辉瑞质量风险管理.ppt

ManagingPharmaceuticalQuality:RiskorUncertaintyManagement?Ajaz S.Hussain,Ph.D.Office of Pharmaceutical ScienceCDER,FDAPQRI Workshop February 1,2005WhatisQuality?lWhatispharmaceuticalquality?lconsistentdeliveryofthelabelperformanceandlackofcontamination.loperationalzedviaasetofpre-specifiedqualityattributes(e.g.,specifications,limits)andthroughtheCGMPregulations.lFDA,initsqualitydefinition,isstanding in for the customeranditisapparentthathealthcarepractitionersandpatientshighlyvalueanadditionaldrugattribute:product availabilitylGood pharmaceutical quality representsanacceptablylowriskoffailingtoachievethedesiredclinicalattributes.http:/ManagementGoalslImprovingqualityandensuringavailabilitylOptimaluseofourresourceslAsystemsapproachtoCMCreviewandCGMPinvestigationslBasedonknowledgeandprocessunderstandinglAchieving“qualitybydesign”lDemonstrating“scienceofdesign”lContinuouslearningandimprovementthrough“manufacturingscience”AnApproachforQualityRiskConnectionlConceptofQuality by Design(QbD)lProductandprocessperformancecharacteristicsarescientifically designed to meet specific objectives,notmerelyempiricallyderivedfromperformanceoftestbatcheslCharacteristicsimportanttodesiredperformancemustbederivedfromacombination of prior knowledge and experimental assessment during product development.lFromthisknowledgeanddata,amultivariate model linking product and process measurements and desired attributes may be constructed.lClinical study would then be viewed as confirmatory performance testing of the model.Woodcock,2004ASystemsApproachScienceofDesignManufacturingScienceDeliverQualitybyDesignStateofControl&ContinuousImprovementQualitycannotbetestedintoaproduct;ithastobebydesign“Market Standards”Science of Design+Manufacturing Science=Quality by DesignRisk/BenefitandQualityHarmAcceptableRisk/BenefitQualityLabelNobenefit(placeboeffect)ManagingPharmaceuticalQualitylQualityofanewmolecularentity(apotentialdrug)lIntrinsicpharmacological&toxicologicalattributeslIdentitylComplexitylArangeofuncertaintywithrespecttoidentityof“activemoiety”,purityandstabilityofmaterialsusedinevaluationofpharmacologicalandtoxicologicalattributes(ifamixture;variabilityaddsadditionaluncertainty)lVariabilityintheextentandrateofdeliveryof“activemoiety”tothesitesofactionandvariabilityinthepharmacological&toxicologicalresponseandmeasurementsystemsfurtheraddsuncertaintyManagingPharmaceuticalQualitylQualityofadrugproductlForestablishingproposedtherapeuticclaim(label)lDrugproductmanufacturedforclinicaltrialslAftersuccessfuldemonstrationoftherapeuticclaim(acceptablerisk-to-benefitratio)lDrugproductmanufacturedforcommercialdistributionlLifecycleoftheproduct(shelf-life,exclusivityperiod,genericcompetition,post-approvalchanges,)lDrugproductmanufacturedatmanydifferentfacilities,changesintheprocess,differentmanufactures,Uncertainty,VariabilityandRisklQualityClinicalConnectionlHowdoesaproductformulationanditsmanufacturingprocessimpactclinicalperformance?lWithoutaclearunderstandingweareuncertain(lackofknowledge)lIndecisionmakingtherearemanyadvantagesindistinguishingbetweenuncertainty,variability(randomvariation)andriskGoalsandCharacteristicsofaQualityDecisionSystem:ExampleGoal:expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labelingCharacteristicsUncertaintyVariabilityRiskPharmaceutical EquivalentSame active,identical amount,same dosage form,and route of administration.Identity,StrengthQuality,Purity.Compendial or other standardsPrior Knowledge(NDA)Post Approval:Monitoring programSuch as MedWatchConsumer ComplaintsTherapeutic Inequivalence Coordinating CommitteeNeed for Bioequivalence AssessmentDo not present a known or potential bioequivalence problem.Acceptable in vitro standardCompendial Dissolution test methodPresent a known or potential bio-problem.Appropriate bioequivalence standard90%Confidence Interval of Test/Ref ratio for rate and extent of absorption in 80-125%rangeAdequately LabeledSimilarity with reference label,medication errors.,Certain differences due to changes in the manufacturer,distributor,pending exclusivity issues,or other characteristicsManufactured in conformance to CGMPsProcess Validation and Quality SystemDeviations,Out of Specifications,.ANDAApplications:LimitedInformationContent(e.g.,IRCapsule)lGenerally1bio-batchlBioequivalencegoalpost80-125%l90%ConfidenceIntervalfortheTest/ReferenceratioforCmaxandAUCinbetweenthegoalpostlNormalhealthysubjects,cross-overdesign,fasting(andfed)conditionslCommonforalloraldrugsi.e.,procrusteanlTocover“worstcase”scenarioslIfmeanis100%and90%CIisoutside80-125say85-126.5?lExecutedbatchrecordandmasterbatchrecord(e.g.,10X)applicationcommitmentlPost-approvalprocess validation and stability commitmentlPostapprovalchangesbasedonSUPAC-IRDemonstrationof“qualitybydesign”?lAnalyticaldata+Executedbatchrecord+bio-study+processvalidationlIQ,OQ,PQ,.lPQ=3consecutivebatchesinconformancelReducedtestinge.g.,compendialtestslForsimple,conventionalproductdesignsworksfinemostofthetime;qualitybydesignisthenthepriorknowledgeandwhateverdevelopmentdataisgenerated(heldatsite)Uncertainty,VariabilityandRiskUncertainty?Variability?Risk?Uncertainty,VariabilityandRisklProcrusteanstandardshavetoaddress“worstcase”scenarioslUncertaintyisnotrisk,currentlywehavenochoicebuttoforcethisequalitylUncertaintyisreducedbyimprovingknowledgelWelearnwhattocontrolandthedegreeofcontrolnecessarytominimizerisklForcontinuousqualityimprovementweshouldfocusonimprovinguncertaintymanagementprocessExampleofaCMCRegulatoryDecision:AcceptabilityofaPostApprovalManufacturingProcessChangelOriginalNDAorANDA=CMCQuality&Performance(“Insurance”)ContractlForexampleinANDAsRegulatorycommitments=ConditionsinexecutedbatchrecordslPriorApprovalSupplement*(PAS)lProductconformswithallestablishedspecificationslBut-“Specificationsdonottellthewholestory”lE.g.,Shelf-lifeand/orbioavailabilitymayhavechangedand/oranewimpuritymaybeintroducedthatmaynotbedetectedwithestablishedanalyticalmethods,sponsormaynotadequatelyqualifychanges(inspectionfrequencymaynotbesufficient),.*prior approval supplementforprocessoptimizationandcontinuousimprovementeffortsCompanyX“GoesLean”l“Cycle-timereductionsubgroupmembers,forexample,examineeachprocessfunction,forexample,dispensing,rollercompactionandcompression,todeterminehowtospeedupchangeoverandgetequipmenttorunfasterandmoreefficiently.”l“Theteamsolicitsideasatregularmeetingsandviaemail.Theideasarethenratedfrom1to10basedonbangforthebucktoreducecycletime,andonhowdifficulttheywouldbetoachieve-e.g.,whethertheywill require validation or prior FDA approval.”PharmaM PostApprovalProcessChange(SUPACGuidance)“Within”(ChangeTargetsetting)“Outside”CurrentUncertaintyManagementlAttheoperationallevelthemostefficientapproachformanaginguncertaintyis“demandmanagement”lStrict“checkingthebox”processusingpre-specifiedrequirements(recommendations)andprocrusteanstandardslFDAguidancedocuments,483observations,.l90%CI80-125%,in-processblenduniformitytests,.SOPs,.CurrentDemandManagement:CharacteristicslForconventionalproductsandmanufacturingprocesses-easytoimplement,supervise,andmangelDecisionresponsibilityisdeferredtoasetof“procrustean”standards-liabilitydistributedtotheentirepharmaceuticalcommunity(e.g.,viaUSP,AAPS,etc.)lForinnovativeand/orcomplexproductsandprocessesnooneiswillingtotakeresponsibilityfordecisions(e.g.,developguidancedocument)decisionliabilityisthenonthepersonwillingtotakeadecision.CurrentDemandManagement:CharacteristicslInnovationandcontinuousimprovementslowsdownandinefficiencyincreaseslThelevelofqualityassuranceachievedisdifficulttomeasureandisburiedinhistoricalmindsetandclinicalvariabilitylWithincreasingcomplexityamajorfailureisnecessarytosignalinadequaciesofthesystemsuchafailureisoftentheonlyapproachtointroducenewregulationsorimproveddecisioncriterialChallengetoandalternateapproachestocurrentprocrusteanstandardsdifficulttoproveanddebatesdrainresourcesWithout Continuous(Community)Learning:Demand Management is“static”until a crisis is created,it then reacts to replace a current procrustean standard with another.ContinuousImprovement:EnhancingCustomerSatisfaction-ReducingVariability“SpecialCause”or“CommonCause”Stable-Yes;Capable?UnstableCorrective ActionsEliminate“Special Cause”Reduce“Common Cause”VariabilityFrequent,MajorOOSMinor,OccasionalOOSStable&CapableOn the Continuous Improvement PathState of ControlImprovingUncertaintyManagementlDemandmanagementlSpecifiedandprocrusteanstandardslE.g.,90%CI80-125%,in-processblenduniformitytests,.SOPs,.l lPassivemanagementPassivemanagementl lQualitybyDesign,demonstrated“robustness”QualitybyDesign,demonstrated“robustness”l lCanwebringasystems(CMCreviewandCGMPinvestigation)Canwebringasystems(CMCreviewandCGMPinvestigation)perspectivetobetterrecognizeacompanysabilitytoachieveperspectivetobetterrecognizeacompanysabilitytoachievequalitybydesignandreducetheneedforpriorapprovalqualitybydesignandreducetheneedforpriorapprovalsupplements?supplements?l lActivemanagementActivemanagementl lContinuouslearningandleveragingknowledgetocreateContinuouslearningandleveragingknowledgetocreateflexibilityflexibilityl lMovetowardsarisk-basedapproachMovetowardsarisk-basedapproachl lContinuousimprovement(qualityandproductivity)Continuousimprovement(qualityandproductivity)OpportunitieslPATGuidancelPATprovidesthepharmaceuticalcontextforLean,SixSigma!lCPG7132c.08lComparabilityProtocollQualitySystemsApproachtoPharmaceuticalCGMPslICHQ8,(9?),(10?)PATGuidancelOpensthedoortorealizethebenefitsofconnectinglFisherto-Shewartto-DeminglFocusonprocessunderstandingleadingtocontrolofprocessend-point!lResearchdataCTD-P2Sec.QbDDrug Substanceor APIIntended UseRoute of administrationPatient population.Product DesignDesign Specifications(Customer requirements)P2.1 and 2.6P2.2,2.4,2.5,2.6Drug ProductContainer Closure SystemMicrobiological AttributesCompatibility(e.g.,recon)Manufacturing ProcessComponents of drug productP2.3Manufacturing Process Development“DesignSpace”=f(IntendedUse*Design*Control)Quality SystemRisk ClassificationProcess Design&ControlSpecificationsProduct DesignIntended UseDesign RequirementsReliabilityTo DeliverDesignRequirementsAssessmentBased on ICH Q8Information/KnowledgeJohnCBerridge,Q8Rapporteur(EFPIA).JohnCBerridge,Q8Rapporteur(EFPIA).FDAManufacturingSubcommittee,July2004FDAManufacturingSubcommittee,July2004KnowledgeBasedDecisions:RequireScientificGeneralizeableKnowledgethe“SUPACGAP”SUPACChangeLevelsbasedonpriorknowledgefromthepharmaceuticalcommunity(AAPSSUPACWorkshops)+Research;Yetdifficulttogeneralizebecauseofmultifactorialaspects+lotofsubjectivityLimitedinformationinNDA/ANDAPriorknowledgewithinacompanyandamovetowardsmechanisticUnderstanding(ICHQ8isintendedtofillthisgap)Gap=UncertaintyUncertaintyManagement:QbD&FlexibilityTimeScale&ModeofResponseUncertaintyManagementSystemModificationQbDFlexibilityOperationalRootcauseinvestigation,Efficiency,etc.LearningtoR&DControlofexcipientsandothersourcesof“commoncause”variabilityReduceCGMPRiskClassificationContinuousImprovementofQualitySystemTacticalOn-linecontrolDesignforManufacturabilityCriticalControlPoints-Robustprocessend-pointRegulatorySpecifications“DesignSpace”RealTimeRelease,ModularValidationReg.CMCApprovalStrategicScienceofDesignDesigntoreduce“Uncertainty”Sci.&Tech.IntegrationContinuousLearning&ImprovementRegulatoryCommunicationIntegrateSci-EnablingTechnologyPlatform“Plug&Play”“TimetoMarket”+“ProductionEfficiency”ScienceofDesignlOftendesignanddevelopmentactivitiesarecarriedoutbasedonexperientialknowledge,intuitionandroughguidelinesdifficulttocommunicatetoindividualsfromdifferentbackgrounds(the“art”argument)lTolearnhowtorepresentdesignsatamuchhigherlevelthanthecurrentdescriptive“recipe”format(e.g.,executedbatchrecords,SOPs)whilerigorouslydocumentingkeyconstrainsAValidatedSystemlWehavebegunupdatingourcurrentthinkingonvalidationlProcess Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval(CPG7132c.08,Sec490.100).lRationalexperimentaldesignandongoingevaluationofdatalAchievingandmaintainingastateofcontrolforaprocessbeginsattheprocessdevelopmentphaseandcontinuesthroughoutthecommercialphaseofaproductslife-cyclelRisk-basedapproaches-inspectionalscrutiny;useofadvancedtechnologies,andtheroleofconformancebatchesintheproductlife-cycle.lAfocusonthreefull-scaleproductionbatcheswouldfailtorecognizethecompletestoryonvalidation.http:/www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm#_Toc84065761Draft Guidance for IndustryQuality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations Traditional goalsTraditional goalsNon-traditional goalsNon-traditional goals(risk based,flexibility,(risk based,flexibility,robustness,scalability,robustness,scalability,continuous improvement,continuous improvement,innovation,innovation,efficiency,.)efficiency,.)CharacteristicsCharacteristicsComplexity,uncertainty Complexity,uncertainty Relationships(between goals&Relationships(between goals&characteristics)characteristics)Knowledge and information Knowledge and information centric relationshipscentric relationshipsFundamental issuesFundamental issuesEngineeringaQualitySystem“ChangeControl”to“ContinuousImprovement”PAT-ICH Q8“Design Space”DevelopmentDevelopmentInnovation&ContinuousImprovementOptionsManufacturing&Manufacturing&Quality AssuranceQuality AssuranceManaged underThe CompanysQuality System;Subject toCGMP Inspections(no-change or variation)MaintainMaintain“State of Control”“State of Control”“Fisher”-“Shewart”-“Deming”“Fisher”-“Shewart”-“Deming”Theory of experimental designTheory of experimental designStatistical Process ControlStatistical Process ControlTheory of VariationTheory of VariationByImprovingUncertaintyManagementwehavebeganaprocessofengineeringaproactivedecisionssystemforpharmaceuticalqualitylReactive(examples)lTestingtodocumentqualitylRepeatingdeviationandoutofspecificationinvestigationslWaitingforFDAguidancetosubmitANDAdemonstratingtherapeuticequivalenceofgenericproductslPotentialformultipleNDACMCreviewcycleslWaitingforFDAtoapproveaprior approval supplementforprocessoptimizationandcontinuousimprovementeffortslFear,apprehensionlProactive(examples)lQualitybydesignandrealtimeprocesscontrolstoachieverealtimerelease”lRightFirstTimelInnovativeapproachesfordemonstratingtherapeuticequivalenceofgenericslSingleNDACMCreviewcyclelProcessoptimizationandcontinuousimprovementeffortswithinafacilitiesqualitysystemlAbilitytoutilizepriorknowledgelEmpowerment,recognition