FDA产品质量风险评估原则翻译

1基于产品质量的风险评估原则H.GreggClaycamp,Ph.D.,CHPCenterforVeterinaryMedicineOfficeofNewAnimalDrugEvaluationhclaycam@June25,20032提纲总前提和问题风险分析的基本要素实施PQ的风险评估的可能阶段实施的风险分级模式?中试放大结论TheopinionsandideaspresentedherearethoseoftheauthoranddonotrepresentpolicyoropinionoftheFDA.Thismaterialisintendedfordiscussionpurposesonly.3前提:工艺中的风险和患者的风险的联系已丢失.风险

工艺检查风险cGMP风险

质量(患者)因素患者相互关系?模型?4目标:重新将cGMP(PQ)风险和对患者的实际风险联系起来风险

工艺检查中的风险

风险

质量(患者)因素cGMP患者5问题…CanRiskManagementtheory,tools,practiceandphilosophybeemployedtore-linkriskstothepatientwiththerisksidentified,perceivedorotherwiseimplicatedinproductqualityterms?风险管理理论,工具,实践和哲学Howcanweshareacommonlanguageaboutrisk,riskmanagement,andscience-baseddecisionmakingsothatwecanfocusondevelopingahigh-qualityriskmanagementmodelforproductquality?6GettingStarted…Whattheories,toolsandlessonslearnedinriskanalysiscanhelpaddressthesequestions?Giventheneedforasignificantshiftintheapproachtoriskmanagement,howdowebeginthechangeprocess?Arethereoff-the-shelfmodelsandtoolsthatmightbeused,i.e.,atapilot-scale?WhatkindsofRMprocessescanbeusedtofosterchangesneededboththeregulatoryandindustrialspheres?7基本风险分析8StartingwiththeSomeBasicsRiskisintuitiveandfamiliartoeveryone,yetfewamongusdefineriskcarefullyandformallyenoughforcomplexriskanalysis.exposureexposureseverityprobabilityharmhazardchanceseverityvalueprobabilitychance9风险=“暴露程度相对于

损失的机会”

(或者,风险=“chanceoflosingsomething

wevalue”)风险=危害x暴露程度风险后果=危害x暴露程度10同时期的风险分析

主要包括四大行动:

危害识别

风险评估

风险管理

风险交流11风险管评估先于风险管理Riskassessmentisnotasingleprocess,but“asystematicapproachtoorganizingandanalysingscientificknowledgeandinformation”tosupportariskdecision.NRC(1994)Variousparadigmsexistfortheexecutionofariskassessmentinpublichealth;however,allparadigmshaveincommonfundamentalscientificprinciples.12风险评估需要问以下问题:什么会出错?出错的可能性是什么?后果是什么?13风险管理需要问以下问题:可以做什么?那些方法是可用的?就风险、利益和成本而言什么是风险的交易物?目前的对将来的管理决定的影响是什么?14Roles/Tasks(--shortlist)Posetheriskquestion.ChargetheRiskAssessorswiththeRiskAssessmentTask.Convenestakeholders.Analyzedecisionoptions.Make/recommendthedecision.Identifydataandgatherinformationonthenature,extent,magnitudeanduncertaintyoftherisk.WritetheRiskAssessment.RecommendschangestoRMquestions.RiskManagersRiskAssessors15风险评估RegulatoryPolicy

RiskAssessment:(e.g.,BiotechnologyRAtodeterminetheneedforriskmanagementregulation.)AppliedRiskAssessment:Todeterminecompliancewitharegulationorpolicy.SafetyAssessments:Highlydefinedriskcalculations.Usuallyundera“brightline”safetypolicy.16Safetyvs.RiskRiskLimite.g.,Limitexceeded“10timesin100”SafetyLimit“Unsafe”“Safe”e.g.,Declared“unsafe”Estimatesofrisk17民主的风险分析风险评估为风险分析提供事实.风险风险风险风险风险风险风险风险评估风险风险风险风险风险风险风险Worst

18RiskAnalysisinaDemocracyTheriskmanagement

decisionsaboutwhichriskstomanagearevalue-ladendecisions.RiskManagementRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskValuesCostsWorst

RiskManagementRank

19TranslatingRiskAnalyticParadigmsRiskAnalysisRiskAssessmentReleaseAssessmentExposureAssessmentConsequenceAssessmentRiskEstimationRiskManagementRiskCommunicationHazardIdentificationWhatcangowrong?Whataretheconsequences?Whatisthelikelihoodthatitwouldgowrong?Whatcanbedone?Whatarethetrade-offsintermsofcosts,benefitsandrisks?WhatistheimpactofdecisionsonfutureRMoptions?RiskAssessmentPQFailuresExposureAssessmentConsequenceAssessmentRiskEstimationAsimplechangetoapplyacontemporarymodel.20PossibleStagesofRiskAssessmentforWorkPlanning21HazardIdentificationWhatcangowrong?Identifyhazards:events

Identifyhazardousagents(chemical,biological,physical)Howseverearethepotentialconsequences?

Giventheeventoccurs,istheconsequencecatastrophic?Mildlyannoying?Howlikelyaretheeventstooccur?Essentiallyacruderiskestimateforinitialprioritizationpurposes.22ExposureAssessmentReleaseAssessment:

How“much”ofthehazardouseventoccurs?

Example:Doesa“non-sterile”eventinvolve1or10,000vials?Pathwayanalysis:Ifthehazardouseventoccurs,whatpathwaysaretherethatexposehumanstothehazard?Extentofexposure:Ifahazardouseventoccurs,howmanypeoplearepotentiallyexposed?23GMPFailure(Release)AssessmentHowfrequentaretheidentifiedPQevents(hazards)?Boundaryofrelease?Processline,plant,warehouse,distributor?Releaserates(“PQFaults”)areobtainedinfaulttreeassessments,empirically,historicaldata,expertanalyses.Example:FMEA24ConsequenceAssessment*Givenexposuretothehazardousevent/agent,whatisthelikelihoodofharmunderapre-definedendpoint?Endpointexamples:DeathIllnessWorryOAI*A.K.A.“Dose-ResponseAssessment”(seenextslide)25ConsequenceAssessmentQuantityofcontamination(“non-sterility”)i.e.,in“bacteriacountspervial”Proportionofexposedpersonswhobecomeill100%50%0%ED5026QualitativeConsequenceAssessmentHighMediumLowRelativeEffect/ImpactQuantitativerelationshipsknowninfewcasesLowMediumHigh(ExposureorDoseMetric)27RiskEstimationBringtogethertheinformationaboutthehazard,theextentofexposuretothehazard,theconsequencesofexposures,andthenestimatetherisk.Includesacriticalanalysisofuncertaintyinboththedataandriskassessmentmodels.28UncertaintiesinRiskAssessmentUNCERTAINTYKnowledgeVariabilityDataParametersModelTemporalSpatialInter-individual29ConceptualModelsforRMinPQInitiative30ThePQRiskManagementProblemDiversePQfailure(hazards)areidentified.Wide-rangingrisk(=chancethatexposuretothehazardwillresultinharm[adverseoutcome]).Wide-rangingconsequences(deathtoworry).Quantitativeriskanalysishazard-by-hazardtoovastanundertaking.Rankingofrisksforre-linkingworstPQriskswithworsthealthrisks,etc.Howcanweobjectivelyrank“applesandoranges”amongthe“potatoesandbeans?”31FromtheBeginning…Isriskanalysisforeachhazard–independently—feasible?32BulbFailsNoelectricityPowerPlantFailsPowerLineFailsGlassBrokenFilamentBrokenConnectorCorrodedVacuumLeakTreeBreaksLineWindBreaksLineImpuritiesVibrationsFaultTreesforeachprocess?33FaultsMagnifiedN-foldforaSimpleManufacturingProcess34DecisionAnalysesforEachHazardMultipliesComplexity!e.g.,35Solution?AMultifactorApproachtoPQRiskManagementMultifactormethodsalreadyexist.Sometools(software)alreadydeveloped.Appropriately-scaledapproachtothequestion,thedataquality,thenatureofthedecision,andtheunderstandingoftheoverallprocess.36StatetheAssumptionsE.g.,assumethathealthriskswerelinkedtoPQ“compliancerisks”previously,i.e.,thehistoricalbasisofregulation.

Historicallybasedassumption:

compliance

Healthrisk

qualityGiventheassumption,canGMP“compliancerisk”bemodeledasasurrogateofhealthrisk?37IdentifythePQFailures(Hazards)Whatcangowrong?

Toplevelorganizationofhazards:Health|Compliance|Resources|SociopoliticalSecondlevel(detail)organization:Sterility(microbialcontamination)Dose(formulation)Toxicity(chemicalcontamination)Physicalhazards(physicalcontamination/defect)Finedetail:“riskfactor”eventdescriptors.38SorttheHazards/RisksbyMajorCategoriesStartwithassumptions.Statequestionstobeanswered.Sortunderthequestions.Re-sortifnewpatternsemerge.Forexample,(nextslide)…39OrganizingaMulti-factorialRiskModel…40FocusedMulti-factorialRiskModelExamplehealthriskendpointsExamplecomplianceriskendpoints41Riskfactorsforagivenendpoint………42EstimatethePrevalenceTheprevalenceofinspectionfindingsforagiventypeofeventareinitialestimatesofprobabilitiesnecessaryforriskmanagementmodeling.Failureanalysis“inplant.”Failureincomplianceinspections.Humanadverseevents.43Foreachhazard…Health

EndpointProbabilityofOccurrenceVeryLowLowMediumHighVeryHighDeathMediumMediumHighHighHighChronicIllnessLowMediumMediumHighHighAcuteIllnessLowLowMediumMediumHighWorryLowLowLowMediumMedium44Themodeler’sview…(forexample)Health

EndpointProbabilityofOccurrenceVeryLowLowMediumHighVeryHighDeath54321ChronicIllness65432AcuteIllness76543Worry8765445Foreachhazard…Compliance

EndpointPriorHistoryofActionsNeverViolationsFewViol.AverageViol.SomeViol.ManyViol.OAIMediumMediumHighHighHighVAILowLowMediumHighHighOther?LowLowLowMediumHigh46Scoring,thenprioritizemultiplehazardsEndpointProbabilityofOccurrenceVeryLowLowMediumHighVeryHighDeathMediumMediumHighHighHighChronicIllnessLowMediumMediumHighHighAcuteIllnessLowLowMediumMediumHighWorryLowLowLowMediumMediumEndpointProbabilityofOccurrenceVeryLowLowMediumHighVeryHighDeathMediumMediumHighHighHighChronicIllnessLowMediumMediumHighHighAcuteIllnessLowLowMediumMediumHighWorryLowLowLowMediumMediumEndpointProbabilityofOccurrenceVeryLowLowMediumHighVeryHighDeathMediumMediumHighHighHighChronicIllnessLowMediumMediumHighHighAcuteIllnessLowLowMediumMediumHighWorryLowLowLowMediumMe