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ManagingPharmaceuticalQuality:RiskorUncertaintyManagement?,AjazS.Hussain,Ph.D.OfficeofPharmaceuticalScienceCDER,FDAPQRIWorkshopFebruary1,2005,WhatisQuality?,Whatispharmaceuticalquality?consistentdeliveryofthelabelperformanceandlackofcontamination.operationalzedviaasetofpre-specifiedqualityattributes(e.g.,specifications,limits)andthroughtheCGMPregulations.FDA,initsqualitydefinition,isstandinginforthecustomeranditisapparentthathealthcarepractitionersandpatientshighlyvalueanadditionaldrugattribute:productavailabilityGoodpharmaceuticalqualityrepresentsanacceptablylowriskoffailingtoachievethedesiredclinicalattributes.,ManagementGoals,ImprovingqualityandensuringavailabilityOptimaluseofourresourcesAsystemsapproachtoCMCreviewandCGMPinvestigationsBasedonknowledgeandprocessunderstandingAchieving“qualitybydesign”Demonstrating“scienceofdesign”Continuouslearningandimprovementthrough“manufacturingscience”,AnApproachforQualityRiskConnection,ConceptofQualitybyDesign(QbD)Productandprocessperformancecharacteristicsarescientificallydesignedtomeetspecificobjectives,notmerelyempiricallyderivedfromperformanceoftestbatchesCharacteristicsimportanttodesiredperformancemustbederivedfromacombinationofpriorknowledgeandexperimentalassessmentduringproductdevelopment.Fromthisknowledgeanddata,amultivariatemodellinkingproductandprocessmeasurementsanddesiredattributesmaybeconstructed.Clinicalstudywouldthenbeviewedasconfirmatoryperformancetestingofthemodel.,Woodcock,2004,ASystemsApproach,CMCReveiw,CGMPInvestigations,ScienceofDesign,ManufacturingScience,DeliverQualitybyDesign,StateofControlithastobebydesign,“MarketStandards”,ScienceofDesign+ManufacturingScience=QualitybyDesign,Risk/BenefitandQuality,ManagingPharmaceuticalQuality,Qualityofanewmolecularentity(apotentialdrug)Intrinsicpharmacologicalvariabilityaddsadditionaluncertainty)Variabilityintheextentandrateofdeliveryof“activemoiety”tothesitesofactionandvariabilityinthepharmacologicalqualitybydesignisthenthepriorknowledgeandwhateverdevelopmentdataisgenerated(heldatsite),Uncertainty,VariabilityandRisk,/cder/gmp/gmp2004/manufSciWP.pdf,Uncertainty?Variability?Risk?,Uncertainty,VariabilityandRisk,Procrusteanstandardshavetoaddress“worstcase”scenariosUncertaintyisnotrisk,currentlywehavenochoicebuttoforcethisequalityUncertaintyisreducedbyimprovingknowledgeWelearnwhattocontrolandthedegreeofcontrolnecessarytominimizeriskForcontinuousqualityimprovementweshouldfocusonimprovinguncertaintymanagementprocess,ExampleofaCMCRegulatoryDecision:AcceptabilityofaPostApprovalManufacturingProcessChange,OriginalNDAorANDA=CMCQualityCapable?,Unstable,CorrectiveActionsEliminate“SpecialCause”,Reduce“CommonCause”Variability,Frequent,MajorOOS,Minor,OccasionalOOS,OntheContinuousImprovementPath,StateofControl,ImprovingUncertaintyManagement,DemandmanagementSpecifiedandprocrusteanstandardsE.g.,90%CI80-125%,in-processblenduniformitytests,.SOPs,.PassivemanagementQualitybyDesign,demonstrated“robustness”Canwebringasystems(CMCreviewandCGMPinvestigation)perspectivetobetterrecognizeacompanysabilitytoachievequalitybydesignandreducetheneedforpriorapprovalsupplements?ActivemanagementContinuouslearningandleveragingknowledgetocreateflexibilityMovetowardsarisk-basedapproachContinuousimprovement(qualityandproductivity),Opportunities,PATGuidancePATprovidesthepharmaceuticalcontextforLean,SixSigma!CPG7132c.08ComparabilityProtocolQualitySystemsApproachtoPharmaceuticalCGMPsICHQ8,(9?),(10?),PATGuidance,OpensthedoortorealizethebenefitsofconnectingFisherto-Shewartto-DemingFocusonprocessunderstandingleadingtocontrolofprocessend-point!Researchdata,CTD-P2Sec.QbD,“DesignSpace”=f(IntendedUse*Design*Control),JohnCBerridge,Q8Rapporteur(EFPIA).FDAManufacturingSubcommittee,July2004,KnowledgeBasedDecisions:RequireScientificGeneralizeableKnowledgethe“SUPACGAP”,SUPACChangeLevelsbasedonpriorknowledgefromthepharmaceuticalcommunity(AAPSSUPACWorkshops)+Research;Yetdifficulttogeneralizebecauseofmultifactorialaspects+lotofsubjectivity,LimitedinformationinNDA/ANDA,PriorknowledgewithinacompanyandamovetowardsmechanisticUnderstanding(ICHQ8isintendedtofillthisgap),Gap=Uncertainty,UncertaintyManagement:QbDuseofadvancedtechnologies,andtheroleofconformancebatchesintheproductlife-cycle.Afocusonthreefull-scaleproductionbatcheswouldfailtorecognizethecompletestoryonvalidation.,/cder/gmp/gmp2004/GMP_finalreport2004.htm#_Toc84065761,DraftGuidanceforIndustryQualitySystemsApproachtoPharmaceuticalCurrentGoodManufacturingPracticeRegulations,/cder/guidance/6452dft.doc,TraditionalgoalsNon-traditionalgoals(riskbased,flexibility,robustness,scalability,continuousimprovement,innovation,efficiency,.)CharacteristicsComplexity,uncertaintyRelationships(betweengoalsSubjecttoCGMPInspections(no-changeorvariation),Maintain“StateofControl”,“Fisher”-“Shewart”-“Deming”TheoryofexperimentaldesignStatisticalProcessControlTheoryofVariation,ByImprovingUncertaintyManagementwehavebeganaprocessofengineeringaproactivedecisionssystemforpharmaceuticalquality,Reactive(examples)TestingtodocumentqualityRepeatingdeviationandoutofspecificationinvestigationsWaitingforFDAguidancetosubmitANDAdemonstratingtherapeuticequivalenceofgenericproductsPotentialformultipleNDACMCreviewcyclesWaitingforFDAtoapproveapriorapprovalsupplementforprocessoptimizationandcontinuousimprovementeffortsFear,apprehension,Proactive(examples)Qualitybydesignandrealt