USP Monograph Development Process and Compendial Updates

Quality Standards for Medicines, Supplements, and Food Ingredients throughout the WorldUSP Monograph DevelopmentProcess and Compendial Updates6 th Annual Long Island ASQ FD&C/FDA ConferenceNovember 6, 2008Karen A. Russo, Ph.D.Vice President, Small MoleculesDocumentary Standards Division

Outline• USP Overview– Legal recognition– Council of Experts• Standards Setting– Process– Flexible monographs– Pending monographs– Reference standards• Compendial Updates– Monograph redesign– General Notices redesign– PF Redesign– Residual Solvents– Heavy Metals

United States PharmacopeialConvention

USP Overview• Nonprofit international public health organization• Private, independent, and self-funded• Global activities and impact• Establishes quality standards (USP, NF, FCC)• Expert volunteers are scientific decision-makers• ISO-9001 and ISO-17025• LocationsRockville, MD (headquarters)Basel, SwitzerlandHyderabad, IndiaShanghai, ChinaSao Paulo, Brazil

Legal Recognition1848 Drug Import Act: USP legislatively mandated1906 Federal Pure Food & Drugs Act: USP standardsrecognized1938 Federal Food, Drug, and Cosmetic Act: USPstandards recognized as FDA-enforceable1994 Dietary Supplement Health & Education Act: Adietary supplement represented as conforming to USP–NFspecifications shall be deemed misbranded if it fails to doso.2003 Medicare Prescription Drug, Improvement, andModernization Act: USP will create Model Guidelines – alist of categories and classes that prescription drug plansmay use as they design their formularies

USP and FDA Responsibilities• USP: Identity, strength, quality, and purity ofofficial articles• FDA: Safety and efficacy• Shared responsibilities: nomenclature,packaging, labeling

2005-2010 Council of ExpertsFood AdditivesExpert Committee

114 Experts are from 31 Countries• Argentina 1• Austria 2• Australia 1• Belgium 3• Brazil 2• Canada 22• Chile 1• China 2• Colombia 2• Denmark 3• France 2• Germany 3• Hungary 1• India 16• Ireland 1• Israel 1• Italy 2• Jordan 1• Mexico 2• The Netherlands 1• Norway 1• Peru 2• Panama 1• Russian Fed 11• Scotland 1• S. Africa 1• S. Korea 2• Sweden 3• Switzerland 4• UK 18• Venezuela 1

2005-2010 Expert Committee DemographicsAcademia (24%)Government (13%)Practitioners &Consultants (13%)Industry (37%)International (13%)2005 – 2010 Revision Cycle

Standards Setting

Why a USP-NF Monograph?• Recognized under the Federal Food, Drug, andCosmetic Act• Assessing quality of drug products in commercialdistribution over their shelf life• Monitoring for counterfeit products and quality ofimported drug products• Data-driven• Transparent processes with public review andcomment• Reviewed and approved by USP Council ofExperts• Continuous revision• Supported by General Chapters and GeneralNotices

Requests for Revision• Written request and/or justification for revision• Submission packages– Indication of regulatory status– Tests, procedures and acceptance criteria– Validation reports/data– Data for three lots of material (ideal)– Chemical names and structures of impurities– Description and solubility– Packaging and storage– Safety-related labeling information

Submission Information on Web Site• Submission guidelineshttp://www.usp.org/USPNF/submitMonograph/subGuide.html• Also on this site– Submission Checklist– Guideline for Suppliers of Reference Standard Materials• High Priority Monograph Listhttp://www.usp.org/USPNF/submitMonograph/newMon.html

Document Disclosure• USP maintains the confidentiality nature ofdocumentation• Confidential documents can be shared with theFDA upon requests• USP Document Disclosure Policy is available athttp://www.usp.org/aboutUSP/governance/policies/overviewStandardsSetting.html

USP Standards Setting ProcessMonograph is received/development initiatedScientific Liaison performs technical reviewand drafts the monographMonograph is published for publicreview and commentScientific Liaison reviews comments; submitscomments to Expert CommitteeNot approvedExpert Committee ballotsApprovedMonograph is published in official publication(USP-NF, FCC)

Pharmacopeial Forum• Your voice in standardsdevelopment• Bimonthly journal with– Proposed revisions to USP-NFstandards for your comments– Official revisions to standards– Updates on internationalharmonization– Stimuli articles

Role of USP Expert Committees• Evaluate submissions and comments• Decide if additional public review and comment isneeded or may incorporate changes before revision isadopted as official• Vote– Simple majority is required– Members with conflicts abstain• Advise– Next steps for items not approved– General strategy

Flexible Monographs: Rationale• Flexible to account for different routes of synthesis– Control of impurities utilizes the approaches contained inICH Q3A, Q3B, and Q3C• Multiple dissolution procedures, especially forextended release products• Considers hydrates/solvates, polymorphs• Unambiguous document in support of ORA inspection• Use of procedure-specific USP Reference Standards

Flexible Monographs: Examples• Ethinyl Estradiol Drug Substance• Loratadine Drug Substance• Meloxicam Drug Substance• Paroxetine Drug Substance• Potassium Chloride Extended-Release Tablets• Theophylline Extended-Release Capsules

Flexible Monograph ExampleLoratadine drug substanceLabeling—If a test for Related compounds other than Test 1 is used,then the labeling states with which Related compoundstest the article complies.Related compounds—NOTE—On the basis of the synthetic route, perform eitherTest 1 or Test 2. Test 2 is recommended if 4,8-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one is a potential related compound.TEST 1—…TEST 2—…

Flexible Monograph ExampleTheophylline Extended Release CapsulesLabeling—The labeling indicates whether theproduct is intended for dosing every 12 or 24hours, and states with which in vitro DissolutionTest the product complies.Dissolution —Test 1—…Test 2—……Test 10—…

USP Publications• Time-tested,international resource• Official authority—FDA-enforceablestandards• More than 4,500monographs• Drug products andsubstances, excipients,dietary supplements• General chapters• Continuously updated

USP PublicationsFood Chemicals CodexUSP Pharmacists’ Pharmacopeia

USP PublicationsUSP Dietary SupplementsCompendiumTarget launch date – February2009

USP Reference Standards

USP Reference Standards• Trusted for pharmaceutical quality controlworldwide• Support FDA-enforceable standards and tests inUSP-NF• Over 2200 Reference Standards now available• Highly characterized• Potency stated on label• Stocked and ready to ship (2-day delivery withinU.S.)• USP Reference Standards Expert Committee

USP RS Development Process1. Create bulk candidate procurementspecifications (1 month)2. Procure candidate material (0-6 months)3. Design test plan (1 month)4. Collaborative testing (2-3 months)5. Review/compile data (0.5 months)6. Expert Committee review and approval (0.5months)7. Package (0.5 months)8. QC testing (1 week)9. QA release (8-14 months total)

Reference Standards Practices• All first-time USP Reference Standardcandidates required in a proposednew/revised monograph or general chapterneed to be received by USP prior topublication in for public review andcomment.• New monographs/chapters and revisionsthat introduce new USP ReferenceStandards will not become official until therequired USP Reference Standard(s) areavailable for sale.

Compendial Updates

Monograph Redesign• Fewer words, simpler formatting• Eliminate cross-references between monographs• Distinct monograph sections– Definition– Identification–Assay– Impurities (Inorganic, Organic)– Specific Tests (water, LOD, pH, etc)– Performance Tests (Dissolution, viscosity)– Additional Requirements (Packaging & Storage, USPReference Standards)

Monograph Redesign• Well defined acceptance criteria• Simplify solution preparation instructions• Consistent naming convention (Related Compoundsand Chrom. Impurities eliminated)• Improved tables and descriptions of gradients• Changes in solution descriptions• Complete equations• “No longer a recipe”—assumes technicalknowledge• Longer monographs

Monograph Redesign Timeline• June 2008: Conversion to new format completed• September 2008: Major subset of monographsavailable at the USP Annual Scientific Meeting• November 2008:– PDFs available for 90 days on USP web sitehttp://www.usp.org/monoRedesign/– Available to all– Registration required– Online commenting system• March 2009: PF 35(2) [Mar-Apr 2009] is publishedusing new format• November 2009: Redesigned monographsincorporated into USP33-NF26• May 2010: USP33-NF26 official

Monograph Redesign

Monograph Redesign Example

General Notices Redesign• Ease of use– Update language– Numbered headings for easier navigation• Refocus– Provide the basic assumptions, definitions, and defaultconditions for the compendia– Move selected text to General Chapters, Mission, etc• Clarify applicability of text– Drug substance/product– Drug/dietary supplement– Manufactured/compounded

General Notices RevisionExcerpt from USP32-NF25 General Notices

General Notices Revision• Timeline– May-Aug 2007: first draft published on USP websitefor comments– Jan-April 2008: Second draft in PF 34(1) and on theweb site; comment period ended April 15, 2008– Spring 2008: Final draft approved (Phase I)– Nov 2008: USP32-NF27 is published with Phase Irevisions– May 1, 2009: USP32-NF27 becomes official

General Notices Phase I Revisions• Legal Status of USP (partial revision)• Definition of units to be taken – eliminated• Compliance to GMPs – partially retained (notcGMP)• ICH’s 0.10% impurity level (instead of 0.1%) notincorporated, yet…• USP will not define testing intervals or define thesize of a “representative” sample• Compliance to water standards outside the USare not specifically addressed• Equivalent or better is required for alternativeprocedures• “Must pass if tested” text strengthened

Major Issues for Phase II• Issues– Change the name of USP-NF? (e.g, USP-NF 2011)– Development of a companion volume– Merging of General Notices across publications– Definition of “Official”– Definition of performance-based procedures and tests• Ongoing discussions with Expert Committees,FDA, stakeholders

Pending Monographs• Enables monograph development and publicationbefore FDA approval has been granted to a genericmanufacturer• Ultimate purpose is to have an official USPmonograph ready as soon as possible after FDAapproval of an application (i.e., ANDA)• USP Pending Monographs web site iswww.usp.org/standards/pending/

Pending Monographs• Sponsors– Who have filed or intend to file with FDA an AbbreviatedNew Drug Application (ANDA) or Abbreviated New AnimalDrug Application (ANADA)– Who have submitted a Drug Master File (DMF) to FDA– Whose substance is or will be the subject of a Time andExtent Application or citizen petition to amend an FDAOTC drug monograph• Documentation– Statement of intent to file an ANDA or ANADA within sixmonths– Copy of the DMF filing letter

Pending Monographs ProcessMonograph development beginsDraft Pending Monograph is posted for90-day public review periodRelevant Expert Committee(s) ballotsIf approvedAuthorized Pending Monograph is postedFDA approves Sponsor’s application (ANDA)Relevant Expert Committee(s) ballotsIf approvedPending Monograph becomes official via Revision BulletinOfficial monograph is published in USP Book or Supplement

PF Redesign• Current situation– Does not allow for “public” notice andcomment, given limited subscription– Inclusion of official text (approved IRAs, Errata) whichoften leads to confusion• Challenges with existing PF format– Difficult to follow and understand– Format, flow and terminology are not intuitive– Readability is challenging with strikeouts and marked-uptext– Overlapping deadlines with USP-NF cause confusion– Long publication lead times for print edition

PF Redesign• Transition to on-line version of PF only– Discontinue print version in 2010– Make publicly available, free of charge• Obtain input from broader group of users• Help avoid situations where companies areunaware of proposed changes until adopted– Retain existing publication schedule (six issues,posted on 1 st day of 1 st month of issue)– Reorganize for greater readability, ease of use inreviewing proposals– Standardize comment period for all proposals at90 days

PF Redesign• Remove official text from PF– PF used only for proposed revisions and relatedinformation– Will no longer contain approved IRAs or Errata• IRAs, Revision Bulletins and Errata will be postedon USP website in new “official text” section• Published in next USP-NF or Supplement andremoved from web site or archived once published• Dual publication of official text in print PF and website in 2009

PF Redesign• Standardize and simplify processes foraccelerated revisions– Guideline on Accelerated Vehicles to be developed– Three types only• IRAs– 90 day notice and comment• Revision Bulletins– No notice and comment required, but may includeopportunity for stakeholder input depending onimpact and feasibility• Errata– Posted on monthly basis at end of each month– Official the 1 st day of second month following postingunless otherwise specified

PF Redesign• Redesign USP-NF Web site for easynavigation• No change to USP-NF and Supplements– Retain print and online versions– Maintain existing publication schedules• Obtain user input– Regular user input throughout process via meetingswith industry Project Team– Seek broader input from customers using variousavenues

PF Redesign• Outstanding Issues– Registration process to monitor “public” access to PF– Enhancements to online PF• Visible publication date• Pagination, line numbers, etc to reference when commenting• Clarification of what changes are being proposed• Use of symbols– High-impact revisions that require additional opportunity forinput• Process for obtaining input prior to 90 day standard notice andcomment period• Must be presented in a readily noticeable way– Need for “archiving” of official text on web site to allowtracking– Harmonization—Stage 6 publication/posting

PF Redesign• September 2008: ASM presentation and discussion• January 2009:– Implement new Guideline on Accelerated Text Vehicles(approving and posting all IRAs, RBs, and Errata monthly)– Revise USP-NF section of web site to include new official textsection– Begin dual presentation of IRAs and Errata in PF and on website for transition year• January 2010:– Online PF only– Remove official text from PF and post on web site only– Revise Guideline to reflect official text on web site only

USP31-NF26 General Notices TextResidual Solvents—The requirements are stated in ResidualSolvents together with information in Impurities in OfficialArticles . Thus all drug substances, excipients, andproducts are subject to relevant control of residual solvents, evenwhen no test is specified in the individual monograph. Therequirements have been aligned with the ICH guideline on this topic. Ifsolvents are used during production, they are of suitable quality. Inaddition, the toxicity and residual level of each solvent are taken intoconsideration, and the solvents are limited according to the principlesdefined and the requirements specified in Residual Solvents ,using the general methods presented therein or other suitablemethods. (Official July 1, 2008)

Residual Solvents• Organic Volatile Impurities– USP XXII, 9 th supp. (1993)– Only 4 solvents are tested (Class 2)– Chapter referenced in specific monographs• Residual Solvents– Intent to align with ICH Q3C (1997)– 59 solvents• Subsequent revisions– PF 32(5) [Sept-Oct 2006]– IRA in PF 33(3) [May-June 2007]– Latest updates – PF 34(3) [May-June 2008]; target officialpublication is the First Supplement to USP32-NF27

Residual Solvents• Testing of drug substances, excipients, and drugproducts for residual solvents should be performedwhen production or purification processes areknown to result in the presence of such residualsolvents.• It is only necessary to test for residual solvents thatare used or produced in the manufacture orpurification processes.• Solvent used or produced in the final manufacturingstep and solvents that are used or produced inearlier manufacturing steps and not removedconsistently by a validated process.

Residual Solvents• Classes of residual solvents based on toxicity– Class 1 – Highest toxicity; should be avoided in alldrugs– Class 2 – Less toxic, should be limited in all drugs– Class 3 – Low toxicity; generally deemed safe to 5000ppm or 0.5%– Other Solvents (“Class 4”) – No AdequateToxicological Data

Proposal - PF34(3) [May-June 2008]Table 5. Headspace Operating Parameters1 2 3Equilibration temperature (°C) 80 105 80Equilibration time (min.) 60 45 45Transfer-line temperature (°C) (Ifappropriate)85 110 105Syringe Temp (°) (If appropriate) 80-85 80-85 80-85Carrier gas (35 cm/sec)Nitrogen or HeliumPressurization time (sec.) ≥60 ≥60 ≥60Injection volume (mL)* 1 1 1*Or follow instrument manufacturer’s recommendations, as long asmethod criteria are met. Injecting less than this amount is allowed aslong as adequate sensitivity is achieved.

Educational Activities• Residual Solvents Short Course• Navigating Chapter Residual Solvents– Web-based course• Check USP web site for dates

Heavy Metals• Significant impact to industry expected• Current methodology is outdated– Difficult to run, not specific– Safety issues– Almost impossible to fail due to poor recovery issues• Stimuli article, Pharmacopeial Forum 34(5):1345-1347[Sept-Oct 2008] and on the USP web site• Revised will be a performance-basedapproach– Chapter will provide acceptance criteria and standards– Any method that meets the criteria is acceptable– Chapter provides default procedure

Heavy Metals• USP is actively seeking industry input– USP Annual Scientific Meeting September 2008– Institute of Medicine Meeting August 2008• Discuss specifications and standards for metals testing• Which Metals?• Risk Assessment and Limit Setting• Modifying Factors for Risk Assessment• Measurements• Scope: drugs, excipients, food, dietary supplements• EMEA Guideline on the Specification Limits for Residues ofMetal Catalysts– USP Advisory Panel– Industry Project Team

Heavy Metals--TimelineSummer2008August2008Sept2008Dec2008Jul-Aug2009August2009Oct2009June2010StimuliArticle fromAdvisoryPanelPosted onwebIOMMetalsToxicologyWorkshopWashington,D.C.Stimuli ArticlePF 34(5) Sept-Oct 2008AnnualScientificMeetingImpuritiesSessionStim articlecommentperiod endsAdvisoryPanel meetsDraftChapterPublishes inPF 35(4)Ref Stds(s)bulks inhouseHeavyMetals WebMeetingsforpublic dialogOct. 15commentperiod endsAdvisoryPanel meetsChapterpublished inSupplement 2to USP 33Dec. 2010Delayed officialdate: ?Ref Stds(s) incatalogDeadlines Dec 15, 2008 Mar 20, 2009Oct 2009 Feb 20102010—General Chapter PublishedOfficial Date to be determinedExpert Committee: General Chapters, James DeMuth, ChairAdvisory Panel: Heavy Metals, Nancy Lewen, ChairProject Team: Heavy Metals and Inorganic Impurities, Fran Byrne, Chair= Where We Are on Timeline

Compendial Toolshttp://www.usp.org/USPNF/compendialTools.html

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Quality Standards for Medicines, Supplements, and Food Ingredients throughout the World