美国FDA原料药查厂重点经验分享

1美國FDA原料藥查廠重點經驗分享2ChemicalSynthesisSterile2%FermentationNonsterile6%CrudeBulkNEC7%Others3%Biotech/CrudeDrug1%ChemicalSynthesisNonsterile81%ProcessesCoveredDuringAPIInspectionsAbroad-FY2001InitialinspectiononECIC3ICHQualityTopicsChecklistAPIInspectionGuideQ1:StabilityQ1A(R):StabilityTestingofNewDrugsandProducts(Revised)Q1B:PhotostabilityTestingQ1C:StabilityTestingforNewDosageFormsQ1D:BracketingandMatrixingDesignsforStabilityTestingofDrugSubstancesandDrugProductsQ2:AnalyticalValidationQ2A:TextonValidationofAnalyticalProceduresQ2B:MethodologyQ3:ImpuritiesQ3A(R):ImpuritiesinNewDrugSubstances(Revised)Q3B(R):ImpuritiesinNewDrugProducts(Revised)Q3C:Impurities:ResidualSolventsQ4:PharmacopoeiasQ4:PharmacopoeialHarmonisationQ5:BiotechnologicalQualityQ5A:ViralSafetyEvaluationQ5B:GeneticStabilityQ5C:StabilityofProductsQ5D:CellSubstratesQ6:SpecificationsQ6A:ChemicalSubstanceswithitsDecisionTreesQ6B:BiotechnologicalSubstancesQ7:GMPQ7A:GMPforActivePharmaceuticalIngredients4SixSystemsQUALITYSYSTEMFACILITIESANDEQUIPMENTSYSTEMSPRODUCTIONSYSTEMLABORATORYCONTROLSYSTEMPACKAGINGANDLABELINGMATERIALSSYSTEMS5QUALITYSYSTEM(FDAComplianceReferenceProgramGuidance)1.EvaluationofwhetherTheQualityUnit(QA)isreviewingandapprovingallSOPsrelatedtoproduction,QC,andQA.2.SeekassurancethattheSOPsareadequatefortheirintendeduse.3.Thisalsoincludesareviewoftheassociatedrecordkeepingaswell.6QUALITYSYSTEM(FDAComplianceReferenceProgramGuidance)4.TheFDAconsidersthefollowingSOPstobecriticalandwillwanttoreviewthemtoseeiftheyarewritten,andiftheyarebeingfollowedaswrittenwherethereuseisrequired.AnnualProductreviewComplaintReviewsDiscrepancyandFailureInvestigationsrelatedtoboththemanufacturingandtesting.“documented,evaluated,investigatedinatimelymanner;includescorrectiveactionwhereappropriate.”7QUALITYSYSTEM(FDAComplianceReferenceProgramGuidance)ChangeControl:“documented;evaluated;approved;andneedforrevalidationassessed.”Validation:statusofrequiredvalidation/revalidationforcomputeruses,manufacturingprocess,andlaboratorymethods.Training/qualificationsofemployeesinthequality(QA)unit.8QUALITYSYSTEM(FDAComplianceReferenceProgramGuidance)5.SOPsfor:ReviewandapprovalbyQAofallproductionandprocesscontrolproceduresandalllaboratorycontrolmechanisms,specifications,standards,samplingplans,testprocedures.AdequatereviewandapprovalbyQAofproductionandcontrolrecordsforeachbatchbeforereleaseanddistribution.AdequateannualproductreviewprocedureandforreviewsbeingperformedincludingOOSandDIRreviews.9QUALITYSYSTEM(ChangeControlProcedure)ChangeApplicationChangeEvaluationRejectApprovalandNotificationQualification/Revalidation10FACILITIESANDEQUIPMENTSYSTEMS(FDAComplianceReferenceProgramGuidance)1.Descriptionandlayoutofanyspecializedair-handlingsystemsincludingIQ/OQandrecordsofmaintenanceandfilterchangesifapplicable.2.IQ/OQforallmajormanufacturingequipment,purifiedwatersystemQClaboratorytestequipment(HPLCsandGCs),refrigerators,freezers,stabilitychambers,etc.andmajorutilities.3.Propercalibrationsofequipment,gauges,temperatureindicators,pHprobes,etc.11FACILITIESANDEQUIPMENTSYSTEMS(FDAComplianceReferenceProgramGuidance)4.Documentationofcleaningprocedures.5.Cleaningvalidationforfinal-stepproductionequipments.6.Validationofpurifiedwatersystem.7.SOPformaintenanceandcheckingofwatersystemonadailybasisforoperationandleaks.8.Equipmentcalibration,maintenance,andusagelogbooks.12FACILITIESANDEQUIPMENTSYSTEMS(FDAComplianceReferenceProgramGuidance)9.SOPforactiontobetakenifanoutofcalibrationsituationisfound.10.Appropriateequipmentidentificationandstatus.11.Qualification/Validationandsecurityofcomputerizedorautomateddatahandlingsystems.13FACILITIESANDEQUIPMENTSYSTEMS(PurifiedWaterSystem)TapeWaterActiveCarbonbedIonExchangeReverseOsmosisPurifiedWater14PRODUCTIONSYSTEMAPIVs.DrugProduct15PRODUCTIONSYSTEM(FDAComplianceReferenceProgramGuidance)1.Training/qualificationofpersonnel2.Controlsystemforimplementingchangesintheprocess3.Adequateproceduresandpracticesforchargingofcomponents4.Identificationofequipmentwithcontentsandwhereappropriatephaseofmanufacturingandstatus.16PRODUCTIONSYSTEM(FDAComplianceReferenceProgramGuidance)5.Validation/verificationofcleaningprocedures.6.Calculationanddocumentationofactualyieldsandpercentageoftheoreticalyields.7.Establishedtimelimitsforcompletionofphasesofproduction.8.Implementationanddocumentationofin-processcontrols,tests,andexaminations(e.g.,pHadequacyofmixing,weightvariation,clarity.)17PRODUCTIONSYSTEM(FDAComplianceReferenceProgramGuidance)9.Justificationandconsistencyofin-processspecificationsanddrugproductfinalspecifications.10.Equipmentcleaningandusagelogs.11.Masterproductionandcontrolrecords12.Issuanceofbatchproductionrecords18PRODUCTIONSYSTEM(In-ProcessSampling&Controls)Lessstringentin-processcontrolsmaybeappropriateinearlyprocessingstepsTightercontrolsmaybeappropriateforlaterprocessingstepsEarlystepsABCDEFAPIDEFAPIIncreasingGMPs19PRODUCTIONSYSTEM(ExamplesofProcessParameters)TemperaturePressureVacuumTime(Duration)FlowRateCoolingRateAgitationSpeed20PRODU