辉瑞质量风险管理教学课件

ManagingPharmaceuticalQuality:RiskorUncertaintyManagement?

AjazS.Hussain,Ph.D.OfficeofPharmaceuticalScienceCDER,FDAPQRIWorkshopFebruary1,20051.WhatisQuality?Whatispharmaceuticalquality?consistentdeliveryofthelabelperformanceandlackofcontamination.operationalzedviaasetofpre-specifiedqualityattributes(e.g.,specifications,limits)andthroughtheCGMPregulations.FDA,initsqualitydefinition,isstandinginforthecustomer—anditisapparentthathealthcarepractitionersandpatientshighlyvalueanadditionaldrugattribute:productavailabilityGoodpharmaceuticalqualityrepresentsanacceptablylowriskoffailingtoachievethedesiredclinicalattributes./toc.asp2.ManagementGoals3.AnApproachforQuality–RiskConnectionWoodcock,20044.ASystemsApproachCMCReveiwCGMPInvestigationsScienceofDesignManufacturingScienceDeliverQualitybyDesignStateofControl&ContinuousImprovement5.“MarketStandards”ScienceofDesign+ManufacturingScience=QualitybyDesign

6.Risk/BenefitandQualityHarmAcceptableRisk/BenefitQualityLabelNobenefit(placeboeffect)7.ManagingPharmaceuticalQualityQualityofanewmolecularentity(apotentialdrug)Intrinsicpharmacological&toxicologicalattributesIdentityComplexityArangeofuncertaintywithrespecttoidentityof“activemoiety”,purityandstabilityofmaterialsusedinevaluationofpharmacologicalandtoxicologicalattributes(ifamixture;variabilityaddsadditionaluncertainty)Variabilityintheextentandrateofdeliveryof“activemoiety”tothesitesofactionandvariabilityinthepharmacological&toxicologicalresponseandmeasurementsystemsfurtheraddsuncertainty8.ManagingPharmaceuticalQuality9.Uncertainty,VariabilityandRiskQuality–ClinicalConnectionHowdoesaproductformulationanditsmanufacturingprocessimpactclinicalperformance?Withoutaclearunderstandingweareuncertain(lackofknowledge)Indecisionmakingtherearemanyadvantagesindistinguishingbetweenuncertainty,variability(randomvariation)andrisk10.GoalsandCharacteristicsofaQualityDecisionSystem:ExampleGoal:expectedtohavethesameclinicaleffectandsafetyprofilewhenadministeredtopatientsundertheconditionsspecifiedinthelabelingCharacteristicsUncertaintyVariabilityRiskPharmaceuticalEquivalentSameactive,identicalamount,samedosageform,androuteofadministration.Identity,StrengthQuality,Purity.CompendialorotherstandardsPriorKnowledge(NDA)PostApproval:MonitoringprogramSuchasMedWatchConsumerComplaintsTherapeuticInequivalenceCoordinatingCommitteeNeedforBioequivalenceAssessmentDonotpresentaknownorpotentialbioequivalenceproblem.AcceptableinvitrostandardCompendialDissolutiontestmethodPresentaknownorpotentialbio-problem.

Appropriatebioequivalencestandard90%ConfidenceIntervalofTest/Refratioforrateandextentofabsorptionin80-125%rangeAdequatelyLabeledSimilaritywithreferencelabel,medicationerrors.,,Certaindifferencesduetochangesinthemanufacturer,distributor,pendingexclusivityissues,orothercharacteristicsManufacturedinconformancetoCGMP'sProcessValidationandQualitySystemDeviations,OutofSpecifications,...11.ANDAApplications:LimitedInformationContent(e.g.,IRCapsule)12.13.Uncertainty,VariabilityandRisk/cder/gmp/gmp2004/manufSciWP.pdfUncertainty?Variability?Risk?14.Uncertainty,VariabilityandRiskProcrusteanstandardshavetoaddress“worstcase”scenariosUncertaintyisnotrisk,currentlywehavenochoicebuttoforcethisequalityUncertaintyisreducedbyimprovingknowledgeWelearnwhattocontrolandthedegreeofcontrolnecessarytominimizeriskForcontinuousqualityimprovementweshouldfocusonimprovinguncertaintymanagementprocess

15.ExampleofaCMCRegulatoryDecision:AcceptabilityofaPostApprovalManufacturingProcessChangeOriginalNDAorANDA=CMCQuality&Performance(“Insurance”)ContractForexampleinANDA’sRegulatorycommitments=ConditionsinexecutedbatchrecordsPriorApprovalSupplement*(PAS)ProductconformswithallestablishedspecificationsBut-“Specificationsdonottellthewholestory”E.g.,Shelf-lifeand/orbioavailabilitymayhavechangedand/oranewimpuritymaybeintroducedthatmaynotbedetectedwithestablishedanalyticalmethods,…sponsormaynotadequatelyqualifychanges(inspectionfrequencymaynotbesufficient),….*priorapprovalsupplementforprocessoptimizationandcontinuousimprovementefforts16.CompanyX“GoesLean”“Cycle-timereductionsubgroupmembers,forexample,examineeachprocessfunction,forexample,dispensing,rollercompactionandcompression,todeterminehowtospeedupchangeoverandgetequipmenttorunfasterandmoreefficiently.”“Theteamsolicitsideasatregularmeetingsandviaemail.Theideasarethenratedfrom1to10basedon"bangforthebuck"toreducecycletime,andonhowdifficulttheywouldbetoachieve--e.g.,whethertheywillrequirevalidationorpriorFDAapproval.”

PharmaM17.PostApprovalProcessChange(SUPACGuidance)“Within”(ChangeTargetsetting)“Outside”18.CurrentUncertaintyManagement19.CurrentDemandManagement:CharacteristicsForconventionalproductsandmanufacturingprocesses-easytoimplement,supervise,andmangeDecisionresponsibilityisdeferredtoasetof“procrustean”standards-liabilitydistributedtotheentirepharmaceuticalcommunity(e.g.,viaUSP,AAPS,etc.)Forinnovativeand/orcomplexproductsandprocessesnooneiswillingtotakeresponsibilityfordecisions(e.g.,developguidancedocument)–decisionliabilityisthenonthepersonwillingtotakeadecision.20.CurrentDemandManagement:CharacteristicsWithoutContinuous(Community)Learning:DemandManagementis“static”untilacrisisiscreated,itthenreactstoreplaceacurrentprocrusteanstandardwithanother.

21.ContinuousImprovement:EnhancingCustomerSatisfaction-ReducingVariability22.“SpecialCause”or“CommonCause”Stable-Yes;Capable?UnstableCorrectiveActionsEliminate“SpecialCause”Reduce“CommonCause”VariabilityFrequent,MajorOOSMinor,OccasionalOOSStable&CapableOntheContinuousImprovementPathStateofControl23.ImprovingUncertaintyManagement24.OpportunitiesPATGuidancePATprovidesthepharmaceuticalcontextforLean,SixSigma!CPG7132c.08ComparabilityProtocolQualitySystemsApproachtoPharmaceuticalCGMP’sICHQ8,(9?),(10?)25.PATGuidanceOpensthedoortorealizethebenefitsofconnectingFisher–to-Shewart–to-DemingFocusonprocessunderstandingleadingtocontrolofprocessend-point!Researchdata26.CTD-P2Sec.QbDDrugSubstanceorAPIIntendedUseRouteofadministrationPatientpopulation…..ProductDesignDesignSpecifications(Customerrequirements)P2.1and2.6P2.2,2.4,2.5,2.6DrugProductContainerClosureSystemMicrobiologicalAttributesCompatibility(e.g.,recon)ManufacturingProcessComponentsofdrugproductP2.3ManufacturingProcessDevelopment27.“DesignSpace”=f(IntendedUse*Design*Control)QualitySystemRiskClassificationProcessDesign&ControlSpecificationsProductDesignIntendedUseDesignRequirementsReliabilityToDeliverDesignRequirementsAssessmentBasedonICHQ8Information/Knowledge28.JohnCBerridge,Q8Rapporteur(EFPIA).FDAManufacturingSubcommittee,July200429.KnowledgeBasedDecisions:RequireScientificGeneralizeableKnowledge–the“SUPACGAP”SUPACChangeLevelsbasedonpriorknowledgefromthepharmaceuticalcommunity(AAPSSUPACWorkshops)+Research;Yetdifficulttogeneralizebecauseofmultifactorialaspects+lotofsubjectivityLimitedinformationinNDA/ANDAPriorknowledgewithinacompanyandamovetowardsmechanisticUnderstanding(ICHQ8isintendedtofillthisgap)Gap=Uncertainty30.UncertaintyManagement:QbD&FlexibilityTimeScale&ModeofResponseUncertaintyManagementSystemModificationQbDFlexibilityOperationalRootcauseinvestigation,Efficiency,etc.–LearningtoR&DControlofexcipientsandothersourcesof“commoncause”variabilityReduceCGMPRiskClassification–ContinuousImprovementofQualitySystemTacticalOn-linecontrol[DesignforManufacturability]CriticalControlPoints-Robustprocessend-pointRegulatorySpecifications“DesignSpace”Real–TimeRelease,ModularValidationReg.CMCApprovalStrategicScienceofDesign–Designtoreduce“Uncertainty”Sci.&Tech.Integration–ContinuousLearning&ImprovementRegulatoryCommunicationIntegrateSci-EnablingTechnologyPlatform–“Plug&Play”“TimetoMarket”+“ProductionEfficiency”31.ScienceofDesignOftendesignanddevelopmentactivitiesarecarriedoutbasedonexperientialknowledge,intuitionandroughguidelines–difficulttocommunicatetoindividualsfromdifferentbackgrounds(the“art”argument)Tolearnhowtorepresentdesignsatamuchhigherlevelthanthecurrentdescriptive“recipe”format(e.g.,executedbatchrecords,SOP’s)whilerigorouslydocumentingkeyconstrains32.AValidatedSystemWehavebegunupdatingourcurrentthinkingonvalidationProcessValidationRequirementsforDrugProductsandActivePharmaceuticalIngredientsSubjecttoPre-MarketApproval(CPG7132c.08,Sec490.100).

Rationalexperimentaldesignandongoingevaluationofdata

Achievingandmaintainingastateofcontrolforaprocessbeginsattheprocessdevelopmentphaseandcontinuesthroughoutthecommercialphaseofaproduct'slife-cycleRisk-basedapproaches-inspectionalscrutiny;useofadvancedtechnologies,andtheroleofconformancebatchesintheproductlife-cycle.

Afocusonthreefull-scaleproductionbatcheswouldfailtoreco