FMEA-辉瑞企业培训资料课件

ManagingPharmaceuticalQuality:RiskorUncertaintyManagement?

AjazS.Hussain,Ph.D.OfficeofPharmaceuticalScienceCDER,FDAPQRIWorkshopFebruary1,2005ManagingPharmaceuticalQualit1WhatisQuality?Whatispharmaceuticalquality?consistentdeliveryofthelabelperformanceandlackofcontamination.operationalzedviaasetofpre-specifiedqualityattributes(e.g.,specifications,limits)andthroughtheCGMPregulations.FDA,initsqualitydefinition,isstandinginforthecustomer—anditisapparentthathealthcarepractitionersandpatientshighlyvalueanadditionaldrugattribute:productavailabilityGoodpharmaceuticalqualityrepresentsanacceptablylowriskoffailingtoachievethedesiredclinicalattributes.WhatisQuality?Whatispharma2ManagementGoalsImprovingqualityandensuringavailabilityOptimaluseofourresourcesAsystemsapproachtoCMCreviewandCGMPinvestigationsBasedonknowledgeandprocessunderstandingAchieving“qualitybydesign”Demonstrating“scienceofdesign”Continuouslearningandimprovementthrough“manufacturingscience”ManagementGoalsImprovingqual3AnApproachforQuality–RiskConnectionConceptofQualitybyDesign(QbD)Productandprocessperformancecharacteristicsarescientificallydesignedtomeetspecificobjectives,notmerelyempiricallyderivedfromperformanceoftestbatchesCharacteristicsimportanttodesiredperformancemustbederivedfromacombinationofpriorknowledgeandexperimentalassessmentduringproductdevelopment.Fromthisknowledgeanddata,amultivariatemodellinkingproductandprocessmeasurementsanddesiredattributesmaybeconstructed.Clinicalstudywouldthenbeviewedasconfirmatoryperformancetestingofthemodel.Woodcock,2004AnApproachforQuality–Risk4ASystemsApproachCMCReveiwCGMPInvestigationsScienceofDesignManufacturingScienceDeliverQualitybyDesignStateofControl&ContinuousImprovementASystemsApproachCMCReveiwCG5Qualitycannotbetestedintoaproduct;ithastobebydesign“MarketStandards”ScienceofDesign+ManufacturingScience=QualitybyDesign

Qualitycannotbetestedinto6Risk/BenefitandQualityHarmAcceptableRisk/BenefitQualityLabelNobenefit(placeboeffect)Risk/BenefitandQualityHarmAc7ManagingPharmaceuticalQualityQualityofanewmolecularentity(apotentialdrug)Intrinsicpharmacological&toxicologicalattributesIdentityComplexityArangeofuncertaintywithrespecttoidentityof“activemoiety”,purityandstabilityofmaterialsusedinevaluationofpharmacologicalandtoxicologicalattributes(ifamixture;variabilityaddsadditionaluncertainty)Variabilityintheextentandrateofdeliveryof“activemoiety”tothesitesofactionandvariabilityinthepharmacological&toxicologicalresponseandmeasurementsystemsfurtheraddsuncertaintyManagingPharmaceuticalQualit8ManagingPharmaceuticalQualityQualityofadrugproductForestablishingproposedtherapeuticclaim(label)DrugproductmanufacturedforclinicaltrialsAftersuccessfuldemonstrationoftherapeuticclaim(acceptablerisk-to-benefitratio)DrugproductmanufacturedforcommercialdistributionLifecycleoftheproduct(shelf-life,exclusivityperiod,genericcompetition,post-approvalchanges,…)Drugproductmanufacturedatmanydifferentfacilities,changesintheprocess,differentmanufactures,…ManagingPharmaceuticalQualit9Uncertainty,VariabilityandRiskQuality–ClinicalConnectionHowdoesaproductformulationanditsmanufacturingprocessimpactclinicalperformance?Withoutaclearunderstandingweareuncertain(lackofknowledge)Indecisionmakingtherearemanyadvantagesindistinguishingbetweenuncertainty,variability(randomvariation)andriskUncertainty,VariabilityandR10GoalsandCharacteristicsofaQualityDecisionSystem: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,...GoalsandCharacteristicsofa11ANDAApplications:LimitedInformationContent(e.g.,IRCapsule)Generally1bio-batchBioequivalencegoalpost80-125%90%ConfidenceIntervalfortheTest/ReferenceratioforCmaxandAUCinbetweenthegoalpostNormalhealthysubjects,cross-overdesign,fasting(andfed)conditionsCommonforalloraldrugs–i.e.,procrusteanTocover“worstcase”scenariosIfmeanis100%and90%CIisoutside80-125say85-126.5?Executedbatchrecordandmasterbatchrecord(e.g.,10X)–applicationcommitmentPost-approvalprocessvalidationandstabilitycommitmentPostapprovalchangesbasedonSUPAC-IRANDAApplications:LimitedInf12Demonstrationof“qualitybydesign”?Analyticaldata+Executedbatchrecord+bio-study+processvalidationIQ,OQ,PQ,..PQ=3consecutivebatchesinconformanceReducedtesting–e.g.,compendialtestsForsimple,conventionalproductdesignsworksfinemostofthetime;qualitybydesignisthenthepriorknowledgeandwhateverdevelopmentdataisgenerated(heldatsite)Demonstrationof“qualitybyd13Uncertainty,VariabilityandRiskUncertainty?Variability?Risk?Uncertainty,VariabilityandR14Uncertainty,VariabilityandRiskProcrusteanstandardshavetoaddress“worstcase”scenariosUncertaintyisnotrisk,currentlywehavenochoicebuttoforcethisequalityUncertaintyisreducedbyimprovingknowledgeWelearnwhattocontrolandthedegreeofcontrolnecessarytominimizeriskForcontinuousqualityimprovementweshouldfocusonimprovinguncertaintymanagementprocess

Uncertainty,VariabilityandR15ExampleofaCMCRegulatoryDecision:AcceptabilityofaPostApprovalManufacturingProcessChangeOriginalNDAorANDA=CMCQuality&Performance(“Insurance”)ContractForexampleinANDA’sRegulatorycommitments=ConditionsinexecutedbatchrecordsPriorApprovalSupplement*(PAS)ProductconformswithallestablishedspecificationsBut-“Specificationsdonottellthewholestory”E.g.,Shelf-lifeand/orbioavailabilitymayhavechangedand/oranewimpuritymaybeintroducedthatmaynotbedetectedwithestablishedanalyticalmethods,…sponsormaynotadequatelyqualifychanges(inspectionfrequencymaynotbesufficient),….*priorapprovalsupplementforprocessoptimizationandcontinuousimprovementeffortsExampleofaCMCRegulatoryDe16CompanyX“GoesLean”“Cycle-timereductionsubgroupmembers,forexample,examineeachprocessfunction,forexample,dispensing,rollercompactionandcompression,todeterminehowtospeedupchangeoverandgetequipmenttorunfasterandmoreefficiently.”“Theteamsolicitsideasatregularmeetingsandviaemail.Theideasarethenratedfrom1to10basedon"bangforthebuck"toreducecycletime,andonhowdifficulttheywouldbetoachieve--e.g.,whethertheywillrequirevalidationorpriorFDAapproval.”

PharmaMCompanyX“GoesLean”“Cycle-ti17PostApprovalProcessChange(SUPACGuidance)“Within”(ChangeTargetsetting)“Outside”PostApprovalProcessChange(18CurrentUncertaintyManagementAttheoperationallevelthemostefficientapproachformanaginguncertaintyis“demandmanagement”Strict“checkingthebox”processusingpre-specifiedrequirements(recommendations)andprocrusteanstandardsFDAguidancedocuments,483observations,..90%CI80-125%,in-processblenduniformitytests,…..SOP’s,…..CurrentUncertaintyManagement19CurrentDemandManagement:CharacteristicsForconventionalproductsandmanufacturingprocesses-easytoimplement,supervise,andmangeDecisionresponsibilityisdeferredtoasetof“procrustean”standards-liabilitydistributedtotheentirepharmaceuticalcommunity(e.g.,viaUSP,AAPS,etc.)Forinnovativeand/orcomplexproductsandprocessesnooneiswillingtotakeresponsibilityfordecisions(e.g.,developguidancedocument)–decisionliabilityisthenonthepersonwillingtotakeadecision.CurrentDemandManagement:Cha20CurrentDemandManagement:CharacteristicsInnovationandcontinuousimprovementslowsdownandinefficiencyincreasesThelevelofqualityassuranceachievedisdifficulttomeasureandisburiedinhistoricalmindsetandclinicalvariabilityWithincreasingcomplexityamajorfailureisnecessarytosignalinadequaciesofthesystem–suchafailureisoftentheonlyapproachtointroducenewregulationsorimproveddecisioncriteriaChallengetoandalternateapproachestocurrentprocrusteanstandardsdifficulttoproveanddebatesdrainresourcesWithoutContinuous(Community)Learning:DemandManagementis“static”untilacrisisiscreated,itthenreactstoreplaceacurrentprocrusteanstandardwithanother.

CurrentDemandManagement:Cha21ContinuousImprovement:EnhancingCustomerSatisfaction-ReducingVariabilityContinuousImprovement:Enhanc22“SpecialCause”or“CommonCause”Stable-Yes;Capable?UnstableCorrectiveActionsEliminate“SpecialCause”Reduce“CommonCause”VariabilityFrequent,MajorOOSMinor,OccasionalOOSStable&CapableOntheContinuousImprovementPathStateofControl“SpecialCause”or“CommonCau23ImprovingUncertaintyManagementDemandmanagementSpecifiedandprocrusteanstandardsE.g.,90%CI80-125%,in-processblenduniformitytests,…..SOP’s,…..PassivemanagementQualitybyDesign,demonstrated“robustness”Canwebringasystems(CMCreviewandCGMPinvestigation)perspectivetobetterrecognizeacompany’sabilitytoachievequalitybydesignandreducetheneedforpriorapprovalsupplements?ActivemanagementContinuouslearningandleveragingknowledgetocreateflexibilityMovetowardsarisk-basedapproachContinuousimprovement(qualityandproductivity)ImprovingUncertaintyManageme24OpportunitiesPATGuidancePATprovidesthepharmaceuticalcontextforLean,SixSigma!CPG7132c.08ComparabilityProtocolQualitySystemsApproachtoPharmaceuticalCGMP’sICHQ8,(9?),(10?)OpportunitiesPATGuidance25PATGuidanceOpensthedoortorealizethebenefitsofconnectingFisher–to-Shewart–to-DemingFocusonprocessunderstandingleadingtocontrolofprocessend-point!ResearchdataPATGuidanceOpensthedoorto26CTD-P2Sec.QbDDrugSubstanceorAPIIntendedUseRouteofadministrationPatientpopulation…..ProductDesignDesignSpecifications(Customerrequirements)P2.1and2.6P2.2,2.4,2.5,2.6DrugProductContainerClosureSystemMicrobiologicalAttributesCompatibility(e.g.,recon)ManufacturingProcessComponentsofdrugproductP2.3ManufacturingProcessDevelopmentCTD-P2Sec.QbDDrugSubstanceI27“DesignSpace”=f(IntendedUse*Design*Control)QualitySystemRiskClassificationProcessDesign&ControlSpecificationsProductDesignIntendedUseDesignRequirementsReliabilityToDeliverDesignRequirementsAssessmentBasedonICHQ8Information/Knowledge“DesignSpace”=f(IntendedU28JohnCBerridge,Q8Rapporteur(EFPIA).FDAManufacturingSubcommittee,July2004JohnCBerridge,Q8Rapporteur29KnowledgeBasedDecisions:RequireScientificGeneralizeableKnowledge–the“SUPACGAP”SUPACChangeLevelsbasedonpriorknowledgefromthepharmaceuticalcommunity(AAPSSUPACWorkshops)+Research;Yetdifficulttogeneralizebecauseofmultifactorialaspects+lotofsubjectivityLimitedinformationinNDA/ANDAPriorknowledgewithinacompanyandamovetowardsmechanisticUnderstanding(ICHQ8isintendedtofillthisgap)Gap=UncertaintyKnowledgeBasedDecisions:Req30UncertaintyManagement: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”UncertaintyManagement:QbD&31ScienceofDesignOftendesignanddevelopmentactivitiesarecarriedoutbasedonexperientialknowledge,intuitionandroughguidelines–difficulttocommunicatetoindividualsfromdifferentbackgrounds(the“art”argument)Tolearnhowtorepresentdesignsatamuchhigherlevelthanthecurrentdescriptive“recipe”format(e.g.,executedbatchrecords,SOP’s)whilerigorouslydocumentingkeyconstrainsScienceofDesignOftendesign32AValidatedSystemWehavebegunupdatingourcurrentthinkingonvalidationProcessValidationRequirementsforDrugProductsandActivePharmaceuticalIngredientsSubjecttoPre-MarketApproval(CPG7132c.08,Sec490.100).

Rationalexperimentaldesignandongoingevaluationofdata

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

Afocusonthreefull-scaleproductionbatcheswouldfailtorecognizethecompletestoryonvalidation.AValidatedSystemWehavebegu33Packaging&LabelingProductionFacilities&EquipmentLaboratoryControlsMaterialsDraftGuidanceforIndustryQualitySystemsApproachtoPharmaceuticalCurrentGoodManufacturingPracticeRegulations

TraditionalgoalsNon-traditionalgoals(riskbased,flexibility,robustness,scalability,continuousimprovement,innovation,efficiency,….)CharacteristicsComplexity,uncertaintyRelationships(betweengoals&characteristics)KnowledgeandinformationcentricrelationshipsFundamentalissuesEngineeringaQualitySystemPackaging&Labeling34“ChangeControl”to“ContinuousImprovement”PAT-ICHQ8“DesignSpace”DevelopmentInnovation&ContinuousImprovementOptionsManufacturing&QualityAssuranceManagedunderTheCompany’sQualitySystem;SubjecttoCGMPInspections(no-changeorvariation)Maintain“StateofControl”“Fisher”-“Shewart”-“Deming”TheoryofexperimentaldesignStatisticalProcessControlTheoryofVariation“ChangeControl”to“Continuou35ByImprovingUncertaintyManagementwehavebeganaprocessofengineeringaproactivedecisionssystemforpharmaceuticalqualityReactive(examples)TestingtodocumentqualityRepeatingdeviationandoutofspecificationinvestigationsWaitingforFDAguidancetosubmitANDAdemonstratingtherapeuticequivalenceofgenericproductsPotentialformultipleNDACMCreviewcyclesWaitingforFDAtoapproveapriorapprovalsupplementforprocessoptimizationandcontinuousimprovementeffortsFear,apprehensionProactive(examples)Qualitybydesignandrealtimeprocesscontrolstoachieverealtimerelease”RightFirstTimeInnovativeapproachesfordemonstratingtherapeuticequivalenceofgenericsSingleNDACMCreviewcycleProcessoptimizationandcontinuousimprovementeffortswithinafacilitiesqualitysystemAbilitytoutilizepriorknowledgeEmpowerment,recognitionByImprovingUncertaintyManag36ManagingPharmaceuticalQuality:RiskorUncertaintyManagement?

AjazS.Hussain,Ph.D.OfficeofPharmaceuticalScienceCDER,FDAPQRIWorkshopFebruary1,2005ManagingPharmaceuticalQualit37WhatisQuality?Whatispharmaceuticalquality?consistentdeliveryofthelabelperformanceandlackofcontamination.operationalzedviaasetofpre-specifiedqualityattributes(e.g.,specifications,limits)andthroughtheCGMPregulations.FDA,initsqualitydefinition,isstandinginforthecustomer—anditisapparentthathealthcarepractitionersandpatientshighlyvalueanadditionaldrugattribute:productavailabilityGoodpharmaceuticalqualityrepresentsanacceptablylowriskoffailingtoachievethedesiredclinicalattributes.WhatisQuality?Whatispharma38ManagementGoalsImprovingqualityandensuringavailabilityOptimaluseofourresourcesAsystemsapproachtoCMCreviewandCGMPinvestigationsBasedonknowledgeandprocessunderstandingAchieving“qualitybydesign”Demonstrating“scienceofdesign”Continuouslearningandimprovementthrough“manufacturingscience”ManagementGoalsImprovingqual39AnApproachforQuality–RiskConnectionConceptofQualitybyDesign(QbD)Productandprocessperformancecharacteristicsarescientificallydesignedtomeetspecificobjectives,notmerelyempiricallyderivedfromperformanceoftestbatchesCharacteristicsimportanttodesiredperformancemustbederivedfromacombinationofpriorknowledgeandexperimentalassessmentduringproductdevelopment.Fromthisknowledgeanddata,amultivariatemodellinkingproductandprocessmeasurementsanddesiredattributesmaybeconstructed.Clinicalstudywouldthenbeviewedasconfirmatoryperformancetestingofthemodel.Woodcock,2004AnApproachforQuality–Risk40ASystemsApproachCMCReveiwCGMPInvestigationsScienceofDesignManufacturingScienceDeliverQualitybyDesignStateofControl&ContinuousImprovementASystemsApproachCMCReveiwCG41Qualitycannotbetestedintoaproduct;ithastobebydesign“MarketStandards”ScienceofDesign+ManufacturingScience=QualitybyDesign

Qualitycannotbetestedinto42Risk/BenefitandQualityHarmAcceptableRisk/BenefitQualityLabelNobenefit(placeboeffect)Risk/BenefitandQualityHarmAc43ManagingPharmaceuticalQualityQualityofanewmolecularentity(apotentialdrug)Intrinsicpharmacological&toxicologicalattributesIdentityComplexityArangeofuncertaintywithrespecttoidentityof“activemoiety”,purityandstabilityofmaterialsusedinevaluationofpharmacologicalandtoxicologicalattributes(ifamixture;variabilityaddsadditionaluncertainty)Variabilityintheextentandrateofdeliveryof“activemoiety”tothesitesofactionandvariabilityinthepharmacological&toxicologicalresponseandmeasurementsystemsfurtheraddsuncertaintyManagingPharmaceuticalQualit44ManagingPharmaceuticalQualityQualityofadrugproductForestablishingproposedtherapeuticclaim(label)DrugproductmanufacturedforclinicaltrialsAftersuccessfuldemonstrationoftherapeuticclaim(acceptablerisk-to-benefitratio)DrugproductmanufacturedforcommercialdistributionLifecycleoftheproduct(shelf-life,exclusivityperiod,genericcompetition,post-approvalchanges,…)Drugproductmanufacturedatmanydifferentfacilities,changesintheprocess,differentmanufactures,…ManagingPharmaceuticalQualit45Uncertainty,VariabilityandRiskQuality–ClinicalConnectionHowdoesaproductformulationanditsmanufacturingprocessimpactclinicalperformance?Withoutaclearunderstandingweareuncertain(lackofknowledge)Indecisionmakingtherearemanyadvantagesindistinguishingbetweenuncertainty,variability(randomvariation)andriskUncertainty,VariabilityandR46GoalsandCharacteristicsofaQualityDecisionSystem: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,...GoalsandCharacteristicsofa47ANDAApplications:LimitedInformationContent(e.g.,IRCapsule)Generally1bio-batchBioequivalencegoalpost80-125%90%ConfidenceIntervalfortheTest/ReferenceratioforCmaxandAUCinbetweenthegoalpostNormalhealthysubjects,cross-overdesign,fasting(andfed)conditionsCommonforalloraldrugs–i.e.,procrusteanTocover“worstcase”scenariosIfmeanis100%and90%CIisoutside80-125say85-126.5?Executedbatchrecordandmasterbatchrecord(e.g.,10X)–applicationcommitmentPost-approvalprocessvalidationandstabilitycommitmentPostapprovalchangesbasedonSUPAC-IRANDAApplications:LimitedInf48Demonstrationof“qualitybydesign”?Analyticaldata+Executedbatchrecord+bio-study+processvalidationIQ,OQ,PQ,..PQ=3consecutivebatchesinconformanceReducedtesting–e.g.,compendialtestsForsimple,conventionalproductdesignsworksfinemostofthetime;qualitybydesignisthenthepriorknowledgeandwhateverdevelopmentdataisgenerated(heldatsite)Demonstrationof“qualitybyd49Uncertainty,VariabilityandRiskUncertainty?Variability?Risk?Uncertainty,VariabilityandR50Uncertainty,VariabilityandRiskProcrusteanstandardshavetoaddress“worstcase”scenariosUncertaintyisnotrisk,currentlywehavenochoicebuttoforcethisequalityUncertaintyisreducedbyimprovingknowledgeWelearnwhattocontrolandthedegreeofcontrolnecessarytominimizeriskForcontinuousqualityimprovementweshouldfocusonimprovinguncertaintymanagementprocess

Uncertainty,VariabilityandR51ExampleofaCMCRegulatoryDecision:AcceptabilityofaPostApprovalManufacturingProcessChangeOriginalNDAorANDA=CMCQuality&Performance(“Insurance”)ContractForexampleinANDA’sRegulatorycommitments=ConditionsinexecutedbatchrecordsPriorApprovalSupplement*(PAS)ProductconformswithallestablishedspecificationsBut-“Specificationsdonottellthewholestory”E.g.,Shelf-lifeand/orbioavailabilitymayhavechangedand/oranewimpuritymaybeintroducedthatmaynotbedetectedwithestablishedanalyticalmethods,…sponsormaynotadequatelyqualifychanges(inspectionfrequencymaynotbesufficient),….*priorapprovalsupplementforprocessoptimizationandcontinuousimprovementeffortsExampleofaCMCRegulatoryDe52CompanyX“GoesLean”“Cycle-timereductionsubgroupmembers,forexample,examineeachprocessfunction,forexample,dispensing,rollercompactionandcompression,todeterminehowtospeedupchangeoverandgetequipmenttorunfasterandmoreefficiently.”“Theteamsolicitsideasatregularmeetingsandviaemail.Theideasarethenratedfrom1to10basedon"bangforthebuck"toreducecycletime,andonhowdifficulttheywouldbetoachieve--e.g.,whethertheywillrequirevalidationorpriorFDAapproval.”

PharmaMCompanyX“GoesLean”“Cycle-ti53PostApprovalProcessChange(SUPACGuidance)“Within”(ChangeTargetsetting)“Outside”PostApprovalProcessChange(54CurrentUncertaintyManagementAttheoperationallevelthemostefficientapproachformanaginguncertaintyis“demandmanagement”Strict“checkingthebox”processusingpre-specifiedrequirements(recommendations)andprocrusteanstandardsFDAguidancedocuments,483observations,..90%CI80-125%,in-processblenduniformitytests,…..SOP’s,…..CurrentUncertaintyManagement55CurrentDemandManagement:CharacteristicsForconventionalproductsandmanufacturingprocesses-easytoimplement,supervise,andmangeDecisionresponsibilityisdeferredtoasetof“procrustean”standards-liabilitydistributedtotheentirepharmaceuticalcommunity(e.g.,viaUSP,AAPS,etc.)Forinnovativeand/orcomplexproductsandprocessesnooneiswillingtotakeresponsibilityfordecisions(e.g.,developguidancedocument)–decisionliabilityisthenonthepersonwillingtotakeadecision.CurrentDemandManagement:Cha56CurrentDemandManagement:CharacteristicsInnovationandcontinuousimprovementslowsdownandinefficiencyincreasesThelevelofqualityassuranceachievedisdifficulttomeasureandisburiedinhistoricalmindsetandclinicalvariabilityWithincreasingcomplexityamajorfailureisnecessarytosignalinadequaciesofthesystem–suchafailureisoftentheonlyapproachtointroducenewregulationsorimproveddecisioncriteriaChallengetoandalternateapproachestocurrentprocrusteanstandardsdifficulttoproveanddebatesdrainresourcesWithoutContinuous(Community)Learning:DemandManagementis“static”untilacrisisiscreated,itthenreactstoreplaceacurrentprocrusteanstandardwithanother.

CurrentDemandManagement:Cha57ContinuousImprovement:EnhancingCustomerSatisfaction-ReducingVariabilityContinuousImprovement:Enhanc58“SpecialCause”or“CommonCause”Stable-Yes;Capable?UnstableCorrectiveActionsEliminate“SpecialCause”Reduce“CommonCause”VariabilityFrequent,MajorOOSMinor,OccasionalOOSStable&CapableOntheContinuousImprovementPathStateofControl“SpecialCause”or“CommonCau59ImprovingUncertaintyManagementDem