FDA Process Validation

ProcessValidationandGMPOverviewRequirementsandRecommendationsCharlesAhn,USFDA,Asst.CountryDirector,ChinaFD&CActDefinesAdulterationandMisbrandingofaDrugProductSection501AdulterationSection502Misbranding501(a)through501(i)(a)referstomanufacturingactivities(b)referstonotmeetingcompendialstandards(c)referstonotmeetingotherestablishedstandards(d)referstomixingforeconomicgain…Adrug...shallbedeemedtobeadulterated...if...Section501(a)(2)(A)oftheFD&CActithasbeenprepared,packed,orheldunderinsanitaryconditionwherebyitmayhavebeencontaminated…DoNotNeedaFailingResultAdrug...shallbedeemedtobeadulterated...if...Section501(a)(2)(B)oftheFD&CActthemethodsusedin,orthefacilitiesorcontrolsusedfor,itsmanufacture,processing,packing,orholdingdonotconformtoorarenotoperatedoradministeredinconformitywithcurrentgoodmanufacturingpracticetoassurethatsuchdrugmeetstherequirementsofthisActastosafetyandhastheidentityandstrength,andmeetsthequalityandpuritycharacteristics,whichitpurportsorisrepresentedtopossess.CFRExplainsCGMPforDrug1978Codeoffederalregulations(CFR)interpretsandprovideswhattheActmeansbycurrentgoodmanufacturingpractice(CGMP)in21CFRparts210and211.“…containtheminimumcurrentgoodmanufacturingpracticeformethodtobeusedin…”ValidationofManufacturingProcessIsimplied,inbothgeneralandspecificterms,bytheCGMPregulationsinsectionsoftheCFRpart211.Theconceptofprocessvalidationisderivedfromthesection211.100(a),whichstatesthat[t]hereshallbewrittenproceduresforproductionandprocesscontroldesignedtoassurethatthedrugproductshavetheidentity,strength,quality,andpuritytheypurportorarerepresentedtopossess1986GuidelineonGeneralPrinciplesofProcessValidationExpressesFDA’sCurrentThinking,1986,onProcessValidationDefinesQualificationsDiscussesProspective,Concurrent,RetrospectiveValidationProtocols,Documentation,DataEvaluation3batches(?),RevalidationGuidanceforIndustry,ProcessValidation:GeneralPrinciplesandPractices,2008FDA’sCurrentThinking,2008,butNotRegulatoryRequirementProvidestheScopeofApplicabilityAlignmentwithICHActivitiesandConceptsCGMPfor21stCentury-ARisk-basedApproachRe-interpretationofCGMPRegulationswithRespecttoProcessValidationGuidanceforIndustry,2008ProcessValidationis…thecollectionandevaluationofdata,fromtheprocessdesignstagethroughoutproduction,whichestablishesscientificevidencethataprocessiscapableofconsistentlydeliveringqualityproducts.CompareThatto1986GuidanceValidation…Establishingdocumentedevidencewhichprovidesahighdegreeofassurancethataspecificprocesswillconsistentlyproduceaproductmeetingitspre-determinedspecificationsandqualityattributesGuidanceforIndustryGuidanceforIndustry-anAdvisoryOpinionandRecommendation–notlegallybinding21CFRPart10.85andPart10.90TheCommissionermayrespondtoanoralorwrittenrequesttotheagency…foranadvisoryopinion…•10.85(d)(1).…anoticetomanufacturersorapreambletoaproposedorfinalregulation…•(d)(3)…compliancepolicyguides…•(d)(4)…otherdocumentsspecificallyidentifiedasadvisoryopinions…10.90(c)recommendationProcessValidationKnowledge-baseDesignSpaceProcessParameters---•Independent&Dependent•Control&Monitor•Equipment,Environment,Facilities,People,Materials,FinishedProductSpecificationsNarrowDownorRemoveVariablesAbilitytoControlwithinSpecificDefinedRangesProcessValidationProtocol•DefineProcess•Identify&QualifyControlledParameters•Identify&QualifyMonitoredParameters•DescribeEvaluationCriteria•EstablishMetricsNoMoreThreePassingBatchesOn-goingEffort,ContinuousAssessmentofVariablesQualityManagementSystem&ProcessValidation/ControlQualitybyKnowledgeQualitybyDesignValidatedProcessNotaStaticStateQualityManagementSystemCapturesProcessKnowledgeNewProcessKnowledgeFeedsBacktoAssessAdequacyofExistingProcessQualityManagementSystem&ProcessValidationAreInseparableCaseStudyAPIFinalDryingProcessDryingProcess•Vacuum0.08MPa•DryingTemp:70~90oC•DryngTime:7~8HoursHistoricalRangeNarrower•75~78oCand7Hours•FixedTimeBasedonR&DValidationDataFirmConsiderstheProcessValidatedValidationIssuesBlender/DryerJacketedwithCoilCirculatingHeatedWaterSourceofHeat:WaterCoilHeat-exchangein“SteamBox”withManualValvetoSteamGeneratorNoCorrelationEstablishedbetweenJacketTemp.andSteamBoxTemp.TheFirmUsesBothJacketandSteamBoxTemperatureReadingsasProcessControlParametersExcessivelyWideTemperatureandDryingTimeRangesSpecifiedValidationConsiderationNeedtoCorrelateJacketTemperatureandHeatSourceTemperatureOneCanOnly“Control”SourceTemperature;andJacketTemperatureisDependentontheSource–Independentvs.DependentDryingTemp.ShouldBeANarrow“Target”RangeExhaustAirTemperatureandEnd-pointDeterminationDryingCurveMaterial’sInitialWetness,PotentialVariable(?)AssumptionofEfficientVacuumDeviationInvestigation#1:November,2008ADryingFailureDeviationWasNotedDuringFinalDryingProcess•TemperatureFellBelowLimitForAShort-while•DidNotIndicateHowLong,WhatCausedDeviationLODTestingConfirmedDryingFailureRe-dryingandRe-millingperModifiedInstructionNoInvestigationIntoCauseofTemperatureFluctuation–OnlyOperatorError(?)NoStabilityProfileDeviationInvestigat