possessed for sale, unless the product is exempted underthe specific provisions of the regulations.Under Regulation 2, CDCR 1984, “Homeopathic medicine” means anypharmaceutical dosage form used in the homeopathic therapeutic in which diseasesare treated by the use of minute amounts of such substances which are capable ofproducing in healthy persons symptoms similar to those of the disease being treated.This would include preparations that are to be chewed, sucked, swallowed wholeand applied topically.Applicants are reminded that it is their responsibility to ensure that their productscomply with these regulations and also other related legislations namely:(i) Sale of Drugs Act 1952(ii) Dangerous Drugs Act 1952(iii) Poisons Act 1952(iv) Medicines (Advertisement & Sale) Act 1956(v) Wildlife Protection Act 19722. EXEMPTIONAll homeopathic products are registrable under the Control of Drugs and CosmeticsRegulations 1984. Exemption to this are:i) single homeopathic potentised dilution;ii) extemporaneous preparation for an individual patient by a registered/ licensedhomeopathic practitioner;iii) All Mother Tinctures;iv) Unmedicated sugar globules and tablets.3. PREPARATION NOT CONSIDERED BY THE AUTHORITY FOR REGISTRATIONThe Authority will only register homeopathic products used for oral administration,nasal or mouth sprays and external application only. The following dosage forms willnot be considered for registration.- Sterile preparations such as eye-drops and injectables;National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 296

Drug Registration Guidance Document (DRGD)- Suppositories and vaginal tablets;- Transdermal patch;- Sublingual preparations;- Preparation in combination with non-homeopathic active ingredient, such asvitamins, minerals and herbs.- Preparations containing substance listed in the Poison List (except Attachment 1).4. INGREDIENTSHomeopathic products are prepared from natural or synthetic sources that arereferenced in pharmacopoeia monographs or other recognized documents. Notconsidering imponderable, the source materials for homeopathic medicines mayconsist of the following:- Plant material such as: roots, stems, leaves, flowers, bark, pollen, lichen, moss,ferns and algae;- Microorganisms such as: fungi, and plant parasites;- Animal materials such as: whole animals, animal organs, tissues, secretions;- Minerals and chemicals.For each medicinal ingredient, a copy of the monograph from the pharmacopoeia towhich the applicant attests must be provided. Also for homeopathic medicines with aspecific claim, it must be supported by the same level of evidence as for traditionalproducts.Products containing a combination of homeopathic and non-homeopathic medicinalingredient will not be evaluated as a homeopathic product.4.1 POSITIVE LISTHomeopathic medicinal ingredients are allowed as multi ingredient inhomeopathic products and the active ingredient must be documented in amonograph as a homeopathic medicinal ingredient as stated in the currentedition of Homeopathic Pharmacopoeias recognized by the Authority listed inAttachment 3.Homeopathic products are allowed to be registered when the homeopathicmedicinal ingredients used in their products are more than 2C or 4X.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 297

Drug Registration Guidance Document (DRGD)4.2 NEGATIVE LISTHomeopathic products containing single or multiple ingredients inAttachment 2 and Attachment 4 will not be registered by the Authority.4.3 LIMIT OF HOMEOPATHIC INGREDIENTS IN MULTI INGREDIENTHOMEOPATHIC PRODUCTSHomeopathic Products are allowed to contain a maximum of 12 potentisedsingle homeopathic dilutions.5. QUALITYA certificate of analysis (CoA) for raw material potentised dilution and finishedproduct must be provided as proof on the dilution used.6. GOOD MANUFACTURING PRACTICEThe requirements for Good Manufacturing Practice of the premises as outlined in theGuidelines on Good Manufacturing Practice (GMP) for Traditional Medicines apply toall homeopathic products.7. LABELLINGThe labelling of homeopathic products is the same as for traditional products inDRGD with the following additional requirements:On the label of this homeopathic product:a) The word „homeopathic product‟, „homeopathic medicine‟, „homeopathicpreparation‟, „homeopathic remedy‟ (either one) - must appear on the innermostlabel of the container.b) The scientific name or common name of the active ingredient.c) Potency and type of scale use.d) Declare the percentage of alcohol contained in the product.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 298

Drug Registration Guidance Document (DRGD)8. INDICATIONS FOR USEIndications allowed for homeopathic product is the same as those allowed fortraditional products in the DRGD.Recommended use or indications for specific claims must be supported by evidencefor the multi ingredient homeopathic products.No indication will be allowed for single homeopathic potentised dilution in the form ofraw material and finished homeopathic product. No indications are also allowed formother tinctures.ATTACHMENTSAttachment 1:List of “Single Homeopathic Potentised Dilution (2C or 4X or 1:10000)”exempted from the Poisons List.No. Ingredient1. Aconite2. Amyl nitrite3. Antimony4. Apomorphine5. Arsenic6. Barium7. Belladonna8. Bismuth9. Boric Acid10. Caffeine11. Cantharidin12. Colchinine13. Coniine14. Creosote15. Curare16. DigitalisNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 299

Drug Registration Guidance Document (DRGD)No. Ingredient17. Ephedra18. Ergot19. Gelsemium20. Hydrogen Cyanide21. Hyoscine22. Iodine23. Jaborandi24. Lead Acetate25. Lobelia Inflata26. Mercury27. Morphine28. Nicotine29. Nux Vomica30. Phosphorus31. Physostigmine32. Picric Acid33. Piper Methysticum (Kava-kava)34. Quebracho35. Quinine36. Radium37. Rauwolfia38. Sabadilla39. Santonin40. Sparteine41. Stavesacre42. Strophanthus43. Thallium44. Veratrum45. Vinca46. YohimbaNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 300

Drug Registration Guidance Document (DRGD)Attachment 2:Negative ListNO.SUBSTANCES1. Mother tincture of NarcoticsHomeopathic ProductsCannabisCocainumCocainum muriaticumCoca leavesNarceinumOpium2. Mother tincture of Radiopharmaceuticals3.UraniumX-rayMother tincture of Animal materials: Nosodes, toxins and bloodproducts4. Mother tincture of human or human organ5. Mother tincture of Bacteria6. Mother tincture of VirusesAttachment 3:Homeopathic Pharmacopoeia from the Following Countries Will Be Acceptedas ReferencesNO. COUNTRIES1. Germany (GHP)2. Britain3. France (Phf)4. USA (HPUS)5. PakistanNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 301

Drug Registration Guidance Document (DRGD)NO. COUNTRIES6. India (HPI)7. European PharmacopoeiaAttachment 4:List of Endangered Animal Species/ Protected WildlifeAs listed in the Wildlife Protection Act.Notes:These lists are not exhaustive and will be amended from time to time as and whenthe need arisesREFERENCESa) List of Ingredients Prohibited and Restricted in Pregnancy1. Benchmarks for training in traditional Chinese medicine (WHO)2. American Pregnancy Association3. Natural Standards4. Health Canada5. TCM Discovery (Contraindication of Chinese Medicinal Herbs)6. Motherlove Herbal Company (Herbs to avoid while Pregnant)7. Green Earth Herbs (Herbs Contraindicated in Pregnancy)8. Home. Caregroup.Org (Herbs during Pregnancy and Lactation)b) Homeopathic Products:1. Safety Issues in the Preparation of Homeopathic Medicines, World HealthOrganization, 2009.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 302

Drug Registration Guidance Document (DRGD)APPENDIX 6:GUIDELINE ON REGULATORY CONTROL OF ACTIVEPHARMACEUTICAL INGREDIENTS (API)(Version 2.1)Outline:1. Introduction2. Definition2.1 Definition of Active Pharmaceutical Ingredient (API)2.2 Classification of Active Pharmaceutical Ingredient (API)3. Scope4. Procedure for Submission4.1 How to Submit4.2 Required Information4.3 Other Considerations4.4 Processing Fee5. Drug Master File (DMF)6. Certificates of Suitability (CEP)7. Full Details of API Information in the Product Dossier Application8. Stability Data of API9. Site Inspection10. Maintenance of Approval StatusNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 303

Drug Registration Guidance Document (DRGD)1. INTRODUCTION1.1. A significant part of the quality of a finished pharmaceutical product isdependent on the quality of the Active Pharmaceutical ingredients (APIs)used for its formulation. Thus, a proper system of qualification of suppliers isnecessary to ensure a constant sourcing of APIs of appropriate quality andto safeguard the public health interests. This will be done throughstandardized quality assessment and inspection procedures.1.2. The National Pharmaceutical Control Bureau (NPCB) under the purview ofthe Ministry of Health Malaysia will introduce mandatory control of APIs aspart of the requirements in the product registration application. This will beimplemented prospectively according to a phased timeline established bythe NPCB.1.3. The implementation will begin with voluntary submission for New ChemicalEntities in April 2011 and followed by;Phase 1 - New Chemical Entity (mandatory in Jan 2012)Phase 2 - Scheduled Poison, (to be determined)Phase 3 - Non-scheduled Poison (to be determined)1.4. The procedure for control of APIs established by the NPCB is based on thefollowing principles:A general understanding of the production and quality control activities ofthe manufacturer;Assessment of API data and information, including changes andvariations, submitted by the product registration holder (PRH)/ APImanufacturer. These data should include the manufacturing process,material specifications and test data and results;Assessment of the manufacturing site(s) for consistency in productionand quality control of raw materials, with specific emphasis on key rawmaterials and APIs during and after purification through compliance withGood Manufacturing Practice (GMP);Random sampling and testing of APIs (post-marketing surveillance);Handling of complaints and recalls; andMonitoring of complaints from other agencies and countries.1.5. This guideline is intended to provide guidance regarding the requirements tobe included for APIs in the quality part of the product dossier.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 304

Drug Registration Guidance Document (DRGD)2. DEFINITION2.1 DEFINITION OF ACTIVE PHARMACEUTICAL INGREDIENT (API)Any substance or mixture of substances intended to be used in themanufacture of a pharmaceutical dosage form and that, when used so,becomes an active ingredient of that pharmaceutical dosage form. Suchsubstances are intended to furnish pharmacological activity or otherdirect effect in the diagnosis, cure, mitigation, treatment or prevention ofdisease or to affect the structure and function of the body (WHOTechnical Report Series No.970,2012).2.2 CLASSIFICATION OF ACTIVE PHARMACEUTICAL INGREDIENT (API)API classification can be divided into:Inorganic substances;Organic substances (isolated from materials of animal or humanorigin); andOrganic substances (synthetic or semi-synthetic or isolated fromherbal sources or micro-organisms).3. SCOPE3.1. This Guideline encompasses the APIs of new products for registration. Thisis applicable to all pharmaceutical products (excluding traditional products,veterinary products, and health supplement products) both locallymanufactured and imported.3.2. Biological active substances and immunological active substances areexcluded from the scope of this Guideline.3.3. APIs used in products for export only (FEO) are exempted from therequirement for submission of the Drug Master File (DMF) and Certificationof Suitability (CEP) in the product application.3.4. The DMF and CEP are only applicable for final APIs and not APIintermediates.3.5. Separate registration of the APIs is not a requirement for the purpose ofproduct registration. However, the required technical documentationNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 305

Drug Registration Guidance Document (DRGD)pertaining to each API should be submitted with the new online productregistration application.3.6. Assessment of an API will be performed once submission of an applicationfor registration of a product using the said API is made by a ProductRegistration Holder.4. PROCEDURE FOR SUBMISSION4.1 HOW TO SUBMIT4.1.1 The PRH of the product registration shall submit Part 2.S ACTD aspart of product application. Where any information required as perACTD is not available the DMF will be required.4.1.2 The DMF may be submitted via an electronic copy (CD) or a hardcopy(optional) directly to the NPCB to maintain confidentiality of thecontents.4.1.3 The NPCB may accept a CEP issued by European Directorate for theQuality of Medicine (EDQM) in lieu of the DMF of an API.4.2 REQUIRED INFORMATIONThe API information can be submitted to National Pharmaceutical ControlBureau (NPCB) in one of the following three options:• Option 1: Drug Master File (DMF) procedure; or• Option 2: Certificate of suitability of the European Pharmacopoeia(CEP); or• Option 3: Full details of “Part II S ACTD” in the Product DossierThe applicant should clearly indicate at the beginning of the API section (inthe Product Dossier) how the information on the API for each APImanufacturer is being submitted. The API information submitted by theapplicant/ FPP manufacturer should include the following for each of theoptions used.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 306

Drug Registration Guidance Document (DRGD)4.2.1 Documents required:Documents required for each option of API Information submissionare summarized as in table below:Table 1:Summary of documents required for API InformationSubmission:OptionOption 1(DMF)Option 2(CEP)Option 3(FullACTD)Documents requiredPart II S ACTD via the online system (Open Partonly)DMF (See Section 5 for details).Current GMP certificate or any other evidence ofGMP compliance from a regulatory authority; and,Certificates of Analysis of API from APIManufacturer and product manufacturer (2batches).Part II S ACTD via the online system (as deemedappropriate)CEP (See Section 6 for details); and,Certificates of Analysis of API from APIManufacturer and product manufacturer (2batches).Full details of Part II S ACTD (See Section 7 fordetails)Current GMP certificate or any other evidence ofGMP compliance from a regulatory authority; and,Certificates of Analysis of API from APIManufacturer and product manufacturer (2batches).4.2.2 In order to gain approval for an API;The data should be sufficient to justify the specifications andtesting of the API (including validated analytical methods).The information should confirm the identity and stability of the APIby providing appropriate structure elucidation and stability studies;and,National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 307

Drug Registration Guidance Document (DRGD)The control of the API manufacturing process as well as the abilityto produce an API with reproducible physical properties andimpurity profiles should be demonstrated.4.2.3 Any additional information regarding the API shall be requested bythe NPCB, as deemed necessary.4.3 Other considerationsIn the spirit of harmonisation of regulatory activities and optimisation ofefficient assessment, The NPCB will take into consideration the evaluationof relevant APIs by the regulatory authorities of the reference countries(Australia, Japan, France, Switzerland, United Kingdom, Canada, Sweden,and the United State of America) and, other PIC/S countries and WorldHealth Organization (WHO).4.4 Processing FeeNot required as the API application is already incorporated in the applicationfor product registration.5. DRUG MASTER FILE (DMF)5.1. The Drug Master File (DMF) is a document that may be used to provideconfidential detailed information about facilities, processes, or articlesused in the manufacturing, processing, packaging, and storing of one ormore human drugs.5.2. The DMF submitted to the NPCB should contain the information asrequired under sections listed in Part 2.S ACTD.5.3. Technical contents of a DMF are reviewed only in connection with thereview of a new application for product registration5.4. DMF‟s are generally created to allow an authorized party other than theholder of the DMF to refer the DMF without disclosing to any other partythe contents of the file.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 308

Drug Registration Guidance Document (DRGD)5.5. The ICH M4Q Technical Guideline and ASEAN Common TechnicalRequirements (ACTR) provide details on the information to be included inthe API sections of an application dossier.5.6. Where the drug substance and the drug product are manufactured by thesame company, information on the production, quality control and stabilityof the drug substance may be submitted as part of the dossier for the drugproduct (ACTD) rather than in a separate DMF. However, the company isnot precluded from submitting a DMF for the drug substance if it prefers todo so.5.7 . The DMF is divided into two parts, namely the Open (or PRH‟s) part andthe Closed (or confidential) part.5.8 The documents required for an application making a reference to a DMFare as follows:From the PRH:o Open part of the DMF from the PRH, as part of the submittedproduct dossier (the open part contains most of the information inPart 2.S (ACTD) - i.e. sections S1, S2.1 and S3 to S7);• S1 General Information1.1 Nomenclature1.2 Structure1.3 General Properties• S2 Manufacture2.1 Manufacture(s)/Site of Manufacture• S3 Characterisation3.1 Elucidation of Structure and other Characteristics3.2 Impurities• S4 Control of API/Drug Substance4.1 Specification4.2 Analytical Procedures4.3 Validation of Analytical Procedures4.4 Batch Analysis4.5 Justification of Specification• S5 Reference Standards or Materials• S6 Container Closure System• S7 StabilityFrom the API Manufacturer:o The complete (open part and closed part) DMF from the APImanufacturer. The closed part contains the confidential informationin section Part 2.S.2. ACTD - i.e. section 2);National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 309

Drug Registration Guidance Document (DRGD)• S2 Manufacture2.1 Manufacture(s)/ Site of Manufacture2.2 Description of Manufacturing Process and ProcessControls2.3 Control of Materials2.4 Controls of Critical Steps and intermediates2.5 Process Validation and/or Evaluation2.6 Manufacturing Process Developmento An original Letter of Access (see below).The Letter of Access authorizes the NPCB to refer to the DMF, insupport of the application for a drug product. Thus, the Letter ofAccess must state the following:The name of the drug product (product name, dosage form andproduct strength) to be registered;The local PRH responsible for finished product registration; and,A declaration that both the local PRH and the NPCB shall benotified of any change in the API specification or in themanufacturing process that will likely affect the product‟s qualityor safety.It is the responsibility of the applicant to ensure that the completeDMF (i.e. both the applicant‟s Open part and the API manufacturer'sclosed part) is supplied to NPCB directly by the API manufacturerand that the applicant has access to the relevant information in theDMF concerning the current manufacture of the API.5.9. The API Manufacturer may submit the DMF via electronic copy (CD) orhardcopy (optional) directly to the NPCB to maintain confidentiality of thecontents. The information contained in the restricted part of the DMF willbe regarded as confidential and will only be evaluated in support of theapplications mentioned in the Letter of Access. The confidentialinformation will not be disclosed to any third party without a writtenauthorization from the API Manufacturer.5.10. Upon receipt of the DMF, a BPFK DMF number will be assigned to theapplication for product registration. For future correspondences, the PRHand the API Manufacture should make a reference to this assigned BPFKDMF number. Should there be deficiencies within the restricted part of theDMF; The NPCB will raise queries directly with the API Manufacturer. ThePRH referencing a DMF is required to include a copy of the APIManufacturer‟s Letter of Access in the application.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 310

Drug Registration Guidance Document (DRGD)5.11. API Manufacturer is responsible to maintain and update the DMF. ThePRH should file a variation once they are notified with the changes to theDMF.5.12. API Manufacturer Obligations:Any change or addition, including a change in authorization related tospecific PRH, shall be submitted to the NPCB in duplicate andadequately cross-referenced to previous submission(s). The referenceshould include the date(s), volume(s), section(s), and/or pagenumber(s) affected.Should any change to a DMF is necessary, the API Manufacturer shallnotify each affected PRH who has referenced the DMF of the pertinentchange. Such notice should be provided well before making thechange in order to permit the PRH to supplement or amend anyaffected application(s) as needed.5.13. A DMF is not required for common inorganic salts (for example, sodiumchloride, and other common electrolytes) used and regarded as API inproducts such as injections and dialysis solutions, and simple organiccompounds available commercially in high purity (for example, naturaloccurring organic acids and their salts, including ascorbic acid and sodiumcitrate, and simple mono- and disaccharides such as glucose andsucrose). Although a DMF is not required for these active ingredients,evidence needs to be submitted by the finished PRH that the substance isobtained from a reliable source and consistently comply with theapplicable pharmacopoeial specifications. Any non-pharmacopoeialspecifications need to be assessed by the NPCB to determine theirappropriateness and adequacy to ensure the quality of the substance.5.14. Where a DMF is submitted for an API controlled according to apharmacopoeia monograph, the DMF should include a discussion of thepotential impurities most likely to arise during synthesis using the actualmanufacturing process described in the DMF together with evidence thatthese impurities are adequately controlled by the test proceduresdescribed in the pharmacopoeial monograph. Where particular impuritiesfound in the substance are not listed in the monograph, a justification(including toxicological data, if appropriate) should be provided. Details onthe principles for the control of impurities (e.g. reporting, identification andqualification) are outlined in the ICH Q3A, Q3B and Q3C guidelines.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 311

Drug Registration Guidance Document (DRGD)6. CERTIFICATES OF SUITABILITY (CEP)6.1. CEP stands for certification of suitability of European Pharmacopoeiamonographs/ Certificate of Pharmacopoeia.6.2. The CEP is a document that is used to demonstrate that the purity of a givensubstance produced by a given manufacturer is suitably controlled by therelevant monograph(s) of the European Pharmacopoeia. By demonstratinggrant a CEP for given API, the suppliers of the API can prove such suitabilityto their pharmaceutical industry clients and the NPCB.6.3. The PRH should include a copy of the most current CEP in the dossier,together with the following:A written assurance that no significant changes in the manufacturingmethods or processing have taken place following the granting of thecertificate or its last revision andA declaration from the API manufacturer that the local PRH and theNPCB shall be notified should there be any future change in the APIspecifications in the manufacturing process that is likely to affect theproduct‟s quality or safety.Note: All such written statements must state the name of the drug product(product name, dosage form and product strength) to be registeredand the local PRH responsible for finished product registration.6.4 If reference is made to a CEP, the PRH should submit a copy of the validCEP, including all annexes, in lieu of a DMF.Along with the CEP, the applicant should supply the following information inthe product dossier.• 3.2.S.1.3 General properties - discussions on any additionalapplicable physicochemical and other relevant API properties that arenot controlled by the CEP and Ph.Eur. monograph, e.g. solubilitiesand polymorphs as per guidance in this section.• 3.2.S.3.1 Elucidation of structure and other characteristics -studies to identify polymorphs (exception: where the CEP specifies apolymorphic form) and particle size distribution, where applicable, asper guidance in this section.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 312

Drug Registration Guidance Document (DRGD)• 3.2.S.4.1 Specification - the specifications of the FPP manufacturerincluding all tests and limits of the CEP and Ph.Eur. monograph andany additional tests and acceptance criteria that are not controlled inthe CEP and Ph.Eur. monograph, such as polymorphs and/or particlesize distribution.• 3.2.S.4.2/ S.4.3 Analytical procedures and validation – for anymethods used by the FPP manufacturer in addition to those in theCEP and Ph.Eur. monograph.• 3.2.S.4.4 Batch analysis - results from two batches of at least pilotscale, demonstrating compliance with Ph. Eur. monograph andincluding any additional tests/ limits listed on the CEP (e.g. residualsolvents, additional impurity tests) or the product manufacturer‟s APIspecifications.* In cases where the drug product manufacturer tests the CEPcertified API according to specification other than Ph.Eur. (i.e.USP, JP, In-House etc.) data covering S 4.1 to S4.5 should besubmitted by the PRH.• 3.2.S.5 Reference standards or materials – information on the FPPManufacturer‟s reference standards.• 3.2.S.6 Container closure system - specifications includingdescriptions and identification of primary packaging components.Exception: where the CEP specifies a container closure system andthe applicant declares to use the same container closure system.• 3.2.S.7 Stability - exception: where the CEP specifies a re-testperiod that is the same as or of longer duration, and storageconditions which are the same or higher temperature and humidity asproposed by the applicant.In the case of sterile APIs, data on the sterilization process of the API,including validation data, should be included in the PD.6.5 The NPCB reserves the right to request for any additional information aboutthe API when deemed appropriate.6.6 . The PRH‟s responsibility to submit the latest CEP updates, with annexes, assoon as it is available from the API manufacturer.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 313

Drug Registration Guidance Document (DRGD)7. FULL DETAILS OF API INFORMATION IN THE PRODUCTDOSSIER APPLICATION7.1. Information on the Active pharmaceutical ingredient sections (ACTD Part IIS), including full details of chemistry, manufacturing process, quality controlsduring manufacturing and process validation for the API, should besubmitted in the product dossier.7.2. The ICH M4Q Technical Guideline and ASEAN Common TechnicalRequirements (ACTR) provide details on the information to be included inthe API sections of an application dossier.7.3. If drug product contains more than one API, the information within Part II S(ACTD) must be provided for each API.7.4. Where the drug substance and the drug product are manufactured by thesame company, information on the production, quality control and stability ofthe drug substance may be submitted as part of the dossier for the drugproduct (ACTD) rather than in a separate DMF. However, the company isnot precluded from submitting a DMF for the drug substance if it prefers todo so.8. STABILITY DATA OF API8.1. Stability test data for an API should be provided, for at least 3 primarybatches. These data should include:Batch details (e.g., batch number, date of manufacture, batch size, useof batch);The general test methodology (e.g., duration of study, storage conditionsof temperature and humidity, time points when samples were removedfor analysis etc.);The analytical test methods (e.g., assay method of quantitation,determination of degradation products, moisture etc);Validation of test methods;Results of tests; and,Conclusions.8.2. In circumstances where an API retest period has not been established andcomplete real time stability data is not available at the time of submission,the minimum stability data required are as follows:National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 314

Drug Registration Guidance Document (DRGD)At least 12 months of real time data and 6 months of accelerated data onat least three primary batches of the API ;The batches should be at least pilot scale-sized and manufactured by amethod that simulates the final commercial process.* In view of this, the re-test date may be extended beyond the end of realtime studies which can be extrapolated not more than 12 months coveredby the real time data.8.3. Where the API is sourced from multiple sites, stability data from each siteshould be provided.8.4. The NPCB may request for additional stability data if deemed necessary forthe evaluation of the application.8.5. Stability data is not required where the CEP specifies a re-test period that isthe same as or of longer duration than the re-test period proposed by theapplicant.9. SITE INSPECTION9.1. Depending on the outcome of the evaluation of the API dossier, a risk-basedapproach will be used in the planning of inspections; the approach will takeinto account the type of APIs as well as the outcome, results and reports ofinspections conducted by other regulatory authorities or competentorganizations.9.2. The NPCB shall plan and coordinate the performance of inspections at themanufacturing site(s) of the APIs and that of the key intermediate (ifrelevant) to assess compliance with the relevant sections of the relevantGMP Guidelines, and will compare the technical information on themanufacturing process given in the API dossier shall be compared with themanufacturing process actually carried out on the manufacturing site.9.3. All such inspections shall be performed by inspectors deemed to possesssufficient qualifications and experience in order to perform such inspections,to be competent in areas such as production and quality control ofpharmaceuticals, and have appropriate experience in the area of GMP.Such inspectors shall perform the inspections and report on its findings inaccordance with established Standard Operating Procedures (SOPs) so asto ensure a standard harmonized approach.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 315

Drug Registration Guidance Document (DRGD)10. MAINTENANCE OF APPROVAL STATUS10.1. Manufacturers of finished products should establish a mechanism by whichmanufacturers/ suppliers of an API shall provide information on any changes(i.e., variations) in manufacture and control that may have impact on thesafety, purity and quality of the API. It is the PRH‟s responsibility to providethe NPCB with the appropriate documentation (referring to relevant parts ofthe dossier) to prove that any intended or implemented variation will nothave an impact on the safety, purity and quality of the API that has beenpreviously approved. For those APIs approved by the NPCB, an evaluationof such variations shall be performed with accordance to the ASEANVariation Guidelines.10.2. Random samples of APIs supplied to manufacturers of finishedpharmaceutical products may be taken for independent testing if there is aneed. Certificates of Analysis released by the API manufacturer as well asspecifications for test methods shall be provided by the API manufacturer orthe PRH to the NPCB for review upon request. In the event of failure to meetthe established criteria for testing, the NPCB shall proceed to investigateand communicate this problem to the manufacturer concerned.10.3. The NPCB may conduct a re-evaluation of the APIs at a 5 year interval. If,as a result of this re-evaluation, it is found that an API and/or specifiedmanufacturing site(s) no longer complies with the recommended standards,such APIs and manufacturing sites will be removed from the approved list.Prior notice to the PRH and API manufacturer shall be issued from theNPCB regarding such decision.10.4. Re-evaluation may also be done in any situation deemed necessary,including the following:If any omissions by the manufacturer in the initial assessment procedureor during the follow-up activities is evident in relation to the requirements.This includes compliance with GMP.If any batch(s) of supplied APIs is considered not to be in compliancewith the agreed specification of the API;If the CEP, or an API for which a CEP dossier was submitted, iscancelled or refused based on the assessment of the dossier for anyother reason; and,National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 316

Drug Registration Guidance Document (DRGD)If in the opinion of the NPCB, changes made in the sourcing of keyintermediates, route of synthesis, facility or other production, require thatreassessment be made.REFERENCES AND GUIDELINESa) Guidelines on the Technical Requirements Related to the Quality of ActivePharmaceutical IngredientsThe technical requirements related to the quality of active pharmaceuticalingredients have already been addressed elsewhere, (such as in the ASEAN,WHO, ICH, EDQM and EMA guidelines), and applicants are advised to refer tothese guidelines available at the relevant website such as:The ASEAN Common Technical Dossier (ACTD) For The Registration OfPharmaceuticals For Human Use Organization Of The Dossier(http://portal.bpfk.gov.my/index.cfm?menuid=46&parentid=15)The Common Technical Document For The Registration Of PharmaceuticalsFor Human Use: Quality – M4Q(R1)(http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R1_Quality/M4Q__R1_.pdf)Guideline on Impurities on New Drug Products.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3B_R2/Step4/Q3B_R2__Guideline.pdfGuideline on Impurities in New Drug Substances Q3Ahttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/Q3A_R2__Guideline.pdfGuidelines on Impurities: Guideline For Residual Solventshttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3C/Step4/Q3C_R5_Step4.pdfGuideline on Submission of Documentation for a Multisource (Generic)Finished Pharmaceutical Product (FPP): Quality Parthttp://apps.who.int/prequal/info_general/documents/TRS970/TRS_970-Annex4.pdfGuideline on Active Pharmaceutical Ingredient Master File (APIMF)Procedure.(http://apps.who.int/prequal/info_applicants/Guidelines/APIMF_Guide.pdf)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 317

Drug Registration Guidance Document (DRGD)Guideline on Summary of Requirements for Active Substances. In TheQuality Part of the Dossier.(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002813.pdf)Content of the Dossier for Chemical Purity and Microbiological Quality(PA/PH/CEP 04 1 4R)http://www.edqm.eu/medias/fichiers/Content_of_the_Dossier_for_Chemical_Purity_Microbiological_Quality.pdfContent of the Dossier for a Substance for TSE Risk Assessment(PA/PH/CEP (06) 2)http://www.edqm.eu/medias/fichiers/Content_of_the_Dossier_for_a_Substance_for_TSE_Risk_Assessment.pdfCertificates of Suitability for Sterile Active Substances (PA/PH/Exp. CEP/T(06) 13, 1R)http://www.edqm.eu/en/New-Applications-29.htmlCertification database for information on Certificates of Suitability (CEPs)granted by the EDQM.https://extranet.edqm.eu/publications/recherches_CEP.shtmlWHO List of Prequalified Active Pharmaceutical Ingredientshttp://apps.who.int/prequal/info_applicants/API_PQ-List.htmb) Guidelines on Stability TestingThe following Guidelines may be consulted in the context of stability testing:WHO Technical Report Series, No. 953, 2009 Annex 2: Stability testing ofActive Pharmaceutical Ingredients and Finished Pharmaceutical Products(http://www.who.int/medicines/publications/pharmprep/PDF_TRS953_WEB.pdf)International Conference on Harmonisation. ICH Q1A (R2): Stability testing ofnew drug substances and products(http://www.ich.org/LOB/media/MEDIA419.pdf)International Conference on Harmonisation. ICH Q1B: Photostability testing ofnew drug substances and products(http://www.ich.org/LOB/media/MEDIA412.pdf)International Conference on Harmonisation. ICH Q1C: Stability testing of newdosage forms(http://www.ich.org/LOB/media/MEDIA413.pdf).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 318

Drug Registration Guidance Document (DRGD)International Conference on Harmonisation. ICH Q1D: Bracketing andmatrixing designs for stability testing of new drug substances and products(http://www.ich.org/LOB/media/MEDIA414.pdf).International Conference on Harmonisation. ICH Q1E: Evaluation for stabilitydata (http://www.ich.org/LOB/media/MEDIA415.pdf).Note for Guidance on Stability Testing: Stability Testing Of New DrugSubstances And Products (CPMP/ICH/2736/99)(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002651.pdf)Note for Guidance on Stability Testing of Existing Active Substances andRelated Finished Products(www.ema.europa.eu/pdfs/vet/qwp/084699en.pdf)ASEAN Stability Guideline(http://portal.bpfk.gov.my/index.cfm?menuid=46&parentid=15)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 319

Drug Registration Guidance Document (DRGD)APPENDIX 7:SPECIAL CONDITIONS FOR REGISTRATION FORPARTICULAR PRODUCT OR GROUP OF PRODUCTSA1. BLOOD PRODUCTSa) Each batch of the products must comply with WHO requirements for theproduct.b) Each batch of the product imported into Malaysia must be accompaniedwith a Batch Release Certificate from the relevant authority in thecountry of manufacture.c) Each batch of the product must be accompanied with a certificateconfirming that the blood or plasma used in the production of the lot istested and found to be negative for HIV antibody, HbsAg, HCV andhigh-risk donors are excluded.d) Each batch of the product must be accompanied with a certificate ofanalysis.2. ETRETINATE/ ACITRETINa) The product shall only be sold or supplied to:i) Dermatologist (Skin Specialist) who are gazetted with the Ministryof Health, Malaysia, or registered with the Academy of Medicine,Malaysia, and National Specialist Registry;ii)A hospital or Institution maintained by the government, having theservices of a skin specialist or registered medical practitioner withexperience in dermatology.b) The container of the product shall be labeled in a conspicuous anddistinct manner, with the following statements:i) “Etretinate/ Acitretin is highly teratogenic.ii)Pregnancy must be avoided during treatment and for at least threeyears after completing treatment.”c) A proper record of product supplied stating the product name, productregistration number, name, address and contact number of purchaser(prescriber) shall be kept and submitted to the Authority upon request.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 320

Drug Registration Guidance Document (DRGD)d) The following records shall be maintained for the product and well keptfor auditing by the Authority.3. HUMAN GROWTH HORMONE (Somatotropin, Somatropin)A proper record of product supplied stating the product name, productregistration number, name, address and contact number of purchaser(prescriber) shall be kept and submitted to the Authority upon request.4. ISOTRETENOIN/ TRETINOINa) The product shall only be sold or supplied to:i) Dermatologist (Skin Specialist) who are gazetted with the Ministryof Health, Malaysia, or registered with the Academy of Medicine,Malaysia, and National Specialist Registry.ii)A hospital or institution maintained by the government, having theservices of a skin specialist or registered medical practitioner withexperience in dermatology.b) The container of the product shall be labelled in a conspicuous anddistinct manner, with the following statements:i) “Isotretinoin/ tretinoin is highly teratogenic.ii) Pregnancy must be avoided during treatment and for at least 1month after completing treatment.”National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 321

Drug Registration Guidance Document (DRGD)c) A proper record of product supplied stating the product name, productregistration number, name, address and contact number of purchaser(prescriber) shall be kept and submitted to the Authority upon request.5. MIDAZOLAMProducts containing midazolam are restricted for use in government andprivate hospitals and specialist clinics only.6. PARACETAMOL IN COMBINATION WITH CAFFEINEa) For products containing a combination of paracetamol and caffeine,dose unit of caffeine for adults is 65mg and maximum dose of caffeineis 520mg per day, meanwhile, dose unit for paracetamol is 500mg withthe maximum dose of 4,000mg per day or 8 tablets daily.b) Products containing caffeine for pediatrics are not allowed.c) Allowable packing size should not exceed 20 tablets/ capsules.7. VACCINESa) Each batch of the product must comply with WHO requirements for theproduct.b) Each batch of the product imported into Malaysia must be accompaniedwith a batch release certificate.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 322

Drug Registration Guidance Document (DRGD)APPENDIX 8:LIST OF PERMITTED, PROHIBITED AND RESTRICTEDSUBSTANCESIMPORTANT NOTES:The following lists are by no means exhaustive.Outline:8.1 List of Prohibited and Restricted Active Ingredients and Combination8.1.1 List of Prohibited Active Ingredients and Combinationsa) Specific Active Ingredientsb) Combinations8.1.2 List of Restricted Active Ingredients and Combinationsa) Specific Active Ingredientsb) Combinations8.2 List of Prohibited and Restricted Excipients8.2.1 List of Prohibited Excipients8.2.2 List of Restricted Excipients8.3 List of Permitted and Restricted Colouring Agents8.3.1 List of Permitted Colouring Agents8.3.2 List of Restricted Colouring AgentsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 323

Drug Registration Guidance Document (DRGD)8.1 LIST OF PROHIBITED AND RESTRICTED ACTIVE INGREDIENTS ANDCOMBINATION8.1.1 LIST OF PROHIBITED ACTIVE INGREDIENTS ANDCOMBINATIONSa) Prohibited Active IngredientsNO.PROHIBITED ACTIVE INGREDIENTS1. Aristolochic Acid2. Aminopyrine/ Amidopyrine3. Astemizole4. Bacillus Coagulans5. Berberine6. Butobarbitone7. Chlormezanone8. Cisapride9. Conjugated Linoleic Acid10. Crinis Carbonisatus11. Danthron12. Dipyrone13. Enterococcus Faecalis14. Enterococcus Faecium15. Ethenzamide16. Euflavine17. Furazolidone18. Fenfluramine/ Dexfenfluramine19. Gentian Violet20. Gamma-Butyrolactone (GBL)21. Gamma-Hydroxybutyric Acid (GHB)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 324

Drug Registration Guidance Document (DRGD)22. Haloquinol23. Hexachlorophene24. Mercurochrome25. Nimesulide26. Novobiocin27. Oxyphenisatin Acetate/ Acetophenolisatin28. Oxyphenbutazone29. Pergolide30. Phenacetin31. Phenazone/ Antipyrine- Propylphenazone- Isopropylphenazone32. Phenylbutazone33. Phenylpropalamine34. Piperazine35. Prenylamine36. Quinalbarbitone37. Salicylamide38. Sibutramine39. Stanozolol40. Sulphaguanide41. Thioridazine42. Tegaserod43. TerfenadineNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 325

Drug Registration Guidance Document (DRGD)b) Prohibited CombinationsNO.PROHIBITED COMBINATIONS1. Ampicillin + Cloxacillin2. Antibiotics + Papain/ Prolase3. Antacid + Charcoal4. Combinations With Any Barbiturates5.6.7.8.Combinations of Two or More Analgesic with the Same Mode ofActionCombinations Of Vitamin (S) With Other Drugs:a. Vitamin (S) + Appetite Suppressantb. Vitamin (S) + Corticosteroidc. Vitamin (S) + Analgesicd. Vitamin (S) + Laxativee. Vitamin (S) + Slimming AgentsCough, Cold and Allergy Products Containing:a. Four or More Pharmacological Groups in One Product.b. Two or More Drugs from the Same Pharmacological Groupc. Antypyretic - Analgesic + Expectorantd. Anticholinergic + Bronchodilatore. Codeine + Ephedrine/ Pseudoephedrinef. Methapyrileneg. Paracetamol + Mucolytic/ ExpectorantCombinations Containing Antacid and Surface Local AnaestheticAgent9. Combinations Containing Dextropropoxyphene10. Combinations Containing Spironolactone11. Corticosteroids + Antihistamines12. Eye Drops Containing Vitamin13. Gripe Water Containing Alcohol14. Propanolol + HydralazineNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 326

Drug Registration Guidance Document (DRGD)NO.PROHIBITED COMBINATIONS15. Propanolol + Spironolactone8.1.2 LIST OF RESTRICTED ACTIVE INGREDIENTS ANDCOMBINATIONSSpecific Active IngredientsNot Allowed in the SpecifiedPreparation(s) or Condition1. Acetic Acid Expectorant2. Allantoin Eye Drop3. Allergen Extracts Vaccines, Diagnostics4. Amphetamine Cough Mixtures, Appetite Suppressants5. Animal Organ All Preparations Except Natural Products6. Antihistamine Topical Use7. Bismuth Salts ExceptBismuth SubcitrateOral Preparations8. Boric Acid/ Borax AndRelated SaltsOral, Topical (Skin), Vaginal, Nasal DosageForm9. Buprenorphine Single Active Ingredient Sublingual TabletFormulation10. Caffeine All Preparations Except for an OralPreparation in Combination withParacetamol/ Acetaminophen orCombination with Ergotamine11. Camphor - Oral- External (Analgesic > 3%, CounterIrritant >11%)12. Chloroform Expectorant13. Codeine Cough Syrup14. Cocillana Liq. Extract Expectorant15. Cyproheptadine Appetite Stimulant16. Dextromethorphan Single Active Ingredient in Tablet Form,including lozenges17. Dihydrostreptomycin Oral AntidiarrhoealsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 327

Drug Registration Guidance Document (DRGD)18. Diphenoxylate Liquid Oral Dosage For Anti-Diarrhoeal19. Quinestrol, Oestrogen Lactation Suppressant20. Ethynodiol Diacetate Oral Contraceptives21. Euphorbia Liquid Extract Expectorant22. Gatifloxacin All Preparations Except for Eye Drop23. Germanium Non Naturally Occurring24. Hydroquinone Oral25. Lactobacillus Acidophillus Antidiarrhoeal26. Loperamide Liquid Oral Dosage For Anti-Diarrhoeal27. Lovastatin In Red Yeast Rice: > 1 % w/w and >10mg/Day28. Lynooestrenol Oral Contraceptives29. L-Tryptophan All Preparations Except Parenteral NutritionProducts And Enteral Feeding Products30. Magnesium AscorbrylPhosphateAntipigmentation31. Menthol Analgesic: > 1.0%, Counter Irritant: >16%32. Mestranol Oral Contraceptives33. Methylene Blue Oral Preparations34. Midazolam All oral preparations, except 7.5mg coatedtablet35. Morphine Cough Mixtures36. Neomycin Oral Antidiarrhoeal, Vaginal Tablets, TopicalPowders, Aerosols, Nasal Preparations37. Noradrenaline Dental Preparations38. Norgestrel Oral Contraceptives39. Paracetamol Liquid Oral 500mg/5ml40. Penicillin Topical Use41. Phenazopyridine Urinary Analgesics42. Phenolphthalein Stimulant Purgative43. Pizotifen Appetite Suppressant44. Podophyllum Resin Oral Preparations45. Pseudoephedrine All Single Active Ingredient FormulationsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 328

Drug Registration Guidance Document (DRGD)46. Sulphonamides Topical Use47. Sulphur All preparations Except External Preparation48. Squill Expectorant49. Terpene Hydrate ExpectorantCombinationsNot Allowed in the SpecifiedPreparation(s)1. Cough, Cold And AllergyProducts Containing:i) Antimony PotassiumTartrateii) Allylisothiocyanate/Mustard Oiliii) Turpentine OilExpectorantNasal Decongestant2. Vitamin(s) Eye DropsExpectorant/ AntitussiveNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 329

Drug Registration Guidance Document (DRGD)8.2 LIST OF PROHIBITED AND RESTRICTED EXCIPIENTS8.2.1 LIST OF PROHIBITEDEXCIPIENTS1. Colouring Agents(Including in Capsule Shells)8.2.2 LIST OF RESTRICTED EXCIPIENTSExcipients1. Colouring Agents(Including in Capsule Shells)Restrictionsa) Amaranth (CI= 16185, FD & CRed No. 2, E123)a) Tartrazine (CI=19140, FD & CYellow No.5,E102)Not allowed in thefollowing preparations:- Oral;- Rectal;- Vaginal or- Nasal Preparationsb) Red 2G Not allowed in thefollowing preparations:2. Sweeteners/ Flavouring Agent 2. Sweeteners/ Flavouring Agent- Oral Preparations; and- Preparations Used forMucosa Membranea) Cyclamates a) Menthol Limited to not more than10mg/dayb) Saccharin andSalts3. Others 3. PreservativesLimited to not more than5mg/kg/daya) Chlorofluorocarbons (CFC)b) Dibutyl Pthalatea) Chloroform Limited to not more than0.5% in Pharmaceuticalsfor Internal Useb) Thiomersal * Not allowed in ophthalmicPreparations* For other preparations, warning as specified in Appendix 9: LabellingRequirement, shall be included in the package insert and product literature ofproducts containing thiomersal.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 330

Drug Registration Guidance Document (DRGD)Additional Information1. Methylene Chloride/ Dichloromethane are not allowed as solvent in filmcoatingonly for locally manufactured products, in order to protect workersduring manufacturing process.2. Alcohol is not allowed unless it is essential to the formulation and no suitablealternatives to alcohol are available. Content of alcohol shall be at theminimum level as possible.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 331

Drug Registration Guidance Document (DRGD)8.3 LIST OF PERMITTED AND RESTRICTED COLOURING AGENTS8.3.1 List of Permitted Colouring AgentsNO.COLOURING AGENTSCOLOURINDEXNUMBER (CI)1. Allura Red AC/ FD & C Red No.40 160352. Anthocyaninsa. Those glycosides of 2-phenylbenzopyrylium salts whichare anthocyaninsb. The following anthocyanidin aglycones :i. Pelargonidinii. Cyanidiniii. Peonidiniv. Delphinidinv. Petunidinvi. Malvidin3. Black PN (Brilliant Black BN) 284404. Brilliant Blue FCF 420905. Calcium Carbonate6. Carbo Medicinals/ Vegetalis; (Charcoal)7. Caramel8. Carmoisine (or Azorubine) 147209. Carotenoidsa. Alpha, Beta, Gamma-Caroteneb. Bixin, Noribixin, Roucouc. Annattod. Capsanthin, Capsorubin, (paprika extract)e. Lycopenef. Beta-Apo-8‟ carotenal (C 30)g. Ethyl ester of Beta-Apo-8 Carotenoic Acid (C30)i. Chlorophyllii. Copper complexes of Chlorophyll andChlorophyllins75120408207581010. Chocolate Brown HT 2028511. Cochineal or Carminic Acid, Carmine from Cochineal 7547012. Curcumin 7530013. Fast Green FCF (FD & C Green No.3) 42053National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 332

Drug Registration Guidance Document (DRGD)NO.COLOURING AGENTSCOLOURINDEXNUMBER (CI)14. Green S (Acid Brilliant Green BS, Lissamine Green)15. Indigo Carmine (Indigotine) 7301516. Lactoflavin, Riboflavin17. Patent Blue V 4205118. Ponceau 4R (Cochineal Red A) 1625519. Quinoline Yellow 4700520. Xanthophyllsa. Flavoxanthinb. Luteinc. Cryptoxanthin (Kryptoxanthin)d. Violoxanthine. Rhodoxanthinf. Canthaxanthin21. The Following Colouring Matters Natural to Edible Fruits orVegetables:408507553022.23.a. Alkanninb. Annatto (including eye)c. Carotene (including eye)d. Chlorophylle. Flavinef. Indigog. Osageh. Orangei. Persian Berryj. Safflowerk. Saffronl. Sandalwoodm. Turmericn. or their pure coloring principles whether isolated fromsuch natural colors or produced syntheticallyBole or Iron Oxide,Carbon Black (or Vegetable Origin),Titanium DioxideThe Aluminium Salts (Lakes) of Any of the ScheduledSynthetic Dyes Approved for Use,(a) Alumina (Dried Aluminium Hydroxide)7789124. TalcNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 333

Drug Registration Guidance Document (DRGD)NO.COLOURING AGENTSCOLOURINDEXNUMBER (CI)25. Indigo Carmine/ FD & C Blue No. 2 7301526. Brilliant Blue FCF Ammonium Salt/ D & C Blue No. 4 4209027. Alizarin Cyanine Green F/ D & C Green No. 5 6157028. Toney Red/ D & C Red No. 17 2610029. Eosin YS Acid Form/ D & C Red No. 21 45380:230. Eosinys Sodium Salt/ D & C Red No. 22 4538031. Phloxine B Acid Form/ D & C Red No. 27 45410:132. Phloxine B Sodium Salt/ D & C Red No. 28 4541033. Helindone Pink CN/ D & C Red No. 30 7336034. Erythrosine/FD & C Red No. 3 4543035. Yellow 2G (Food Yellow)37.Orange Yellow S Sunset Yellow FCF(FD & C Yellow No. 6, E110)15985National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 334

Drug Registration Guidance Document (DRGD)8.3.2 List of Restricted Colouring AgentsThe following colouring agents are ALLOWED in preparations as stated in theparentheses:NO.1.2.3.4.5.6.7.8.9.10.11.12.13.14.15.COLOURING AGENTSDihydroxyacetone(external use with specific drugs only)Bismuth Oxychloride(external use only, including eye)Ferric Ammonium Ferrocyanide(external use only, including eye)Ferric Ferrocyanide(external eye only)Chromium Hydroxide Green(external use only)Chromium Oxide Green(external use only, including eye)Guanine(external use only)Prophyllite(external use only)Mica(external use only, including eye)Bronze(external use only, including eye)Copper(external use only, including eye)Zinc Oxide(external use only, including eye)Quinizarine Green SS/ D & C Green No. 6(external use only)Pyranine Concentrated/ D & C Green No. 8(external use only)Orange II/ D & C Orange No. 4(external use only)COLOURINDEXNUMBER (CI)7716377289751707701977947615655904015510National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 335

Drug Registration Guidance Document (DRGD)NO.16.17.18.19.20.21.22.23.24.25.26.27.28.COLOURING AGENTSDibromofluorescein/ D & C Orange No. 5(mouth wash, dentifrices, external use only)Diiodofluorescein/ D & C Orange No. 10(external use only)D & C Orange No. 11(external use only)Ponceau SX/ FD & C Red No. 4(external use only)Lithol Rubin B/ D & C Red No. 6(may be use in combination; total not more than 5mg/day)Lithol Rubin B CA/ D & C Red No. 7(may be used in combination; total not more than 5mg/day)D & C Red No. 31(external use only)Deep Maroon/ D & C Red No. 34(external use only)D & C Red No. 39(external use only, not more than 0.1%)Uranine Acid Form/ D & C Yellow No. 7(external use only)EXT. D & C Yellow No. 7(external use only)Uranine Sodium Salt/ D & C Yellow No. 8(external use only)Tartrazine/ FD & C Yellow No. 5/MA Yellow A-2/ Aluminic Lake(external use only)COLOURINDEXNUMBER (CI)4537045425147001585015850:115880:145350:14535019140National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 336

Drug Registration Guidance Document (DRGD)APPENDIX 9:LABELLING REQUIREMENTSThis appendix comprises of two (2) parts:a) General Labelling Requirements for:i) Section D : Label (Mock-Up) for Immediate Container and Outer Cartonii) Section Diii) Section E8/ F8: Proposed Package Insert (PI): Patient Information Leaflet (PIL)b) Specific Labelling RequirementsNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 337

Drug Registration Guidance Document (DRGD)9.1 GENERAL LABELLING REQUIREMENTS9.1.1 LABEL (MOCK-UP) FOR IMMEDIATE CONTAINER AND OUTER CARTONThe following information in Table 1 shall present on the label of a product at outercarton, immediate container or blister/ strips:No. ParametersOuter Carton(Unit Carton)ImmediateLabelsBlister/Strips1. Product Name 2. Dosage Form * NA3. Name of Active Substance(s) **4. Strength of Active Substance(s) **5. Batch Number 6. Manufacturing Date * NA7. Expiry Date 8. Route of Administration NA9. Storage Condition * NA10. Country‟s Registration Number * NA11.12.13.Name & Address of ProductRegistration Holder (PRH)Name & Address ofManufacturerWarnings and/or SpecificLabelling(if applicable) *At least nameof town/ cityand country ofmanufacturer*At least nameof town/ cityand countryofmanufacturerName/ LogoofManufacturer/ProductOwnerNA * NA14. Pack Sizes (unit/ volume) NA15.Name & content ofpreservative(s) where present NANational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 338

Drug Registration Guidance Document (DRGD)No. ParametersOuter Carton(Unit Carton)ImmediateLabelsBlister/Strips16.17.18.19.20.21.Name & content of alcohol,where presentTo declare source ofingredients derived from animalorigin, including gelatin (active,excipient, and/or capsule shell)Recommended daily allowance(RDA) for vitamins/multivitamins/ mineralpreparations used as dietarysupplementsThe words “Keep medicine outof reach of children” or wordsbearing similar meaning in bothBahasa Malaysia & EnglishOther country specific labellingrequirements(if applicable)The words “ControlledMedicine/ Ubat Terkawal”(For scheduled poison only) NA NA NA * NA * NA * NA22. Security Label (Hologram) * NANA : Not Applicable* Exempted for small labels such as used in ampoules/ cartridge and vials** For multi-vitamins and minerals preparations it is suggested to label as multivitaminsand mineralsNo. 15, 19, 21 & 22 of the above are country specific requirements for Malaysia.Additional Information:a) If the product is without an outer carton, the inner label shall bear all theinformation that is required.b) Official website of the company or website for any purpose of product promotionfrom the PRH/ product owner/ manufacturer is not allowed to be printed on theproduct label (applicable to all categories of products inclusive of importedNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 339

Drug Registration Guidance Document (DRGD)products). However, the email address of the company is permissible on thelabel.c) The colours of labels shall be differentiated between strengths of products aswell as between products containing different active ingredients which belong tothe same holder.d) Only a single label artwork is permitted for all pack sizes of a registeredproduct.e) No stick-on label is permitted. Any usage of stick-on label shall have priorapproval by the Authority. The Authority will only consider the followingsituations:i) Stick-on label of such information and printing of registration number for labelredressing of a registered product is permitted:Words with “Controlled Medicine”/ Ubat Terkawal, Jauhi daripada kanakkanak,information of Product Registration Holder, Malaysia SpecificLabelling Requirements shall be printed in a single label.ii) The label shall be made from good quality material and not easy to be tornout.iii) However, registration number shall be printed permanently on the product(ink-jet) and it is not allowed to be printed on the stick-on label.f) Please refer to Figure 1 as an example of a product label which in accordanceto the labelling requirements.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 340

Drug Registration Guidance Document (DRGD)Figure 1:PRHNote:Numerical notations shown in the above figure are in line with the numberingfor the parameters, shown in Table 1 above, to be included in the product label(as identified and adopted by the ACCSQ-PPWG).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 341

Drug Registration Guidance Document (DRGD)9.1.2 PROPOSED PACKAGE INSERTPackage insert (PI) is required for products containing scheduled poison. PI mayalso be submitted for OTC products. The draft copy of the PI shall be submitted forevaluation.Sharing of PI is only allowed for products having the same active ingredient(s) butwith different strengths.The following information is required to be included in the PI:a) Brand or Product Nameb) Name and Strength of Active Substance(s)c) Product Descriptiond) Pharmacodynamics/ Pharmacokineticse) Indicationf) Recommended Dosageg) Route of Administrationh) Contraindicationsi) Warnings and Precautionsj) Interactions with Other Medicamentsk) Statement on usage during pregnancy and lactationl) Adverse Effects/ Undesirable Effectsm) Overdose and Treatmentn) Incompatibilities (For injections only)o) Storage Conditions (may be omitted if the information is stated on the labelor outer carton labels)p) Dosage forms and packaging availableq) Name and address of manufacturer/ product registration holderr) Date of revision of PINational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 342

Drug Registration Guidance Document (DRGD)9.1.3 PATIENT INFORMATION LEAFLETPatient Information Leaflet (PIL) or in Bahasa Malaysia known as RisalahMaklumat Ubat Pesakit (RiMUP), is compulsory for products which are selfadministeredby patients, including:a) Scheduled poisons (Category A);b) Over-the-Counter, OTC products (Category X);c) Health supplements with high claims (disease risk reduction).For details, please refer to:i) Direktif Penguatkuasaan Keperluan Mengemukakan Risalah Maklumat Ubatuntuk Pengguna (RiMUP) Bil. 5 Tahun 2011 Bil (15) dlm BPFK/PPP/01/03 Jld 1ii) Garispanduan Pelaksanaan Risalah Maklumat Ubat untuk Pengguna (RiMUP)The draft copy of the PIL in both English and Bahasa Malaysia shall be submitted forevaluation.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 343

Drug Registration Guidance Document (DRGD)9.2 SPECIFIC LABELLING REQUIREMENTSPlease refer Table 2: List of Substances Which Requires Specific LabellingRequirements and Table 3: Details of Specific Labelling Requirements.Table 2: List of Substances Which Requires Specific Labelling Requirements:NO.SUBSTANCES1. 5-ALPHA REDUCTASE INHIBITOR (5-ARI)2. ACE INHIBITORS3. ACETYLSALICYLIC ACID (ASPIRIN)4. ACTIVATED CHARCOAL/ ATTAPULGITE5. ALBENDAZOLE & BENZIMIDAZOLE ANTIHELMINTICS6. ALFALFA (MEDICO SATIVA)7. ALLOPURINOL8. ALPHA DIHYDROERGOCRYPTINE9. ALPRAZOLAM10. AMIODARONE11. ANTIDEPRESSANTS12. ANTIEPILEPTICS13. ANTIPSYCHOTIC AGENTS14. APOMORPHINE15. ARGININE16. ARIPIPRAZOLE17. ASPARTAME18. BEE POLLEN19. BENZOYL PEROXIDE20. BENZYL ALCOHOL21. BLACK COHOSH (CIMICIFUGAE RACEMOSAE)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 344

Drug Registration Guidance Document (DRGD)NO.SUBSTANCES22. BROMAZEPAM23. BROMOCRIPTINE24. BROMPHENIRAMINE25. CAMPHOR26. CARBAMAZEPINE27. CARBIMAZOLE28. CABERGOLINE29. CEFTRIAXONE30. CETIRIZINE31. CHELIDONIUM MAJUS32. CHITOSAN33. CHLORPHENIRAMINE34. CHORIONIC GONADOTROPHIN35. CLEMASTINE36. CLINDAMYCIN37. CLOBAZAM38. CLOPIDOGREL39. CLOZAPINE40. COLCHICINE41. COX-2 INHIBITORS42. CYPROTERONE ACETATE43. CYTOTOXIC AGENT44. DEXBROMPHENIRAMINE45. DEXTROMETHORPHAN46. DIAZEPAMNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 345

Drug Registration Guidance Document (DRGD)NO.SUBSTANCES47. DICLOFENAC SODIUM48. DICYCLOMINE49. DIPHENHYDRAMINE50. DIPHENOXYLATE51. DOPAMINERGIC INGREDIENT52. EPHEDRINE53. FAMOTIDINE54. FIBRATES55. FLUCLOXACILLIN56. FLUORIDE57. FLUOROQUINOLONES58. FLURAZEPAM HYDROCHLORIDE59. GADOBENIC ACID60. GADOBUTROL61. GADODIAMIDE62. GADOLINIUM OXIDE63. GADOTERIC ACID64. GADOVERSETAMIDE65. GADOXETIC ACID66.GADOLINIUM BASED CONTRAST MEDIUM FOR MAGNETICRESONANCE IMAGING67. GENTAMICIN TOPICAL PREPARATIONS68. GINKGO BILOBA/ GINKGO EXTRACT69. GINSENG70. GLUCOSAMINE71. HIV PROTEASE INHIBITORSNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 346

Drug Registration Guidance Document (DRGD)NO.SUBSTANCES72. HYDROQUINONE73. IMMUNOSUPPRESANTS74. INSULIN75. INGREDIENTS DERIVED FROM SEAFOOD76. KAOLIN, PECTIN, KAOLIN-PECTIN77. KETOCONAZOLE78. KETOROLAC TROMETHAMOL (KETOROLAC TROMETHAMINE)79. LEVODOPA80. LINCOMYCIN81. LISURIDE82. LIQUID PARAFFIN83. LOPERAMIDE84. LORATADINE85. LORAZEPAM86. METHYL SALICYLATE87. METHYLPHENIDATE HCL88. METOCLOPRAMIDE89. MICONAZOLE90. MIDAZOLAM91. MINOXIDIL92. MUCOLYTIC AGENT93. NEVIRAPINE94. NIFEDIPINE95. NITRATES96. NITRAZEPAMNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 347

Drug Registration Guidance Document (DRGD)NO.SUBSTANCES97. NORFLOXACIN98. NORMAL GLOBULIN99. NOSCAPINE100. NONSTEROIDAL ANTI-INFLAMMATORY DRUG (NSAID)101. OLANZAPINE102. PARACETAMOL103. PARACETAMOL WITH CAFFEINE IN COMBINATION104. PELARGONIUM SIDOIDES105. PENICILLIN106. PHENIRAMINE107. PHENYLEPHRINE108. PIRIBEDIL109. PIROXICAM110. PRAMIPEXOLE111. PROMETHAZINE HCL112. PROPAFENONE113. PROPOFOL114. PROPOLIS (TOPICAL)115. PROPYLTHIOURACIL116. PSEUDOEPHEDRINE117. PSYCHOTROPIC PRODUCTS118. QUETIAPINE119. QUINAGOLIDE120. RISPERIDONE121. ROPIRINOLENational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 348

Drug Registration Guidance Document (DRGD)NO.SUBSTANCES122. ROSIGLITAZONE123. ROYAL JELLY124. SALBUTAMOL125. SEDATIVE – HYPNOTIC PRODUCTS126. SELENIUM SULPHIDE127. SENNA LEAF (CASSIA) AND RHUBARB/ RADIX et RHIZOMA RHEI128. SODIUM METABISULPHITE (EXCIPIENT)129. SODIUM VALPROATE130. ST. JOHN‟S WORT (Hypericum perforatum)131. STATINS132. SULPHONAMIDES/ TRIMETHOPRIM133. TERBUTALINE134. TETRACYCLINE SYRUP135. THIOMERSAL136. THROMBOLYTIC AGENTS137. TIAPROFENIC ACID138. TRETINOIN (TOPICAL)139. TRIAZOLAM140. TRIPROLIDINE141. VARENICLINE142. VITAMIN K143. WARFARIN144. ZIPRASIDONE145. ZOLPIDEM TARTRATE146. ZOPICLONENational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 349

Drug Registration Guidance Document (DRGD)Table 3: Details of Specific Labelling RequirementsNO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)1. 5-ALPHA REDUCTASE INHIBITOR (5-ARI)The following statement shall be included in the package inserts of productscontaining 5-ARI:1.1 PRODUCT CONTAINING FINASTERIDE 5MGWARNINGS AND PRECAUTIONSIncreased Risk of High-Grade Prostate CancerMen aged 55 and over with a normal digital rectal examination and PSA≤3.0 ng/mL at baseline taking finasteride 5 mg/day in the 7-year ProstateCancer Prevention Trial (PCPT) had an increased risk of Gleason score 8-10 prostate cancer (finasteride 1.8% vs placebo 1.1%). Similar resultswere observed in a 4-year placebo-controlled clinical trial with another 5-alpha reductase inhibitor (dutasteride, AVODART) (1% dutasteride vs0.5% placebo).5-alpha reductase inhibitors may increase the risk of development of highgradeprostate cancer. Whether the effect of 5-alpha reductase inhibitorsto reduce prostate volume, or study-related factors, impacted the results ofthese studies has not been established.Increased Risk of Breast CancerBreast cancer has been reported in men taking finasteride 5 mg during thepost-marketing period. Physicians should instruct their patients to promptlyreport any changes in their breast tissue such as lumps, pain,gynaecomastia or nipple discharge.ADVERSE EVENTS: POST MARKETING EXPERIENCEMale breast cancer1.2 PRODUCT CONTAINING FINASTERIDE 1MGWARNINGS AND PRECAUTIONSIncreased Risk of High-Grade Prostate CancerMen aged 55 and over with a normal digital rectal examination and PSA≤3.0 ng/mL at baseline taking finasteride 5 mg/day (5 times the dose of[Brand Name]) in the 7-year Prostate Cancer Prevention Trial (PCPT) hadan increased risk of Gleason score 8-10 prostate cancer (finasteride 1.8%vs placebo 1.1%). Similar results were observed in a 4-year placebocontrolledclinical trial with another 5-alpha reductase inhibitorNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 350

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)(dutasteride, AVODART) (1% dutasteride vs 0.5% placebo).5-alpha reductase inhibitors may increase the risk of development of highgradeprostate cancer. Whether the effect of 5-alpha reductase inhibitorsto reduce prostate volume, or study-related factors, impacted the results ofthese studies has not been established.Increased Risk of Breast CancerBreast cancer has been reported in men taking finasteride 1 mg during thepost-marketing period. Physicians should instruct their patients to promptlyreport any changes in their breast tissue such as lumps, pain,gynaecomastia or nipple discharge.ADVERSE EVENTS: POST MARKETING EXPERIENCEMale breast cancer1.3 PRODUCT CONTAINING DUTASTERIDEWARNINGS AND PRECAUTIONSIncreased Risk of High-Grade Prostate CancerIn men aged 50 to 75 years with a prior negative biopsy for prostatecancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL takingAVODART in the 4-year Reduction by Dutasteride of Prostate CancerEvents (REDUCE) trial, there was an increased incidence of Gleasonscore 8-10 prostate cancer compared with men taking placebo(AVODART 1.0% versus placebo 0.5%). In a 7-year placebo-controlledclinical trial with another 5-alpha reductase inhibitor (finasteride 5 mg,PROSCAR), similar results for Gleason score 8-10 prostate cancer wereobserved (finasteride 1.8% versus placebo 1.1%).5-alpha reductase inhibitors may increase the risk of development of highgradeprostate cancer. Whether the effect of 5-alpha reductase inhibitorsto reduce prostate volume, or study­related factors, impacted the results ofthese studies has not been established.Reference:a) Circular Bil (19) dlm BPFK/PPP/01/03 Jld 1: Direktif untuk Memuatkan KenyataanAmaran Berkaitan dengan Risiko High-Grade Prostate Cancer dalam SisipBungkusan Semua Produk 5-Arib) Circular Bil (64) dlm BPFK/PPP/01/03 Jld 1: Direktif untuk Memuatkan KenyataanAmaran Berkaitan dengan Risiko Kanser Payudara Di Kalangan Pesakit Lelaki dalamSisip Bungkusan Semua Produk Yang Mengandungi FinasterideNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 351

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)2. ACE INHIBITORSThe following statement shall be included in the package inserts of productscontaining ACE inhibitors:WARNINGINCREASED RISK OF BIRTH DEFECTS, FOETAL AND NEONATALMORBIDITY AND DEATH WHEN USED THROUGHOUT PREGNANCYUSE IN PREGNANCYINCREASED RISK OF BIRTH DEFECTS, FOETAL AND NEONATALMORBIDITY AND DEATH WHEN USED THROUGHOUT PREGNANCYReference: Circular Bil (65) dlm BPFK/02/5/1.3: Produk yang Mengandungi 'ACE Inhibitors'3. ACETYLSALICYLIC ACID (ASPIRIN)For products containing Acetylsalicylic acid, the following warning shall beincluded on the labels in two languages (Bahasa Malaysia and English):AMARANTIDAK BOLEH DIBERI KEPADA KANAK-KANAK BERUMUR KURANGDARIPADA 16 TAHUN.WARNINGNOT TO BE GIVEN TO CHILDREN UNDER 16 YEARS OF AGE.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 352

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)4. ACTIVATED CHARCOAL/ ATTAPULGITE4.1 The following boxed warning shall be included on the labels of productscontaining Activated charcoal/ attapulgite:NOT RECOMMENDED FOR TREATMENT OF DIARRHOEAIN CHILDREN UNDER 6 YEARS OF AGE4.2 The following statements shall be included in the package inserts ofproducts containing Activated charcoal/ attapulgite:Not recommended for treatment of diarhoeain children under 6 years of ageWARNINGActivated charcoal/ attapulgite may interfere with the absorption of otherdrugs, including antibiotics, when administered concurrently.PRECAUTIONAppropriate fluid and electrolyte therapy should be given to protect againstdehydration. Oral rehydration therapy which is the use of appropriate fluidsincluding oral rehydration salts remains the most effective treatment fordehydration due to diarrhoea. The intake of as much of these fluids aspossible is therefore imperative.5. ALBENDAZOLE & BENZIMIDAZOLE ANTIHELMINTICSThe following statement shall be included on the labels and in the packageinserts of products containing Albendazole or Benzimidazole antihelmintics:SHOULD NOT BE ADMINISTERED DURING CONFIRMED OR SUSPECTEDPREGNANCY6. ALFALFA (MEDICO SATIVA)The following boxed warning shall be included on the labels of productscontaining Alfalfa (Medico sativa):This product contains Alfalfa (Medico sativa).Individual with a predisposition to systemic lupus erythematosusshould consult their physician before consuming this product.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 353

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)7. ALLOPURINOLThe following statement shall be included in the package inserts of productscontaining Allopurinol:WARNINGAllopurinol should be discontinued at the first appearance of skin rash or othersigns which may indicate an allergic reaction. Hypersensitivity to allopurinolusually appears after some weeks of therapy, and more rarely immediatelyafter beginning treatment.In some instances, a skin rash may be followed by more severe reactions suchas exfoliative, urticarial and purpuric lesion as well as Stevens-Johnsonsyndrome, and/or generalized vasculitis, irreversible hepatotoxicity and evendeath.8. ALPHA DIHYDROERGOCRYPTINEPlease refer to DOPAMINERGIC INGREDIENT9. ALPRAZOLAMPlease refer to SEDATIVE – HYPNOTIC PRODUCTS10. AMIODARONEThe following boxed warning shall be included on the package inserts ofproducts containing Amiodarone:National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 354

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)11. ANTIDEPRESSANTSThe following statement shall be included in the package inserts of productsused as antidepressants:WARNINGSuicidality in Children and AdolescentsAntidepressants increase the risk of suicidal thinking and behavior(suicidality) in children and adolescents with major depressive disorder(MDD) and other psychiatric disorders.Anyone considering the use of an antidepressant in a child or adolescentfor any clinical use must balance the risk of increased suicidality with theclinical need.Patients who are started on therapy should be observed closely for clinicalworsening, suicidality, or unusual changes in behavior.Families and caregivers should be advised to closely observe the patientand to communicate with the prescriber.The indication(s) approved in paediatric for the particular drug should beclearly stated / included.Reference: Circular Bil(41)dlm BPFK/02/5/1.3: Keputusan Pihak Berkuasa Kawalan Dadah(PBKD) Berhubung Tambahan Amaran Berkaitan Dengan 'Suicidality In Children AndAdolescents Treated With Antidepressants'12. ANTIEPILEPTICSThe following statement shall be included in the package inserts of productsused as antiepileptics:WARNING AND PRECAUTIONPotential for an increase in risk of suicidal thoughts or behaviors.Reference: Circular Bil (43) dlm. BPFK/PPP/01/03: Kenyataan Amaran Berkaitan Dengan“Potential for an Increase in Risk of Suicidal Thoughts or Behaviours” yang Perlu DimuatkanPada Sisip Bungkusan Produk AntiepileptikNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 355

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)13. ANTIPSYCHOTIC AGENTS13.1 ALL ANTIPSYCHOTIC AGENTSThe following statement shall be included in the package inserts ofproducts containing antipsychotic:PREGNANCY AND LACTATIONNeonates exposed to antipsychotic drugs during the third trimester ofpregnancy are at risk for extrapyramidal and/or withdrawal symptomsfollowing delivery. There have been reports of agitation, hypertonia,hypotonia, tremor, somnolence, respiratory distress, and feeding disorderin these neonates. These complications have varied in severity; while insome cases symptoms have been self-limited, in other cases neonateshave required intensive care unit support and prolonged hospitalisation.[BRAND NAME] should be used during pregnancy only if the potentialbenefit justifies the potential risk to the foetus.Reference: Circular Bil (16) dlm BPFK/PPP/01/03 Jld 1: Direktif Kenyataan AmaranBerkaitan Dengan Risiko Extrapyrimidal And/or Withdrawal Symptoms Bagi NeonatYang Terdedah Kepada Produk Antipsikotik Semasa Trimester Ketiga Kehamilan PadaSisip Bungkusan Semua Produk Antipsikotik13.2 ATYPICAL ANTIPSYCHOTIC AGENTSThe following statement shall be included in the package inserts ofproducts containing atypical antipsychotic agents:a. Clozapineb. Olanzepinec. Risperidoned. Quetiapinee. Ziprasidonef. AripiprazoleWARNINGHyperglycemia and Diabetes MellitusHyperglycemia in some cases extreme and associated with ketoacidosisor hyperosmolar coma or death, has been reported in patients treatedwith atypical antipsychotics. Assessment of the relationship betweenatypical antipsychotics use and glucose abnormalities is complicated bythe possibility of an increased background risk of diabetes mellitus inpatients with schizophrenia and the increasing incidence of diabetesmellitus in the general population. Given this confounders, theNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 356

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)relationship between atypical antipsychotic use and hyperglycemiarelatedadverse events is not completely understood. However,epidemiological studies suggest an increased risk of treatment-emergenthyperglycemia-related adverse events in patients treated with the atypicalantipsychotics. Precise risk estimates for hyperglycemia-related adverseevents in patients treated with atypical antipsychotics are not available.Patients with an established diagnosis of diabetes mellitus who arestarted on atypical antipsychotics should be monitored regularly forworsening of glucose control. Patients with risk factors for diabetesmellitus (e.g. obesity, family history of diabetes) who are startingtreatment with atypical antipsychotics should undergo fasting bloodglucose testing at the beginning of treatment and periodically duringtreatment. Any patient treated with atypical antipsychotics should bemonitored for symptoms of hyperglycemia including polydipsia, polyuria,polyphagia, and weakness. Patients who develop symptoms ofhyperglycemia during treatment with atypical antipsychotics shouldundergo fasting blood glucose testing. In some cases, hyperglycemia hasresolved when the atypical antipsychotic was discontinued; however,some patients required continuation of anti-diabetic treatment despitediscontinuation of the suspect drug.Reference: Circular Bil (31)dlm BPFK/02/5/1.3: Tambahan Amaran Berkaitan DenganHyperglycemia Bagi Keluaran 'Atypical Antipsychotic Agents'14. APOMORPHINEPlease refer to DOPAMINERGIC INGREDIENT15. ARGININEThe following statement shall be included on the labels and in the packageinserts of oral preparations containing Arginine for health supplementproducts:WARNINGArginine is not recommended for patients following a heart attack.Reference: Circular Bil (64) dlm BPFK/02/5/1.3: Pernyataan Amaran Produk Mengandungi'Arginine'16. ARIPIPRAZOLEPlease refer to DOPAMINERGIC INGREDIENTNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 357

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)17. ASPARTAMEThe following statement shall be included on the labels and in the packageinserts of products containing Aspartame:WARNINGUnsuitable for phenylketonurics.18. BEE POLLENThe following statement shall be included on the labels and in the packageinserts of product containing bee pollen:This product contains Bee Pollen and may cause severe allergic reactions,including fatal anaphylactic reactions in susceptible individuals.Asthma and allergy sufferers may be at greater risks.19. BENZOYL PEROXIDEThe following statement shall be included on the labels and in the packageinserts of products containing Benzoyl peroxide:WARNINGDo not use this medication if you have sensitive skin or if you are sensitive tobenzoyl peroxide. This product may cause irritation, characterized by redness,burning, itching, peeling, or possible swelling.20. BENZYL ALCOHOLThe following statement shall be included on the labels and in the packageinserts of products containing Benzyl alcohol:As this preparation contains benzyl alcohol, its use should beavoided in children under two years of age.Not to be used in neonates.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 358

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)21. BLACK COHOSH (CIMICIFUGAE RACEMOSAE)The following statement shall be included on the labels and in the packageinserts of products containing Black Cohosh (Cimicifugae Racemosae):WARNINGStop taking this product if signs and symptoms suggestive of liver injurydevelop such as tiredness, loss of appetite, yellowing of the skin and eyes orsevere upper stomach pain with nausea and vomiting or dark urine andconsult your doctor immediately.Patients using herbal medicinal products should tell their doctor about it.Reference: Circular Bil (61) dlm BPFK/02/5/1.3: Pernyataan Amaran Produk Mengandungi'Black Cohosh'22. BROMAZEPAMPlease refer to SEDATIVE – HYPNOTIC PRODUCTS23. BROMOCRIPTINEPlease refer to DOPAMINERGIC INGREDIENT24. BROMPHENIRAMINEThe following statement shall be included on the labels and in the packageinserts of liquid oral products containing Brompheniramine:WARNINGWhen used for treatment of cough and cold:(a) Not to be used in children less than 2 years of age(b) To be used with caution and doctor‟s/ pharmacist‟s advice in children2 to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 359

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)25. CAMPHOR25.1 The following boxed warning shall be included on the labels of productscontaining Camphor:CAN CAUSE CONVULSIONCONTRAINDICATED IN CHILDREN BELOW 2 YEARS OF AGE.CAUTION MUST BE EXERCISED WHEN OLDER CHILDREN ARETREATEDAVOID DIRECT APPLICATION INTO THE NOSTRILS25.2 The following warning and precaution shall be included in the packageinsert of products containing Camphor:WARNINGThis product is contraindicated in children below 2 years of age. Cautionmust be exercised when older children are treated.PRECAUTION:It is dangerous to place any camphor containing product into the nostrilof children. A small amount applied this way may cause immediatecollapse.26. CARBAMAZEPINEThe following statement shall be included in the package insert of productscontaining Carbamazepine:Severe dermatologic reactions including Stevens - Johnson syndrome andtoxic epidermal necrolysis (Lyell‟s Syndrome) have been reported withcarbamazepine. Patients treated with carbamazepine should closely bemonitored for signs of hypersensitivity reactions, particularly during the firstmonth of therapy. Immediate discontinuation of therapy should be madewhen cutaneous reactions occur.Potential for an increase in risk of suicidal thoughts or behaviours.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 360

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)27. CARBIMAZOLEThe following statement shall be included in the package inserts of productscontaining Carbimazole:WARNINGCarbimazole may cause white cell disorders such as neutropenia andagranulocytosis, which may be fatal if treatment with carbimazole is notstopped promptly. These reactions usually occur during the first 3 months oftherapy, and in most cases, are reversible on stopping treatment. Sinceagranulocytosis can develop very rapidly, periodic leucocyte counts alone maynot be effective in the early detection of these reactions.28. CABERGOLINEPlease refer to DOPAMINERGIC INGREDIENT29. CEFTRIAXONEThe following statement shall be included in the package inserts of productscontaining Ceftriaxone:CONTRAINDICATIONCeftriaxone is contraindicated in neonates (≤28 days of age) if they require (orare expected to require) treatment with calcium-containing intravenoussolutions, including calcium-containing infusions such as parenteral nutrition,because of the risk of precipitation of ceftriaxone-calcium.WARNINGIn patients other than neonates, Ceftriaxone and calcium-containingsolutions may be administered sequentially to one another if the infusionlines are thoroughly flushed between infusions with a compatible fluid.Diluents containing calcium, such as Ringer‟s solution or Hartmann‟ssolution, are not to be used to reconstitute Ceftriaxone vials or to furtherdilute a reconstituted vial for intravenous administration because aprecipitate can form. Ceftriaxone must not be administeredsimultaneously with calcium-containing intravenous solutions, includingcontinuous calcium-containing infusions such as parenteral nutrition via aY-site, because precipitation of ceftriaxone-calcium can occur.Reference: Circular Bil (48) dlm. BPFK/PPP/01/03: Pindaan Pada Kenyataan AmaranBerkaitan Dengan "Potential Risk Associated With Concomitant Use Of Ceftriaxone WithCalcium - Containing Intravenous Solutions" Yang Perlu Dimuatkan Pada Sisip BungkusanProduk CeftriaxoneNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 361

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)30. CETIRIZINEThe following statement shall be included in the package insert of productscontaining Cetirizine:PRECAUTIONActivities Requiring Mental Alertness: In clinical trials the occurrence ofsomnolence has been reported in some patients taking Cetirizine: due cautionshould therefore be exercised when driving a car or operating potentiallydangerous machinery.31. CHELIDONIUM MAJUSThe following statement shall be included on the label of products containingChelidonium majus in 2 languages (Bahasa Melayu and English) in bold font:WARNINGThis product may cause adverse reaction to the liver.AMARANProduk ini mungkin boleh menyebabkan kesan sampingan pada hepar (hati).Reference: Circular (bil 17) dlm bpfk02/5/1.3: Label Amaran Tentang Penggunaan BahanChelidonium majus32. CHITOSANThe following statement shall be included on the labels and package inserts ofproducts containing chitosan.“DERIVED FROM SEAFOOD”Reference: Circular Bil (52) dlm BPFK/02/5/1.3: Muatkan Kenyataan 'Derived FromSeafood' Pada Label Produk Jika Bahan AKtif Adalah Dari Sumber Laut'National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 362

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)33. CHLORPHENIRAMINEThe following statement shall be included on the labels and package inserts ofliquid oral products containing Chlorpheniramine:WARNINGWhen used for treatment of cough and cold;(a) Not to be used in children less than 2 years of age(b) To be used with caution and doctor‟s/ pharmacist‟s advice in children2 to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)34. CHORIONIC GONADOTROPHINThe following statement shall be included in the package inserts of productscontaining Chorionic gonadotrophin:The ovulation cycle should be monitored with oestriol levels andultrasonography35. CLEMASTINEThe following statement shall be included on the labels and package inserts ofliquid oral products containing Clemastine:WARNINGWhen used for treatment of cough and cold:(a) Not to be used in children less than 2 years of age(b) To be used with caution and doctor‟s/ pharmacist‟s advice in children2 to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 363

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)36. CLINDAMYCINThe package insert must emphasize the possibility of pseudomembranouscolitis with the use of the drug.The package insert must include the following boxed or emphasizedstatements/ warning:Clindamycin therapy has been associated with severe colitis which mayend fatally.It should be reserved for serious infections where less toxic antimicrobialagents are inappropriate.It should not be used in patients with nonbacterial infections, such asmost upper respiratory tract infections.Its use in newborns is contraindicated.37. CLOBAZAMPlease refer to SEDATIVE – HYPNOTIC PRODUCTSNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 364

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)38. CLOPIDOGRELThe following statement shall be included in the package inserts of productscontaining Clopidogrel:SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USEPharmacogenetics: Based on literature data, patients with genetically reducedCYP22C19 function (intermediate or poor metabolisers) have lower systemicexposure to the active metabolite of clopidogrel and diminished antiplateletresponses, and generally exhibit higher cardiovascular event rates followingmyocardial infarction than do patients with normal CYP2C19 function.INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHERFORMS OF INTERACTIONSince clopidogrel is metabolised to its active metabolite by CYP2C19, use ofdrugs that inhibit the activity of this enzyme would be expected to result inreduced drug levels of the active metabolite of clopidogrel and a reduction inclinical efficacy. Concomitant use of drugs that inhibit CYP2C19 (e.g protonpump inhibitors) should be discouraged.PHARMACOKINETIC PROPERTIESThe oxidative step is regulated primarily by Cytochrome P450 ISOENZYMES2B6, 3A4, 1A1, 1A2 and 2C19.Reference: Circular Bil (42) dlm. BPFK/PPP/01/03: Kenyataan Amaran Berkaitan Dengan“Possible Interaction Between Clopidogrel and Proton Pump Inhibitors” yang Perlu DimuatkanPada Sisip Bungkusan Produk Clopidogrel39. CLOZAPINEPlease refer to ANTIPSYCHOTIC AGENTNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 365

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)40. COLCHICINEThe following statement shall be included in the package inserts of productscontaining Colchicines:INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHERFORMS OF INTERACTION:Potential risk of severe drug interactions, including death, in certainpatients treated with colchicine and concomitant P-glycoprotein or strongCYP3A4 inhibitors such as clarithromycin, cyclosporin, erythromycin, calciumchannel antagonists (e.g Verapamil and Diltiazem), telithromycin,ketoconazole, itraconazole, HIV protease inhibitors and nefazodone.P-Glycoprotein or strong CYP3A4 inhibitors are not to be used in patientswith renal or hepatic impairment who are taking colchicine.A dose reduction or interruption of colchicine treatment should beconsidered in patients with normal renal and hepatic function if treatment witha P-glycoprotein or a strong CYP3A4 inhibitor is required. Avoid consuminggrapefruit and grapefruit juice while using colchicine.Reference: Circular Bil (45) dlm. BPFK/PPP/01/03: Kenyataan Amaran Berkaitan Dengan“Severe Drug Interaction Between Colchicine and P-Glycoprotein or Strong CYP3A4Inhibitors” Yang Perlu Dimuatkan Pada Sisip Bungkusan Produk ColchicineNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 366

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)41. COX-2 INHIBITORSThe following statement shall be included in the package insert for COX-2Inhibitors products containing Celecoxib and Etoricoxib:Contraindication for patients who have increased risk of cardiovasculardisease (ischeamic heart disease and stroke).Warning to prescriber when prescribing COX-2 Inhibitors to patients withrisk factors of heart disease, hypertension (high blood pressure),hyperlipidemia, diabetes, smoking patient and patient with peripheralarterial disease.Statement on limiting the period and dosing is written as „Given theassociation between cardiovascular risk and exposure to COX-2Inhibitors, doctors are advised to use the lowest effective dose for theshortest possible duration of treatment‟.Contraindication for patient using Etoricoxib is written as „Contraindicationfor Etoricoxib in patients with hypertension (high blood pressure) whoseblood pressure is not under control‟.Reference: Circular Bil (46) dlm BPFK/02/5/1.3: Keputusan Mesyuarat PBKD - Tindakantindakanregulatori terhadap Cox-2 Inhibitors: Celecocib dan Etoricoxib42. CYPROTERONE ACETATEThe following statement shall be included in the package inserts of productscontaining Cyproterone acetate:WARNINGDirect hepatic toxicity, including jaundice, hepatitis and hepatic failure, whichhas been fatal in some cases, has been reported in patients treated with100mg or more of cyproterone acetate. Most reported cases are in men withprostatic cancer. Toxicity is dose-related and develops, usually, severalmonths after treatment has begun. Liver function tests should be performedpre-treatment and whenever any symptoms or signs suggestive ofhepatotoxicity occur. If hepatotoxicity is confirmed, cyproterone acetate shouldnormally be withdrawn, unless the hepatotoxicity can be explained by anothercause, e.g. metastatic disease, in which case cyproterone acetate should becontinued only if the perceived benefit outweighs the risk.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 367

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)43. CYTOTOXIC AGENTThe following boxed statement shall be included on the label of productscontaining Cytotoxic agents:CAUTION : CYTOTOXIC AGENTNote: The label caution should be printed prominently on the label.44. DEXBROMPHENIRAMINEThe following statement shall be included on the labels and package inserts ofliquid oral products containing Dexbrompheniramine:WARNINGWhen used for treatment of cough and cold:(a) Not to be used in children less than 2 years of age(b) To be used with caution and doctor‟s/ pharmacist‟s advice in children2 to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)45. DEXTROMETHORPHANThe following statement shall be included on the labels and package inserts ofliquid oral products containing Dextromethorphan:WARNINGWhen used for treatment of cough and cold:(a) Not to be used in children less than 2 years of age(b) To be used with caution and doctor‟s/ pharmacist‟s advice in children2 to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 368

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)46. DIAZEPAMPlease refer to SEDATIVE – HYPNOTIC PRODUCTS47. DICLOFENAC SODIUMThe following statement shall be included in the package inserts of productscontaining Diclofenac sodium:PRECAUTIONSevere cutaneous reactions, including Stevens - Johnson syndrome and toxicepidermal necrolysis (Lyell‟s syndrome), have been reported with diclofenacsodium. Patients treated with diclofenac sodium should be closely monitoredfor signs of hypersensitivity reactions. Discontinue diclofenac sodiumimmediately if rash occurs.Adverse effects: Dermatological: Occasional - rashes or skin eruptions Casesof hair loss, bullous eruptions, erythema multiforme, Stevens- Johnsonsyndrome, toxic epidermal necrolysis (Lyell‟s syndrome), and photosensitivityreactions have been reported.48. DICYCLOMINEThe following boxed warning shall be included on the labels and in thepackage inserts of products containing Dicyclomine:WARNINGDicyclomine is not recommended for use in infantsunder the age of six monthNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 369

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)49. DIPHENHYDRAMINEThe following statement shall be included on the labels and in the packageinserts of products containing Diphenhydramine:WARNINGWhen used for treatment of cough and cold:(a) Not to be used in children less than 2 years of age(b) To be used with caution and doctor‟s/ pharmacist‟s advice in children2 to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 370

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)50. DIPHENOXYLATE50.1 The following boxed warning shall be included on the labels of productscontaining Diphenoxylate:NOT RECOMMENDED FOR CHILDREN UNDER 6 YEARS OF AGE.50.2 The following statement shall be included in the package insert ofproducts containing Diphenoxylate:WARNINGNot recommended for children under 6 years of age.PRECAUTIONAppropriate fluid and electrolyte therapy should be given to protectagainst dehydration in all cases of diarrhoea. Oral rehydration therapywhich is the use of appropriate fluids including oral rehydration saltsremains the most effective treatment for dehydration due to diarrhoea.The intake of as much of these fluids as possible is therefore imperative.Drug-induced inhibition of peristalsis may result in fluid detention in theintestine, which may aggravate and mask dehydration and depletion ofelectrolytes, especially in young children. If severe dehydration ofelectrolyte imbalance is present, diphenoxylate should be withheld untilappropriate corrective therapy has been initiated.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 371

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)51. DOPAMINERGIC INGREDIENTThe following warning/ statement related to “Sudden sleep onset” shall beincluded in the package insert and product literature of products containingdopaminergic ingredients:a. alpha-dihydroergocryptineb. apomorphinec. bromocriptined. cabergolinee. levodopaf. lisurideg. piribedilh. pramipexolei. quinagolidej. ropiniroleSPECIAL WARNING & SPECIAL PRECAUTIONS FOR USE……. has been associated with somnolence and episodes of sudden onset,particularly in patients with Parkinson‟s diseases. Sudden onset of sleepduring daily activities, in some cases without awareness or warning signs, hasbeen reported very rarely. Patients must be informed of this and advised toexercise caution while driving or operating machines during treatment with……. Patients who have experienced somnolence and/or an episode ofsudden sleep onset must refrain from driving or operating machines.Furthermore a reduction of dosage or termination of therapy may beconsidered.EFFECTS ON ABILITY TO DRIVE AND USE MACHINESPatients being treated with ……. and presenting with somnolence and/orsudden sleep episodes must be informed to refrain from driving or engaging inactivities where impaired alertness may put themselves or others at risk ofserious injury or death (e.g. operating machines) until such recurrent episodesand somnolence have resolved (see also section on special warnings andspecial precautions for use).UNDESIRABLE EFFECTS……. is associated with somnolence and has been associated very rarely withexcessive daytime somnolence and sudden sleep onset episodes.Reference: Circular (bil 14) dlm bpfk02/5/1.3: keluaran yang mengandungi bahan aktifdopaminergik- tanda amaran berkaitan dengan ' sudden sleep onset'National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 372

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)52. EPHEDRINEThe following statement shall be included on the labels and in the packageinserts of products containing Ephedrine:WARNINGWhen used for treatment of cough and cold:(a) Not to be used in children less than 2 years of age(b) To be used with caution and doctor‟s/ pharmacist‟s advice in children2 to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)53. FAMOTIDINEThe following statement shall be included in the package inserts of productscontaining Famotidine:DOSAGEDosage adjustment is required for patients with moderate to severe renalinsufficiency. Since CNS adverse effects have been reported in patients withmoderate to severe renal insufficiency, to avoid excess accumulation of thedrug, the dose of famotidine may be reduced to half the recommended dose orthe dosing interval may be prolonged to 36 - 48 hours as indicated by thepatient‟s clinical response.PRECAUTIONAs elderly patients are more likely to have decreased clearance of famotidine,care should be taken in dose selection and it may be useful to monitor renalfunction.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 373

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)54. FIBRATESThe following statement shall be included in the package inserts of productscontaining Fibrates:a. Clofibrate,b. Bezafibratec. Ciprofibrate, Etofibrated. Fenofibratee. Simfibratef. etc.DRUG INTERACTIONConcurrent use of fibates with HMG-CoA reductase inhibitors may causesevere myositis and myoglobinuria.55. FLUCLOXACILLINThe following warning shall be included in the package insert of productscontaining Flucloxacillin:WARNINGLiver ToxicityFlucloxacillin can cause severe hepatitis and cholestatic jaundice,which may be protracted. This reaction is more frequent in olderpatients and those who take the drug for prolonged periods (seePrecaution, Adverse Reactions)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 374

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)56. FLUORIDEAll toothpastes containing Fluorides should be labeled with the followingadditional information:a. DIRECTIONS ON USEDo not swallow – spit and rinse after use.b. FOR CHILDREN BELOW 6 YEARSUse a pea-sized amount of toothpaste (less than 5mm).Supervise child‟s brushing.c. DIRECTIONS ON DENTAL HEALTHBrush at least twice a day.Restrict the amount and frequency of sugary food.Visit your dentist at least once a year.d. GRAPHICS AS SHOWNChild‟s useAdult‟s useNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 375

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)57. FLUOROQUINOLONESThe following statement shall be included in the package inserts of productscontaining fluoroquinolones:WARNING AND PRECAUTIONExacerbation of myasthenia gravisFluoroquinolones have neuromuscular blocking activity and may exacerbatemuscle weakness in person with myasthenia gravis. Post marketing seriousadverse events, including deaths and requirement for ventilator support havebeen associated with flouroquinolones use in persons with myasthenia gravis.Avoid flouroquinolones in patients with known history of myasthenia gravisADVERSE REACTIONS/SIDE EFFECTSExacerbation of myasthenia gravisPost Marketing ExperienceReference: Circular Bil (20) dlm BPFK/PPP/01/03 Jld 1: Direktif untuk MemperkukuhkanAmaran Berkaitan dengan Exacerbation of Myasthenia Gravis dalam Sisip Bungkusan SemuaProduk Antibiotik dalam Kumpulan Fluoroquinolones58. FLURAZEPAM HYDROCHLORIDEPlease refer to SEDATIVE – HYPNOTIC PRODUCTS59. GADOBENIC ACIDPlease refer to GADOLINIUM BASED CONTRAST MEDIUM FOR MAGNETICRESONANCE IMAGING60. GADOBUTROLPlease refer to GADOLINIUM BASED CONTRAST MEDIUM FOR MAGNETICRESONANCE IMAGINGNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 376

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)61. GADODIAMIDEPlease refer to GADOLINIUM BASED CONTRAST MEDIUM FOR MAGNETICRESONANCE IMAGING62. GADOLINIUM OXIDEPlease refer to GADOLINIUM BASED CONTRAST MEDIUM FOR MAGNETICRESONANCE IMAGING63. GADOTERIC ACIDPlease refer to GADOLINIUM BASED CONTRAST MEDIUM FOR MAGNETICRESONANCE IMAGING64. GADOVERSETAMIDEPlease refer to GADOLINIUM BASED CONTRAST MEDIUM FOR MAGNETICRESONANCE IMAGING65. GADOXETIC ACIDPlease refer to GADOLINIUM BASED CONTRAST MEDIUM FOR MAGNETICRESONANCE IMAGING66. GADOLINIUM BASED CONTRAST MEDIUM FOR MAGNETICRESONANCE IMAGINGThe following boxed warning and warning shall be included in the packageinserts of products containing:a. Gadobenate Dimeglumineb. Gadobenic acidc. Gadobutrold. Gadodiamidee. Gadolinium oxidef. Gadoteric acidg. Gadoversetamideh. Gadoxetic acidNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 377

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)BOXED WARNING- Exposure to gadolinium – based contrast agents (GBCAs) increasesthe risk for Nephrogenic Systemic Fibrosis (NSF) in patients with:acute or chronic severe renal insufficiency (glomerular filtrationrate < 30mL/min/1.73m²), oracute renal insufficiency of any severity due to the hepato-renalsyndrome or in the perioperative liver transplantation period.- NSF is a debilitating and sometimes fatal disease affecting the skin,muscle, and internal organs- Avoid use of GBCAs unless the diagnotic information is essential andnot available with non-contrast enhanced magnetic resonance imaging(MRI).- Screen all patients for renal dysfunction by obtaining a history and/ orlaboratory tests.- When administering a GBCA, do not exceed the dose recommendedin product labelling. Allow sufficient time for elimination of the GBCAprior to any readministration.WARNINGAmong the factors that may increase the risk for NSF are repeated orhigher than recommended doses of a GBCA.For patients receiving haemodialysis, healthcare professionals mayconsider prompt haemodialysis following GBCA administration in orderto enhance the contrast agent‟s elimination. However, it is unknown ifhaemodialysis prevents NSF.Determine the renal function of patients by obtaining a medical historyof conducting laboratory tests that measure renal function prior to usingGBCA.The risk, if any, for developing NSF among patients with mild tomoderate renal insufficiency or normal renal function is unknown.Post-marketing reports have identified the development of NSFfollowing single and multiple administrations of GBCAs.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 378

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)Reference: Circular Bil (2) dlm. BPFK/PPP/01/03 Jld. 1: PENAMBAHAN AMARANBERKOTAK DAN AMARAN TERKINI KE DALAM SISIP BUNGKUSAN SEMUA AGEN"CONTRAST MEDIUM" YANG BERASASKAN GADOLINIUM (GADOLINIUM BASED)UNTUK TUJUAN 'MAGNETIC RESONANCE IMAGING' "67. GENTAMICIN TOPICAL PREPARATIONSThe following boxed statement shall be included in the package inserts oftopical Gentamicin preparations:Use of topical gentamicin preparations in closed hospital settings isactively discouraged68. GINKGO BILOBA/ GINKGO EXTRACTThe following statements shall be included on the labels and in the packageinserts of products containing Gingko biloba/ Gingko extract:As the use of Ginkgo may increase the tendency of bleeding, please consultyour physician/ pharmacist if you are on or intend to start using any othermedicines and before you undergo any surgical/dental procedure.(Memandangkan Ginkgo boleh meningkatkan kemungkinan pendarahan, silarujuk kepada doktor/ ahli farmasi sekiranya anda sedang atau akanmenggunakan ubat lain dan sebelum prosedur pembedahan / dentaldijalankan).Reference: Circular Bil (47) dlm BPFK/02/5/1.3: Pernyataan Amaran Pada Label Dan SisipBungkusan Produk Yang Mengandungi Ginkgo Biloba / Ginkgo Ekstrak69. GINSENGThe following statements shall be included on the labels and in the packageinserts of products containing Ginseng (including all Panax genus):Contraindicated in pregnant women.Safe use in lactating women and children has not been established.Do not exceed the stated dose.Safety on long term use has not been established.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 379

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)70. GLUCOSAMINE70.1 The following statement shall be included on the labels and packageinserts of products containing Glucosamine (derived from seafood);“DERIVED FROM SEAFOOD”70.2 The following statement shall be included in the package inserts ofproducts containing Glucosamine:SIDE EFFECTCardiovascularPeripheral oedema, tachycardia were reported in a few patientsfollowing larger clinical trials investigating oral administration inosteoarthritis. Causal relationship has not been established.Central nervous systemDrowsiness, headache, insomnia have been observed rarely duringtherapy (less than 1%).GastrointestinalNausea, vomiting, diarrhoea, dyspepsia or epigastric pain,constipation, heartburn and anorexia have been described rarelyduring oral therapy with glucosamine.SkinSkin reactions such as erythema and pruritus have been reportedwith therapeutic administration of glucosamine.Reference:a) Circular Bil (52) dlm BPFK/02/5/1.3: Muatkan Kenyataan 'Derived From Seafood'Pada Label Produk Jika Bahan AKtif Adalah Dari Sumber Laut'b) Circular Bil (72) dlm BPFK/02/5/1.3: Mengemaskini dan menyelaraskan maklumatmengenai kesan sampingan pada label & sisip bungkusan produk yang mengandungiglucosamine71. HIV PROTEASE INHIBITORSThe following statement shall be included in the package inserts of productscontaining HIV Protease inhibitors:ADVERSE REACTIONAlthough a causal relationship has not been definitively established, proteaseinhibitors may contribute to increase in blood sugar levels and even diabetesin HIV patients. Close monitoring of blood glucose level is recommended.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 380

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)72. HYDROQUINONEThe following warning shall be included on the outer labels of productscontaining Hydroquinone:WARNING:Some users of this product may experience skin irritations. Should this occur,stop using and consult a medical doctor.For hydroquinone products that do not contain any sun screening agent, astatement should be included in the package insert to advise users to eitheruse a sun screening agent or protect themselves from sunlight or to use theproducts only at night.Reference: Circular (bil 26) dlm bpfkweb.bpkp.3.2000: Amaran bagi Produk MengandungiHydroquinone73. IMMUNOSUPPRESANTSThe following information shall be included in the package inserts of productscontaining the following immunosuppressants:a) Sirolimusb) Cyclosporinc) Mycophenolate mofetild) Mycophenolic acide) TacrolimusWARNINGS AND PRECAUTIONSImmunosuppressed patients are at increased risk for opportunistic infections,including activation of latent viral infections. These include BK virus associatednephropathy which has been observed in patients receivingimmunosuppressants. These infections may lead to serious, including fataloutcomes.Reference: Circular Bil (44) dlm. BPFK/PPP/01/03: Kenyataan Amaran Berkaitan Dengan“Increased Risk For Opportunistic Infections Such As Activation of Latent Viral InfectionsIncluding BK Virus – Associated Nephropathy” Yang Perlu Dimuatkan Pada Sisip BungkusanProduk Immunosuppressant74. INSULINThe label of the product shall state clearly the source of insulin.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 381

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)75. INGREDIENTS DERIVED FROM SEAFOODThe following statement shall be included on the labels and package inserts ofproducts.“DERIVED FROM SEAFOOD”Reference: Circular Bil (52) dlm BPFK/02/5/1.3: Muatkan Kenyataan 'Derived FromSeafood' Pada Label Produk Jika Bahan AKtif Adalah Dari Sumber Laut'76. KAOLIN, PECTIN, KAOLIN-PECTINThe following boxed warning shall be included on the labels:NOT RECOMMENDED FOR CHILDREN UNDER 6 YEARS OF AGE.The following statement shall be included in the package inserts of productscontaining kaolin and/ or pectin:WARNINGNot recommended for children under 6 years of age.Severe constipation, which may lead to faecal impaction, may rarely occur inchildren and the elderly patients taking kaolin and pectin. Kaolin and pectinmay interfere with the absorption of other drugs, including antibiotics,administered concurrently.PRECAUTIONAppropriate fluid and electrolyte therapy should be given to protect againstdehydration. Oral rehydration therapy with the use of appropriate fluidsincluding oral rehydration salts - remains the most effective treatment fordehydration due to diarrhoea. The intake of as much of these fluids aspossible is therefore imperative.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 382

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)77. KETOCONAZOLEThe following statement shall be included in the package inserts of productscontaining ketoconazole:CONTRAINDICATIONSIn patients with acute or chronic liver disease.WARNINGS & PRECAUTIONSBecause of the risk for serious hepatotoxicity, [BRAND NAME] should beused only when the potential benefits are considered to outweigh thepotential risks, taking into consideration the availability of other effectiveantifungal therapy.Assess liver function, prior to treatment to rule out acute or chronic liverdisease, and monitor at frequent and regular intervals during treatment,and at the first signs or symptoms of possible hepatotoxicity.HepatotoxicityVery rare cases of serious hepatotoxicity, including cases with a fatal outcomeor requiring liver transplantation have occurred with the use of oralketoconazole. Some patients had no obvious risk factors for liver disease.Cases have been reported that occurred within the first month of treatment,including some within the first week.The cumulative dose of the treatment is a risk factor for serious hepatotoxicity.Factors which may increase the risk of hepatitis are prolonged treatment withketoconazole tablets, females over 50 years of age, previous treatment withgriseofulvin, a history of liver disease, known drug intolerance and concurrentuse of medication which compromises liver function. A period of one monthshould be allowed between cessation of griseofulvin treatment andcommencement treatment with ketoconazole tablets because of an apparentassociation between recent griseofulvin therapy and hepatic reactions toketoconazole tablets.Monitor liver function in all patients receiving treatment with ketoconazoletablets (see Monitoring of hepatic function).Patients should be instructed to promptly report to their physician signs andsymptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue,jaundice, abdominal pain or dark urine. In these patients, treatment should bestopped immediately and liver function should be conducted.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 383

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)Monitoring of hepatic functionMonitor liver function in all patients receiving treatment with ketoconazoletablets. Monitor liver function prior to treatment to rule out acute or chronicliver disease (see CONTRAINDICATIONS), after two weeks of treatment andthen on a monthly basis and at the first signs or symptoms of possible hepatictoxicity. When the liver function tests indicate liver injury, the treatment shouldbe stopped immediately.A risk and benefit evaluation should be made before oral ketoconazole is usedin cases of non-life threatening diseases requiring long treatment periods.In patients with elevated liver enzymes, or who have experienced liver toxicitywith other drugs, treatment should not be started unless the expected benefitexceeds the risk of hepatic injury. In such cases, close monitoring of the liverenzymes is necessary.UNDESIRABLE EFFECTSPost-marketing ExperienceHepato-biliary DisordersVery rare: serious hepatotoxicity, including hepatitis cholestatic, biopsyconfirmedhepatic necrosis, cirrhosis, hepatic failure including cases resultingin transplantation or death (see WARNINGS & PRECAUTIONS).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 384

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)78. KETOROLAC TROMETHAMOL (KETOROLAC TROMETHAMINE)The following statements shall be included in the package inserts of productscontaining Ketorolac tromethamol:THE PRODUCT SHALL BE INDICATED FOR THE FOLLOWINGFor short-term management of moderate to severe acute post-operative painfollowing surgical procedures associated with low risk of haemorrhage.DOSAGE AND DURATION OF TREATMENTParenteral administration: The starting dose should be 10mg with subsequentdoses of 10-30mg four to six hourly as required. The lowest effective doseshould be used. The total daily dose of 90mg for the non-elderly and 60mg forthe elderly should not be exceeded. Maximum duration of parenteral treatmentis 2 days for all age groups. In patients who have received parenteral ketorolacand are converted to oral tablets, the total combined daily dose of all forms ofketorolac should not exceed 90mg for non-elderly and 60mg for the elderly.Maximum duration of treatment for the oral formulation is 7 days.CONTRAINDICATIONSA history of peptic ulceration or gastrointestinal bleedingA history of haemorrhagic diathesisA history of confirmed or suspected cerebrovascular bleedingOperations associated with a high risk of haemorrhageA history of asthmaModerate or severe renal impairment (serum creatinine > 160mol/L)Hypovolaemia or dehydration from any causeHypersensitivity to NSAIDs or aspirinDuring pregnancy, labour, delivery or lactationConcomitant administration with other NSAIDs, anticoagulant includinglow dose heparin79. LEVODOPAPlease refer to DOPAMINERGIC INGREDIENTNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 385

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)80. LINCOMYCINFor all products containing Lincomycin:The package insert must emphasize the possibility of pseudomembranouscolitis with the use of the drug and must include the following boxed oremphasized statement/ warning:a. Lincomycin therapy has been associated with severe colitis which mayend fatally.b. It should be reserved for serious infections where less toxicantimicrobial agents are inappropriate.c. It should not be used in patients with nonbacterial infections, such asmost upper respiratory tract infections.d. Its use in newborns is contraindicated.81. LISURIDEPlease refer to DOPAMINERGIC INGREDIENT82. LIQUID PARAFFINThe following statement shall be included on the labels of products containingLiquid paraffin as laxative:Not recommended for use in children below 3 years of age;Not recommended for use in pregnant women;Repeated use is not advisable;Consult your doctor if laxatives are needed every day, if you havepersistent abdominal pain or have a condition which makes swallowingdifficult.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 386

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)83. LOPERAMIDE83.1 The following boxed warning shall be included on the labels of productscontaining Loperamide:NOT RECOMMENDED FOR CHILDREN UNDER 6 YEARS OF AGE83.2 The following statement shall be included in the package inserts ofproducts containing Loperamide:WARNINGNot recommended for children under 6 years of age. Its use has beenassociated with fatal episodes of paralytic ileus in infants and youngchildren.PRECAUTIONAppropriate fluid and electrolyte therapy should be given to protectagainst dehydration in all cases of diarrhoea. Oral rehydration therapywhich is the use of appropriate fluids including oral rehydration saltsremains the most effective treatment for dehydration due to diarrhoea.The intake of as much of these fluids as possible is therefore imperative.Drug-induced inhibition of peristalsis may result in fluid retention in theintestine, which may aggravate and mask dehydration and depletion ofelectrolytes. If severe dehydration or electrolyte imbalance is presentLoperamide should be withheld until appropriate corrective therapy hasbeen initiated.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 387

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)84. LORATADINEThe following boxed warning shall be included in the package inserts ofproducts containing Loratadine:WARNINGDrugs known to inhibit hepatic metabolism should be co-administered withcaution until definitive interaction studies can be completed. The numberof subjects who concomitantly received macrolide antibiotics,ketoconazole, cimetidine, ranitidine, or theophylline along with loratadinein controlled clinical trials is too small to rule out possible drug interactions.85. LORAZEPAMPlease refer to SEDATIVE – HYPNOTIC PRODUCTS86. METHYL SALICYLATEThe following statements shall be included in the package inserts and productliterature of topical preparations containing methyl salicylate ≥5%:CAUTIONThis product contains methyl salicylate and when applied or rub on to the skin,can be absorbed through the skin into the blood. For patients taking warfarin,excessive application on to the skin for muscle or joint pains may increase thechances of bleeding.87. METHYLPHENIDATE HCLThe following boxed statement shall be included on the labels and in thepackage insert of products containing Methylphenidate HCl:FOR SPECIALIST‟S USE ONLYNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 388

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)88. METOCLOPRAMIDEThe following statements shall be included in the package inserts of productscontaining Metoclopramide:DOSAGETotal daily dose of metoclopramide, especially for children and young adults,should not normally exceed 0.5mg/kg body weight.WARNINGAvoid doses exceeding 0.5mg/kg/day.Extrapyramidal effects, especially dystonic reaction of metoclopramideare more likely to occur in children shortly after initiation of therapy, andusually with doses higher than 0.5mg per kg of body weight per day.89. MICONAZOLEThe following boxed warning shall be included on the labels and in thepackage inserts of intravaginal preparations containing Miconazole:Sila dapatkan nasihat doktor atau ahli farmasi sebelum menggunakankeluaran ini jika anda mengambil ubat warfarin, iaitu sejenis ubatantipembekuan darah, kerana lebam/ pendarahan pada gusi/ hidungboleh berlaku secara spontan.(Please consult your physician/ pharmacist before using this product ifyou are on the anticoagulant medicine warfarin, because bleeding fromnose/ gums or bruising may accur spontaneously).Reference: Circular (bil 45) dlm bpfkweb.bpkp.2.2001: Keputusan Mesyuarat Pihakberkuasa Kawalan Dadah (PBKD) ke 122 Berhubung Amaran Berkaitan Interaksi Ubat BagiSemua Keluaran ANTIFUNGAL INTRAVAGINAL Yang Mengandungi MiconazoleNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 389

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)90. MIDAZOLAMThe following statements shall be included in the package inserts of IVpreparations containing Midazolam:WARNINGIV Midazolam has been associated with severe respiratory depression andrespiratory arrest, especially when used for conscious sedation. In somecases, where this was not recognized promptly and treated effectively, deathor hypoxic encephalopathy resulted. IV Midazolam should be used only inhospital or ambulatory care settings that provide for continuous monitoring ofrespiratory and cardiac functions. Assure immediate availability of resuscitativedrugs, equipments, appropriate antidote and personnel trained in their use.Dosage of IV Midazolam must be individualized for each patient. Lower dosesare usually required for elderly, debilitated or higher risk surgical patients.When Midazolam is administered intravenously for conscious sedation, itshould be injected slowly (over at least 2 minutes); it should not beadministered by rapid or single bolus IV injection because of respiratorydepression and/or arrest, especially in elderly or debilitated patients. The initialdose may be as little as 1mg, but should not exceed 2.5mg in a normal healthyadult; administer over at least 2 minutes and allow additional 2 or moreminutes to fully evaluate sedative effect. If further titration is necessary, usesmall increments to the appropriate level of sedation, allowing an additional 2or more minutes after each increment to fully evaluate sedative effect. SeeDosage and Administration for complete dosing information.Please refer to SEDATIVE – HYPNOTIC products for additional information.91. MINOXIDILThe label and the package insert shall include the following statement:To be supplied only on the prescription of a registered medical practitioner.Note: The statement is exempted for external use preparation containing notmore than 5% of Minoxidil; its salts; its derivatives(Please refer latest Poison List: Preparations for external use containing not morethan 5% of Minoxidil; its salts; its derivatives, which is under Group C)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 390

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)92. MUCOLYTIC AGENTThe following warning shall be included in the package inserts of productscontaining:a) Acetylcysteineb) Carbocysteinec) Methylcarbocysteine (Mecysteine)CONTRAINDICATIONSContraindicated in children below two (2) years of age.Reference: Circular Bil (7) dlm BPFK/PPP/01/03 Jld 1: Kemaskini Kenyataan Amaran“Contraindicated In Children Under 2 Years Of Age” Yang Wajib Dimuatkan Pada SisipBungkusan Semua Produk Carbocysteine, Acetylcysteine Dan Methylcarbocysteine(Mecysteine)93. NEVIRAPINEThe following statement shall be included in the package insert of product thatcontains Nevirapine:Addition of this statement at approved Indication:“Avoid usage of Nevirapine in patient with CD4+cell count greater than250cells/mm3”.Reference: Circular Bil (43) dlm BPFK/02/5/1.3: Pendaftaran Produk Yang MengandungiNevirapine94. NIFEDIPINEThe following statement shall be included in the package inserts of “shortacting” Nifedipine products:WARNING/ PRECAUTIONSeveral well documented studies have described profound hypotension,myocardial infarction and death when immediate release nifedipine capsulesare used sublingually for acute reduction of blood pressure.DOSAGELower doses may be required in elderly patients as a result of reduceddrug clearance.For hypertension, the dose used should not exceed 60mg daily.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 391

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)95. NITRATESThe following statements shall be included in the package inserts of all“NITRATES FOR STABLE ANGINA PECTORIS”:An appropriate statement concerning the development of tolerance(under precaution section). A suggested statement would be asfollows: „Development of tolerance may occur with all forms of nitratetherapy particularly with the long acting preparations that maintaincontinuously high plasma nitrate concentration‟.An appropriate recommendation on dosage regimens. Therecommended dosage regimens should be one that is able to provide alow-nitrate period or a nitrate-free period of 8-12 hours every 24 hoursto prevent the development of tolerance and thus maintain theantianginal effects.96. NITRAZEPAMPlease refer to SEDATIVE – HYPNOTIC PRODUCTS97. NORFLOXACINThe following statement shall be included in the package inserts of productscontaining Norfloxacin:PRECAUTIONi. Should not be used in children or pregnant womenii. Phototoxicity may occur98. NORMAL GLOBULININTRAMUSCULAR (IM)The following statement shall be included in the package inserts of Normalglobulin IM preparations:WARNINGDo not administer this preparation intravenously because of potential forserious hypersensitivity reactions.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 392

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)99. NOSCAPINE99.1 The following contraindication shall be included on the labels ofproducts containing Noscapine:Contraindicated in Women of Child-bearing Potential99.2 The following statement shall be included in the package inserts ofproducts containing Noscapine:WARNINGExperimental data now suggests that noscapine may exhibit a mutageniceffect in vitro. Because of the possible consequent risk to the developingfoetus, the products containing noscapine is contraindicated in women ofchild bearing potential, therefore pregnancy should be excluded beforetreatment, and effective contraception maintained throughout treatmentwith such products.PRECAUTIONIn view of potential mutagenicity shown in vitro, potential risks should bebalanced against anticipated benefits when treating children andneonates.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 393

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)100. NONSTEROIDAL ANTI-INFLAMMATORY DRUG (NSAID)The following statement shall be included in the package insert of productscontaining NSAID including COX-2 Inhibitors:WARNINGRisk of GI Ulceration, Bleeding and Perforation with NSAIDSerious GI toxicity such as bleeding, ulceration and perforation can occur atany time, with or without warning symptoms, in patients treated with NSAIDtherapy. Although minor upper GI problems (e.g. dyspepsia) are common,usually developing early in therapy, prescribers should remain alert forulceration and bleeding in patients treated with NSAIDs even in the absence ofprevious GI tract symptoms.Studies to date have not identified any subset of patients not at risk ofdeveloping peptic ulceration and bleeding. Patients with prior history of seriousGI events and other risk factors associated with peptic ulcer disease (e.g.alcoholism, smoking, and corticosteroid therapy) are at increased risk. Elderlyor debilitated patients seem to tolerate ulceration or bleeding less than otherindividuals and account for most spontaneous reports for fatal GI events.101. OLANZAPINEPlease refer to ANTIPSYCHOTIC AGENT102. PARACETAMOLThe following statement shall be included on the labels and in the packageinserts of products containing Paracetamol:WARNINGThis preparation contains PARACETAMOL.Do not take any other paracetamol containing medicines at the same time.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 394

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)103. PARACETAMOL WITH CAFFEINE IN COMBINATIONThe following statement shall be included on the labels and in the packageinserts of products containing Paracetamol with Caffeine in combination:WARNINGAvoid other caffeine containing products. Too much caffeine may causerapid heart rate, nervousness or sleeplessness.Ask a doctor or pharmacist before use if you have high blood pressure,glaucoma, or overactive bladder syndrome.DO NOT exceed 8 tablets in 24 hours.DO NOT take more than the recommended dose unless advised by yourdoctor. Use the smallest effective dose. Taking more than the maximumdaily dose may cause severe or possibly fatal liver damage.DO NOT use with other drugs containing paracetamol.NOT recommended for children under 12 years104. PELARGONIUM SIDOIDESThe following warning shall be included on the labels and in the packageinserts of products containing Pelargonium Sidoides:WARNINGIn very rare cases, pelargonium sidoides may cause hypersensitivity reactions.105. PENICILLINThe following statement shall be included on the labels of products containingpenicillin:„Not to be used in patients with known hypersensitivity to Penicillin‟National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 395

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)106. PHENIRAMINEThe following statement shall be included on the label and in the packageinserts of liquid oral products containing Pheniramine:WARNINGWhen used for treatment of cough and cold:(a) Not to be used in children less than 2 years of age(b) To be used with caution and doctor‟s/ pharmacist‟s advice inchildren 2 to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)107. PHENYLEPHRINEThe following statement shall be included on the labels and in the packageinsert of liquid oral products containing Phenylephrine:WARNINGWhen used for treatment of cough and cold:(a) Not to be used in children less than 2 years of age(b) To be used with caution and doctor‟s/ pharmacist‟s advice inchildren 2 to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)108. PIRIBEDILPlease refer to DOPAMINERGIC INGREDIENTNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 396

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)109. PIROXICAMThe following additional information shall be included in the package inserts ofproducts containing Piroxicam:WARNING AND PRECAUTIONTreatment should always be initiated by a physician experienced inthe treatment of rheumatic diseases.Use the lowest dose (no more than 20mg per day) and for theshortest duration possible. Treatment should be reviewed after 14days.Always consider prescribing a gastro-protective agent.CONTRAINDICATIONPiroxicam should not be prescribed to patient who is more likely todevelop side effects, such as those with a history of gastro-intestinaldisorders associated with bleeding, or those who have had skinreactions to other medicines.Piroxicam should not be prescribed in association with any otherNSAID or an anticoagulant.Reference: Circular Bil (80) dlm BPFK/02/5/1.3: Menghadkan Indikasi bagi Produk untukKegunaan Systemic yang Mengandungi Piroxicam kepada 'For the symptomatic relief of painand inflammation in patients with osteoarthritis, rheumatoid arthritis and ankylosing spondylitis'dan Tambahan Amaran dan Kontraindikasi terkini pada sisip bungkusan110. PRAMIPEXOLEPlease refer to DOPAMINERGIC INGREDIENTNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 397

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)111. PROMETHAZINE HCLThe following additional information shall be included on the label and in thepackage insert of liquid oral products containing Promethazine HCl:WARNINGWhen used for treatment of cough and cold(a) “It (brand or generic names) should not be used in pediatric patientsless than 2 years of age because of the potential for fatal respiratorydepression”.(b) To be used with caution and doctor‟s/ pharmacist‟s advice in children 2to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)112. PROPAFENONEThe following warning shall be included in the package insert of productscontaining propafenone:Propafenone is not recommended for treatment of less severearrhythmias such as nonsustained ventricular tachycardias or frequentpremature ventricular contractions even if the patients are symptomatic,because of recent evidence in the US of increase mortality in patientswith non-lifethreatening arrhythmias who were treated with encainideand flecainide.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 398

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)113. PROPOFOLThe following statement shall be included in the package inserts of productscontaining Propofol:WARNINGPropofol is not recommended for paediatric general anaesthesia and sedationbecause its safety and effectiveness in these patients have not beenestablished. There have been recent reports of adverse cardiac events anddeaths associated with its use in paediatric intensive care. Although there is noevidence of a causal link of death with propofol in these cases, the drug couldnot be ruled out as a contributing factor. Until further data establishing itssafety and delineating its appropriate dose range are available, propofolshould not be used in paediatric intensive care.There have been very rare reports of epileptiform movement in epileptics andnon-epileptics occurring during induction orbemergence from anaesthesiainduced by propofol.114. PROPOLIS (TOPICAL)The following information shall be included on the labels and/ or packageinserts of products containing Propolis (for topical use):WARNINGSPropolis may cause allergic skin reaction.Reference:a) Circular Bil (48) dlm BPFK/02/5/1.3: Pernyataan Amaran Pada Label Dan SisipBungkusan Produk Yang Mengandungi Propolis (Topikal) dan Royal Jelly (SemuaBentuk)b) Bil (56) dlm BPFK/02/5/1.3: Pernyataan Amaran pada Label dan Sisip BungkusanProduk yang Mengandungi Propolis (topikal) dan Royal Jelly (Semua Bentuk)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 399

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)115. PROPYLTHIOURACIL115.1 The following statement shall be included in the package inserts ofproducts containing propylthiouracil:1 WARNING AND PRECAUTIONPotential risk of serious hepatoxicity or liver injury including liver failureand death. Patients who are initiated with propylthiourasil should beclosely monitored for signs and symptoms of liver injury (e.g. fatigue,weakness, vague abdominal pain, loss of appetite, itching, easybruising or yellowing of the eyes or skin) especially during the first sixmonths. If liver injury is suspected, promptly discontinuepropylthiouracil therapy.Propylthiouracil should not be used in pediatric patients unless thepatient is allergic to or intolerant of the alternatives available.115.2 2 The following boxed warning shall be included in the package insertsof products containing propylthiouracil:BOXED WARNINGSevere liver injury and acute liver failure, in some cases fatal, havebeen reported in patients treated with propylthiouracil. These reportsof hepatic reactions include cases requiring liver transplantation inadult and pediatric patients.Propylthiouracil should be reserved to patients who cannot toleratecarbimazole/ methimazole and in whom radioactive iodine therapy orsurgery are not appropriate treatments for management ofhyperthyroidism.Because of the risk of fetal abnormalities associated withcarbimazole/ methimazole, propylthiouracil may be the treatment ofchoice when an antithyroid drug is indicated during or just prior to thefirst trimester of pregnancy (See Warnings & Precautions).Reference:Circular 1 Bil (41) dlm. BPFK/PPP/01/03: Kenyataan Amaran Berkaitan Dengan “Potential foran Increase in Risk of Hepatotoxicity” yang Perlu Dimuatkan Pada Sisip Bungkusan ProdukPropylthiouracilCircular 2 Bil (55) dlm. BPFK/PPP/01/03: Kenyataan Amaran Berbentuk “Boxed Warning”Yang Wajib Dimuatkan Pada Sisip Bungkusan Produk Propylthiouracil Dengan “Severe LiverInjury”National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 400

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)116. PSEUDOEPHEDRINEThe following statement shall be included on the labels and in the packageinserts of liquid oral products containing Pseudoephedrine:WARNINGWhen used for treatment of cough and cold:(a) Not to be used in children less than 2 years of age(b) To be used with caution and doctor‟s/ pharmacist‟s advice inchildren 2 to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)117. PSYCHOTROPIC PRODUCTSThe following statement shall be included conspicuously on the labels of allpsychotropic products:CAUTION:This preparation may be habit forming on prolonged use.118. QUETIAPINEPlease refer to ANTIPSYCHOTIC AGENT119. QUINAGOLIDEPlease refer to DOPAMINERGIC INGREDIENT120. RISPERIDONEPlease refer to ANTIPSYCHOTIC AGENTNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 401

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)121. ROPIRINOLEPlease refer to DOPAMINERGIC INGREDIENT122. ROSIGLITAZONE122.1 The following black boxed warning shall be included in the packageinserts of products containing Rosiglitazone as single ingredient or incombination with other active ingredients :Rosiglitazone is contraindicated in patients with established NYHAClass I to IV heart failure and in patients with known ischaemicheart disease, particularly in those taking nitrates.Thiazolidinediones, including rosiglitazone, cause or exacerbatecongestive heart failure in some patients. Patients on rosiglitazoneshould be monitored carefully for signs and symptoms of heartfailure (including excessive, rapid weight gain, dyspnea, and/oredema). If these signs and symptoms develop, the heart failureshould be managed according to current standards of care.Furthermore, discontinuation or dose reduction of rosiglitazonemust be considered.122.2 The following information shall be included in the package inserts ofproducts containing Rosiglitazone as single ingredient or in combinationwith other active ingredients :CONTRAINDICATIONSRosiglitazone is contraindicated in patients with NYHA Class I to IVheart failure or history of cardiac failure, patients with known ischaemicheart disease and patients with Acute Coronary Syndrome (unstableangina, non-ST segment elevation myocardial infarction (NSTEMI) andST segment elevation myocardial infarction.WARNING & PRECAUTIONSRosiglitazone has been shown to be associated with an increased riskof myocardial ischaemia (angina, infarction) in pooled short term clinicalstudies compared to combined active/placebo control ( 2.00% versus1.53%). Death from myocardial ischaemic events occurred in 0.15% onrosiglitazone – containing regimens and 0.12% on comparator regimen.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 402

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)Reference: Circular Bil (6) dlm BPFK/PPP/01/03 Jld 1: Direktif MemperketatkanPenggunaan Rosiglitazone dan Memperkukuhkan Amaran Berkaitan Dengan Risiko KesanAdvers Kardiovaskular Pada Sisip Bungkusan Semua Produk Rosiglitazone Termasuk ProdukKombinasi123. ROYAL JELLYThe following information shall be included on the labels and/or packageinserts of products containing Royal jelly:WARNINGSThis product contains royal jelly and may cause severe allergic reactionsincluding fatal anaphylactic reactions in susceptible individuals. Asthma andallergy sufferers may be at the greater risk.Reference:a) Circular Bil (48) dlm BPFK/02/5/1.3: Pernyatan Amaran Pada Label Dan SisipBungkusan Produk Yang Mengandungi Propolis (Topikal) dan Royal Jelly (SemuaBentuk)b) Circular Bil (56) dlm BPFK/02/5/1.3: Pernyataan Amaran pada Label dan SisipBungkusan Produk yang Mengandungi Propolis (topikal) dan Royal Jelly (SemuaBentuk)c) Circular Bil (12) dlm. BPFK/PPP/01/03: Pernyataan amaran pada label dan sisipbungkusan produk yang mengandungi royal jelly (produk kosmetik)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 403

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)124. SALBUTAMOL124.1 The following information shall be included in the package inserts ofproducts containing Salbutamol in injection dosage form:As maternal pulmonary oedema and myocardial ischaemia havebeen reported during or following premature labour in patientsreceiving beta2 – agonists, careful attention should be given to fluidbalance and cardio-respiratory function, including ECG monitoring.If signs of pulmonary oedema and myocardial ischaemia develop,discontinuation of treatment should be considered.Due to the risk of pulmonary oedema and myocardial ischaemiathat has been observed during the use of beta2-agonists in thetreatment of premature labour, before these products are given toany patient with known heart disease, an adequate assessment ofthe patients‟s cardiovascular status should be made by a physicianexperienced in cardiology.Cautious use of salbutamol injections is required in pregnantpatients when it is given for relief of bronchospasm so as to avoidinterference with uterine contractibility. During IV infusion ofsalbutamol, the maternal pulse should be monitored and notnormally allowed to exceed a steady rate of 140 beats per minute.124.2 The following information shall be included in the package inserts andproduct literature of products containing Salbutamol in oral tablet/capsule dosage form:As maternal pulmonary oedema and myocardial ischaemia havebeen reported during or following premature labour in patientsreceiving beta2 – agonists, careful attention should be given tofluid balance and cardio-respiratory function, including ECGmonitoring. If signs of pulmonary oedema and myocardialischaemia develop, discontinuation of treatment should beconsidered.Due to the risk of pulmonary oedema and myocardial ischaemiathat has been observed during the use of beta2-agonists in thetreatment of premature labour, before these products are givento any patient with known heart disease, an adequateassessment of the patients‟s cardiovascular status should bemade by a physician experienced in cardiology.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 404

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)124.3 The following warning statement shall be included in the packageinserts of products containing Salbutamol in injection and oral dosageform under section of Warning & Precautions:Tocolysis: Serious adverse reactions including death have beenreported after administration of terbutaline/ salbutamol to womenin labor. In the mother, these include increased heart rate,transient hyperglycaemia, hypokalaemia, cardiac arrhythmias,pulmonary oedema and myocardial ischaemia. Increased fetalheart rate and neonatal hypoglycaemia may occur as a result ofmaternal administration.Reference:a) Circular Bil (6) dlm. BPFK/PPP/01/03: Kenyataan Amaran Mengenai InsidenMyocardial Ischaemia pada Wanita Mengandung yang Menerima Rawatan BetaAgonist bagi Rawatan Melambatkan Kelahiran Pramatang pada Sisip BungkusanKumpulan Produk Inib) Circular Bil (18) dlm BPFK/PPP/01/03 Jld 1: Direktif untuk MemperkukuhkanAmaran Berkaitan dengan Risiko Kesan Advers Serius pada Jantung TermasukKematian dengan Penggunaan Produk Suntikan dan Oral Beta Agonis dalamRawatan Kelahiran Pra-MatangNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 405

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)125. SEDATIVE – HYPNOTIC PRODUCTSThe following statement shall be included in the package inserts under sectionon „Warning‟ and „Precaution‟ of products containing:a. Alprazolamb. Bromazepamc. Clobazamd. Diazepame. Flurazepam hydrochloridef. Lorazepamg. Midazolamh. Nitrazepami. Triazolamj. Zolpidem tartratek. ZopicloneWARNING/ PRECAUTIONAnaphylaxis (severe allergic reaction) and angioedema (severe facialswelling) which can occur as early as the first time the product is takenComplex sleep – related behaviors which may include sleep driving,making phone calls, preparing and eating food while asleepReference: Circular Bil (75) dlm BPFK/02/5/1.3: Pernyataan Amaran Pada Sisip BungkusanSemua Produk Sedatif-Hipnotik Oral Berkaitan dengan Risiko Complex Sleep - RelatedBehaviors Which May Include Sleep Driving, Making Phone Calls, Preparing and Eating Food(While Asleep)126. SELENIUM SULPHIDEThe following statement shall be included on the labels of products containingSelenium sulphide:WARNINGDo not use on broken skin or inflamed. Avoid contact with eyes.(AMARAN: Selenium sulphide tidak boleh digunakan pada kulit yang pecahdan radang. Elakkan daripada terkena mata.)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 406

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)127. SENNA LEAF (CASSIA) AND RHUBARB/ RADIX et RHIZOMA RHEIThe following statement shall be included on the labels of products containingsenna leaf (cassia) and rhubarb/ radix et rhizoma rhei:Do not use when abdominal pain, nausea or vomiting are presentFrequent or prolong use of this preparation may result independence towards the product and „Imbalanced electrolytes‟128. SODIUM METABISULPHITE (EXCIPIENT)The following statement shall be included in the package inserts of productscontaining Sodium metabisulphite:WARNINGThis preparation contains Sodium metabisulphite that may cause seriousallergic type reactions in certain susceptible patients. Do not use if known tobe hypersensitive to bisulphites.129. SODIUM VALPROATEThe following boxed warning shall be included in the package inserts ofproducts containing Sodium valproate:PANCREATITIS:CASES OF LIFE-THREATENING PANCREATITIS HAVE BEENREPORTED IN BOTH CHILDREN AND ADULTS RECEIVINGVALPROATE. SOME OF THE CASES HAVE BEEN DESCRIBED ASHEMORRHAGIC WITH A RAPID PROGRESSION FROM INITIALSYMPTOMS TO DEATH. CASES HAVE BEEN REPORTED SHORTLYAFTER INITIAL USE AS WELL AS AFTER SEVERAL YEARS OF USE.PATIENTS AND GUARDIANS SHOULD BE WARNED THATABDOMINAL PAIN, NAUSEA, VOMITING, AND/OR ANOREXIA CAN BESYMPTOMS OF PANCREATITIS THAT REQUIRE PROMPT MEDICALEVALUATION. IF PANCREATITIS IS DIAGNOSED, VALPROATESHOULD BE DISCONTINUED.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 407

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)130. ST. JOHN‟S WORT (Hypericum perforatum)The following boxed statement shall be included on the labels of productscontaining St. John‟s Wort:Please consult your physician/ pharmacist before using this product if youare on any prescription medicines as there is possibility that interactionsmay occur with certain drugs.(Sila dapatkan nasihat doktor/ ahli farmasi sebelum menggunakan produkini, kerana kemungkinan berlakunya interaksi dengan penggunaan ubatperkripsi).131. STATINSThe following statement shall be included in the package inserts of productscontaining statins:a. Atorvastatinb. Cerivastatinc. Cilastatind. Fluvastatine. Lovastatinf. Pravastating. Simvastatinh. Somatostatini. etc.DRUG INTERACTION:Concurrent use of fibrates may cause severe myositis and myoglobinuria.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 408

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)132. SULPHONAMIDES/ TRIMETHOPRIM132.1 The following statement shall be included on the labels of productscontaining Sulphonamides and Trimethoprim as single ingredient or incombination of both ingredients:Discontinue treatment with this drug immediately if skin rash or any signof adverse reaction occurs.132.2 The following statement shall be included in the package inserts ofproducts containing Sulphonamides and Trimethoprim as singleingredient or in combination of both ingredients:Fatalities associated with the administration of sulphonamides andtrimethoprim, either alone or in combination, have occurred due to severereactions, including Steven-Johnson syndrome, toxic epidermal necrolysisand other reactions. The drug should be discontinued at the firstappearance of skin rash or any sign of adverse reaction.133. TERBUTALINE133.1 The following statement shall be included in the package inserts ofproducts containing Terbutaline in injection dosage form:As maternal pulmonary oedema and myocardial ischaemia havebeen reported during or following premature labour in patientsreceiving beta2 – agonists, careful attention should be given to fluidbalance and cardio-respiratory function, including ECG monitoring.If signs of pulmonary oedema and myocardial ischaemia develop,discontinuation of treatment should be considered.Due to the risk of pulmonary oedema and myocardial ischaemiathat has been observed during the use of beta2-agonists in thetreatment of premature labour, before these products are given toany patient with known heart disease, an adequate assessment ofthe patients‟s cardiovascular status should be made by a physicianexperienced in cardiology.Cautious use of terbutaline injections is required in pregnantpatients when it is given for relief of bronchospasm so as to avoidNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 409

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)interference with uterine contractibility. During IV infusion ofterbutaline, the maternal pulse should be monitored and notnormally allowed to exceed a steady rate of 140 beats per minute.133.2 The following information shall be included in the package insert andproduct literature of products containing Terbutaline in oral tablet/capsule dosage form:As maternal pulmonary oedema and myocardial ischaemia havebeen reported during or following premature labour in patientsreceiving beta2 – agonists, careful attention should be given to fluidbalance and cardio-respiratory function, including ECG monitoring. Ifsigns of pulmonary oedema and myocardial ischaemia develop,discontinuation of treatment should be considered.Due to the risk of pulmonary oedema and myocardial ischaemia thathas been observed during the use of beta2-agonists in the treatmentof premature labour, before these products are given to any patientwith known heart disease, an adequate assessment of the patients‟scardiovascular status should be made by a physician experienced incardiology.133.3 The following warning statement shall be included in the packageinserts of products containing Salbutamol in injection and oral dosageform under section of Warning & Precautions:Tocolysis: Serious adverse reactions including death havebeen reported after administration of terbutaline/ salbutamol towomen in labor. In the mother, these include increased heartrate, transient hyperglycaemia, hypokalaemia, cardiacarrhythmias, pulmonary oedema and myocardial ischaemia.Increased fetal heart rate and neonatal hypoglycaemia mayoccur as a result of maternal administration.Reference:a) Circular Bil (6) dlm. BPFK/PPP/01/03: Kenyataan Amaran Mengenai InsidenMyocardial Ischaemia pada Wanita Mengandung yang Menerima Rawatan BetaAgonist bagi Rawatan Melambatkan Kelahiran Pramatang pada Sisip BungkusanKumpulan Produk Inib) Circular Bil (18) dlm BPFK/PPP/01/03 Jld 1: Direktif untuk MemperkukuhkanAmaran Berkaitan dengan Risiko Kesan Advers Serius pada Jantung TermasukKematian dengan Penggunaan Produk Suntikan dan Oral Beta Agonis dalamRawatan Kelahiran Pra-MatangNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 410

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)134. TETRACYCLINE SYRUPThe following boxed warning shall be included on the label and in the packageinserts of products containing Tetracycline (syrup)NOT TO BE GIVEN TO CHILDREN UNDER 12 YEARS OF AGE135. THIOMERSALNote: Thiomersal is not allowed in ophthalmic preparations as preservative.The following statement shall be included on the label and package inserts ofproducts containing thiomersal for preparations other than ophthalmicpreparation:WARNING„RISK OF SENSITIZATION IN RELATION TO THIOMERSAL AND OTHERPRESERVATIVES‟Reference: Circular Bil (34)dlm BPFK/02/5/1.3: Penggunaan Thiomersal Dalam PersediaanVaksinNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 411

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)136. THROMBOLYTIC AGENTSThe following caution shall be disclosed prominently in the package inserts ofproducts containing “systemic thrombolytic agent” in particular “the tissueplasminogen activators”:WARNINGSevere bleeding such as intracranial haemorrhage may occur followingadministration of the drug, particularly in the elderly patients. The risk must bebalanced against the potential benefit of thrombolysis.The following precautions need to be observed:Patients should be carefully observed for clinical signs during and followingadministration of the drug for early detection of bleeding. Frequenthaematological tests such as blood coagulation tests are mandatory.To prevent bleeding at the site of centesis or other regions, caution must beexercised concerning procedures and management of arterial/ venuspuncture.The use of heparin in conjunction with the thrombolytic agent for the purposeof prevention of reocclusion may increase the risk of intracranial haemorrhage.Close monitoring of patients is strongly recommended.137. TIAPROFENIC ACIDThe following statement shall be included in the package inserts of productscontaining Tiaprofenic acid:PRECAUTIONUrinary symptoms (bladder pain, dysuria, and frequency), haematuria orcystitis may occur. In certain exceptional cases, the symptoms have becomesevere on continued treatment. Should urinary symptoms occur, treatmentwith tiaprofenic acid must be stopped.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 412

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)138. TRETINOIN TOPICALThe following statement shall be included in the package inserts of productscontaining Tretinoin used topically:USE IN PREGNANCY:Studies in animal have shown that oral tretinoin is fetotoxic in rats given500 times the topical human dose and teratogenic in rats given 1,000times the topical human dose. Topical tretinoin has caused delayedossification in a number of bones in the offspring of rats and rabbits given100 to 320 times the topical human dose, respectively. There has beenincreasing incidence of foetal malformation following topical administrationof tretinoi. Use of topical tretinoin is not recommended during pregnancy,especially the first trimester.139. TRIAZOLAMPlease refer to SEDATIVE – HYPNOTIC PRODUCTS140. TRIPROLIDINEThe following statement shall be included on the label and in the packageinserts of liquid oral products containing Triprolidine:WARNINGWhen used for treatment of cough and cold:(a) Not to be used in children less than 2 years of age(b) To be used with caution and doctor‟s/ pharmacist‟s advice inchildren 2 to 6 years of age.Reference: Circular Bil (34) dlm. BPFK/PPP/01/03: Kenyataan Amaran Pada Label danSisip Bungkusan Produk Persediaan Cecair Oral Untuk Rawatan Batuk dan Selsema (Coughand Cold) yang Mengandungi Antihistamin, Antitusif dan Dekongestan (Sebagai Bahan AktifTunggal atau Kombinasi)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 413

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)141. VARENICLINEThe following statement shall be included in the package inserts of productscontaining Varenicline:SPECIAL WARNINGS AND PRECAUTIONS FOR USEEffect of smoking cessation:Smoking cessation, with or without pharmacotherapy has been associatedwith the exacerbation of underlying psychiatric illness (eg. depression). Careshould be taken with patients with a history of psychiatric illness and patientsshould be advised accordingly.Depression, rarely including suicidal ideation and suicide attempt, has beenreported in patients undergoing a smoking cessation attempt.UNDESIRABLE EFFECTSPost marketing cases of MI, depression and suicidal ideation have beenreported in patients taking varenicline.Reference: Circular Bil (83) dlm. BPFK/17/FV/28: Maklumat dari European MedicinesAgency (EMEA) berkaitan penggunaan produk Champix (Varenicline) untuk rawatan berhentimerokok (smoking cessation).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 414

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)142. VITAMIN K142.1 The following statement shall be included in the label and package insertof health supplement products containing Vitamin K as combinedingredients with other vitamins and minerals in oral preparation:„Consult a healthcare practitioner if you are on anticoagulant/blood thinner products.142.2 The following statement shall be included in the package inserts ofproducts containing Vitamin K1 (phytomenadione) as single ingredientused intravenously:WARNINGSevere reactions, including fatalities, have occurred during andimmediately after intravenous injection of Vitamin K1. Restrictintravenous use to emergency case. When intravenous administration isnecessary, the rate of injection should not exceed 1mg per minute.ADMINISTRATION:In severe bleeding, or situations where other routes are not feasible,Vitamin K1 may be given by very slow intravenous injection, at a ratenot exceeding 1mg per minute.143. WARFARINThe following statement shall be included in the package inserts of productscontaining Warfarin:CAUTIONTopical preparations containing methyl salicylate should be used with care inpatients on Warfarin and excessive usage is to be avoided as potentiallydangerous drug interaction can occur.144. ZIPRASIDONEPlease refer to ANTIPSYCHOTIC AGENTNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 415

Drug Registration Guidance Document (DRGD)NO.SPECIFIC LABELLING REQUIREMENTS (SUBSTANCE SPECIFIC)145. ZOLPIDEM TARTRATEPlease refer to SEDATIVE – HYPNOTIC PRODUCTS146. ZOPICLONEPlease refer to SEDATIVE – HYPNOTIC PRODUCTSNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 416

Drug Registration Guidance Document (DRGD)APPENDIX 10GUIDELINE ON PATIENT DISPENSING PACK FORPHARMACEUTICAL PRODUCTS IN MALAYSIAOutline:10.1 Purpose10.2 Objective10.3 Definition10.4 Benefits10.5 Criteria for Implementation of Patient Dispensing Pack10.6 Products Exempted from this Requirements10.7 Other Considerations for Implementation10.8 Implementation Timeline10.9 ConclusionNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 417

Drug Registration Guidance Document (DRGD)10.1 PURPOSETo provide guidance on the implementation of patient dispensing pack ororiginal dispensing pack for pharmaceutical products in Malaysia.10.2 OBJECTIVEImprove patient‟s safety by:maintaining product integrity;prevent unnecessary exposure of the product;avoid product contamination due to handling especially in non-GMPpremise; andFewer steps in dispensing process hence less possibility for errors andimprovement in efficiency.10.3 DEFINITIONPatient dispensing pack or original dispensing pack is a ready-to-dispensepack with sufficient quantity equivalent to an amount not more than one monthsupply or per treatment for one patient‟s use.10.4 BENEFITSKey benefits identified:Ensuring patients on how to take medications and the importance of it,which will eventually increase patient‟s compliance.Clear identification of the medicine, by whom and where it wasmanufactured.Providing complete instructions on the use of the medicine.Original packing will maintain the integrity of the pack therefore ensuringthe stability of the product.Original packing will carry batch number and expiry date.Prevent mix-ups (or contamination) during repacking and dispensing.Facilitate recall of products since the required information can only befound on the original pack.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 418

Drug Registration Guidance Document (DRGD)10.5 CRITERIA FOR IMPLEMENTATION OF PATIENT DISPENSING PACKThe patient dispensing pack size should be based on the medication,intended use, recommended dosage and dosage form sufficient for onemonth supply or per treatment for one patient‟s use.This requirement does not apply for blister or strip pack.Maximum permitted supply is one month but may be less depending onthe intended use of the medication.The Product Registration Holder (PRH) is responsible to justify theproposed patient dispensing pack size based on these criteria as thedosing regimen for certain medication may equate to high numbers oftablets/ capsules. Justification should also address the definition of onemonth i.e. 28, 30 or 31 days.Blister or strip pack are strongly recommended for solid oral dosageforms (e.g. tablets and capsules) and bulk loose pack for supply morethan one month are not permitted unless justified by the PRH.Oral chemotherapeutics in tablet or capsule must be packed in blister toreduce personnel exposure and presumably risk which can minimise thetoxic effect of the chemotherapeutics.10.6 PRODUCTS EXEMPTED FROM THIS REQUIREMENTSThe requirements do not apply to the following products:Injectables, eye, ear and nasal drops, suppositories and pessaries.Products for export only (FEO).Drug where the risk of issuing more than the amount required by thepatient outweigh the benefits of the patient dispensing pack e.g. productscontaining substances with potential for abuse or cytotoxic agents whereprecise dosing are required.Drugs where the dosing needs to be tailored according to patient‟s bodyweight e.g. drugs used in oncology, HIV etc.Medically critical products and hospital packs for rare diseases with verylow volumes where it is not viable to produce special packs for a singlemarket.Products sold with devices with a fixed number of dosesSituations where a patient dispensing pack is not appropriate will beconsidered on a case to case basis.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 419

Drug Registration Guidance Document (DRGD)10.7 OTHER CONSIDERATIONS FOR IMPLEMENTATIONVARIATION APPLICATIONSChange in patient pack size with or without involving new pack type shallbe submitted to Variation Section, Centre for Post Product Registration.Supporting documents required are:a. Justification for the new pack size and/or type;b. Accelerated stability data (3 or 6 months) and stability report for newpack types; andc. Commitment to provide complete real time stability data and reportwhen available.List of products with recommended pack sizes for oral liquid preparationsand dermatological are as in Table 1 and Table 2 respectively.For tablets and capsules in loose pack, the maximum packing size willdepend on the highest dosage and frequency per patient‟s treatment orone month supply.10.8 IMPLEMENTATION TIMELINEImplementation of patient dispensing pack has been conducted in aphased manner to ensure smooth transition while ensuring no supplydisruption to patients. This implementation is effective since 1 March2008 on a voluntary basis and mandated on 1 September 2008.All products manufactured from 1 September 2008 regardless whether itis imported or locally manufactured will need to conform to the principlesof this guide.10.9 CONCLUSIONPatient Dispensing Pack is convenient, safe and improves quality ofdispensed medicines. It will increase efficiency in dispensing and improvesafety by reducing the risk and possibility of error. It will also result in areduction in drug waste and better use of resources.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 420

Drug Registration Guidance Document (DRGD)TABLE 1:Oral Liquid Preparation Maximum Pack Size Recommendations forPharmaceutical ProductsR05R05AR05CR05DATC CodeCough & cold preparationCold preparationAntitussivesExpectorantsRecommended Pack sizesMax 120ml(except for Pholcodine – Max 90ml)R06A Antihistamines systemicR03Anti-asthma & COPD productsR03A Beta2 stimulantsR03B Xanthines (theophyllines)R03C Non-steroidal respiratory anti-inflammatory (ketotifen)Max 120ml(except for Hydroxyzine HCl Syrup- 200ml )Max 120mlN02B Non-narcotic analgesics Max 120mlM01A Antirheumatics non-steroid Max 120mlH02H02ASystemic corticosteroidsPlain corticosteroids(except for Procaterol - 250ml)Max 120mlM06A Anti-inflammatory enzymes Max 500mlA02AA02BAntacid antiflatulentsAntiulcerantsMax 250mlA06A Laxatives Max 120mlA03A03AA03EA03FA07Functional GI disorder drugsAntispasmodicOther GI combinations (Colimix)Gastroprokinetics(Metoclopramide, Motilium)Antidiarrhoea(except for Lactulose - 500ml)Max 120mlNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 421

Drug Registration Guidance Document (DRGD)ATC CodeA04A Antiemetic + AntinauseantsN07C Antivertigo productsN03A AntiepilepticsRecommended Pack sizesMax 120mlMax 250ml(Except for Sodium ValproateSyrup - 300ml)N06A Antidepressant & MoodstabilizerMax 250mlN06D Anti DementiaN07D Anti-Alzheimer productsN05A AntipsychoticsP01B AntihelminticsN05C Tranquillizers/ AnxiolyticsA05B Hepatic protector – lipotropicsJ05 Antivirals for systemic useJ05B Antivirals excluding Anti-HIVJ05C HIV antiviralsJ01 Antibiotics systemicJ01A Tetracyclines & combinationJ01B Chloramphenicols + combinationsJ01C1 Oral broad spectrum PenicillinsJ01D1 Oral CephalosporinsJ01E Trimethoprim combinationsJ01F Macrolides & similar typeJ01H Medium & narrow spectrumpenicillinsJ01X Other antibioticsJ02A Systemic Antifungals AgentsN06D NootropicsN06E Neurotonics & MiscellaneousG01A1 TrichomonacidesMax 20ml for dropsMax 60mlMax 250mlMax150mlMax 250mlMax 120mlMax 125 mlMax 120mlNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 422

Drug Registration Guidance Document (DRGD)TABLE 2:DERMATOLOGICALS PREPARATION MAXIMUM PACK SIZERECOMMENDATIONS FOR PHARMACEUTICAL PRODUCTSATC CodeRecommended Pack sizesD01A Antifungals for topical use Liquid preparation - max 250mlOthers - max 60gD02A Emollients and protectives Non poisons (liquid preparation) - 250mlOthers - 60g (max 500g for emollients)Except D02AC Soft paraffin and fatproducts andD02AX Other emollients and protectives(Aq. Cream) - max 500gD03Preparations for treatment ofwounds and ulcersMax 500ml to 1LNotes:• Chlorhexidine gluconate aqueous 1L• Povidon 10% 500ml• Povidon-iodine 1L• Dermacyn 500ml• Hydrogen peroxide 1L• Prontosan 500ml• Octenisan 500ml• Acetic acid 500ml• Cetrimide 500mlD04A Antipruritics, anesthetics,etc.Except D04AA Antihistamines fortopical use (not allowed forregistration)Liquid – max 250mlOthers – 60gNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 423

Drug Registration Guidance Document (DRGD)ATC CodeD05A Antipsoriatics for topical useRecommended Pack sizesLiquid – max 500ml (with a dispenser).Others – max *500gBar – max 100g* Notes:• Tar Preparations• Coal Tar Ointment/ Solution• Liquor Picis Carbonis (LPC) 500g• Dithranol Ointment 500g• Cocois Co Lotion 500mlD06A Antibiotics for topical use Max 20gExcept D06BB Antivirals - Max 10gD06B A 01 Silver Sulphadiazine formanagement of burns - 500gD07ACorticosteroids, plainD07AA Corticosteroids, weak (group I)D07AB Corticosteroids, moderatelypotent (group II)D07AC Corticosteroids, potent(group III)D07AD Corticosteroids, very potent(group IV)D07AA – Max 100g to **500gD07AB – Max 50g to **500gD07AC – Max 15gD07AD – Max 15g** Note:Pack size of 500g is allowed for hospitalsand skin specialist clinics.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 424

Drug Registration Guidance Document (DRGD)ATC CodeRecommended Pack sizesD07C Corticosteroids,combinations with antibioticsD07CA Corticosteroids, weak,combinations with antibioticsD07CB Corticosteroids, moderatelypotent, combinations withantibioticsD07CC Corticosteroids, potent,combinations with antibioticsD07CD Corticosteroids, very potent,combinations with antibioticsD07CA - Max 100gD07CB - Max 50gD07CC - Max 15gD07CD - Max 15gD08A Antiseptics anddisinfectantsLiquid antiseptics/ disinfectants - 1LitreOthers - max 60gD10A Anti-acne preparations fortopical useExcept for D10AA Corticosteroids,combinations for treatment of acneD11AF Wart and anti-cornpreparationsLiquid preparation - max 250ml(recommended to be used with adispenser)Bar - max 100gAll others - max 60gMax 15mlM02A Topical products for jointand muscular painD11AX11 HyperpigmentationLiquid – 250mlOthers, Max – 60gMax 60gReference: Circulars(bil 16) dlm bpfk02/5/1.3.pdfBil (22) dlm BPFK/02/5/1.3.pdfBil (21) dlm.BPFK/02/5/1.3.pdfBil (24) dlm BPFK/02/5/1.3.pdf(1) dlm. BPFK/02/5/1.4Bil (4) dlm BPFK/PPP/01/03 Jld 1National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 425

Drug Registration Guidance Document (DRGD)APPENDIX 11:GUIDELINE ON FILLING THE ONLINE APPLICATION FORMFOR PRODUCT REGISTRATION VIA QUEST SYSTEMIMPORTANT NOTES:Online application forms are available for different product categories in the QUESTsystem:a) Pharmaceuticals;b) Health Supplements and Natural Products.This appendix may not follow the sequence of the online registration forms.Applicant shall follow and comply with all requirements in the online applicationforms as well as any supplementary documentation requested by the Authority,whichever it may deems fit.Applicant shall ensure that you have clicked on the appropriate section of the displaypanel and fill the correct application form.Applicants are advised to read the explanatory notes in this appendix, as well asrelevant ASEAN or ICH guidelines and checklists, for full information on requirementfor product registration. In order to facilitate the evaluation process the Authority,applicants shall conform to these guidelines as well as the main guidance document.The Authority reserves the right to request for supplementary information in certaincases.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 426

Drug Registration Guidance Document (DRGD)Outline:11.1 Product Classification11.1.1 Pharmaceuticals11.1.2 Health Supplements and Natural Products11.2 Submission of Application11.2.1 Step 1: Product Validation11.2.2 Step 2: New Registration Application FormPart I – Administrative Data and Product Information- Section A: Product Particulars- Section B: Product Formula- Section C: Particulars of Packing- Section D: Label (Mockup) for Immediate Container, Outer Carton andProposed Package Insert- Section E/ Section F: Supplementary DocumentationPart II, III & IV – Quality , Nonclinical Document & Clinical DocumentNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 427

Drug Registration Guidance Document (DRGD)11.2 PRODUCT CLASSIFICATIONApplicant shall ensure correct product category as listed below in order to determinethe method of evaluation i.e. full evaluation (*) or abridged evaluation (**) in whichavailable as separate modules for application.11.2.1 Pharmaceuticalsi) New Drug Products *ii) Biologicals *iii) Generics (Scheduled Poison) *iv) Generics (Non-Scheduled Poison) (or known as OTC/ non-prescription) -other than listed at v) *v) Generics (Non-Scheduled Poison) **, which include, but not limited to thefollowing:Antiseptics/ skin disinfectants;Locally-acting lozenges/ pastilles;Topical analgesic/ counter-irritants;Topical nasal decongestants;Emollient/ demulcent/ skin protectants;Keratolytics;Anti-dandruff;Oral care;Anti-acne;Medicated plasters/ patch/ pad; andTopical antibacterial.11.2.2 Health Supplements and Natural Products **Application form for registration for Health Supplements; and Natural Products(or termed as Traditional Products) are available under Abridged module.Do not use the pharmaceuticals module for these product categories.11.2 SUBMISSION OF APPLICATIONAny application for a product registration shall follow a 2-step process i.e. Step 1(Product Validation) and Step 2, as described below:National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 428

Drug Registration Guidance Document (DRGD)11.2.2 STEP 1: PRODUCT VALIDATIONAll fields are compulsory to be entered.Option is given either to accept the validation result and submit; or overrideand manually select.Once validation is verified and submitted, the related application form underStep 2 will be displayed.Information entered in Step 1 will be captured in the database and need notbe re-entered at Step 2.[1] Product NameProduct name, dosage form and strength shall be entered.(e.g. X Brand Paracetamol Tablet 500mg)Product name is defined as a name given to a product which may beeither a proprietary name (an invented name); or a generic name(common name) or scientific name, together with a trade mark or thename of the manufacturer.Product name shall not imply the following:a. Tricky, confusion and against the law;b. Scandal and offensive;c. Prejudice;d. Well-known;e. The name which may sound like or had been used for a product thathas been revoked due to safety concerns;f. Any other name which deemed inappropriate by the Authority.The invented name shall not be liable to confusion with the commonname.The generic name means the international non-proprietary namerecommended by WHO (rINN), or if one does not exist, the usualapproved name.The product name shall be shown on the product labelling i.e. immediatelabel, outer unit carton, package insert and patient information leaflet.Dosage form and strength of product would need to be entered as part ofproduct name to allow for multiple dosage forms (e.g. tablet, capsule) andstrengths (e.g. 200mg and 400mg) for any particular named (proprietary orgeneric) product.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 429

Drug Registration Guidance Document (DRGD)In any event if found that the product name is similar to another registeredproduct, NPCB reserves the rights to request for the change of the productname.[2] Dosage FormPlease select dosage form and further select „in the form of‟ from the dropdownlist.For example, a tablet may be in the form of chewable, coated (enteric,film, or sugar), uncoated, dispersible, effervescent, extended release,subligual, etc.The form that correctly describes it in terms of its product quality controlspecifications and performance shall be selected.A separate application for registration is required for each dosage form.[3] Active Ingredientsi) Name of Active Ingredient:Please refer Appendix 8.1 List of Prohibited and Restricted ActiveIngredients and Combinations.Please select active ingredient from the search database by clickingbutton „click here to search‟. If an active ingredient is not listed in thedatabase, please click button „Not Listed Ingredient‟. Automatic e-mailwill be send to NPCB for verification. Please ensure that the spelling isaccurate.The actual raw material that is employed in the manufacturing processshall be named. For example:- Where the raw material used is the salt (e.g. ampicillin trihydrate)which will yield an equivalent effective component from its basecontent (i.e. ampicillin), the substance name is the salt and theequivalent base component should be indicated in remarks onsubstance (if any) field. ***- Similarly where a chemical is a component in the ingredient (e.g.iron in ferrous sulfate; or EPA and DHA in fish oil), the componentdetails shall be stated in the remarks field if a label claim of theNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 430

Drug Registration Guidance Document (DRGD)component is made for the product, and the actual raw materialused declared as the active ingredient.International Non-proprietary Names (INN), approved names,pharmacopoeia names of ingredients shall be used whenever possible.After each ingredient entry is correctly made, click the button „add/save‟. The button „remove‟ will allow for corrections to an entry underthis heading. To remove item, please select item from the listing andclick „remove‟.ii) Strength of active ingredient:Please enter strength of active ingredient (numerical) and then selectunit weights and measures from the drop-down list.Content of ingredients shall be expressed as appropriate in thefollowing manner :a. quantity per dose unit(e.g. for unit dose formulations - tablet, capsule, lozenge, etc.)b. percentage composition - %w/w, %w/v, %v/v, etc.(e.g. for products without defined dose unit such as ointments,creams, solutions, etc.)c. weight per ml.(e.g. for solutions, injections, etc.)d. quantity (percentage or amount) per measured dose(e.g. oral liquids, metered aerosols, drops, etc.)Metric weights and measures shall be used.In cases where product contains active ingredient(s) that cannot bedefinitely identified (e.g. certain biological products) state the name ofthe material to which activity is ascribed and, where appropriate, thepotency or activity of the product.iii) Remarks on active ingredient (if any):***This field shall be used where the raw material in product formulationyields an equivalent active component.After each ingredient entry is correctly made, click the „add/ save‟ button. Theremove button will allow for corrections to an entry under this heading. Toremove item, select item from the listing and click remove.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 431

Drug Registration Guidance Document (DRGD)[4] ExcipientPlease refer Appendix 8.2 List of Prohibited and Restricted Excipients; andAppendix 8.3 Lists of Permitted and Restricted Colouring Agents.Details are as for [3] Active Ingredients stated above.Please enter function of excipients, e.g. sweetener, preservative,thickening agent, etc. which can be selected from the drop-down list.[5] Any Animal OriginClick the appropriate button „Yes‟ or „No‟.[6] ManufacturerDefinition of Manufacturer: A company that carries out at least one stepof production as well as the final release of the finished product.Click button „click here to search‟ to select manufacturer listed in thedatabase. For a new manufacturer which is not listed in the databasesearch, please click „Not Listed Manufacturer‟ button. Automatic e-mail willbe send to NPCB for verification.[7] Is The Selected Manufacturer a Contract Manufacturer?Status as to whether the declared manufacturer is a contract manufactureror otherwise, has to be entered. Click the appropriate button „Yes‟ or „No‟.[8] Is This Product Second Source?Click the appropriate button „Yes‟ or „No‟.If yes, please attach letter of declaration stating that this product is asecond source product; and provide registration number and productname of the first source.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 432

Drug Registration Guidance Document (DRGD)[9] Does This Product Contain Any Premix?Click the appropriate button „Yes‟ or „No‟.If yes, please provide the following details:i) State your premix formj) Manufacturer namek) Manufacturer addressl) Certificate of Good Manufacturing Practice (GMP)m) Formulationn) Manufacturing Processo) Specification of Analysisp) Certificate of Analysis (CoA)[10] Is This a Replacement Product?Click the appropriate button „Yes‟ or „No‟.If yes, please attach letter of declaration stating that this product is areplacement product; and provide registration number and product nameof the replaced product.[11] Other Manufacturer (Repacker)Click the appropriate button „Yes‟ or „No‟.Please enter name of company and click button „search‟ to select othermanufacturer (repacker) listed in the database. For a new othermanufacturer (repacker) which is not listed in the database search, pleaseclick „Not Listed Manufacturer‟ button. Automatic e-mail will be send toNPCB for verification.Select from processing type drop-down list, e.g. assembly, packing,production, labelling, fill and finish, others.[12] Is This an Imported Product?Click the appropriate button „Yes‟ or „No‟.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 433

Drug Registration Guidance Document (DRGD)11.2.2 STEP 2: NEW REGISTRATION APPLICATION FORMPlease click at „Section List‟ button to display the application form at Step 2. Therequirement displayed will depend on the category of product being selected forregistration submission:Abridged Evaluation for certain **OTCs, health supplements and naturalproducts;Generic Pharmaceutical Products - Parts I & II;Existing chemical or biological entity(s) in new dosage form - Parts I & IItogether with pharmacokinetic data;NDP and Biologics - Parts I to Part IV:- Part I - Administrative Data and Product Information- Part II - Quality(For details of Part II, please refer Section C: Quality Control inthe main DRGD)- Part III - Nonclinical Document- Part IV - Clinical Document.Please refer Glossary developed for the ACTD and ACTR. The definitions used inthe glossary have been developed for the ASEAN Common Technical Dossier(ACTD) and Common Technical Requirements (ACTR). They are not necessarilymeaningful outside the scope of the specific parts of ACTD and ACTR to which theyrefer.PART I – ADMINISTRATIVE DATA AND PRODUCT INFORMATIONSECTION A: PRODUCT PARTICULARSDetails of the following as entered under Step 1 will appear automatically in theapplication form:1. Product name;2. Name and Strength of Active IngredientsName and Strength of Excipients; and3. Dosage form.Other fields as follow, shall be completed:4. Product Description:State, briefly on visual and physical characteristics of the product,including (where applicable):Shape, size, superficial markings for identification purposes, colour, odour,taste, consistency, type of tablet coating, type of capsule, etc.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 434

Drug Registration Guidance Document (DRGD)When describing liquids, state clearly whether it is in the form of a solution(clear), suspension, emulsion, etc.5. Pharmacodynamics (for full evaluation only)Please provide a concise and comprehensive summary of thepharmacological profile:Main and supplementary pharmacological effects (mechanism of action,actions other than the therapeutic effects);Relevant pharmacokinetics (absorption, plasma-protein binding,distribution, biotransformation, metabolism, excretion, etc);Bioavailability and bioequivalence studies in man.6. Pharmacokinetics (for full evaluation only)Details are as for A5.1 Pharmacodynamics stated above.7. IndicationState briefly on the recommended clinical use(s) of product, indicatingclearly whether curative, palliative, adjunctive, diagnostic, etc.Indications should be specific; phrases such as „associated conditions‟ or„allied diseases‟ would not normally be considered appropriate.Indications other than those specified and accepted at the time ofregistration must not be included in any product literature, data sheets,package inserts, labels, etc. without prior permission of the Authority.Should it be desired to include new indications, an application shall be filedto the Authority together with supporting clinical documentation onevidence of efficacy and safety for the additional uses (indications).In the case of products which are to be used as health supplements, noclaims shall be made for the prevention and treatment of disease states.For natural products, please state briefly on recommended use(s) of theproduct, starting with the phrase “Traditionally used for...../Homeopathyically used for......”.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 435

Drug Registration Guidance Document (DRGD)8. Recommended Dose OR Dose/ Use InstructionRecommended Dose (for full evaluation only):Please state the dose (normal dose, dose range) and dosage schedule(frequency, duration); and route of administration appropriate for eachtherapeutic indication.Dosage for adults, and, children (where appropriate) shall be stated.Dosage adjustments for special conditions, e.g. renal, hepatic, cardiac,nutritional insufficiencies (where relevant) shall be stated.Where appropriate, diluents and instructions for dilution, reconstitution anduse or administration of the product shall be clearly stated.Distinction shall be made between therapeutic and prophylactic doses,and between dosages for different clinical uses, where applicable.Ensure that dosage recommendation is relevant and appropriate for theproduct.Dose/ Use Instruction (for abridged evaluation only):State the dose (normal dose, dose range) and dosage schedule(frequency, duration) [and route of administration appropriate for eachtherapeutic indication]. Dosage for adults, and where appropriate children,should be stated.Dosage adjustments for special conditions e.g. renal, hepatic, cardiac,nutritional insufficiencies, where relevant, shall be stated.9. Route of Administration (for full evaluation only)Details are as for Recommended Dose stated above.Please select route of administration from the drop-down list, e.g.intramuscular, oral, rectal, sublingual, etc.10. ContraindicationPlease state conditions for which or under which the product shall not beused.Indicate clearly which conditions are :National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 436

Drug Registration Guidance Document (DRGD)- absolutely contraindicated;- contraindicated but may be used under special circumstances andwhat precautions to be taken in such cases.Where there is likelihood that additives are added, especially forintravenous solutions, foreseeable contraindicated additives shall bementioned (where applicable).Concurrent drug therapy which are contraindicated shall also be includedwhere possible (where applicable).11. Warnings and PrecautionsPlease state briefly on warnings and precautions, where necessary toensure safe use; and efficacious (where applicable) of the product;(e.g. caution against giving to children and elderly; against driving motorvehicles or manning heavy machinery after intake of product; use inpregnancy and lactation; in infants; etc.)12. Interactions With Other MedicamentsPlease state interactions which are observed and/or for which there ispotential clinical significance.Interactions may occur with:- medicinal products used for the same indication;- medicinal products used for other indications;- meals, or specific types of food.13. Pregnancy and LactationUse in Pregnancy:The following shall be stated:a) conclusions from the animal reproduction/ fertility study and the humanexperience;b) the risk in humans at different stages of pregnancy, as assessed froma);c) information on the possibility of using the medical product in fertile andpregnant women.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 437

Drug Registration Guidance Document (DRGD)Use in Lactation:When the active substance(s) or its metabolites are excreted in milk,recommendations as to whether to stop or continue breast feeding, andthe likelihood and degree of adverse reaction in infant shall be stated.For abridged evaluation, please state any effect on pregnancy and lactation, ifapplicable.14. Side Effects/ Adverse ReactionsPlease state in order for severity and frequency, the side effects, adversereactions, toxic effects, etc. (i.e. reactions, toxic effects, other than thosedesired therapeutically) including reactions such as allergy,hypersensitivity, drug dependence, addiction, carcinogenicity, tolerance,liver/ kidney toxicity etc.Indicate also symptoms and sites of effects/ reactions.Reactions, whether minor or serious shall be stated.Severity, reversible, frequency of occurrence shall be indicated, whereverpossible.Clinical tests for detection of „sensitive‟ patients, measure for managementof adverse reactions developed shall be described wherever possible.15. Signs and Symptoms of Overdose and TreatmentPlease state briefly symptoms of overdose/ poisoning, and where possible,recommended treatment and antidotes for overdose/ poisoning.16. Storage ConditionsPlease state the recommended storage conditions (temperature, humidity,light etc.).Information include storage condition before first opening, afterreconstitution and/or after opening and for all the listed pack types shallalso be provided, where applicable. Stability data to support such storagecondition shall be submitted.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 438

Drug Registration Guidance Document (DRGD)17. Shelf LifeShelf life for all the listed pack types shall be supported by stability data.Information include shelf life before first opening, after reconstitutionand/or after opening where applicable shall also be provided. Stability datato support such shelf life shall be submitted.Evidence is required to demonstrate that the product is stable which meetsthe finished product shelf life specifications throughout its proposed shelflifeand toxic decomposition products are not produced in significantamounts during this period; potency, sterility and efficacy of preservative,etc. are maintained.18. Therapeutic CodePlease indicate WHO assigned ATC code for each distinct therapeuticindication proposed for a product, if such a code is available. Click button„click here to search‟ to search the code via database athttp://www.whocc.no/atcddd/.For natural products, please select “Traditional/ Homeopathy” from thelisted button.After completion of Section A has been done, please click Section List for display ofmain page of application form and select Section B: Product Formula, or click button„next‟ after saving the entered data.SECTION B: PRODUCT FORMULAa) For full evaluation requirement, B1.1 and B1.2 as described below is requiredunder Section B: Product Formula. Data pertaining to quality of product isrequired to be submitted under Part II: Quality of Product.B1.1 Batch Manufacturing FormulaPlease state batch size and actual batch manufacturing masterformula.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 439

Drug Registration Guidance Document (DRGD)Data from validation step will be captured in terms of substance name,type (active or excipient ingredient), function and quantity per unitdose.Other information such as overage (where applicable) shall be entered.B1.2 Attachment of the Batch Manufacturing Formula DocumentationThe attachment shall be submitted.b) For abridged evaluation requirement, Batch Manufacturing Formula is requiredunder B1.1 and Attachment of the Batch Manufacturing Formula documentationis required under B4 of the same section i.e. Section B.Whereas B2.1, B3, B4 and B5 appear as below:B2.1 Manufacturing processPlease state a brief description of the manufacturing process.Essential points of each stage of manufacturing process and adescription of the assembling of the product into final containers shallbe covered. If the product is repacked/ assembled by anothermanufacturer, details of repacking/assembly and quality control shallbe supplied.An attachment of the manufacturing process, in the form of a flowchart can be submitted under B2.2.B3. In-Process Quality ControlPlease attach document for In-Process Quality Control to provide asummary of the tests performed, stages at which they are done, andthe frequency of sampling and number of samples taken each time.Specifications for quality assurance of the product shall be supplied.B4. Attachment of Finished Product Specification DocumentationPlease attach document for Finished Product Specification to providedetails of quality control specifications, including a list of tests for bothrelease and shelf life specifications (if they are different); and state thelimits of acceptance.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 440

Drug Registration Guidance Document (DRGD)B5. Attachment of Stability Data DocumentationReports of stability studies shall provide details of :- the batches placed under study (a minimum of 2 batches arerequired);- containers/ packaging type;- conditions of storage during study (temperature, humidity, etc);- duration of study and frequency (interval) of the tests/ observations;- the tests performed (including degradation products beingmonitored) and acceptance limits.SECTION C: PARTICULARS OF PACKINGThis section is subjected to requirements as stated in Appendix 10: Guide forImplementation of Patient Dispensing Pack for Pharmaceutical Products inMalaysia. Please refer the appendix for details.Please enter particulars of packing in the following sub-sections:C1 : Pack Size- Please select pack size by weight or volume or quantity; and unitC2 : Immediate Container Type- Please select container type, e.g. aluminium, glass, metal, paper, plastic,others (if others, please specify)- Please enter description of container type- Please attach attachment of container type at table appeared after „Add‟button at the bottom page is clickedC3 : Barcode/ Serial No.- Please key in if any (optional)C4 : Recommended Distributor‟s Price- Please key in if any (optional)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 441

Drug Registration Guidance Document (DRGD)C5 : Recommended Retail Price- Please key in if any (optional)and then click button „Add‟ to save all the entered informations.Note:To add next particulars, repeat the same process until all packings are listedaccordingly. To remove any item from the listing, select item from the listing andclick the “Remove” button.SECTION D: LABEL (MOCKUP) FOR IMMEDIATE CONTAINER, OUTERCARTON AND PROPOSED PACKAGE INSERTThis section is subjected to requirements as stated in Appendix 9: LabellingRequirements and other appendices (where applicable). Please refer theappendices for details.Please attached label (mock-up) i.e. draft of the actual product label andproposed package insert at the following sub-sections:D1. Label (Mock-up) for Immediate ContainerD2. Label (Mock-up) for Outer Carton (Unit Carton)D3. Proposed Package InsertSECTION E/ SECTION F: SUPPLEMENTARY DOCUMENTATION (ANDPARTICULARS OF PRODUCT OWNER, MANUFACTURER, IMPORTER ANDOTHER MANUFACTURER)a) Product OwnerPlease select one of the following for status of product owner:- Manufacturer or- Product registration holder or- Product registration holder & manufacturer or- Others (If the product owner is neither of the above status) – Please entername and address of the product owner.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 442

Drug Registration Guidance Document (DRGD)b) Letter of Authorization from Product OwnerAll applications for registration shall be accompanied with Letter ofAuthorization from product owner.(Not applicable if the Product Registration Holder is Product Owner).Letters of Authorization (LOA) shall be valid and current at the time ofsubmission.The LOA shall be on the product owner‟s original letterhead and be dated andsigned by the Managing Director, President, CEO or an equivalent personwho has overall responsibility for the company or organization.The LOA shall state the name of the product concerned and also the nameand actual plant address of the manufacturer(s) involved in the manufactureof the product.c) Letter of Appointment of Contract Manufacturer from Product OwnerPlease attach (if applicable).Applicable for product which is contract manufactured by a manufacturer whois not the product owner.d) Letter of Acceptance from Contract ManufacturerPlease attach (if applicable).The letter of acceptance from the manufacturer shall be on the manufacturer‟soriginal letterhead and be dated and signed by the Managing Director,President, CEO or an equivalent person who has overall responsibility for thecompany or organization.The letter of acceptance shall state the name of the product concerned andalso the name and actual plant address of the manufacturer(s) involved in themanufacture of the product.e) Is the active ingredients patented in Malaysia?Click the appropriate button „Yes‟ or „No‟.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 443

Drug Registration Guidance Document (DRGD)If yes, please attach the related document.Applicants who hold valid patents shall provide documentary evidence of thenature and extent of their patents.f) Certificate of Pharmaceutical Product (CPP), Certificate of Free Sale (CFS)and Certificate of Good Manufacturing Practice (GMP)Please attach the certificates.Please key in issuing body, date of issue, date of expiry of the certificates. Ifthe issuing body is not listed, please select „Not Listed‟ button. Automaticemail will be sent to NPCB for verification.The certificates shall be valid and current at the time of submission.For imported products, the following requirements shall be furnished, either a:i) CPP from the competent authority in the country of origin; OR(Note: In the event a CPP is not available from the country manufacture,e.g. where a product is not licensed for sale in said country because itsmanufacturer is manufacturing under contract only for product owner fromanother country, the following alternatives may be considered: GMPCertification/ Manufacturing License for the manufacturer from the relevantcompetent authority, together with CPP from the country of the productowner; or CPP from country of release, if CPP from the country of theproduct owner is not available)ii) CFS and GMP from the relevant competent authorities is deemedacceptable by the Authority for health supplements and natural productsonly.CPP shall be in the format of the WHO Certification Scheme on the Quality ofPharmaceutical Products Moving in International Commerce & be issued bythe Health Authorities listed in the WHO Certification Scheme (list is availablefrom WHO website: http://www.who.int).CPP which is issued by EMA for products registered through the centralizedprocedure in EU will be accepted.CPP issued by the manufacturer or other authorities are not acceptable.If more than one manufacturer is involved in the manufacture of a product,GMP certification shall be available for all the manufacturers.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 444

Drug Registration Guidance Document (DRGD)The Authority reserves the right to conduct an inspection on anymanufacturing site.Unless otherwise supported by justifications acceptable to the Authority, thefollowing products are unlikely to be registered:i) products not licensed/ certified for sale in the country of manufacture/product owner;ii) products manufactured for export only (imported products).g) Is this product licensed to be placed on the market for use in the exportingcountry?If no, please state the reason.h) Is the product on the market in the exporting country?If no, please state the reason.i) Summary of Product Characteristics (SPC)Please attach (where applicable).j) Patient Information Leaflet (PIL)Please attach (where applicable).k) Attachment of Protocol Analysis, Analytical ValidationPlease attach (where applicable).l) Certificate of Analysis (CoA) for Finished ProductFor two (2) batches.Compulsory for imported product.Please attach the certificate (which must be complete with the productspecification and results).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 445

Drug Registration Guidance Document (DRGD)m) Importer and Store AddressPlease key in (where applicable).n) Other Supporting DocumentPlease attach (if any).PART II, III & IV – QUALITY , NONCLINICAL DOCUMENT & CLINICALDOCUMENTIn order to complete these parts, please refer the main DRGD as well as ASEANCommon Technical Requirements Guidance Documents, and the followingdocuments (where applicable):a) Appendix 2: Requirements for Product Registrationb) Appendix 3: Guidelines on Registration of Biologicsc) Appendix 4: Guideline on Registration of Health Supplementsd) Appendix 5: Guideline on Registration of Natural Productse) Appendix 6: Guideline on Regulatory Control of Active PharmaceuticalIngredients (API)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 446

Drug Registration Guidance Document (DRGD)APPENDIX 12CONDITIONS AND SUPPORTING DOCUMENTS REQUIRED FOR AN APPLICATION OFVARIATIONa) VARIATION TYPE I (MINOR VARIATION)NO.VARIATION TYPE I(MINOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED1. Change in name ofmanufacturer and/or othermanufacturers withoutany change in address ofsite.E13(manufacturer)E14 (othermanufacturers)D1D2D3E6E12E2 (manufacturer)E3 (othermanufacturers)D1D2D3F6F12CONDITIONS1. The manufacturing/ other manufacturing site of thedrug product remains unchanged.2. No other changes to the label/ package insertexcept for the change of the name of amanufacturer/ other manufacturers of the drugproduct.3. The manufacturing site remains the same.SUPPORTING DOCUMENTS1. For local manufacturers/ other manufacturers:Certificate of name change i.e. Form 13 CompanyAct 1965.(Please attach the supporting document at E12/F12).2. For foreign manufacturers/ other manufacturers:A valid Good Manufacturing Practice (GMP)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 447

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE I(MINOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIEDcertificate.3. Official letter from product owner authorizing themanufacturer with new name to manufacture thedrug product.4. Revised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).2. Replacement, addition ordeletion of company logoon the packagingcomponents (without anychanges ongraphic or label content)D1D2D3D1D2D3SUPPORTING DOCUMENTRevised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 448

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE I(MINOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED3. Change in product owner E1.1E1.2E2.1E2.2E12D1D2D3(if applicable)E1F1F2.1F2.2F12D1D2D3(if applicable)CONDITIONS1. The Product Registration Holder remains the same.Submission shall be done by current PRH.2. The manufacturing site remains the same.SUPPORTING DOCUMENTS1. Letter of confirmation for change in productownership countersigned by both old and newproduct owner.2. Official letter from the new product owner declaringthe change, and authorizing the local license holderto be responsible for the product license.3. In the case of a contract manufacturer, newproduct owner to issue Letter Of Appointment tocontract manufacturer and contract manufacturer toissue Letter Of Acceptance.4. Revised labels and package insert (if applicable).4. Change in importer/ storeaddress.E13.1(importer)E15(store address)E2.1(importer)E4(store address)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 449

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE I(MINOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED5. Change or addition ofimprints, bossing orother markings (exceptscoring/break lines) ontablets or printing oncapsules, includingreplacement, or additionof inks used for productmarking.A4P1P5.1P5.2D3E8(if applicable)E9A2D3F8(if applicable)B4F9CONDITIONS1. Any new ink must be of oral pharmaceutical/ foodgrade and not a listed banned substance.2. Release and end-of-shelf life specifications of thedrug product remain unchanged except forappearance.3. New markings do not cause confusion with otherregistered products.SUPPORTING DOCUMENTS1. Revised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).2. Release and end-of-shelf life specifications of thedrug product with the new product description.3. Certificate of analysis (CoA) of new ink.4. Details of the proposed new inks (whereapplicable)5. Detailed drawing or written description of thecurrent and proposed imprint/ bossing/ markings.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 450

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE I(MINOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED6. Change in shape ordimensions of thecontainer or closurewithout any otherchanges.P7C (if applicable)C (if applicable)CONDITIONS1. The primary packaging material of container orclosure remains the same.2. Not applicable for sterile products.3. No change is made to the product shelf life and/orstorage conditions.4. No change in the qualitative or quantitativecomposition of the container and/or closure and thechange do not affect the delivery, use, safety orstability of the drug product.SUPPORTING DOCUMENTSRevised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).7. Change in pack size ofthe drug product(Finished product),without change inprimary packagingmaterial.Change in the numberor units (e.g. tablets,ampoules) in a pack.CD1D2D3E8(if applicable)P7CD1D2D3F8(if applicable)CONDITIONS1. The primary packaging material of container orclosure remains the same. Primary packagingmaterial is the material that is in contact with thefinished product and may affect the delivery, use,safety or stability.2. No other changes to the label/ package insertexcept for the pack size.3. The new size is consistent with the dosageregimen and duration of use as approved in theNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 451

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE I(MINOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIEDpackage insert.Change in volume ofnon sterilepreparationsSUPPORTING DOCUMENTSRevised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).8. Tightening of specificationlimits of drug product(finished product ) and/ordrug substance (activeingredient )E9E10E11P5.1P5.2P5.4S4.1S4.2S 4.4B4F9F10(finished product)F11(active ingredient)CONDITION1. Any change should be within the range of currentlyapproved limits.SUPPORTING DOCUMENTS1. Tabulation of the current and revised release andshelf life specifications of the drug product/drugsubstance with changes highlighted.2. Certificate of Analysis (CoA) for drug product ordrug substance.3. Protocol analysis for drug product/ drug substance.4. Revised specification of drug substance.5. Specifications of drug product.6. Batch analysis of drug product.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 452

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE I(MINOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED9. Change in particular ofmanufacturer of drugsubstance (activeingredient ) without anychange in specificationa. Change inmanufacturer of drugsubstanceS2.1S4.4F11CONDITIONS1. Finished product release and end of shelf lifespecification remains the same.2. Method of preparation and route of synthesisremain the same.3. For (c), the manufacturing site of the drugsubstance remains the same.SUPPORTING DOCUMENTSb. Addition ofmanufacturer of drugsubstancec. Change in name and/orrephrasing of addressof a manufacturer ofdrug substance.For (a) & (b):1. Certificate of Analysis (CoA) for drug substance(Also include CoA from all of the drug substancemanufacturers proposed to be retained) or batchanalysis of drug substance.2. Certificate of Suitability (CEP) for the drugsubstance or Drug Master File; or reference toDMF by USFDA, TGA or JFDA (if applicable).3. Tabulation of the differences compared with theregistered manufacture information (if applicable).For (c):1. Updated information of the manufacturer of thedrug substance.2. Official document/ evidence when required.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 453

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE I(MINOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED10. Change in secondarypackaging material (orchange in any part of theprimary packagingmaterial that is not incontact with the finishedproduct (e.g. colour of flipoff caps, colour code ringson ampoules, change ofneedle shields i.e.different plastic used).CD2D3P7CD2D3CONDITIONS1. The primary packaging material of container orclosure remains the same.2. The change does not affect the delivery, use,safety or stability of the finished productSUPPORTING DOCUMENTRevised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).11. Change in testingprocedure of an excipientP4.2P4.3Not applicableCONDITIONSpecifications of the excipient and drug product(finished product) remain the same.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 454

Drug Registration Guidance Document (DRGD)b) VARIATION TYPE II (MAJOR VARIATION)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED1. Change of product name. A1D1D2D3E4(if applicable)E8 (if applicable)A1D1D2D3(if applicable)F4(if applicable)F8 (if applicable)CONDITIONS1. No change to product (formulation, specificationetc) except for the product name2. No confusion with other already registeredproduct‟s name.3. The new name does not (1) suggest greater safetyor efficacy than supported by clinical data (2)imply a therapeutic use (3) imply superiority overanother similar product (4) imply the presence ofsubstance(s) not present in the product.4. Health Supplements & Natural Products - Pleaserefer Appendix 4 and Appendix 5, respectively.SUPPORTING DOCUMENTS1. Revised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).2. Letter confirming change in name only issued bythe product owner or PRH.3. A declaration from the applicant that there is nochange to the product/ label except name.4. Updated CPP if applicable.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 455

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED2. Change in content ofleaflet or prescribinginformation/ PIL/ SPC.A1 – A17D1D2D3E7E8(if applicable)A1 – A13D1D2D3F7F8F12CONDITIONAs a subsequent change due to revision of datasheetapproved by regulatory authority e.g. Summary ofProduct Characteristics (SPC), or US Package Insert(USPI) or equivalent document.For natural products:Proposed indication shall be within those listed underAppendix 5.SUPPORTING DOCUMENTS1. For all types of product please provide reviseddrafts of the package insert and labelingincorporating the proposed variation with:a. Copy with amendments clearly marked.b. Clean copy of the proposed new packageinsert.2. For innovator product please provide:a. Datasheet approved by regulatory authoritye.g. Summary of Product Characteristics(SPC), or US Package Insert (USPI) orequivalent document.b. Conclusion or abstract of recent PeriodicSafety Update Report where applicable.c. Expert Clinical Report (if applicable)d. Company Core Datasheet where applicable.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 456

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED3. For generic product please provide supportingdocuments e.g. Martindale or equivalentdocument to support the change.4. For natural products, please provide:a) Justification for the proposed change.b) Supporting documents from the clinicalpapers, Chinese Pharmacopoeia and/orherbal monograph/ compendium on thetherapeutic uses and safety aspect of therelevant active ingredient/s.3. Change in content of labelinclusive of change ingraphics/ artwork.D1D2D3D1D2D3CONDITIONSFor Natural Products Please refer to (List ofProhibited Visuals/ Graphics On Label of NaturalProducts in Appendix 5)SUPPORTING DOCUMENTRevised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 457

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED4. Change in manufacturingprocess of the finishedproductE11P3.2P3.2.1P3.3P3.4P5.1P5.4P8B2.1B2.2B3B4B5F10(CoA offinishedproduct)CONDITIONS1. The same currently approved manufacturing site.2. The change does not cause a negative impact onthe quality, safety and efficacy of the drug product.3. Finished product specification is not adverselyaffected.SUPPORTING DOCUMENTS1. Description of the proposed change inmanufacturing process.2. Comparative batch analysis data between thecurrently approved and proposed manufacturingprocesses OR Certificate of Analysis (CoA), whereapplicable.3. Stability data of drug product (please refer toASEAN Guideline on Stability Study of DrugProduct) where applicable.4. Comparative dissolution profile data between theproducts manufactured in the currently approvedand proposed manufacturing process for oral soliddosage forms as per compendium and validationbatches, where applicable.5. Justification for not submitting a newbioequivalence study according to ASEANGuidelines for the Conduct of Bioavailability andBioequivalence Studies, where applicable.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 458

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIEDFor abridged-products, only supporting documents(1), (2) and (3) are required.Process validation report may be requested whendeemed necessary.5. Change in overage ofactive ingredientB1.2E11P5.4E12P8B1.2F10F12B5CONDITIONFinished product release and end of shelf lifespecification remains the same.SUPPORTING DOCUMENTS1. Certificate of Analysis (CoA) of drug product.2. Justification for the change.3. Stability data of drug product (please refer toASEAN Guideline on Stability Study of DrugProduct) where applicable.4. Batch manufacturing formula.5. Comparative batch analysis data of drug product.6. Table of comparison of proposed and currentbatch manufacturing formula.7. Letter of commitment to undertake the proposedchange under real time stability study.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 459

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED6. Replacement of anexcipient with acomparable excipientand/or change in contentof excipient.A2.1B1.2P1P4.1P4.2P3.2P3.2.1E11P5.4P8E12D1D2D3(if applicable)A4.2B1.2B2.1B2.2B3B4B5F10F12D1D2D3(if applicable)CONDITIONS1. Finished product release and end of shelf lifespecification remains the same.2. There is no change in dissolution profile for oralsolid dosage forms (where applicable).3. Replacement of an excipient with a comparableexcipient of the same functional characteristics.4. No changes on the specification of the excipientfor product specific requirements (e.g. particle sizeprofiles, polymorphic form, etc.), if applicable.5. Any new excipient does not include the use ofmaterials of human or animal origin for whichassessment is required of viral safety data.SUPPORTING DOCUMENTS1. Comparison of new and existing formula.2. Batch Manufacturing Formula.3. Excipient specification (if applicable).4. Manufacturing process with amendments.5. Certificate of Analysis (CoA) of drug product.6. Justification for not submitting a newbioequivalence study according to ASEANGuidelines for the Conduct of Bioavailability andBioequivalence Studies (where applicable).7. Comparative dissolution profile data of at leastone representative pilot/production batch of thedrug product between the currently approved andNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 460

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIEDproposed solid dosage forms formulation (whereapplicable).8. Stability data of drug product (please refer toASEAN Guideline On Stability Study of DrugProduct)9. Revised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).10. Batch analysis data.11. Product interchangeability/ equivalent evidence (ifany).12. Justification for the change supported byappropriate development of pharmaceutics.13. New unit formula for coating agent (whereapplicable).7. Change in batch size B1.2E11P5.4P3.4E12P3.2P3.2.1(if applicable)B1.2F10F12B2.1B2.2(if applicable)CONDITIONS1. The change does not affect the reproducibilityand/or consistency of the product.2. No change to the manufacturing method nor to thein-process controls other that those necessitatedby the change in batch-size, e.g. use of differentsize equipment.3. Finished product release and end of shelf lifespecification remains the same.SUPPORTING DOCUMENTS1. Comparative tabulated format of the proposed andNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 461

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIEDcurrent manufacturing formula.2. New batch manufacturing formula.3. Batch analysis data (in a comparative table).4. Certificate of analysis for 2 batches of drugproduct.5. Process validation report (may be requested whendeemed necessary).6. Justification for the change.7. Letter of commitment to undertake the proposedbatch size under real time stability studies.8. Description of the manufacturing process (ifapplicable).8. Change in hard capsuleshell (colour, size orsource)A4P1P8E11P4.5P5.4E12P5.1E9D1D2D3(if applicable)A2A3.2B4B5F9F10D1D2D3(if applicable)CONDITIONS1. Includes change of hard gelatin capsule tovegetable capsule but does not apply change fromhard gelatin capsule to soft gel capsule.2. Any new coloring agent used must be of oralpharmaceutical/ food grade and not a listedbanned substance.3. Same functional characteristics, no change indissolution profile for solid dosage forms4. Finished product release and shelf lifespecifications remain the same except for theproduct description.SUPPORTING DOCUMENTS1. Stability data of drug product (please refer toNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 462

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIEDASEAN Guideline on Stability Study of DrugProduct) where applicable.2. Certificate of analysis (CoA) of drug product withthe new description.3. For empty hard capsule made of ruminantssource, Transmitting Animal SpongiformEncephalopathy (TSE)-free certificate issued fromrelevant veterinary authority of the issuing country.4. Certificate of analysis of the new capsule shell.5. Revised specifications of drug product.6. Batch analysis data.7. Comparative dissolution profile data of drugproduct.8. Revised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 463

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED9. Change in finishedproduct or activeingredient specification(includes addition of anew test parameter)E9E10E11P5.1P5.4P5.6S4.1S4.2S4.3S4.4B4F9F10F11CONDITIONSThe change should not be the result of unexpectedevents arising during manufacture or because ofstability concerns.SUPPORTING DOCUMENTS1. For change in finished product specifications:a. Certificate of analysis of drug product as perthe new specifications:b. Comparative table of approved and proposedspecifications with justificationc. Appropriate analytical validation datad. Revised specifications of drug product.e. Revised analytical procedures.f. Batch analysis data of drug product.2. For change in active ingredient/ drug substancespecifications:a. Comparative table of approved and proposedspecifications with justificationb. Specification of drug substance,c. Analytical procedures of drug substance,d. Validation of analytical procedures,e. Batch analysis of drug substanceNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 464

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED10. Change to in-processtests or limits appliedduring manufacture of theproduct.P3.3P3.4E9E10B3F9CONDITIONS1. Includes tightening of in-process limits andaddition of new tests2. Release and shelf-life specifications of drugproduct remain unchangedSUPPORTING DOCUMENTS1. A description of the analytical methodology andsummary of validation data must be provided forall new analytical methods (where applicable).2. Revised in-process specifications together withjustification and relevant process validation data.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 465

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED11. Change or addition inprimary packagingmaterialCD1D2D3P3.2P3.2.1P7P8E8(if applicable),E12CD1D2D3(if applicable),B5,F8(if applicable)F12CONDITIONSRelease and shelf life specification remainsthe same.SUPPORTING DOCUMENTS1. Assembly process for the new packaging material/revised manufacturing process and revised flowchart (if any)2. Stability data of drug product (please refer toASEAN Guideline on Stability Study of DrugProduct) where applicable.3. Revised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).4. Justification for the change in packaging materialand appropriate scientific studies on the newpackaging.5. For semisolid and liquid dosage forms, proof mustbe provided that no interaction between thecontent and the packaging material occurs.(e.g. no migration of components of the proposedmaterial into the content and no loss ofcomponents of the product into the pack).6. Container closure system (if applicable).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 466

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED12. Change in shelf life offinished product:-a) As packaged for saleb) After first openingA16P8E12D1D2D3A13B5F12D1D2D3CONDITIONS1. For (a) & (b) - The studies must showconformance to the current shelf life specification.2. For (c) - Studies must show conformance to thecurrent shelf life specification for the reconstitutedproduct.c) After dilution/reconstitutionSUPPORTING DOCUMENTS1. Results of appropriate real time stability studiescovering the duration of proposed shelf-life of atleast 2 pilot/ production scale batches of theproduct in the authorized packaging materialas a package for sale and/orafter first opening and/orafter the dilution/ reconstitutionIn accordance with the ASEAN Guidelines on StabilityStudy of Drug Product; results of appropriatemicrobiological testing should be included (whereappropriate).2. Revised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).3. Justification letter for the change of shelf life of thedrug product (if applicable).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 467

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED13. Change in storageconditionsA15P8D1D2D3A12B5D1D2D3CONDITIONThe studies must show conformance to the currentshelf life specification.SUPPORTING DOCUMENTS1. Results of appropriate real time stability studiescovering the duration of currently approved endof-shelflife (at proposed storage condition) of atleast 2 pilot/ production scale batches of theproduct and in the authorized packaging materialin accordance with the ASEAN Guidelines onStability Study of Drug Product.2. Revised drafts of the package insert and labelingincorporating the proposed variation (ifapplicable).14. Appointment, deletion orchange of othermanufacturersD1D2D3E14E12E3F12D1D2D3SUPPORTING DOCUMENTS1. GMP certificates of the proposed othermanufacturers.2. Description of the manufacturing activity of allother manufacturers involved (includingassembling process).3. Letter of appointment and acceptance for contractof other manufacturers.4. Revised drafts of the labeling incorporating theproposed variation (where applicable).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 468

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIED15. Addition ordeletion of scoring/break line ontabletA4P1D1D2(if applicable)D3E9E11P5.1P5.4E12A2B4F9F10F12D1D2D3(if applicable)CONDITIONSFinished product release and shelf life specificationsremain the same except for the product description.SUPPORTING DOCUMENTS1. Certificate of analysis (CoA) FPQC X 1 batch(shall include data on the test of uniformity ofcontent of the subdivided parts of tablets atrelease).2. Revised drafts of the package insert and labelingincorporating the proposed variation (whereapplicable).3. Release and end-of-shelf life specifications of thedrug product with the new product description.16. Change in test procedureor analytical protocols offinished product.E9E10E11P5.4B4F9F10CONDITIONS1. Finished product specifications are not adverselyaffected.2. Appropriate analytical validation or re-validationstudies have been performed in accordance withrelevant guidelines.3. Results of method validation show new testprocedure to be at least equivalent to the formerprocedure.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 469

Drug Registration Guidance Document (DRGD)NO.VARIATION TYPE II(MAJOR VARIATION)FULLEVALUATIONAFFECTED FIELDSABRIDGEDEVALUATIONSUPPORTING DOCUMENTS REQUIRED ANDCONDITIONS APPLIEDSUPPORTING DOCUMENTS1. Appropriate verification/ validation data andcomparative analytical results between thecurrently approved and proposed test.2. Revised protocol of analysis.3. Certificate of analysis of drug product.17. Change or addition of fillvolume and/or change ofshape or dimension ofcontainer or closure for asterile solid and liquiddrug productP3.4P8E12CD1D2D3(if applicable)Not applicableCONDITIONS1. Release and end-of-shelf life specifications of thedrug product are not affected.2. The packaging material remains the same.SUPPORTING DOCUMENTS1. Justification that the proposed pack size isconsistent with the dosage regimen and durationof use as approved in the package insert.2. Validation data of the manufacturing process,sterilization and container closure system (ifapplicable).3. Stability data of drug product (please refer toASEAN Guideline on Stability Study of DrugProduct) where applicable.4. Revised drafts of the package insert and labelingincorporating the proposed variation, whereapplicable.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 470

Drug Registration Guidance Document (DRGD)APPENDIX 13:SUPPORTING DOCUMENTS REQUIRED FOR CHANGE OFMANUFACTURING SITE (COS) APPLICATIONNoDocument To Be Submitted1. Letter of authorization/ appointment from theproduct owner to authorize Product RegistrationHolder to submit the change of site application.In case of a contract manufacturer, a letter ofacceptance from the proposed contractmanufacturer to manufacture the product.TypeITypeIITypeIIITypeIVTypeV√ √ √ √ √2. Letter from the manufacturer/ product owner toclarify/ explain the need to change site ofmanufacture.For Type I:Letter of declaration stating the reason(s) forchange of manufacturing site and clearly state theproposed and current name and address ofmanufacturer3. Written declaration from the manufacturer to certifythat the manufacturing process, and the releaseand expiry (check) specifications of the product asthe same as already approved.OR√ √ √ √ √√ √ √ √ √If there are minor changes, to declare the „minorchanges‟ & justify the need for such changes.4. „Release‟ and „end-of-shelf life‟ specifications fromproposed site. √ √ √ √ √5. Original copy of the Certificate of Free Sale (CFS)and Good Manufacturing Practice (GMP)/Certificate of Pharmaceutical Product (CPP) fromthe source country of the new manufacturing site inthe case of an imported productOR√ √ √ √ √Letter of confirmation on GMP status or validmanufacturer‟s license for the new manufacturingsite.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 471

Drug Registration Guidance Document (DRGD)NoDocument To Be SubmittedTypeITypeIITypeIII6. Original copy of Certificate of Analysis (CoA) fromthe new manufacturing site. √ √ √TypeIVTypeV7. “Accelerated” and on-going stability data as perASEAN Guideline on Stability Study of DrugProduct and a letter of commitment to submit realtime stability data.For Type I:√ √ √ √Letter of commitment to submit stability datareport.8. Amended immediate label, outer label andpackage insert for the product from the proposedsite.√ √ √ √ √9. Process validation report as per ASEAN GuidelineOn Submission Of Manufacturing ProcessValidation Data For Drug Registration.For Type I:√ √ √ √Letter of commitment to submit process validationreport, if applicable10. Declaration and commitment that the manufacturerwill carry out continuous quality monitoring on thepost change products√11. Letter of commitment to submit stability data,certificate of analysis, process validation report(where applicable) and sample for laboratorytesting within 6 months of approval of site change.√12. A written plan for assessing the effect of thechange of site on the quality of the product with theobjective of demonstrating that the pre- and postchangeproducts are equivalent.√ √ √National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 472

Drug Registration Guidance Document (DRGD)NoDocument To Be SubmittedTypeITypeIITypeIIITypeIVTypeV13. Comparative dissolution profile between theproposed and current site for oral solid dosageforms that are entitled for “biowaiver”.For further information, please refer circular:Bil (31) dlm. BPFK/PPP/01/03ORReport of bioavailability and bioequivalencestudies for generic products.√√ORComparative dissolution profile between theproposed and current site for oral solid dosageforms for innovator products, if applicable.(Please refer to ASEAN Guidelines and list ofproducts requiring BA and BE study).14. Letter of commitment to submit comparativedissolution profile between the proposed andcurrent site for oral solid dosage forms that areentitled for “biowaiver”.For further information, please refer circular:Bil (31) dlm. BPFK/PPP/01/03ORLetter of commitment to submit report ofbioavailability and bioequivalence studies forgeneric products.√√ORLetter of commitment to submit comparativedissolution profile between the proposed andcurrent site for oral solid dosage forms forinnovator products, if applicable.(Please Refer to ASEAN Guidelines and list ofproducts requiring BA and BE study).National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 473

Drug Registration Guidance Document (DRGD)LIST OF UPDATESUPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCE1.January2013Section A, 7.Use of HalalLogoAddition of the following:a) Reference: Circular (95)dlm.BPFK/PPP/01/03 Jld. 2 at a)Generics (non-scheduled poison), excluding parenteraldosage form and veterinary products.b) As last paragraph:Applicant shall submit application for variation type II toNPCB for approval to affix halal logo on product label of aregistered product of which a halal certification has beengranted. A copy of the halal certificate must be submittedas a supporting document.Circular(95)dlm.BPFK/PPP/01/03Jld. 2, 26 December 2012:Penggunaan Logo HalalBagi ProdukFarmaseutikal berdaftarkategori produk bukanracun, OTC2.January2013Section A,1.3.2Classification ofFDI ProductsAddition of the following:Notes:Applicant shall verify on FDI product classification with NPCB inorder to determine whether the product shall be registered bythe Authority or otherwise.Reference: Circular (97)dlm.BPFK/PPP/01/03 Jld. 2Circular(97)dlm.BPFK/PPP/01/03Jld. 2, 27 December 2012:Pengkelasan ProdukFood-Drug InterfaceNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 474

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCE3.January2013Section E, 14.Maintenance ofRegistrationAt 14. Maintenance of Registration:Addition of the following paragraph:In order to maintain registration of an imported product, startingon 1 st January 2014, applicant shall comply with GMPrequirement as stated in the directive issued by the Director ofPharmaceutical Services under Regulation 29, CDCR 1984Arahan Bil. 1 Tahun 2012 Syarat Pendaftaran ProdukFarmaseutikal Dari Luar Negara Berkaitan Keperluan AmalanPerkilangan Baik (APB) (Reference: Circulars Bil (25) dlmBPFK/PPP/01/03 Jld 1 and Bil (96)dlm.BPFK/PPP/01/03 Jld. 2).The Authority shall not consider any renewal application thatfails to comply with the stipulated requirement.At 16.2.2 Conditions on Good Manufacturing Practice (GMP):Addition of a hyperlink of Bil (96)dlm.BPFK/PPP/01/03 Jld. 2), 28December 2012: Surat Pekeliling Bagi Direktif Mengenai SyaratPendaftaran Produk Farmaseutikal Dari Luar Negara BerkaitanKeperluan Amalan Perkilangan Baik (APB)Directive Bil (25) dlmBPFK/PPP/01/03 Jld 1, 9February 2012: DirektifMengenai SyaratPendaftaran ProdukFarmaseutikal Dari LuarNegara BerkaitanKeperluan AmalanPerkilangan Baik (APB)andCircular(96)dlm.BPFK/PPP/01/03Jld. 2, 28 December 2012:Surat Pekeliling BagiDirektif Mengenai SyaratPendaftaran ProdukFarmaseutikal Dari LuarNegara BerkaitanKeperluan AmalanPerkilangan Baik (APB)National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 475

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCE4.January2013Section A,1.3.2Classification ofFDI ProductsAddition of examples and a hyperlink of the related circularfor gamat (Stichopus spp.) at a) Main Criteria, number ii)Substances or ingredients used for therapeutic purposes shallnot be added to food. For examples: gypsum fibrosum, pearlpowder and gamat (stichopus spp.).Circular(98)dlm.BPFK/PPP/01/03Jld. 2, 8 January 2013:Keperluan PendaftaranProduk Food-DrugInterface yangmengandungi bahan aktifgamat (Stichopus spp)5.January2013Section D, 13.2LicenseApplicationFormAddition of a hyperlink at number 4, Import License, regardingrequirement of Certificate of Analysis (CoA) for each batch ofregistered product which is imported into Malaysia.Circular(99)dlm.BPFK/PPP/01/03Jld. 2, 11 January 2013:Sijil Analisa (Certificate ofAnalysis, COA) UntukSetiap Kelompok ProdukBerdaftar Yang DiimportKe MalaysiaNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 476

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCE6.January2013Appendix 5,Guideline onRegistration ofNaturalProducts- Amendment at 2.1.3 Prohibited/ Banned Ingredients:a) Table 1: Botanicals (and botanical ingredients) containingscheduled poisons as listed under the Poisons Act 1952,for ingredient “Valerian”, as follows:Species: Deletion of “Extract only”Constituent(s) of concern: Addition of “Valepotriates”.b) Table 4: List B: Botanicals which may be Adulterated withAristolochic Acid:Addition of botanical name starting at Cocculusorbiculatus DC. [Common or Other Names: Mokuboui(Japanese)] to the last botanical namesStephania tetrandra S. Moore and Vladimiria souliei(franch.) LingMemo from Sub-Section ofComplementary Medicine(53)dlm.BPFK/PPP/06/17Jilid 29, 18 January 2013- Amendment at 2.7.1 Statement to be stated on productlabel:“If symptoms persist, please consult a doctor.” and “This is anatural medicine/ Ini adalah ubat tradisional.” OR “This is ahomeopathy medicine/ Ini adalah ubat homeopati.” TOFor product with an indication “For general health/ wellbeing” or “Untuk kesihatan umum”, please state:- “Please consult your pharmacist / doctor before takingNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 477

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCEthis product or Sila merujuk kepada ahli farmasi/ doktorsebelum mengambil produk ini.”For product with an indication “To relieve symptomsfor…. (any illness)” or “untuk mengurangkan tandatanda/simptom….”, please state:- “Please consult your pharmacist/ doctor if symptomspersist/ worsen or Sila merujuk kepada ahli farmasi/doktor jika simptom berlarutan/ bertambah teruk.”“This is a traditional medicine/Ini adalah ubat tradisional.”OR “This is a homeopathy medicine/Ini adalah ubathomeopati.”Unless otherwise supported, all herbal/ traditionalproducts label shall state the following generalcautionary statement, EXCEPT for product withindication for men‟s health or product for children useonly:“Pregnancy and breastfeeding: Insufficient reliabledata”- Amendment at 2.7.2 Specific Labelling Statements/ Warning& Precautions:a) For product containing Royal Jelly: Addition of “(for oraluse)” after the word of “Royal Jelly”.b) Addition of new active ingredient i.e. “For productNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 478

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCEcontaining Propolis (for oral use), please state:- “This product contains propolis and may causesevere allergic reactions including fatalanaphylactic reaction in susceptible individuals.- Asthma and allergy sufferers may be at a greaterrisk.”Updates according to the circular (100)dlm.BPFK/PPP/01/03Jld. 2, 21 January 2013: Pemansuhan Pengeluaran SijilPerakuan Pendaftaran Produk (SPP), i.e.:7.January2013Section A,8.5.3 Certificateof RegistrationForm 1 (Certificate of Registration) for a product with theprovisions, conditions, limitations and etc. of the registration, asstipulated in Regulation 8(8) of CDCR 1984, has been deletedfrom the regulation in year 2006 via amendment of PU(A)336/06. Therefore, the certificate will no longer be issued by theAuthority.Circular(100)dlm.BPFK/PPP/01/03Jld. 2, 21 January 2013:Pemansuhan PengeluaranSijil Perakuan PendaftaranProduk (SPP)Applicant shall refer to the product registration approvalnotification sent by the Authority or the Approved ProductRegistration List in NPCB website.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 479

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCE1.March2013Appendix 5,Guideline onRegistration ofNaturalProducts- Replacement of information at 2.1.3 (c) ASEANHarmonisation Negative List of Ingredients with (c)Ingredients (Botanicals and Substance Derived fromAnimals) which are banned due to safety reasons.- Renumbering of tables in the appendix.Memo from Sub-Section ofComplementary Medicine(11)dlm.BPFK/PPP/06/17Jilid 30, 20 February 20132.March2013Appendix 8:List ofPermitted,Prohibited andRestrictedSubstancesAt 8.1.2 List of Restricted Active Ingredients and Combinations:Amendment on substance No. 16 Dextromethorphan from“Single Active Ingredient Tablet Formulation” to “Single ActiveIngredient in Tablet Form, including lozenges”Drug EvaluationCommittee No. 5/2013,6 March 2013Amendment from:3.March2013Appendix 9:LabellingRequirementsPatient Information Leaflet (PIL) or in Bahasa Malaysia knownas Risalah Maklumat Ubat Pesakit (RiMUP), is compulsory forproducts containing scheduled poison which are selfadministeredby patients.For details, please refer to Direktif Penguatkuasaan KeperluanMengemukakan Risalah Maklumat Ubat Pengguna (RiMUP) Bil.5 Tahun 2011 Bil (15) dlm BPFK/PPP/01/03 Jld 1 andGarispanduan Pelaksanaan Risalah Maklumat Ubat untukPengguna (RiMUP)Memo from Center forPost-Registration ofProducts(16)dlm.BPFK/17/FV/14,14 March 2013National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 480

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCEPIL may also be submitted for OTC products in place of apackage insert (PI). However, if the product is intended to besold without a PI or PIL, the information required to beingincluded in the PI or PIL shall be included in the unit outer cartonof the product.The draft copy of the PIL in both version of English and BahasaMalaysia shall be submitted for evaluation.Amendment to:Patient Information Leaflet (PIL) or in Bahasa Malaysia knownas Risalah Maklumat Ubat Pesakit (RiMUP), is compulsory forproducts which are self-administered by patients, including:d) Scheduled poisons (Category A);e) Over-the-Counter, OTC products (Category X);f) Health supplements with high claims (disease riskreduction).For details, please refer to:iii) Direktif Penguatkuasaan Keperluan MengemukakanRisalah Maklumat Ubat untuk Pengguna (RiMUP) Bil.5 Tahun 2011 Bil (15) dlm BPFK/PPP/01/03 Jld 1iv) Garispanduan Pelaksanaan Risalah Maklumat Ubatuntuk Pengguna (RiMUP)The draft copy of the PIL in both English and Bahasa Malaysiashall be submitted for evaluation.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 481

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCEAddition of the paragraph and link:12.1 FOREIGN GMP INSPECTIONPRH must provide acceptable evidence to show that themanufacturer of the product follows an internationally acceptedstandard of Good Manufacturing Practice (GMP) and recognizedby the Authority in Malaysia.4.March2013Section D:Inspection &LicensingThe Control of Drugs and Cosmetics Regulations 1984 (CDCR)requires that the standard of manufacture and quality control ofmedicinal products manufactured outside Malaysia is taken intoconsideration before the products are registered with theAuthority. NPCB as the secretariat to the DCA is responsible toensure all manufacturers of registered products in Malaysia areable to provide acceptable evidence that the manufacturingpremises conform to current GMP requirements. Hence, foreignmanufacturers are also subjected to GMP conformityassessments through acceptable GMP evidence or GMPinspection.Premises InspectionEvaluation Committee No.3/2013, 14 March 2013For details and forms, please refer Guidance Document onForeign GMP Inspection.National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 482

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCE5.March2013Section E: PostRegistrationProcessDeletion of „EMEA‟ and addition of „Switzerland‟ in thefollowing paragraph, as highlighted in yellow:16.4.2 VERIFICATION PROCESSFor new indication which has been registered in EuropeanCountries/ EMEA (United Kingdom, Sweden and/or France) andone of the other Authority‟s reference countries (United States ofAmerica, Australia, Canada, and Japan and Switzerland).Memo from Section ofNew Medicine(2)dlm.BPFK/PPP/06/17Jilid 31, 13 March 2013Addition of the following paragraph:6.March2013Appendix 2:Requirementsfor ProductRegistrationEffective 1 st March 2013, biowaiver may be granted to genericimmediate release oral solid dosage form products containingBCS Class I active ingredients listed in the Guidance OnBiopharmaceuticals Classification System (BCS) – BasedBiowaiver document. BCS Based biowaivers takes the threemajor factors that govern the rate and extent of drug absorptionfrom immediate-release solid dosage forms into accounts i.e.solubility and permeability of the drug substance/ API, anddissolution characteristics of the dosage form. This BCSapproach provides an opportunity to waive in vivopharmacokinetic bioequivalence testing for certain categories ofimmediate-release drug products.(Directive Arahan di Bawah Peraturan 29, Peraturan-peraturanKawalan Dadah dan Kosmetik 1984 Bil. 1 Tahun 2013, 14October 2011, 28 February 2013, Bil (101)dlm.BPFK/PPP/01/03Jld 2).Memo from Sub-Section ofGeneric Medicine(7)dlm.BPFK/PPP/06/17Jilid 31, 21 March 2013National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 483

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCE2.4 Product NameItem No. 11:Issue: Addition of „or referring to the profession‟.Example: Addition of „Herbalist, Doctor‟.7.March2013Appendix 5,Guideline onRegistration ofNaturalProducts*For Ginseng:Appendix 4,Appendix 5 andAppendix 9Addition of new item which is numbered as No. 13:Issue:Prohibited use of product names referring to any religiouscontentExample: Maksum, Mahmudah, Arifbillah2.7 Labelling Requirementd) Example of label approved by the AuthorityReplacement with a new example.2.7.2 Specific Labelling Statements/ Warning & Precautionsa) Amendment from:For products containing GINSENG (including all Panaxgenus), please state:- “Safe use of ginseng in pregnant women and children hasnot been established.”- “Do not exceed the stated dose.”“Safety on long term use has not been established.”Memo from Sub-Section ofComplementary Medicine(24)dlm.BPFK/PPP/06/17Jilid 31, 29 March 2013To:National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 484

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCEFor products containing GINSENG (including all PANAXgenus), please state:- “Contraindicated in pregnant women.”- “Safe use in lactating women and children has not beenestablished.”- “Do not exceed the stated dose.”- “Safety on long term use has not been established.”b) Addition of the following:For product containing naturally occurring SALICYLICACID (e.g. Willow Salix spp.), please state:“People allergic to aspirin/ other NSAID should avoid thisproduct.”For products containing GAMAT/ STICHOPUS spp. forORAL USE ONLY, please state:“Please consult your pharmacist, doctor, or other healthcareproviders about any other supplements/ medications you aretaking and other health care problems. There may be apotential for interactions or side effects.”2.7.4 Prohibited Visual/ Graphics/ Statement On Label OfNatural Productsa) Amendment of the title 2.7.4 to the following:“Prohibited Visual/ Graphics/ Statement on PackagingNational Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 485

Drug Registration Guidance Document (DRGD)UPDATESNO.REVISIONSECTION/APPENDIXDETAILSREFERENCEMaterial (Label, Box, Package Insert or Patient InformationLeaflet)”b) Addition of the following paragraph under this title 2.7.4:"General requirement: The graphics printed on outer and innerlabel has to be standardized to avoid confusion to thecustomers."National Pharmaceutical Control Bureau (NPCB)First Edition, January 2013 Page | 486