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ManagingPharmaceuticalQuality:RiskorUncertaintyManagement?AjazS.Hussain,Ph.D.OfficeofPharmaceuticalScienceCDER,FDAPQRIWorkshopFebruary1,2005WhatisQuality?attributes.Whatispharmaceuticalquality?consistentdeliveryofthelabelperformanceandlackofcontamination.operationalzedviaasetofpre-specifiedqualityattributes(e.g.,specifications,limits)andthroughtheCGMPregulations.FDA,initsqualitydefinition,isstandinginforthecustomer—anditisapparentthathealthcarepractitionersandpatientshighlyvalueanadditionaldrugattribute:productavailabilityGoodpharmaceuticalqualityrepresentsanacceptablylowriskoffailingtoachievethedesiredclinicalImprovingqualityandensuringavailabilityOptimaluseofourresourcesAsystemsapproachtoCMCreviewandCGMPinvestigationsBasedonknowledgeandprocessunderstandingAchieving“qualitybydesign”Demonstrating“scienceofdesign”Continuouslearningandimprovementthrough“manufacturingscience”AnApproachforQuality–RiskConnectionConceptofQualitybyDesign(QbD)Productandprocessperformancecharacteristicsarescientificallydesignedtomeetspecificobjectives,notmerelyempiricallyderivedfromperformanceoftestbatchesCharacteristicsimportanttodesiredperformancemustbederivedfromacombinationofpriorknowledgeandexperimentalassessmentduringproductdevelopment.Fromthisknowledgeanddata,amultivariatemodellinkingproductandprocessmeasurementsanddesiredattributesmaybeconstructed.Clinicalstudywouldthenbeviewedasconfirmatoryperformancetestingofthemodel.Woodcock,2004ASystemsApproachScienceofDesignManufacturingScienceDeliverQualitybyDesignStateofControl&ContinuousImprovementQualitycannotbetestedintoaproduct;ithastobebydesign“MarketStandards”ScienceofDesign+ManufacturingScience=QualitybyDesignRisk/BenefitandQualityHarmAcceptableRisk/BenefitQualityLabelNobenefit(placeboeffect)ManagingPharmaceuticalQualityQualityofanewmolecularentity(apotentialdrug)Intrinsicpharmacological&toxicologicalattributesIdentityComplexityArangeofuncertaintywithrespecttoidentityof“activemoiety”,purityandstabilityofmaterialsusedinevaluationofpharmacologicalandtoxicologicalattributes(ifamixture;variabilityaddsadditionaluncertainty)Variabilityintheextentandrateofdeliveryof“activemoiety”tothesitesofactionandvariabilityinthepharmacological&toxicologicalresponseandmeasurementsystemsfurtheraddsuncertaintyManagingPharmaceuticalQualityQualityofadrugproductForestablishingproposedtherapeuticclaim(label)DrugproductmanufacturedforclinicaltrialsAftersuccessfuldemonstrationoftherapeuticclaim(acceptablerisk-to-benefitratio)DrugproductmanufacturedforcommercialdistributionLifecycleoftheproduct(shelf-life,exclusivityperiod,genericcompetition,post-approvalchanges,…)Drugproductmanufacturedatmanydifferentfacilities,changesintheprocess,differentmanufactures,…Uncertainty,VariabilityandRiskQuality–ClinicalConnectionHowdoesaproductformulationanditsmanufacturingprocessimpactclinicalperformance?Withoutaclearunderstandingweareuncertain(lackofknowledge)Indecisionmakingtherearemanyadvantagesindistinguishingbetweenuncertainty,variability(randomvariation)andriskGoalsandCharacteristicsofaQualityDecisionSystem: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,...ANDAApplications:LimitedInformationContent(e.g.,IRCapsule)Generally1bio-batchBioequivalencegoalpost80-125%90%ConfidenceIntervalfortheTest/ReferenceratioforCmaxandAUCinbetweenthegoalpostNormalhealthysubjects,cross-overdesign,fasting(andfed)conditionsCommonforalloraldrugs–i.e.,procrusteanTocover“worstcase”scenariosIfmeanis100%and90%CIisoutside80-125say85-126.5?Executedbatchrecordandmasterbatchrecord(e.g.,10X)–applicationcommitmentPost-approvalprocessvalidationandstabilitycommitmentPostapprovalchangesbasedonSUPAC-IRDemonstrationof“qualitybydesign”?Analyticaldata+Executedbatchrecord+bio-study+processvalidationIQ,OQ,PQ,..PQ=3consecutivebatchesinconformanceReducedtesting–e.g.,compendialtestsForsimple,conventionalproductdesignsworksfinemostofthetime;qualitybydesignisthenthepriorknowledgeandwhateverdevelopmentdataisgenerated(hel