美国FDA验证高级培训资料.ppt

1,美国FDA验证高级培训DenisKluba博士吴培栋博士,2,目录TableOfContents,验证定义CGMP对验证的要求验证历史与期望验证综述验证主方案与规划实施验证的方法验证的技术内容要求执行验证方案工作流程改变控制再验证总结,3,PartOne:WhatisValidation?,?,第一部分：验证定义,4,WhatisValidation?,ForthisSeminaritreferstotwothings:1.TheUSAFDArequirementsthatmustbemetinordertosuccessfullyandcontinuallyselldrugproductsintheUSA2.Activitiesthatwillcontributetothesuccessofthecompanyinthemanufactureofdrugproducts,验证的含义？,5,Validation,“Anythingwhichyoucannotunderstandisindistinguishablefrommagic.”ArthurC.Clark“Validationmaynotbemagic!”C.Edwards,业内对验证的理解,6,ValidationIs.,“Documentedevidencewhichprovidesahighdegreeofassurancethataspecificprocesswillconsistentlyproduceaproductmeetingitspredeterminedspecificationsandqualityattributes.”,FDA对验证的定义,7,ToConsistentlyProduceADesiredKnownProduct,WhyDoWeValidate?,ConfirmDesign,EstablishOperatingBoundaries,EstablishBaselines,ProductCompliance,TestwithinSpecification,验证的作用/目的,8,HowDoWeValidate?,DetailsWillFollowButThisistheGeneralModel,IdentifyEquipmentSystems,DevelopTests,WriteProtocols,ConductTests,EvaluateData,ReportResults,ResultsOK?,yes,No,AmendProtocol,AmendTest,CollectData,ValidatedSystem,SystemModified?,验证流程图,9,FirstthreestepstoCGMPcompliance,documentdocumentdocument,符合CGMP要求的头三步,10,BoundariesofValidation,Engineering,COMMISSIONINGSTART-UPTROUBLESHOOTINGTRIALRUNSCYCLEDEVELOPMENTPROCESSDEVELOPMENTENGINEERINGSTUDIESVENDORSERVICEREPORTSFACTORYACCEPTANCETEST“AS-BUILT”DRAWINGS,STANDARDOPERATINGPROCEDURESMFGBATCHRECORDSPERSONNELTRAININGCALIBRATIONPREVENTATIVEMTCECHANGECONTROLCOMPLIANCEVENDORAUDITSANNUALREVIEWSCOMPLAINTSSAFETY,Operations/QA,Validation,验证的界限/范围,11,ValidationLifeCycleApproach,Prospective/Concurrent,DefineSpecificationsEquipmentProcessRequirements,Procedures,New/RevisedProcess/Product,验证生命周期:新的/修改过的工艺/产品,12,ValidationLifeCycleApproach,Retrospective,DefineSystemSpecificationsEquipmentProcedures,ExistingProcess/Product,验证生命周期:现有工艺/产品,13,BenefitsofValidation,IncreasedThroughputReductionInRejectionsandReworksReductionInUtilityCostsAvoidanceOfCapitalExpendituresFewerComplaintsAboutProcessRelatedFailuresReducedTestingIn-processandFinishedGoodsMoreRapid/AccurateInvestigationsIntoProcessUpsetsMoreRapidandReliableStartupOfNewEquipmentEasierScale-upFromDevelopmentWorkEasierMaintenanceOfTheEquipmentImprovedEmployeeAwarenessOfProcessesMoreRapidAutomation,验证带来的好处,14,ElementsOfContemporaryValidationInTheUS,EquipmentCalibration-ProcessandValidationEquipmentEquipmentQualification-InstallationandOperationalProcessDevelopmentProcessDocumentationPerformanceQualification-ValidationMaintenanceofValidation-ProcessandEquipmentChangeControl,当今美国验证包含的内容,15,cGMPandISO-9000-Similarities,AimedatQualityRequireDocumentationRequireSpecificQualityProgramQAandQCIncluded,CGMP和ISO9000的相似之处,16,cGMPandISO-9000-Differences,cGMPAimedatProductISO-9000IncludesDesignandService,aswellcGMPCoversActivitiesDirectlyRelatedtoManufacturingISO-9000CoversBroaderRangeofActivities(e.g.Purchasing)cGMPRequiresFormalValidationISO-9000RequiresApplicableStatisticalMethods,CGMP和ISO9000的不同之处,17,BenefitsoftheSystemsApproachtoValidation,MoreRigorousControlOverOperationsCentralizedPlanningforallValidationRelatedAspectsTiesExistingSub-elementsintoCohesiveSystemEstablishesValidationasaProgram,notaProjectProvidesforContinuityofApproachAffirmsValidationasaDisciplineMuchlikeOthersAllowsForPersonnelGrowthwithintheValidationExpertiseUsuallyResultsinCentralizationofValidationExpertiseMoreCompatiblewiththeAccomplishmentofaCorporateObjectiveforValidation,系统验证方法的好处,18,TheValidationProgram,EstablishGoalsandObjectivesastoWhatMustbeValidatedQualifyorRe-qualifytheEquipmentEstablishValidationProtocolsforeach,andobtainApprovaloftheProtocolsEstablishPersonnelRequirementsandTrainingRecordsProcedureDesignandConductExperiments.CollectDataEvaluatetheDataPrepareSummaryReportsOutliningtheResultsoftheExperiments.ObtaintheNecessaryApprovalsEstablishandMaintainValidationFilesIncludingRawDataInstituteaChangeControlProceduretoInsuretheOngoingAcceptabilityoftheWork,验证项目/规划,19,PartTwo:GMPRequirements,第二部分：GMP对验证的要求,20,GMPrequirements,Part211:Currentgoodmanufacturingpracticeforfinishedpharmaceuticals211.68-Automatic,mechanical,andelectronicequipment.211.84-Testingandapprovalorrejectionofcomponents,drugproductcontainers,andclosures.211.110-Samplingandtestingofin-processmaterialsanddrugproducts.211.113-Controlofmicrobiologicalcontamination.211.165-Testingandreleasefordistribution.211.166-Stabilitytesting.,GMP要求,21,cGMPinthePharmaceuticalIndustry,GMPistheabbreviationof“GoodManufacturingPractice”whichisadoptedbythemedicalandhealthrelatedindustriesincludingthepharmaceuticalindustryinanefforttomaintainthehigheststandardsofqualityinthedevelopment,manufactureandcontrolofmedicinalproducts.Sincetheindustrystandardsaresubjecttocontinuousimprovement,thelettercintheabbreviation“cGMP”refersmorespecificallytothecurrentorthelatestversionoftheGMPrequirements.,制药行业的cGMP,22,RegulatoryRequirementsforValidation.,Therequirementofprocessvalidationisimplicitinthelanguageof21CFR211.100oftheCurrentGoodManufacturingregulationswhichstates:“Thereshallbewrittenproceduresforproductandprocesscontroltoassurethatdrugproductshavetheidentity,strength,quality,andpuritytheypurportorarerepresentedtopossess.,监管部门对验证的要求,23,GMPRegulatoryRequirementsforCleaningValidation,1978cGMPRegulations(part211.67(a)Equipmentcleaningandmaintenancestates:“Equipmentandutensilsshallbecleaned,maintained,andsanitizedatappropriateintervalstopreventmalfunctionsorcontaminationthatwouldalterthesafety,identity,strength,quality,orpurityofthedrugproductbeyondtheofficialorotherestablishedrequirements”.,GMP条例对清洗验证的要求,24,GMPRegulatoryRequirementsforTestMethodValidation,LaboratoryControls21CFR211.165(e)states:Theaccuracy,sensitivity,specificityandreproducibilityoftestmethodsemployedbythefirmshallbeestablishedanddocumented.SuchvalidationanddocumentationmaybeaccomplishedinaccordancewithPart211.194(a)(2).,GMP条例对化验方法验证的要求,25,GMPRegulatoryRequirementsforTestMethodValidation,Part211.194(a)(2)states:Astatementofeachmethodused.shallindicatethelocationofdatathatestablishthatthemethodsusedinthetestingofthesamplemeetproperstandardsofaccuracyandreliabilityasappliedtotheproducttested.Thesuitabilityofalltestingmethodsusedshallbeverifiedunderactualconditionsofuse.,GMP条例对化验方法验证的要求,26,GMPRegulatoryRequirementsforTestMethodValidation,U.S.FederalCourtdecision:UnitedStatesvsBarrLabsCleaningValidation:.itwasruledforcleaningtobeeffective,thespecifictestmethodshadtobeshowntobeeffective.,GMP条例对化验方法验证的要求,27,PROCESSVALIDATION,21CFR211.110“suchcontrolproceduresshallbeestablishedtomonitortheoutputandtovalidatetheperformanceofthosemanufacturingprocessesthatmayberesponsibleforcausingvariabilityinthecharacteristicsofin-processmaterialandthedrugproduct”,工艺验证,28,PartThree:HistoryandExpectations,AsappliedbytheFDAandImplementedbyIndustry,第三部分：验证历史与FDA和制药行业对验证的期望,29,Historyandexpectations,LearnfortheexperiencesoftheUSAmanufacturersandindustryorganizationsCurrentapplicationsPastcitationsIndustryguidelinesICHQ7AISPEPDAEtc.,历史与期望,30,ValidationTargets,EarlyYearsSterilizationAsepticOperationsMiddleYearsNon-sterileProcessesOralDosageForms,RecentYearsBiologicalProcessesBulkOrganicSynthesisDevelopmentalandPilotOperationsSupportingServicesCurrentlyTotalOperationsReviewbySystemsQualitySystemProductionSystemLaboratoryControlsPackagingandLabeling,MaterialsandFacilitiesEquipmentManufacturing.,验证目标,31,HistoryofValidation,ValidationinTheEarlyYears-1972to1978RegulatoryBasedtoSatisfyFDAPressuresDefensivetoProtectProductLineValidationinItsAdolescence-1978To1983PrimarilyDefensiveSomeEffortsatProcessOptimizationIncludesSomePeripheralConcernsValidationintheUSToday-1983toPresentNon-RegulatoryinManyAreasGearedTowardsOptimizationandfocusedonSystems,验证历史,32,validationvs.VALIDATION,validationDefensiveTestingOrientedCostlyQualityControlNarrowFocus,VALIDATIONOptimizationTotalProcessControlCostEffectiveQualityAssuranceDiverseApplication,如何正确理解验证,33,ElementsofContemporaryValidationintheUS,EquipmentCalibration-ProcessandValidationEquipmentEquipmentQualification-InstallationandOperationalProcessDevelopmentProcessDocumentationPerformanceQualification-ValidationMaintenanceofValidation-ProcessandEquipmentChangeControl,当今美国验证所包含的内容/要素,34,Expectations,ValidationisaProgramnotaProjectValidationContributestotheStabilityoftheOperationsValidationisnotSomeoneElsesJob!,对验证的期望,35,PartFour:Validation,AnOverview,第四部分：验证概述,36,WhoValidates?,ValidationStaff,Engineering,QualityAssurance,QualityControl,Manufacturing,谁进行验证？,37,Validation,v,Design,Testing,Operation,验证,运作,38,Validation,v,Vendor,SystemsIntegrator,Owner/User,验证,系统集成者,39,Validation,v,EngineeringR-AnalogInputs;-AnalogOutputs;-DigitalInputs;-DigitalOutputs;-OneSpeedMotor;-TwospeedMotor.TheappropriateproceduretofollowwhenperformingTagCheckouts,isdescribedontheformsmentionedabove.AlistofinstrumentstobetagcheckedwillbeattachedtothepackageOQProtocol.ThecompletionofInstrumenttagcheckoutforaspecificpackageisconfirmedonpackageOQCheckoutSheet.,EXAMPLE,标签校验,126,ConstructionCleaning-ProcessProductionProblems;ProductionFailures,工艺验证,227,CGMPAnnualReview,21CFR211.180(e)RequiresaRetrospectiveOverallEvaluationoftheAdequacyoftheQualityStandardsAtLeastAnnuallyDrugProductsDirectlyImpactedDrugSubstancesImpactedPerPreamble(1978),CGMP年度评审,228,CGMPAnnualReview,95RetrospectiveReviewRepresentative#ofBatchesforEa.ProductIfCheckRevealsanAdverseQualityGoto100%ReviewComputersUseEncouragedAsaComplimenttoHumanJudgment&Intervention,CGMP年度评审,229,CGMPAnnualReview,95ProposedRevisions-ValidationImplementRevalidationProceduresWheneverThereAreChanges,IncludingReprocessing,ThatCouldAffectProductEffectivenessorCharacteristics,CGMP年度评审,230,PlannedChanges,ProposeChange,DocumentReason(Manufacturing,Development,Etc.)FileFormalRequestDetermineNeedForValidationOfProcessWithChangeImplementedImplementChangeExecuteandReportValidationTestingReviewandApproveUpdateDrawings,SOPsandOperatingRecords,计划的改变,231,EmergencyChanges,OnlyToSaveProductInProcessImpoundProductPendingEvaluationOfChangeDocumentChange-FormalRequestFormDetermineNeedForValidationOfChangeDetermineIfChangeShouldBePermanentValidationTesting,IfNecessaryAcceptOrRejectImpoundedProductUpdateDrawingsandProcedures,AsRequired,紧急状况下的改变,232,PartEleven:Revalidation,etc,CalibrationProgramPreventativeMaintenanceChangeControlProgramSoftwareEquipmentLogsSOPsRegularQAReviews,第十一部分：再验证等,233,Revalidation,ValidationofaPreviouslyValidatedSystemthathasbeenChangedorModifiedNeedtoperformisEstablishedintheChangeControlProgramEventBasedTimeBased,再验证,234,Calibration,DefineCriticalProcessVariables-EffectOnQuality-EffectOnYieldOrAccountability-EffectOnOperatorSafetySOP-GeneralProcedureForCriticalVariables-SpecificProcedureForEachInstrument-AcceptableRangeDefinition-FrequencyOfRecalibration-ExceptionReportingTraceability-NISTTraceableStandards-RecalibrationOfStandards,校准,235,EssentialPartsofaCalibrationProgram,StatementOfPurposeandScopeCriteriaForTrainingPersonnelWrittenCalibrationProceduresMetrologyLaboratoryCalibrationRecordsSystemForInstrumentRecallForCalibrationAlertProcedureForOutOfCalibrationInstruments,校准项目的核心部分,236,Maintenance,CorrectiveAdaptivePreventative,维护,237,PreventativeMaintenance,HousekeepingFiltersTemperature,RHRoutineDiagnosticsMfg.RecommendedProgram,预防性维护,238,Software,Changesmadetocorrecterrorsandfaultsinthesoftwarearecorrectivemaintenance.Changesmadetothesoftwaretoimprovetheperformance,maintainability,orotherattributesofthesoftwaresystemareperfectivemaintenance.Softwarechangestomakethesoftwaresystemusableinachangedenvironmentareadaptivemaintenance.Whenchangesaremadetoasoftwaresystem,eitherduringinitialdevelopmentorduringpostreleasemaintenance,sufficientregressionanalysisandtestingshouldbeconductedtodemonstratethatportionsofthesoftwarenotinvolvedinthechangewerenotadverselyimpacted.Thisisinadditiontotestingthatevaluatesthecorrectnessoftheimplementedchange(s).,软件,239,EquipmentLogs,Awrittenrecordofmajorequipmentcleaning,maintenance(exceptroutinemaintenancesuchaslubricationandadjustments),anduseshallbeincludedinindividualequipmentlogsthatshowthedate,time,product,andlotnumberofeachbatchprocessed.Ifequipmentisdedicatedtomanufactureofoneproduct,thenindividualequipmentlogsarenotrequired,providedthatlotsorbatchesofsuchproductfollowinnumericalorderandaremanufacturedinnumericalsequence.Incaseswherededicatedequipmentisemployed,therecordsofcleaning,maintenance,anduseshallbepartofthebatchrecord.Thepersonsperforminganddouble-checkingthecleaningandmaintenanceshalldateandsignorinitialthelogindicatingthattheworkwasperformed.Entriesinthelogshallbeinchronologicalorder.,设备记录,240,SOPs,EstablishedtoEnsurethatActivitiesarePerformedtheSameWayatallTimesPeriodicReviewandUpdatingDefinedApprovalProcess,whichincludesSignatoryResponsibilityTrainingontheSOPContentASystemofArchivingandVersionControl,标准操作规程,241,RegularQAReviews,Thereshallbeaqualitycontrolunitthatshallhavetheresponsibilityandauthoritytoapproveorrejectallcomponents,drugproductcontainers,closures,in-processmaterials,packagingmaterial,labeling,anddrugproducts,andtheauthoritytoreviewproductionrecordstoassurethatnoerrorshaveoccurredor,iferrorshaveoccurred,thattheyhavebeenfullyinvestigated.Thequalitycontrolunitshallberesponsibleforapprovingorrejectingdrugproductsmanufactured,processed,packed,orheldundercontractbyanothercompany.,QA定期审阅,242,RegularQAReviews,Alldrugproductproductionandcontrolrecords,includingthoseforpackagingandlabeling,shallbereviewedandapprovedbythequalitycontrolunittodeterminecompliancewithallestablished,approvedwrittenproceduresbeforeabatchisreleasedordistributed.Anyunexplaineddiscrepancy(includingapercentageoftheoreticalyieldexceedingthemaximumorminimumpercentagesestablishedinmasterproductionandcontrolrecords)orthefailureofabatchoranyofitscomponentstomeetanyofitsspecificationsshallbethoroughlyinvestigated,whetherornotthebatchhasalreadybeendistributed.Theinvestigationshallextendtootherbatchesofthesamedrugproductandotherdrugproductsthatmayhavebeenassociatedwiththespecificfailureordiscrepancy.Awrittenrecordoftheinvestigationshallbemadeandshallincludetheconclusionsandfollowup.,QA定期审阅,243,QAReviews21CFR211.180(e),GeneralrequirementsSubpartJ-RecordsandReports,ThecGMPregulationscallforatleastanannualevaluationofeachdrugproductsqualitystandardstodeterminetheneedforchangesinproductspecificationsormanufacturingorcontrolprocedures.Therulealsorequiresfirmstoestablishandfollowwrittenproceduresforconductingthoseevaluations.Suchanevaluationwouldbeincompleteifthestandardoperatingproceduresforproductionandprocesscontrolswerethemselvesnotreviewed.DuringYourestablishmentinspections,whenauditingforcompliancewithsection211.180,determineifthefirmhasestablished,andisfollowing,thoseevaluationprocedures.AlsochecktoseeiftheprocedurescallforreviewingSOPs.,QA审阅,244,PartTwelve:SHOWSTOPPERS,第十二部分：总结,245,SHOWSTOPPERSGeneralQualityAssurance,Thefailuretohavewrittenproceduresinplacethathavebeenapprovedbythequalityunit.PersonnelperformingcriticaloperationswholackadequatetrainingorexperienceThefailuretohaveaqualityunitreviewforproductreleasethatincludesreviewoffailures,yielddiscrepancies,anddeviationsfromprocedures.,质量保障,246,SHOWSTOPPERSLaboratoryControls,AnalyticalmethodnotvalidatedNotStabilityIndicatingRelatedcompoundsnotdistinguishedFailuretotestfinishedproductStabilityprograminadequate/notobservedPoorinvestigationofoutofspec.findingsAnalystsand/orequipmentnotqualifiedPreservative/mediaeffectivenesstesting,实验控制,247,SHOWSTOPPERSFacilitiesandEquipment,NocleaningvalidationNoenvironmentalmonitoringObviousavenuesofcontaminationEquipmentoperatingparametersnotdocumentedBatchsizeexceedscapacityofequipmentWaterandairsystemsnotvalidated,设施和设备,248,SHOWSTOPPERSProductionandProcessControls,ProcessnotvalidatedComponentsnotindependentlycheckweighedProcessdeviationsandrejectedproductsnotadequatelycontrolled/investigatedYieldsnotcheckedorinvestigatedifoutofrangeReprocessingwithoutapprovalorcontrol,生产与工艺控制,249,SHOWSTOPPERSPackagingandLabeling,FailuretocheckincominglabelsagainstmastersorspecificationsUncontrolledstorageoflabelingmaterialsInadequateclearanceoflinesFailuretoelectronicallyexamineorvisuallydoublecheckfinish