FDA產(chǎn)品質(zhì)量風(fēng)險(xiǎn)評(píng)估原則翻譯

1基于產(chǎn)品質(zhì)量的風(fēng)險(xiǎn)評(píng)估原則H.GreggClaycamp,Ph.D.,CHPCenterforVeterinaryMedicineOfficeofNewAnimalDrugEvaluationhclaycam@June25,20032提綱總前提和問(wèn)題風(fēng)險(xiǎn)分析的基本要素實(shí)施PQ的風(fēng)險(xiǎn)評(píng)估的可能階段實(shí)施的風(fēng)險(xiǎn)分級(jí)模式?中試放大結(jié)論TheopinionsandideaspresentedherearethoseoftheauthoranddonotrepresentpolicyoropinionoftheFDA.Thismaterialisintendedfordiscussionpurposesonly.3前提:工藝中的風(fēng)險(xiǎn)和患者的風(fēng)險(xiǎn)的聯(lián)系已丟失.風(fēng)險(xiǎn)

工藝檢查風(fēng)險(xiǎn)cGMP風(fēng)險(xiǎn)

質(zhì)量(患者)因素患者相互關(guān)系?模型?4目標(biāo):重新將cGMP(PQ)風(fēng)險(xiǎn)和對(duì)患者的實(shí)際風(fēng)險(xiǎn)聯(lián)系起來(lái)風(fēng)險(xiǎn)

工藝檢查中的風(fēng)險(xiǎn)

風(fēng)險(xiǎn)

質(zhì)量(患者)因素cGMP患者5問(wèn)題…CanRiskManagementtheory,tools,practiceandphilosophybeemployedtore-linkriskstothepatientwiththerisksidentified,perceivedorotherwiseimplicatedinproductqualityterms?風(fēng)險(xiǎn)管理理論,工具,實(shí)踐和哲學(xué)Howcanweshareacommonlanguageaboutrisk,riskmanagement,andscience-baseddecisionmakingsothatwecanfocusondevelopingahigh-qualityriskmanagementmodelforproductquality?6GettingStarted…Whattheories,toolsandlessonslearnedinriskanalysiscanhelpaddressthesequestions?Giventheneedforasignificantshiftintheapproachtoriskmanagement,howdowebeginthechangeprocess?Arethereoff-the-shelfmodelsandtoolsthatmightbeused,i.e.,atapilot-scale?WhatkindsofRMprocessescanbeusedtofosterchangesneededboththeregulatoryandindustrialspheres?7基本風(fēng)險(xiǎn)分析8StartingwiththeSomeBasicsRiskisintuitiveandfamiliartoeveryone,yetfewamongusdefineriskcarefullyandformallyenoughforcomplexriskanalysis.exposureexposureseverityprobabilityharmhazardchanceseverityvalueprobabilitychance9風(fēng)險(xiǎn)=“暴露程度相對(duì)于

損失的機(jī)會(huì)”

(或者,風(fēng)險(xiǎn)=“chanceoflosingsomething

wevalue”)風(fēng)險(xiǎn)=危害x暴露程度風(fēng)險(xiǎn)后果=危害x暴露程度10同時(shí)期的風(fēng)險(xiǎn)分析

主要包括四大行動(dòng):

危害識(shí)別

風(fēng)險(xiǎn)評(píng)估

風(fēng)險(xiǎn)管理

風(fēng)險(xiǎn)交流11風(fēng)險(xiǎn)管評(píng)估先于風(fēng)險(xiǎn)管理Riskassessmentisnotasingleprocess,but“asystematicapproachtoorganizingandanalysingscientificknowledgeandinformation”tosupportariskdecision.NRC(1994)Variousparadigmsexistfortheexecutionofariskassessmentinpublichealth;however,allparadigmshaveincommonfundamentalscientificprinciples.12風(fēng)險(xiǎn)評(píng)估需要問(wèn)以下問(wèn)題:什么會(huì)出錯(cuò)?出錯(cuò)的可能性是什么?后果是什么?13風(fēng)險(xiǎn)管理需要問(wèn)以下問(wèn)題:可以做什么?那些方法是可用的?就風(fēng)險(xiǎn)、利益和成本而言什么是風(fēng)險(xiǎn)的交易物?目前的對(duì)將來(lái)的管理決定的影響是什么?14Roles/Tasks(--shortlist)Posetheriskquestion.ChargetheRiskAssessorswiththeRiskAssessmentTask.Convenestakeholders.Analyzedecisionoptions.Make/recommendthedecision.Identifydataandgatherinformationonthenature,extent,magnitudeanduncertaintyoftherisk.WritetheRiskAssessment.RecommendschangestoRMquestions.RiskManagersRiskAssessors15風(fēng)險(xiǎn)評(píng)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民主的風(fēng)險(xiǎn)分析風(fēng)險(xiǎn)評(píng)估為風(fēng)險(xiǎn)分析提供事實(shí).風(fēng)險(xiǎn)風(fēng)險(xiǎn)風(fēng)險(xiǎn)風(fēng)險(xiǎn)風(fēng)險(xiǎn)風(fēng)險(xiǎn)風(fēng)險(xiǎn)風(fēng)險(xiǎn)評(píng)估風(fēng)險(xiǎn)風(fēng)險(xiǎn)風(fēng)險(xiǎn)風(fēng)險(xiǎn)風(fēng)險(xiǎn)風(fēng)險(xiǎn)風(fēng)險(xiǎn)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”P(pán)roportionofexposedpersonswhobecomeill100%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