美國FDA原料藥查廠重點(diǎn)經(jīng)驗(yàn)分享1美國FDA原料藥查廠重點(diǎn)經(jīng)驗(yàn)分享1ProcessesCoveredDuringAPIInspectionsAbroad-FY2001InitialinspectiononECIC2ProcessesCoveredDuringAPIIICHQualityTopicsChecklistAPIInspectionGuideQ1:Stability

Q1A(R):StabilityTestingofNewDrugsandProducts(Revised)

Q1B:PhotostabilityTesting

Q1C:StabilityTestingforNewDosageForms

Q1D:BracketingandMatrixingDesignsforStabilityTestingofDrugSubstancesandDrugProducts

Q2:AnalyticalValidationQ2A:TextonValidationofAnalyticalProceduresQ2B:MethodologyQ3:Impurities

Q3A(R):ImpuritiesinNewDrugSubstances(Revised)Q3B(R):ImpuritiesinNewDrugProducts(Revised)

Q3C:Impurities:ResidualSolventsQ4:PharmacopoeiasQ4:PharmacopoeialHarmonisationQ5:BiotechnologicalQuality

Q5A:ViralSafetyEvaluation

Q5B:GeneticStabilityQ5C:StabilityofProductsQ5D:CellSubstratesQ6:SpecificationsQ6A:ChemicalSubstances

withitsDecisionTreesQ6B:BiotechnologicalSubstances

Q7:GMP

Q7A:

GMPforActivePharmaceuticalIngredients

3ICHQualityTopicsChecklistAPSixSystems

QUALITYSYSTEM

FACILITIESANDEQUIPMENTSYSTEMS

PRODUCTIONSYSTEM

LABORATORYCONTROLSYSTEM

PACKAGINGANDLABELING

MATERIALSSYSTEMS4SixSystemsQUALITYSYSTEMFQUALITYSYSTEM

(FDAComplianceReferenceProgramGuidance)EvaluationofwhetherTheQualityUnit(QA)isreviewingandapprovingallSOPsrelatedtoproduction,QC,andQA.SeekassurancethattheSOPsareadequatefortheirintendeduse.Thisalsoincludesareviewoftheassociatedrecordkeepingaswell.5QUALITYSYSTEM

(FDAComplianceQUALITYSYSTEM

(FDAComplianceReferenceProgramGuidance)TheFDAconsidersthefollowingSOPstobecriticalandwillwanttoreviewthemtoseeiftheyarewritten,andiftheyarebeingfollowedaswrittenwherethereuseisrequired.AnnualProductreviewComplaintReviewsDiscrepancyandFailureInvestigationsrelatedtoboththemanufacturingandtesting.“documented,evaluated,investigatedinatimelymanner;includescorrectiveactionwhereappropriate.”6QUALITYSYSTEM

(FDAComplianceQUALITYSYSTEM

(FDAComplianceReferenceProgramGuidance)ChangeControl:

“documented;evaluated;approved;andneedforrevalidationassessed.”Validation:statusofrequiredvalidation/revalidationforcomputeruses,manufacturingprocess,andlaboratorymethods.Training/qualificationsofemployeesinthequality(QA)unit.

7QUALITYSYSTEM

(FDAComplianceQUALITYSYSTEM

(FDAComplianceReferenceProgramGuidance)SOPsfor:ReviewandapprovalbyQAofallproductionandprocesscontrolproceduresandalllaboratorycontrolmechanisms,specifications,standards,samplingplans,testprocedures.AdequatereviewandapprovalbyQAofproductionandcontrolrecordsforeachbatchbeforereleaseanddistribution.AdequateannualproductreviewprocedureandforreviewsbeingperformedincludingOOSandDIRreviews.8QUALITYSYSTEM

(FDAComplianceQUALITYSYSTEM

(ChangeControlProcedure)ChangeApplicationChangeEvaluationRejectApprovalandNotificationQualification/Revalidation9QUALITYSYSTEM

(ChangeControlFACILITIESANDEQUIPMENTSYSTEMS

(FDAComplianceReferenceProgramGuidance)Descriptionandlayoutofanyspecializedair-handlingsystemsincludingIQ/OQandrecordsofmaintenanceandfilterchangesifapplicable.IQ/OQforallmajormanufacturingequipment,purifiedwatersystemQClaboratorytestequipment(HPLCsandGCs),refrigerators,freezers,stabilitychambers,etc.andmajorutilities.Propercalibrationsofequipment,gauges,temperatureindicators,pHprobes,etc.10FACILITIESANDEQUIPMENTSYSTEFACILITIESANDEQUIPMENTSYSTEMS

(FDAComplianceReferenceProgramGuidance)Documentationofcleaningprocedures.Cleaningvalidationforfinal-stepproductionequipments.Validationofpurifiedwatersystem.SOPformaintenanceandcheckingofwatersystemonadailybasisforoperationandleaks.Equipmentcalibration,maintenance,andusagelogbooks.11FACILITIESANDEQUIPMENTSYSTEFACILITIESANDEQUIPMENTSYSTEMS

(FDAComplianceReferenceProgramGuidance)SOPforactiontobetakenifanoutofcalibrationsituationisfound.Appropriateequipmentidentificationandstatus.Qualification/Validationandsecurityofcomputerizedorautomateddatahandlingsystems.12FACILITIESANDEQUIPMENTSYSTEFACILITIESANDEQUIPMENTSYSTEMS

(PurifiedWaterSystem)TapeWaterActiveCarbonbedIonExchangeReverseOsmosisPurifiedWater13FACILITIESANDEQUIPMENTSYSTEPRODUCTIONSYSTEM

APIVs.DrugProduct14PRODUCTIONSYSTEM

APIVs.DruPRODUCTIONSYSTEM

(FDAComplianceReferenceProgramGuidance)Training/qualificationofpersonnelControlsystemforimplementingchangesintheprocessAdequateproceduresandpracticesforchargingofcomponentsIdentificationofequipmentwithcontentsandwhereappropriatephaseofmanufacturingandstatus.15PRODUCTIONSYSTEM

(FDACompliaPRODUCTIONSYSTEM

(FDAComplianceReferenceProgramGuidance)Validation/verificationofcleaningprocedures.Calculationanddocumentationofactualyieldsandpercentageoftheoreticalyields.

Establishedtimelimitsforcompletionofphasesofproduction.Implementationanddocumentationofin-processcontrols,tests,andexaminations(e.g.,pHadequacyofmixing,weightvariation,clarity.)16PRODUCTIONSYSTEM

(FDACompliaPRODUCTIONSYSTEM

(FDAComplianceReferenceProgramGuidance)Justificationandconsistencyofin-processspecificationsanddrugproductfinalspecifications.Equipmentcleaningandusagelogs.MasterproductionandcontrolrecordsIssuanceofbatchproductionrecords17PRODUCTIONSYSTEM

(FDACompliaPRODUCTIONSYSTEM

(In-ProcessSampling&Controls)Lessstringentin-processcontrolsmaybeappropriateinearlyprocessingsteps

TightercontrolsmaybeappropriateforlaterprocessingstepsEarlystepsABCDEFAPIDEFAPIIncreasingGMPs18PRODUCTIONSYSTEM

(In-Process

PRODUCTIONSYSTEM

(ExamplesofProcessParameters)TemperaturePressureVacuumTime(Duration)FlowRateCoolingRateAgitationSpeed19

PRODUCTIONSYSTEM

(ExamplesoPRODUCTIONSYSTEM

(清潔方法的維護(hù)與確效)計(jì)劃書之發(fā)展*撰寫*核準(zhǔn)*訓(xùn)練設(shè)備*取樣位置選擇*表面積計(jì)算*概要圖分析標(biāo)的物選擇及允收標(biāo)準(zhǔn)*活性成份*賦形劑*清潔劑清潔SOP*撰寫*核準(zhǔn)*訓(xùn)練分析方法發(fā)展分析方法確效計(jì)劃書執(zhí)行*清潔*樣品*測試通過確效報(bào)告*撰寫*核準(zhǔn)定期監(jiān)測變更管制再確效事件調(diào)查YesNo發(fā)展階段計(jì)劃階段執(zhí)行階段維護(hù)階段20PRODUCTIONSYSTEM

(清潔方法的維護(hù)與確效)LABORATORYCONTROLSYSTEM

(FDAComplianceReferenceProgramGuidance)Training/qualificationofpersonnelCalibrationandmaintenanceprogramsformajoranalyticalinstrumentsandequipment.SOPforactiontobetakenifanoutofcalibrationsituationisfound.Referencestandards:source,purityandassay,andteststoestablishequivalencytocurrentofficialreferencestandards.SystemsuitabilitychecksonGCandHPLCsystems.21LABORATORYCONTROLSYSTEM

(FDALABORATORYCONTROLSYSTEM

(FDAComplianceReferenceProgramGuidance)Specifications,standards,andrepresentativesamplingplans.AdherencetothewrittenmethodsofanalysisValidation/verificationofanalyticalmethodsControlsystemforimplementingchangesinlaboratoryoperationsRequiredtestingisperformedonthecorrectsamples.22LABORATORYCONTROLSYSTEM

(FDALABORATORYCONTROLSYSTEM

(FDAComplianceReferenceProgramGuidance)Documentedinvestigationsintounexpecteddiscrepanciesspecificallyoutofspecificationresults(OOS).SOPfordealingwithOOSresultsthatincludestimelycompletionoftheinvestigation.Qualityandretentionofrawdata(e.g.chromatogramsandspectra.)SOPforhandlingvoidedchromatogramsandotherdata.23LABORATORYCONTROLSYSTEM

(FDALABORATORYCONTROLSYSTEM

(FDAComplianceReferenceProgramGuidance)Adequatereservesamples.SOPforexaminationofreservesamplesonaregularbasisalongwiththeappropriatedocumentation.Stabilitytestingprogramincludingdemonstrationofthestabilityindicatingcapabilityofthetestmethods24LABORATORYCONTROLSYSTEM

(FDALABORATORYCONTROLSYSTEM

(OOSProcedure)SampletestOutofspecificationSampleretest

Re-samplingtest(Analyst1)Re-samplingtest

(Analyst2)ReleaseRejectfailpassRe-samplingtestRejectRejectReleasepasspasspassfailfailfail25LABORATORYCONTROLSYSTEM

(OOSPACKAGINGANDLABELING

(FDAComplianceReferenceProgramGuidance)Controlsystemforimplementingchangesinpackagingcomponentsorlabels.Controlofissuanceoflabelsexaminationofissuedlabelsandreconciliationofusedlabels.Examinationofthelabeledfinishedproduct.Ifrequired,destructionofeitherunusedlabels,orlabelsthatneedtobedestroyed.26PACKAGINGANDLABELING

(FDACoMATERIALSSYSTEMS

APIVs.DrugProduct27MATERIALSSYSTEMS

APIVs.DruMATERIALSSYSTEMS

(FDAComplianceReferenceProgramGuidance)IdentificationofComponentsInventoryofcomponentsAppropriatequarantinestorageRawmaterialsamplingandtestingproceduresAppropriateretesttimesandSOPsinplace28MATERIALSSYSTEMS

(FDACompliaMATERIALSSYSTEMS

(FDAComplianceReferenceProgramGuidance)Finishedproductdistributionrecordsbylot.Adequatewrittenproceduresforstorage,handlingandquarantineofmaterials.Adequateidentificationofcomponents,containers,andclosures.Adequatestorageconditions.29MATERIALSSYSTEMS

(FDACompliaMATERIALSSYSTEMS

(FDAComplianceReferenceProgramGuidance)Storageunderquarantineuntiltested,orexaminedandreleased.UseofFIFOsystem.Adequatequarantineofrejectedmaterials/componentsAdequateinventory/usagerecordsforrawmaterialsandcomponents.30MATERIALSSYSTEMS

(FDACompliaPreparationsforFDAInspectionDiagramofthePurifiedwatersystemshowinglocationoffilters,samplingpoints.DiagramoftheHVACsystem,especiallyforthecleanroom.ProcessFlowdiagramOrganizationChartDevelopmentreportValidationdocumentsListofSOPs31Pre