FDA+产品质量的风险评估原则(翻译).ppt

1,基于产品质量的风险评估原则,H.GreggClaycamp,Ph.D.,CHPCenterforVeterinaryMedicineOfficeofNewAnimalDrugEJune25,2003,2,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,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?,6,GettingStarted,Whattheories,toolsandlessonslearnedinriskanalysiscanhelpaddressthesequestions?Giventheneedforasignificantshiftintheapproachtoriskmanagement,howdowebeginthechangeprocess?Arethereoff-the-shelfmodelsandtoolsthatmightbeused,i.e.,atapilot-scale?WhatkindsofRMprocessescanbeusedtofosterchangesneededboththeregulatoryandindustrialspheres?,7,基本风险分析,8,StartingwiththeSomeBasics,Riskisintuitiveandfamiliartoeveryone,yetfewamongusdefineriskcarefullyandformallyenoughforcomplexriskanalysis.,9,风险=“暴露程度相对于损失的机会”(或者,风险=“chanceoflosingsomethingwevalue”),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?,14,Roles/Tasks(-shortlist),Posetheriskquestion.ChargetheRiskAssessorswiththeRiskAssessmentTask.Convenestakeholders.Analyzedecisionoptions.Make/recommendthedecision.,Identifydataandgatherinformationonthenature,extent,magnitudeanduncertaintyoftherisk.WritetheRiskAssessment.RecommendschangestoRMquestions.,RiskManagers,RiskAssessors,15,风险评估,RegulatoryPolicyRiskAssessment:(e.g.,BiotechnologyRAtodeterminetheneedforriskmanagementregulation.)AppliedRiskAssessment:Todeterminecompliancewitharegulationorpolicy.SafetyAssessments:Highlydefinedriskcalculations.Usuallyundera“brightline”safetypolicy.,16,Safetyvs.Risk,17,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,18,RiskAnalysisinaDemocracy,Theriskmanagementdecisionsaboutwhichriskstomanagearevalue-ladendecisions.,Worst,RiskManagementRank,19,TranslatingRiskAnalyticParadigms,RiskAnalysis,RiskAssessmentReleaseAssessmentExposureAssessmentConsequenceAssessmentRiskEstimation,RiskManagement,RiskCommunication,HazardIdentification,20,PossibleStagesofRiskAssessmentforWorkPlanning,21,HazardIdentification,Whatcangowrong?Identifyhazards:eventsIdentifyhazardousagents(chemical,biological,physical)Howseverearethepotentialconsequences?Giventheeventoccurs,istheconsequencecatastrophic?Mildlyannoying?Howlikelyaretheeventstooccur?Essentiallyacruderiskestimateforinitialprioritizationpurposes.,22,ExposureAssessment,ReleaseAssessment:How“much”ofthehazardouseventoccurs?Example:Doesa“non-sterile”eventinvolve1or10,000vials?Pathwayanalysis:Ifthehazardouseventoccurs,whatpathwaysaretherethatexposehumanstothehazard?Extentofexposure:Ifahazardouseventoccurs,howmanypeoplearepotentiallyexposed?,23,GMPFailure(Release)Assessment,HowfrequentaretheidentifiedPQevents(hazards)?Boundaryofrelease?Processline,plant,warehouse,distributor?Releaserates(“PQFaults”)areobtainedinfaulttreeassessments,empirically,historicaldata,expertanalyses.Example:FMEA,24,ConsequenceAssessment*,Givenexposuretothehazardousevent/agent,whatisthelikelihoodofharmunderapre-definedendpoint?Endpointexamples:DeathIllnessWorryOAI*A.K.A.“Dose-ResponseAssessment”(seenextslide),25,ConsequenceAssessment,Quantityofcontamination(“non-sterility”)i.e.,in“bacteriacountspervial”,Proportionofexposedpersonswhobecomeill,100%,50%,0%,26,QualitativeConsequenceAssessment,High,Medium,Low,RelativeEffect/Impact,Low,Medium,High,(ExposureorDoseMetric),27,RiskEstimation,Bringtogethertheinformationaboutthehazard,theextentofexposuretothehazard,theconsequencesofexposures,andthenestimatetherisk.Includesacriticalanalysisofuncertaintyinboththedataandriskassessmentmodels.,28,UncertaintiesinRiskAssessment,UNCERTAINTY,Knowledge,Variability,DataParametersModel,TemporalSpatialInter-individual,29,ConceptualModelsforRMinPQInitiative,30,ThePQRiskManagementProblem,DiversePQfailure(hazards)areidentified.Wide-rangingrisk(=chancethatexposuretothehazardwillresultinharmadverseoutcome).Wide-rangingconsequences(deathtoworry).Quantitativeriskanalysishazard-by-hazardtoovastanundertaking.Rankingofrisksforre-linkingworstPQriskswithworsthealthrisks,etc.,Howcanweobjectivelyrank“applesandoranges”amongthe“potatoesandbeans?”,31,FromtheBeginning,Isriskanalysisforeachhazardindependentlyfeasible?,32,FaultTreesforeachprocess?,33,FaultsMagnifiedN-foldforaSimpleManufacturingProcess,34,DecisionAnalysesforEachHazardMultipliesComplexity!,e.g.,35,Solution?AMultifactorApproachtoPQRiskManagement,Multifactormethodsalreadyexist.Sometools(software)alreadydeveloped.Appropriately-scaledapproachtothequestion,thedataquality,thenatureofthedecision,andtheunderstandingoftheoverallprocess.,36,StatetheAssumptions,E.g.,assumethathealthriskswerelinkedtoPQ“compliancerisks”previously,i.e.,thehistoricalbasisofregulation.Historicallybasedassumption:complianceHealthriskqualityGiventheassumption,canGMP“compliancerisk”bemodeledasasurrogateofhealthrisk?,37,IdentifythePQFailures(Hazards),Whatcangowrong?Toplevelorganizationofhazards:Health|Compliance|Resources|SociopoliticalSecondlevel(detail)organization:Sterility(microbialcontamination)Dose(formulation)Toxicity(chemicalcontamination)Physicalhazards(physicalcontamination/defect)Finedetail:“riskfactor”eventdescriptors.,38,SorttheHazards/RisksbyMajorCategories,Startwithassumptions.Statequestionstobeanswered.Sortunderthequestions.Re-sortifnewpatternsemerge.Forexample,(nextslide),39,OrganizingaMulti-factorialRiskModel,40,FocusedMulti-factorialRiskModel,41,Riskfactorsforagivenendpoint,42,EstimatethePrevalence,Theprevalenceofinspectionfindingsforagiventypeofeventareinitialestimatesofprobabilitiesnecessaryforriskmanagementmodeling.Failureanalysis“inplant.”Failureincomplianceinspections.Humanadverseevents.,43,Foreachhazard,44,Themodele