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1 02 (1)

  1. 1. Good Manufacturing PracticeGood Manufacturing Practice(“GMP”) Compliance:(“GMP”) Compliance:GMPs EXPLAINEDGMPs EXPLAINEDPresented byRaymond A. BonnerNathan C. SheersSIDLEY AUSTIN BROWN & WOOD, LLPWashington, D.C.(202) 736-8000ToThe Fourth Annual PharmaceuticalRegulatory and Compliance Congressand Best Practices ForumNovember 13, 2003
  2. 2. 2Good Manufacturing PracticeGood Manufacturing PracticeRegulationsRegulations Establishes minimum GMP for methodsEstablishes minimum GMP for methodsto be used, and the facilities or controls toto be used, and the facilities or controls tobe used for, the manufacture, processing,be used for, the manufacture, processing,packing or holding of a drug to assurepacking or holding of a drug to assurethat the drug is:that the drug is: SafeSafe Has the appropriate identity and strengthHas the appropriate identity and strength Meets quality and purity characteristicsMeets quality and purity characteristics21 C.F.R. 210 and 21121 C.F.R. 210 and 211
  3. 3. 3cGMP Violations --cGMP Violations --Severe ConsequencesSevere ConsequencesProduct is “adulterated”Product is “adulterated”Shutdown of manufacturing facilityShutdown of manufacturing facilitySeizure of productSeizure of productRecall productRecall productFront page press coverageFront page press coverageCompetitive disadvantageCompetitive disadvantage
  4. 4. 4Severe ConsequencesSevere Consequences (cont.)(cont.)GMP Hold on product applicationsGMP Hold on product applications International sitesInternational sitesInjunction / Consent decreeInjunction / Consent decree Schering Plough ($500 Million)Schering Plough ($500 Million) Abbott Laboratories ($100 Million)Abbott Laboratories ($100 Million) Wyeth–Ayerst Laboratories ($30 Million)Wyeth–Ayerst Laboratories ($30 Million) Individual DefendantsIndividual DefendantsCriminal Investigations and IndictmentsCriminal Investigations and IndictmentsLawsuitsLawsuits United States ex rel. KingUnited States ex rel. King
  5. 5. 5cGMP: Current TrendscGMP: Current Trends 21st Century: Risk-Based Approach21st Century: Risk-Based Approach Risk-based assessmentRisk-based assessment Up-to-date Science-based policies and standardsUp-to-date Science-based policies and standards• Part 11Part 11 Integrated Systems approachIntegrated Systems approach• Quality / Facilities and Equipment / Materials /Quality / Facilities and Equipment / Materials /Production / Packaging and Labeling / LaboratoryProduction / Packaging and Labeling / LaboratoryControlControl International cooperationInternational cooperation• ICH: International Conference on HarmonisationICH: International Conference on Harmonisation Proposed amendments regarding validationProposed amendments regarding validationand cross-contaminationand cross-contamination
  6. 6. 6cGMP: The BasicscGMP: The Basics Quality ControlQuality Control Product meets specificationsProduct meets specifications Quality AssuranceQuality Assurance Systems ensure control and consistencySystems ensure control and consistency Validation, validation, validationValidation, validation, validation DocumentationDocumentation If it is not documented, it did not happenIf it is not documented, it did not happen
  7. 7. 7cGMP: Raw MaterialscGMP: Raw Materials Active ingredientsActive ingredients ExcipientsExcipients Audit suppliers on regular basisAudit suppliers on regular basis Before entering into contract, review regulatoryBefore entering into contract, review regulatoryhistoryhistory Monitor regulatory complianceMonitor regulatory compliance Test incoming raw materialTest incoming raw material
  8. 8. 8cGMP: Buildings and FacilitiescGMP: Buildings and Facilities Separate or defined areas as are necessarySeparate or defined areas as are necessaryto prevent contamination or mixupsto prevent contamination or mixups Air filtration systems (HVAC) inAir filtration systems (HVAC) inproduction areasproduction areas SanitationSanitation21 C.F.R. 211.42-5821 C.F.R. 211.42-58
  9. 9. 9cGMP: Production and ProcesscGMP: Production and ProcessControlsControls (“SOPs”)(“SOPs”)Written production and process controlWritten production and process controlprocedures shall be followed in manufacturing andprocedures shall be followed in manufacturing andshall be documented at the time of performance.shall be documented at the time of performance.Any deviation from these procedures shall beAny deviation from these procedures shall berecorded and explained or justified.recorded and explained or justified.21 C.F.R. 211.10021 C.F.R. 211.100
  10. 10. 10cGMP: In Process TestingcGMP: In Process Testing Must have written procedures and testing of productMust have written procedures and testing of productwhile being manufactured to assure batch uniformitywhile being manufactured to assure batch uniformityand integrityand integrity Control procedures shall be established to monitorControl procedures shall be established to monitoroutput and to validate manufacturing processes thatoutput and to validate manufacturing processes thatcould cause variabilitycould cause variability21 C.F.R. 211.11021 C.F.R. 211.110
  11. 11. 11cGMP: Expiration DatingcGMP: Expiration Dating To assure that a drugTo assure that a drugproduct meets applicableproduct meets applicablestandards of identity,standards of identity,strength, quality andstrength, quality andpurity at the time of use, itpurity at the time of use, itshall bear an expirationshall bear an expirationdate determined bydate determined byappropriate stabilityappropriate stabilitytesting described intesting described inSection 211.166.Section 211.166.21 C.F.R. 211.137 (a)21 C.F.R. 211.137 (a) Expiration dates shall beExpiration dates shall berelated to any storagerelated to any storageconditions stated on theconditions stated on thelabeling, as determined bylabeling, as determined bystability studies describedstability studies describedin Section 211.166.in Section 211.166.21 C.F.R. 211.137 (b)21 C.F.R. 211.137 (b)
  12. 12. 12cGMP: Packaging and LabelingcGMP: Packaging and LabelingOperationsOperations Company must have written proceduresCompany must have written proceduresdesigned to assure that correct labels, labelingdesigned to assure that correct labels, labelingand packaging materials are used for drugand packaging materials are used for drugproducts; such written procedures shall beproducts; such written procedures shall befollowed.followed. Label mix ups have been a major reason forLabel mix ups have been a major reason fordrug product recalls.drug product recalls.21 C.F.R. 211.13021 C.F.R. 211.130
  13. 13. 13cGMP: Laboratory ControlscGMP: Laboratory Controls Testing and release for distributionTesting and release for distribution For each batch of drug product, there shall beFor each batch of drug product, there shall belaboratory determination of satisfactorylaboratory determination of satisfactoryconformance to final specifications for the drugconformance to final specifications for the drugproduct, including the identity and strength of eachproduct, including the identity and strength of eachactive ingredient prior to release.active ingredient prior to release. There shall be appropriate laboratory testing, asThere shall be appropriate laboratory testing, asnecessary, of each batch required to be free ofnecessary, of each batch required to be free ofobjectionable microorganisms.objectionable microorganisms.21 C.F.R. 211.165 (a) & (b)21 C.F.R. 211.165 (a) & (b)
  14. 14. 14cGMP: Stability TestingcGMP: Stability TestingA written testing program designed toA written testing program designed toassess stability characteristics isassess stability characteristics isrequired. Stability testing results mustrequired. Stability testing results mustbe used in determining storagebe used in determining storageconditions and expiration dates.conditions and expiration dates.21 C.F.R. 211.16621 C.F.R. 211.166
  15. 15. 15cGMP: Production RecordcGMP: Production RecordReviewReview Production and control records shall be reviewedProduction and control records shall be reviewedand approved by the quality control unit toand approved by the quality control unit todetermine compliance with all established,determine compliance with all established,approved written procedures before a batch isapproved written procedures before a batch isreleased or distributed.released or distributed. Product Impact AssessmentProduct Impact Assessment Trend AnalysisTrend Analysis Distributed ProductDistributed Product21 C.F.R. 211.19221 C.F.R. 211.192
  16. 16. 16cGMP: Deviation InvestigationscGMP: Deviation Investigations Any unexplained discrepancy or the failure of a batchAny unexplained discrepancy or the failure of a batchor any of its components to meet any of itsor any of its components to meet any of itsspecifications must be investigated whether or not thespecifications must be investigated whether or not thebatch has already been distributed.batch has already been distributed. Investigate other batches of same drug productInvestigate other batches of same drug product Investigate other drug products thatInvestigate other drug products thatmay have been associated with themay have been associated with thespecific failure or discrepancyspecific failure or discrepancy Written record of investigationWritten record of investigation
  17. 17. 17cGMP: Deviation InvestigationscGMP: Deviation Investigations(cont.)(cont.) Documenting the Investigation is CriticalDocumenting the Investigation is Critical Hypotheses should be scientifically basedHypotheses should be scientifically based Subject matter experts should be consultedSubject matter experts should be consultedthroughout the investigation, including the initialthroughout the investigation, including the initialidentification of hypothesesidentification of hypotheses Once a hypothesis is identified, it must beOnce a hypothesis is identified, it must beinvestigatedinvestigated All hypotheses should be validated or invalidatedAll hypotheses should be validated or invalidated
  18. 18. 18cGMP: Deviation InvestigationscGMP: Deviation Investigations(cont.)(cont.) Corrective and Preventative Action ProgramCorrective and Preventative Action Program As part of deviation investigations...As part of deviation investigations... Root cause identification and definitive correctiveRoot cause identification and definitive correctiveactionsactions• Company Program / System should audit:Company Program / System should audit:– Timeliness of corrective / preventative actionsTimeliness of corrective / preventative actions– Effectiveness of actionsEffectiveness of actions– DocumentationDocumentation• Example:Example:– Environmental monitoring/CleaningEnvironmental monitoring/Cleaning
  19. 19. 19cGMP: Deviation InvestigationscGMP: Deviation Investigations(cont.)(cont.) Corrective and Preventative Action ProgramCorrective and Preventative Action Program (cont.)(cont.) After an FDA inspection...After an FDA inspection... Establish scientifically sound corrective andEstablish scientifically sound corrective andpreventative actionspreventative actions• Realistic timeframesRealistic timeframes Ensure compliance with commitments to FDAEnsure compliance with commitments to FDA• SystemsSystems• Specific IssuesSpecific Issues– E.g., Change Control / TrainingE.g., Change Control / Training
  20. 20. 20cGMP: Responsibility andcGMP: Responsibility andAuthority of Quality ControlAuthority of Quality Control Quality control unit “shall have the responsibility andQuality control unit “shall have the responsibility andauthority to approve or reject all components, drugauthority to approve or reject all components, drugproduct containers, closures, in-process materials,product containers, closures, in-process materials,packaging material, labeling, and drug products, andpackaging material, labeling, and drug products, andthe authority to review production records to assurethe authority to review production records to assurethat no errors have occurred or, if errors havethat no errors have occurred or, if errors haveoccurred, that they have been fully investigated. Theoccurred, that they have been fully investigated. Thequality control unit shall be responsible for approvingquality control unit shall be responsible for approvingor rejecting drug products manufactured, processed,or rejecting drug products manufactured, processed,packed, or held under contract by another company.”packed, or held under contract by another company.”21 CFR 211.22(a)21 CFR 211.22(a)
  21. 21. 21cGMP: ComplaintscGMP: Complaints Written procedures describing the handling ofWritten procedures describing the handling ofall written and oral complaintsall written and oral complaints Review by Quality Control unitReview by Quality Control unit Possible failure to meet any specificationPossible failure to meet any specification Determine need for deviation investigationDetermine need for deviation investigation Adverse Drug Experience report assessmentAdverse Drug Experience report assessment Documentation of complaint and investigationDocumentation of complaint and investigationor reason for not investigatingor reason for not investigating21 C.F.R. 211.19821 C.F.R. 211.198
  22. 22. 22cGMP: Records and ReportscGMP: Records and ReportsContemporaneous documentation criticalContemporaneous documentation critical Laboratory and production recordsLaboratory and production records Trending analysisTrending analysisData IntegrityData IntegrityInternal review: OOS results, complaints, R&DInternal review: OOS results, complaints, R&DExternal review: FDA inspections, business dealsExternal review: FDA inspections, business deals(due diligence), and products liability cases(due diligence), and products liability cases
  23. 23. 23cGMP: ReportscGMP: Reports (cont.)(cont.) Field Alert ReportsField Alert Reports §§ 314.81(b)(1)314.81(b)(1) LabelingLabeling Failure to meet specifications — STABILITY FAILURESFailure to meet specifications — STABILITY FAILURES Within 3 working days of receiptWithin 3 working days of receipt Warner Lambert criminal caseWarner Lambert criminal case Adverse Drug Experience ReportsAdverse Drug Experience Reports §§ 314.80314.80 ASAP but no later than 15 calendar days of initial receiptASAP but no later than 15 calendar days of initial receipt Foreign and domesticForeign and domestic Recall Procedures and PreparationRecall Procedures and Preparation
  24. 24. 24cGMP: AuditingcGMP: Auditing Independent Audit GroupIndependent Audit Group ResourcesResources AuthorityAuthority Global Approach - Harmonization of QualityGlobal Approach - Harmonization of QualityStandardsStandards Audit priority systems / specific issuesAudit priority systems / specific issues Follow-up auditsFollow-up audits
  25. 25. Good Manufacturing PracticeGood Manufacturing Practice(“GMP”) Compliance:(“GMP”) Compliance:GMPs EXPLAINEDGMPs EXPLAINEDPresented byRaymond A. BonnerNathan C. SheersSIDLEY AUSTIN BROWN & WOOD, LLPWashington, D.C.(202) 736-8000ToThe Fourth Annual PharmaceuticalRegulatory and Compliance Congressand Best Practices ForumNovember 13, 2003

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