International Pharmaceutical Excipients Council ... - IPEC Europe

International Pharmaceutical Excipients Council EuropeJanuary 2000IPEC Europe NewsContents of this issue:IPEC Europe Newsletter…………………………...1Good Distribution Practicesfor bulk pharmaceutical Excipients……….…….1,2Towards a World Inventoryof pharmaceutical excipients…………………….. .3Harmonization Committee…………………………4New aspects certificates of suitability…………….5IPEC Europe membership 1999………….………6IPEC Europe Seminar……………………….…….7Good Manufacturing Practices……………………7******************************************International PharmaceuticalExcipients Council EuropeCarl MrozChairman IPEC EuropeColorconFlagship House Victory WayCrossways DartfordKent DA2 6QDUnited KingdomTel +44-1322 293 000Fax +44-1322 627 200E-mail: cmroz@colorcon.com******************************************IPEC Europe NewsletterCarl Mroz, Chairman IPEC Europe**************************************************I would like to welcome all members to thisthe first newsletter from IPEC Europe. Ihope this issue and those planned for thefuture will be a valuable source ofinformation to our members.Also welcome to a new decade, century andindeed millennium. It is at times like this thatone becomes reflective on issues from thepast, takes stock of what is current and looksforward to the future.The pharmaceutical industry itself has beensubject to many changes in recent history,with a contraction in the number companiesdue to mergers and acquisitions, howeverstill managing to generate above averagegrowth in the sector.The past year has presented manychallenges to the industry and its suppliers,issues such as BSE/TSE, geneticmodification, residual solvents and dioxincontamination have kept all of us on ourtoes. Indeed I have heard the commentrepeated many times by excipient producers,that in order just to stand still, without anygrowth in the business, there is a continuedneed for companies to allocate extraresource to respond to issues such as these,in an attempt to respond to customerconcerns.Evert IzeboudExecutive coordinator to IPEC EuropeKerkweide 272265 DM LeidschendamThe NetherlandsTel +31-70-320 9894Fax +31-70-320 3759E mail: eizeboud@worldonline.nlInternet: http://www.ipec.org/europe.htmThe road to international harmonisation ofthe rules and regulations controlling thepharmaceutical industry appears to be along one, with frustratingly slow progressbeing made along it. However we mustwelcome the efforts of the PharmaceuticalDiscussion Group and ICH on theirachievements to date, which help to create alevel playing field in what is a very lucrativeand competitive market(continued on page 2)

International Pharmaceutical Excipients Council EuropeNews________________________________________________________________(continued from page 1)With the advancement of the Internet andincreased use of e-commerce, internationalboundaries will disappear much faster thanpreviously anticipated, thus creating a globalmarket whether our regulators or marketingcolleagues like it or not.We still find today that the manufacture andsupply of excipients to the pharmaceuticalindustry is an unregulated activity.However there appears to be something realon the horizon with guidelines and legislationin preparation to control all starting materialsused in medicines. Most of us involved withthe production and use of excipients willwelcome the clarification such guidelinesshould provide and if thoughtfully preparedwill make life easier for both parties.In February 1999 the Directorate General IIIof the European commission in Brusselsissued the last draft of a directive amending75/319/EEC requiring GMP for themanufacture of all starting materials used formedicinal products. In that directive, theactivities of distributors of excipients are alsodefined as “manufacture”, especially if theyrepack and relabel materials. That meansalso the supply chain of starting materialswill be covered by GMP in the EC. This is inlinewith the requirements for startingmaterials in the US regulation and necessaryregarding the regulatory basis of the mutualrecognition agreement between USA andthe EC leading to equivalence of both.After the terrible accident with contaminatedGlycerin in Haiti 1996 WHO held aconference on control and safe trade ofstarting materials in Geneva 1998.Many talk of the “excipient industry”, inreality there is no such thing. Principallywhat we have is a collection of bulk chemicalmanufacturers who sell some of their outputto pharmaceutical applications. Thisdiversity of companies manufacturingproducts to be used in medicines highlightsthe need for organisations like IPEC to exist,where they can share a common platformwith their customers and to have a two wayroute of communication with the industry’sregulators.Finally, the pharmaceutical industry alwayscreates a very dynamic environment inwhich to work and I am sure that you sharemy sense of both foreboding and excitementat the forthcoming challenges of the 21stcentury.***************************************************Good Distribution PracticesFrank Milek***************************************************GMP issues of the supply chain of excipientsare increasingly receiving the attention ofregulatory bodies, authorities and otherorganizations because many problems hadbeen recognized.There WHO realized deficiencies in safetyof starting materials and published astatement about necessary future GMPrequirements for starting materials and therelated supply chain, because an unsafe anduncontrolled supply chain could made thataccident possible. The first outcome is theAnnex 5 of WHO-GMP (Suppl. Guidelinesfor the manufacture of pharm. Excipients)published in May 1999 which does not coverspecial supply chain topics yet.(continued on page 3)______________________________________________________________________________________January 2000 2 IPEC Europe Newsletter________________________________________________________________

International Pharmaceutical Excipients Council EuropeNews________________________________________________________________(continued from page 2)Beside this CEFIC published two guidelinesto improve the supply chain of excipients:Guidelines for handling and distribution ofPropylene Glycol USP/EP and EuropeanSingle Assessment for Chemical Distributors(ESAD, Appendix B). Both contain the sameprinciples improving quality, traceability anddocumentation while reducing the risk ofcross contamination within the supply chainof excipients.At the GMP-Workshop during the 1999Annual Meeting IPEC Europe started todiscuss this issue. Dr. Mathias Brenken(DOW Deutschland) and Dr. Frank Milek(Hedinger) held short lectures aboutchallenges and GMP`s for the supply chain.At a follow-up workshop in June 1999 asubcommittee of the GMP-Committee hasbeen formed. Members of this subcommitteeare Dr. Frank Milek (Hedinger,CHAIR), Dr. Mathias Brenken (DOWDeutschland Inc.). Alan Ritchie (ISP Europe)and Steve Campbell (SmithKline Beecham).On the basis of a draft Guideline forDistributors of Bulk PharmaceuticalExcipients of IPEC America thesubcommittee now works on a harmonizedguideline on Good Distribution Practice(GDP) for the whole of IPEC. The structureis like a questionnaire which should be usedas a supplementary guideline to IPEC`sGMP for Bulk Pharmaceutical Excipients(1995) for auditing distributors.The subcommittee intends to create someadditional guidance for the use of thatquestionnaire and a position paper aboutIPEC Europe`s opinion and activitiesconcerning GDP. All that will be channeledto WHO supporting their work for moresafety within the whole supply chain.If there are any volunteers interested insupporting this subcommittee, pleasecontact:Dr. Frank MilekAug. Hedinger GmbH,Heiligenwiesen 26,D-70327 Stuttgart, GermanyE-mail: hedinger@t-online.de;Fax: +49 711 4020535;Tel: +49 711 402050******************************************A first attempt to create a WorldInventory of Excipients used inpharmaceutical formulationsFernand PellerinHenk de Jong (Servier)Anne Bonnetto (Servier)***************************************************************When consulting the Pharmacopoeia's anddictionaries containing monographs ofpharmaceutical excipients (e.g. VIDAL inFrance, Rote Liste in Germany, etc.), onearrives at an impressive list of "inactiveingredients".Within the International PharmaceuticalExcipients Council Europe, it was thoughtuseful to try to establish a world inventory ofexcipients already in use in marketed, i.e.approved, pharmaceutical products. The firstuse would be for formulators in thepharmaceutical industry to have a quick andeasy reference as to the regulatory status ofan ingredient. The second use would be forregulators to cross-check statuses withterritories outside their own one.Ideally a future inventory would consist of aworld picture on all excipients in the form ofa collection of monographs describingidentity, properties, quality, type of use,safety data, route of administration, admittedmaximum dose, etc. In this first attempt, weonly created a listing of excipients byconsulting public sources of informationavailable to us:(continued on page 4)______________________________________________________________________________________January 2000 3 IPEC Europe Newsletter________________________________________________________________

International Pharmaceutical Excipients Council EuropeNews________________________________________________________________(continued from page 3)-The European Pharmaopoeia-The United States Pharmacopoeia andNational Formulary-The Japanese Pharmacopoeia togetherwith Japanese Pharmaceutical Excipients (apro-pharmacopoeia)-The Japanese Pharmaceutical ExcipientsDirectory (1994)-Inactive Ingredient Guide (FDA 1996)-VIDAL (marketed medicinal products inFrance)-Repertorio Farmaceutico Italiano (marketedpharmaceutical products in Italy)From this first listing, a number of substancehave been voluntarily excluded: activeingredients, flavours and fragrances, thevitamins (with an exception of theantioxidants, vitamins C and E) and thecolorants. The listing is presented in twoformats: alphabethical and by "chemicalclass". Both entries have their difficulties.The absence of an INN system for excipientsleads to a cacaphony of names: chemicalnames, traditional names, fantasy names,brand names, etc. many excipients havemore than one chemical functionality.We are strongly aware of the fact that thislist is not complete and it surely containssome errors. Readers are asked to forwardtheir comments, proposals for correctionsand additions to:***************************************************Professor Fernand Pellerin51 Rue Desnouettes75015 Paris (France)Fax: +33-1-4530 5069***************************************************During the Annual Meeting (January 21st2000), a proposal will be made to the IPECEurope membership to create a Committeeon this subject.**************************************************Dankward Jaekel, Chairman**************************************************Within the systematic working program ofthe Committee activities focus is at presenton the following topics:1. European Pharmacopoeia:General monograph on ExcipientsThe series of general monographs is atpresent further extended, including in futurealso a general monograph on excipients. Afirst draft had been discussed in theHarmonization Committee's workshop duringthe May 1998 IPEC Europe Symposium inNice, France. Many of our comments to theEuropean Pharmacopoeia, based on theresults of that workshop, have been takeninto consideration for the second draft of thegeneral monograph, published inPharmeuropa Volume 11, No 3.The draft requires that all excipients alsocomply with the requirements of the generalmonographs on:- products derived from recombinant DNAtechnology- Products derived from warm bloodedanimals- Products of fermentation- Residual solventsUnless otherwise justified and authorized therequirements apply as well to excipients thatare not the subject of a pharmacopoeialmonograph. Implications of the generalmonograph on excipients are currently underevaluation by the HarmoniszationCommittee. The Committee requests IPECEurope members for input:(continued on page 5)(continued from page 4)______________________________________________________________________________________January 2000 4 IPEC Europe Newsletter________________________________________________________________

International Pharmaceutical Excipients Council EuropeNews________________________________________________________________2. Cooperation with CEFIC on 1,2-PropyleneglycolWhile 1,2 propylene glycol is widely used fortechnical applications, only a very lowpercentage of the world production is usedas a pharmaceutical excipient. Due tocontamination/mix up with toxic diethyleneglycol, this product caused the death ofmany people. In order to ensure the safeuse of 1,2 propylene glycol inpharmaceuticals from production via thevarious distribution channels to the end usera CEFIC Working Group has developed atpresent a suitable protocol for distribution ofthis product (See also Dr Frank Milek'scontribution on Good Distribution Practices).In this context the CEFIC working Groupcontacted the Harmonisation Committee tojointly elaborate a proposal for a harmonizedcompendial monograph on 1,2 propyleneglycol. Work made good progress and a finaldraft is expected to become available in thefirst semester of 2000.3. Polyols and PEGClose cooperation with our collegues fromIPEC Americas and JPEC on common IPECproposals for harmonized monographs onpolyols (sorbitol,mannitol, maltitol and xylitol)and polyethylene glycols, PEG)4. Glyoxal determinationThe colorimetric method used at present forthe quantitative determination and limitationof glyoxal detects only free but not boundglyoxal, which is split off again under invivoconditions. Development of a method todetrmine both, free and bound, glyoxalwithout interference from other substancesturned out to be difficult. The Committee islooking for practical experience from otherlaboratories to solve this problem.******************************************Dankward JaekelChair Harmonisation CommitteeC/0 Novartis PharmaE-mail:dankward.jaekel@pharma.novartis.comFax: +41-62-868 7069******************************************New Aspects of the procedure forthe Certification of Suitability ofMonographs of the EuropeanPharmacopoeia.E. Izeboud (with permission of CarolineLarsen-Le Tarnec of the EDQM)More than 240 experts in the area of thequality of medicines from 24 Europeancountries and also from Argentina, Israel,Egypt, Japan, India and the United States,participated in the International Conferenceon the procedure for the Certification ofSuitability of Monographs of the EuropeanPharmacopoeia, organized by the EuropeanDirectorate for the Quality of Medicines.IPEC Europe was well presented by 29representatives of the membership. Dr BrianCarlin of FMC Biopolymer, Chair of IPECEurope's Excipient Masterfile Committee,presented a lecture on IPEC Europe'sproposals to extend the procedure ofEuropean Drug Masterfiles topharmaceutical excipients. After thepresentation it became evident that theEMEA does not consider this topic ashaving a high priority.The objectives of this conference wereparticularly important since they involvedreviewing the results of five yearsexperience sharing the points of view with(continued on page 6)(continued from page 5)______________________________________________________________________________________January 2000 5 IPEC Europe Newsletter________________________________________________________________

International Pharmaceutical Excipients Council EuropeNews________________________________________________________________principal users and examining the currentsituation as regards the quality of rawmaterials used in the pharmaceuticalindustry.After two days of exchanging views , threemain ideas for future development hadbecome apparent:1. Extending the scope of the Certificationprocedure to products with risk of TSE(transmissible spongiform encephalopathy)2. Strenghtening cooperation between thevarious partners.3. Improving the transparency of thecertificates and making it possible theassess stability studies to facilitate theevaluation of licensing dossier by nationalauthorities and avoid duplication of work.******************************************IPEC Europe Membership 1999E.Izeboud**************************************************The last year of the 2nd millennium was adynamic year for the IPEC Europemembership: a merger, a take-over and acompany in financial difficulties were thecause of the loss of three full members.IPEC Europe's membership recruitmentprogram however was strong enough tocope with these circumstances, whicheventually resulted in the fact that theobjective of 1999 (60 full members) wasexceeded by one. IPEC Europe has thusbecome the unified voice of excipient usersand producers. In 1999 the IPEC EuropeBoard approved the applications of thefollowing members:Eli Lilly (user)Lyondell (maker)Wolff Walsrode (maker)Quadrant Healthcare (user)Banner Pharmacaps Europe (maker)Akzo-Nobel (user/maker)Metsa Specialty Chemicals (maker)Pfizer (user)Firmenich (maker)Mustafa Nevzat (user)Dr Paul Lohmann (maker)Of special interest is the representation ofthe Turkish company Mustafa Nevzat inIPEC Europe. In view of the outcome of theEuropean Union's considerations for newmember states, Turkey was defined as aserious candidate. For a long time in historyTurkey has been the stronghold for tradetransactions with the neighboring Asiancountries.***************************************************NoteDuring the IPTS seminar in September 1998in Ankara I discovered that in the Turkishlanguage the word IPEK stands for silk….Evert Izeboud******************************************European Pharmacopoeia 2000******************************************Since November 1999 the CD-ROM 2000version of the European Pharmacopoeia isavailable at the European Directorate for theQuality of Medicines. It has beensupplemented with 200 new or revisedstandards, entering into force on January 1st2000.The CD-ROM 2000 includes all texts (inEnglish and/or French) of the 3rd Edition ofthe European Pharmacopoeia andsupersedes all the previous versions(1997,1998 and 1999). The CD-ROM 2000contains about 1450 monographs, 276general methods of analysis, the full list of1300 reagents as well as the latestcatalogue of 1150 chemical referencesubstances or biological referencepreparations.The CD-ROM is very user friendly, makinguse of useful hyperlinks form the text of themonograph to the corresponding analyticalmethods and chemical reagents. For heavyusers of the European Pharmacopeia animprovement in efficiency.______________________________________________________________________________________January 2000 6 IPEC Europe Newsletter________________________________________________________________

International Pharmaceutical Excipients Council EuropeNews________________________________________________________________Program IPEC Europe SeminarSheraton Brussels AirportJanuary 20th 2000.1. IntroductionMr Carl Mroz (Colorcon, Chair of IPECEurope)10.30-10.452. Genetically Modified OrganismsMaize from GMO sourcesDr Holger Mahlmann (Cerestar)10.45-11.153. BSE/TSEMr Kevin Mahoney (Glaxo Wellcome)11.15-11.454. Products from FermentationMr Cees van der Vlies ( Sertipharm,European Pharmacopeia Commission)11.45-12.15Mr Allert Wiersema (DSM Anti-Infectives)Validation of fermentation processes12.15-12.45-----------------------------LUNCH 13.00-14.00-----------------------------5. ICH Guidelines on Residual SolventsProf Henk de Jong (Servier)14.00-14.306. Good Manufacturing PracticesMrs Anne Papin (EFPIA)14.30-15.007. WHO GMP… controlling the supplychain of pharmaceutical excipients.Mrs Patricia Rafidison (Dow Corning)15.00-15.308. Panel Discussion15.30-16.00******************************************Good Manufacturing PracticesE. Izeboud**************************************************In the area of Good Manufacturing Practices,currently three working committees areactive within IPEC Europe:1. Good Distribution Practices (see article byFrank Milek)2.Guidance tools IPEC Good ManufacturingPractices, andThe GMP Guidance tools Committee hasdefined as its mission to elaborate guidancedocuments and templates for GMP subjectswhich need to be clarified. With reference tothe outcome of the GMP Forum on January21st 1999 in Brussels and the follow-up onJune 16th 1999 in Amsterdam two prioritysubjects have been set: impurities inpharmaceutical excipients (groupleader, MrsDoris Wangel of Flamel Technologies andvalidation protocols (groupleaders, MalcolmDixon of Eli Lilly and David Spence ofICI/Uniqema).3. Regulatory Survey CommitteeThe Regulatory Survey Committee ( MrsPatricia Maillere of Servier and Mr Jean-Claude Lumaret of Roquette) is working onconstructing a database of legislativedocuments (worldwide) relating to GoodManufacturing Practices. For the purpose tocommunicate this information to the IPECEurope membership a dedicated page onIPEC Europe's Internetsite is underconstruction. During the Annual Meeting onJanuary 21st 2000 in Brussels the GoodManufacturing Practices page will beopened.______________________________________________________________________________________January 2000 7 IPEC Europe Newsletter________________________________________________________________

International Pharmaceutical Excipients Council EuropeNews______________________________________________________________________________________________________________________________________________________January 2000 8 IPEC Europe Newsletter________________________________________________________________