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 CHPCenterforVeterinaryMedicineOfficeofNewAnimalDrugEvaluationhclaycam cvm fda govJune25 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 chancethatexposuretothehazardwillresultinharm adverseoutcome Wide rangingconsequences deathtoworry Quantitativeriskanalysishazard by hazardtoovastanundertaking Rankingofrisksforre linkingworstPQriskswithworsthealthrisks etc Howcanweobjectivelyrank applesandoranges amongthe potatoesandbeans 31 FromtheBeginning Isriskanalysisforeachhazard independently feasible 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 compliance Healthrisk qualityGiventheassumption 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 Themodeler