美国FDA验证高级培训.ppt

美国美国FDA验证高级培训验证高级培训Denis Kluba 博士博士吴培栋吴培栋 博士博士1目录TableOfContents1.验证定义验证定义2.CGMP对验证的要求对验证的要求3.验证历史与期望验证历史与期望4.验证综述验证综述5.验证主方案与规划验证主方案与规划6.实施验证的方法实施验证的方法7.验证的技术内容要求验证的技术内容要求8.执行验证方案执行验证方案9.工作流程工作流程10.改变控制改变控制11.再验证再验证12.总结总结2PartOne:WhatisValidation?第一部分：验证定义3WhatisValidation?ForthisSeminaritreferstotwothings:1.TheUSAFDArequirementsthatmustbemetinordertosuccessfullyandcontinuallyselldrugproductsintheUSA2.Activitiesthatwillcontributetothesuccessofthecompanyinthemanufactureofdrugproducts验证的含义？4Validation“Anything which you cannot understand is indistinguishable from magic.”Arthur C.Clark“Validation may not be magic!”C.Edwards业内对验证的理解5Validation Is.“Documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.”FDA对验证的定义6ToConsistentlyProduceADesiredKnownProductWhy Do We Validate?ConfirmDesignEstablish OperatingBoundariesEstablish BaselinesProductComplianceTest withinSpecification验证的作用/目的7How Do We Validate?DetailsWillFollowButThisistheGeneralModelIdentify EquipmentSystemsDevelop TestsWrite ProtocolsConduct TestsEvaluate DataReport ResultsResults OK?yesNoAmendProtocolAmendTestCollect DataValidated SystemSystem Modified?验证流程图8FirstthreestepstoCGMPcompliancedocumentdocumentdocument符合CGMP要求的头三步9BoundariesofValidationCOMMISSIONING START-UP TROUBLE SHOOTING TRIAL RUNS CYCLE DEVELOPMENT PROCESS DEVELOPMENT ENGINEERING STUDIES VENDOR SERVICE REPORTS FACTORY ACCEPTANCE TEST “AS-BUILT”DRAWINGS STANDARD OPERATING PROCEDURES MFG BATCH RECORDS PERSONNEL TRAINING CALIBRATION PREVENTATIVE MTCE CHANGE CONTROL COMPLIANCE VENDOR AUDITS ANNUAL REVIEWS COMPLAINTS SAFETYDOCUMENTEDDOCUMENTED PROGRAM PROGRAM HIGH DEGREE OF HIGH DEGREE OFASSURANCEASSURANCECONSISTENTLYCONSISTENTLYMEETSMEETSPREDETERMINEDPREDETERMINEDSPECIFICATIONSSPECIFICATIONS验证的界限/范围10ValidationLifeCycleApproachProspective/ConcurrentDefine SpecificationsEquipment Process RequirementsProceduresDesign/Specify EquipmentDefine Process Develop Procedure Spec.Install Equipment Verify Procedure SpecificationsQualify Equipment Develop ValidationProtocol Obtain Data on Process Obtain Data on Process Data One LotConcurrent Validation ReportThree LotsProspectiveAcceptanceOngoingEvaluationChange ControlNew/Revised Process/Product验证生命周期:新的/修改过的工艺/产品11ValidationLifeCycleApproachRetrospectiveDefine SystemSpecificationsEquipment ProceduresQualifyEquipmentReview Process Capability,Specifications,Procedures,Operating InstructionsDevelop ValidationProtocol Validation ReportAcceptanceOngoingEvaluation Data Conduct Testing(If Needed)Change ControlExisting Process/Product验证生命周期:现有工艺/产品12Benefits of ValidationIncreased ThroughputReduction In Rejections and ReworksReduction In Utility CostsAvoidance Of Capital ExpendituresFewer Complaints About Process Related FailuresReduced Testing In-process and Finished GoodsMore Rapid/Accurate Investigations Into Process UpsetsMore Rapid and Reliable Startup Of New EquipmentEasier Scale-up From Development WorkEasier Maintenance Of The EquipmentImproved Employee Awareness Of ProcessesMore Rapid Automation验证带来的好处13ElementsOfContemporaryValidationInTheUSEquipmentCalibration-ProcessandValidationEquipmentEquipmentQualification-InstallationandOperationalProcessDevelopmentProcessDocumentationPerformanceQualification-ValidationMaintenanceofValidation-ProcessandEquipmentChangeControl当今美国验证包含的内容14cGMPandISO-9000-SimilaritiesAimedatQualityRequireDocumentationRequireSpecificQualityProgramQAandQCIncludedCGMP和ISO9000的相似之处15cGMPandISO-9000-DifferencescGMPAimedatProductISO-9000IncludesDesignandService,aswellcGMPCoversActivitiesDirectlyRelatedtoManufacturingISO-9000CoversBroaderRangeofActivities(e.g.Purchasing)cGMPRequiresFormalValidationISO-9000RequiresApplicableStatisticalMethodsCGMP和ISO9000的不同之处16BenefitsoftheSystemsApproachtoValidationMoreRigorousControlOverOperationsCentralizedPlanningforallValidationRelatedAspectsTiesExistingSub-elementsintoCohesiveSystemEstablishesValidationasaProgram,notaProjectProvidesforContinuityofApproachAffirmsValidationasaDisciplineMuchlikeOthersAllowsForPersonnelGrowthwithintheValidationExpertiseUsuallyResultsinCentralizationofValidationExpertiseMoreCompatiblewiththeAccomplishmentofaCorporateObjectiveforValidation系统验证方法的好处17TheValidationProgramEstablishGoalsandObjectivesastoWhatMustbeValidatedQualifyorRe-qualifytheEquipmentEstablishValidationProtocolsforeach,andobtainApprovaloftheProtocolsEstablishPersonnelRequirementsandTrainingRecordsProcedureDesignandConductExperiments.CollectDataEvaluatetheDataPrepareSummaryReportsOutliningtheResultsoftheExperiments.ObtaintheNecessaryApprovalsEstablishandMaintainValidationFilesIncludingRawDataInstituteaChangeControlProceduretoInsuretheOngoingAcceptabilityoftheWork验证项目/规划18PartTwo:GMPRequirements第二部分：GMP对验证的要求19GMPrequirementsPart 211:Current good manufacturing practice for finished pharmaceuticals211.68-Automatic,mechanical,andelectronicequipment.211.84-Testingandapprovalorrejectionofcomponents,drugproductcontainers,andclosures.211.110-Samplingandtestingofin-processmaterialsanddrugproducts.211.113-Controlofmicrobiologicalcontamination.211.165-Testingandreleasefordistribution.211.166-Stabilitytesting.GMP要求20cGMPinthePharmaceuticalIndustryGMPistheabbreviationof“GoodManufacturingPractice”whichisadoptedbythemedicalandhealthrelatedindustriesincludingthepharmaceuticalindustryinanefforttomaintainthehigheststandardsofqualityinthedevelopment,manufactureandcontrolofmedicinalproducts.Sincetheindustrystandardsaresubjecttocontinuousimprovement,thelettercintheabbreviation“cGMP”refersmorespecificallytothecurrentorthelatestversionoftheGMPrequirements.制药行业的cGMP21RegulatoryRequirementsforValidation.The requirement of process validation is implicit in the language of 21 CFR 211.100 of the Current Good Manufacturing regulations which states:“There shall be written procedures for product and process control to assure that drug products have the identity,strength,quality,and purity they purport or are represented to possess.监管部门对验证的要求22GMPRegulatoryRequirementsforCleaningValidation1978 cGMP Regulations(part 211.67(a)Equipment cleaning and maintenance states:“Equipmentandutensilsshallbecleaned,maintained,andsanitizedatappropriateintervalstopreventmalfunctionsorcontaminationthatwouldalterthesafety,identity,strength,quality,orpurityofthedrugproductbeyondtheofficialorotherestablishedrequirements”.GMP条例对清洗验证的要求23GMPRegulatoryRequirementsforTestMethodValidationLaboratory Controls 21 CFR 211.165(e)states:Theaccuracy,sensitivity,specificityandreproducibilityoftestmethodsemployedbythefirmshallbeestablishedanddocumented.SuchvalidationanddocumentationmaybeaccomplishedinaccordancewithPart211.194(a)(2).GMP条例对化验方法验证的要求24GMPRegulatoryRequirementsforTestMethodValidationPart 211.194(a)(2)states:Astatementofeachmethodused.shallindicatethelocationofdatathatestablishthatthemethodsusedinthetestingofthesamplemeetproperstandardsofaccuracyandreliabilityasappliedtotheproducttested.Thesuitabilityofalltestingmethodsusedshallbeverifiedunderactualconditionsofuse.GMP条例对化验方法验证的要求25GMPRegulatoryRequirementsforTestMethodValidationU.S.Federal Court decision:UnitedStatesvsBarrLabsCleaningValidation:.itwasruledforcleaningtobeeffective,thespecifictestmethodshadtobeshowntobeeffective.GMP条例对化验方法验证的要求26PROCESS VALIDATION21 CFR 211.110“such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product”工艺验证27PartThree:HistoryandExpectationsAsappliedbytheFDAandImplementedbyIndustry第三部分：验证历史与FDA和制药行业对验证的期望28HistoryandexpectationsLearnfortheexperiencesoftheUSAmanufacturersandindustryorganizationsCurrentapplicationsPastcitationsIndustryguidelinesICHQ7AISPEPDAEtc.历史与期望29ValidationTargetsEarlyYearsSterilizationAsepticOperationsMiddleYearsNon-sterileProcessesOralDosageFormsRecentYearsBiologicalProcessesBulkOrganicSynthesisDevelopmentalandPilotOperationsSupportingServicesCurrentlyTotalOperationsReviewbySystemsQualitySystemProductionSystemLaboratoryControlsPackagingandLabeling,MaterialsandFacilitiesEquipmentManufacturing.验证目标30HistoryofValidationValidationinTheEarlyYears-1972to1978RegulatoryBasedtoSatisfyFDAPressuresDefensivetoProtectProductLineValidationinItsAdolescence-1978To1983PrimarilyDefensiveSomeEffortsatProcessOptimizationIncludesSomePeripheralConcernsValidationintheUSToday-1983toPresentNon-RegulatoryinManyAreasGearedTowardsOptimizationandfocusedonSystems验证历史31validationvs.VALIDATIONvalidationDefensiveTestingOrientedCostlyQualityControlNarrowFocusVALIDATIONOptimizationTotal Process ControlCost EffectiveQuality AssuranceDiverse Application如何正确理解验证32ElementsofContemporaryValidationintheUSEquipmentCalibration-ProcessandValidationEquipmentEquipmentQualification-InstallationandOperationalProcessDevelopmentProcessDocumentationPerformanceQualification-ValidationMaintenanceofValidation-ProcessandEquipmentChangeControl当今美国验证所包含的内容/要素33ExpectationsValidationisaProgramnotaProjectValidationContributestotheStabilityoftheOperationsValidationisnotSomeoneElsesJob!对验证的期望34PartFour:ValidationAnOverview第四部分：验证概述35Who Validates?Validation StaffEngineeringQuality AssuranceQuality ControlManufacturing谁进行验证？36ValidationvDesignTestingOperation验证运作37ValidationvVendorSystemsIntegratorOwner/User验证系统集成者38ValidationvEngineeringR&DValidation TeamMaintenanceManufacturingQuality Assurance验证制造质量保障39WriteProtocols起草方案40Example Data Sheets数据单样品41ConductTestingChemical TestsCareful Review andMarkup of Prints,SpecsMicrobiologicalTestsPhysical Tests(Temp.,Press.,Flow)Computer Tests进行测试42InstallationQualification(IQ)IQdocumentsthatsystemisinstalledinaccordancewithapproveddesign,specificationandregulatorycodesmanufacturersinstallationrecommendationhavebeentakenintoconsiderationIQsimplementedconcurrentlywithconstructionofeachsystem安装合格确认43OperationalQualification(OQ)OQdocumentsthattheequipment:canoperateasdesignedandintendediscapableofrepeatableoperationovertheentireoperatingrangeofprocessvariablesOQexecutedwhenequipmentcanbestartedup运转/运作合格确认44ProcessQualification(PQ)PQdocumentscriticalsystemswhichcanbechallengedtestproceduresproductqualityattributestobeevaluatedacceptancecriteriaalert/actionlevelssystemvalidatedunderworstcaseconditionsgenerally3consecutivesuccessfulrunsrequired工艺合格确认45DefinitionofProcessValidation 1978Validation is:Documented evidence that provides a high degree of assurance that a specific process will consistently produce a product of a certain predetermined quality.工艺验证定义46Definition of Process ValidationIn addition to documented evidence that a process will perform reliably and repeatedly,validation,in its highest form,provides an understanding of why.1993工艺验证定义47StagesoftheLife-CycleR&DDesignConstructionTestingSOPs/MaintenanceChange Control生命周期的阶段48BenefitsofValidationIncreasedThroughputReductioninRejectionsandReworksReductioninUtilityCostsAvoidanceOfCapitalExpendituresFewerComplaintsAboutProcessRelatedFailuresReducedTestingIn-processandFinishedGoodsMoreRapid/AccurateInvestigationsIntoProcessUpsetsMoreRapidandReliableStartupOfNewEquipmentEasierScale-upFromDevelopmentWorkEasierMaintenanceOfTheEquipmentImprovedEmployeeAwarenessOfProcessesMoreRapidAutomation验证的好处49DocumentationofValidationMasterPlanProtocolDataSheetsReportProcedures验证文件50ValidationProtocolsProvideanOutlineoftheValidationEffortIncludeaClearDefinitionofWhatWillBeValidatedIsUniquelyIdentifiedIsDatedApprovedByCompetentIndividualsInResponsibleAreasAreSuitableForReviewByRegulatoryAgencies验证方案51ValidationProtocolEssentialElementsIntroduction/AbstractDescriptionofProcessorSystemTestPlanResponsibilitiesAcceptanceCriteriaApprovalsAppendDataSheets,Etc.验证方案的核心要素52ValidationReportsFunctionsRestricttoOneTaskorSubjectHasaUniqueIdentificationIsDatedFormallyReviewedandApprovedIdentifiesProtocol(s)UsedintheStudyIsSuitableforReviewbyFDA验证报告功能53ValidationReport-ContentsAbstractOrSummaryConclusionPlanOfStudyExperimentalResultsConclusionsProtocolReferenceDiagramsAnyMiscellaneousInformationApprovals验证报告内容54InstallationQualification(IQ)IQDocumentsThatThe:SystemisInstalledinAccordancewithApprovedDesign,SpecificationsandRegulatoryCodesManufacturersInstallationRecommendationshavebeentakenintoConsiderationIQisImplementedConcurrentlywithConstructionofEachSystem安装合格确认55DesignDocumentationDesignandProcurementDocumentationSupportofIQ:PFDs/P&IDsCriticalSystemInstallationDrawings(E.G.WaterSystemIsometrics,SanitaryDuctDrawings)PurchaseandInstallationSpecificationsVendorManualsandPrintsComputerSoftwareDocumentation设计文件56ConstructionDocumentationConstructionDocumentsInSupportOfIQ:SlopeChecksPipingPressureTestReportsMotorCheckoutReportsWeldInspectionReportsCleaning,PassivationandSanitizationProceduresandReportsHVACTestandBalanceReportsOtherAppropriateConstructionDocumentation建造文件57TheP&ID(Piping&Instrumentation Diagram,Engineering Flow Diagram)ProcessEquipmentSupportVesselsInterconnectingLinesUtilityLinesInstruments/InstrumentFunctionsSchematicNoScale-NotSpatiallyPreciseShowsRelationshipsandRelativePosition管线和仪器图58OperationalQualification(OQ)OQDocumentsThatTheEquipment:CanOperateasDesignedandIntendedIsCapableofRepeatableOperationOvertheEntireOperatingRangeofProcessVariablesOQImplementedAfterEquipmenthasbeenStartedUporCommissioned运作合格确认59ProcessQualification(PQ)PQDocumentsThat:ProcessesOperateasRequiredattheNormalOperatingLimitsofCriticalParametersSystemsOperateConsistentlyandReliablyAppropriateChallengesAreEmployed工艺合格确认60ReviewandApprovalsDesignDrawingsandSpecificationsMasterPlanProtocolsReportsProcedures审阅和批准61PartFive:ValidationMasterPlanning第五部分：主验证规划62Planning“Ifyoudontknowwhereyouaregoing,youarelikelytoendupsomeplaceelse!”-LewisCarrollLikeanyotherimportantactivityinacomplexorganizationvalidationmustbemanaged.Thisisespeciallytruegiventhemulti-disciplinednatureofmanyvalidationactivities.规划63ExistingPlantsThesamelevelofmanagementisnecessaryforthevalidationofanexistingfacility,whetherfullyvalidatedornot.Validationiseasierwhenitisanintegralpartoftheday-to-dayoperationofthefacility.现有工厂64MasterPlanDefines and Establishes the Validation Approach and the Acceptance Criteriaand more!主方案65Facilities,ProcessesorProductsWhatneedstobedone?Whowilldoit?Howwilltheydoit?Howlongwillittake?Howmuchwillitcost?设施，工艺或产品66MasterPlan-GeneralIntroductiontoFacilityPurposeandDesignIntentFacility/ProcessDescriptionProcessControlConsiderationsSystemDefinitionsPlanning/Scheduling主方案概述67MasterPlan-WhyProjectFamiliarization/TrainingManagementIntroductionFDAIntroduction/FamiliarizationValidationProgramFoundationBasicProceduresProtocolOutlines/BasesResourcePlanning/SchedulingContractExecutionInteractionCodifiesPriorDecisionsStructuresValidationActivitiesFacilitatesRegulatoryComplianceUsefulinRegulatoryandClientInteractionsUseWith3rdPartiesConvertibleIntoDrugMasterFileInternalAuditPreparation为什么需要主方案？68MasterPlan-WhatIntroductionFacility/Process/ProductDescriptionProcessControlConsiderati