Q9 质量风险管理 中英文对照

QUALITYRISKMANAGEMENTQ9工业指南Q9质量风险管理美国健康与公众服务部食品药品监督管理局（FDA）

药品评价与研究中心（CDER）

生物评价与研究中心（CBER）2006年6月人用药物注册技术要求国际协调会议（ICH）

TableofContents目录1.INTRODUCTION引言2.SCOPE范围3.PRINCIPLESOFQUALITYRISKMANAGEMENT质量风险管理原理4.GENERALQUALITYRISKMANAGEMENTPROCESS质量风险管理基本程序4.1Responsibilities职责分配4.2InitiatingaQualityRiskManagementProcess质量风险管理的启动4.3RiskAssessment风险评估4.4RiskControl风险控制4.5RiskCommunication风险交流4.6RiskReview风险回顾5.RISKMANAGEMENTMETHODOLOGY风险管理方法学6.INTEGRATIONOFQUALITYRISKMANAGEMENTINTOINDUSTRYANDREGULATORYOPERATIONS工业及监管与质量风险管理的整合7.DEFINITIONS定义8.REFERENCES参考资料AnnexI:RiskManagementMethodsandTools附件I:风险管理方法及工具I.1BasicRiskManagementFacilitationMethodsI.1基本风险管理简易方法I.2FailureModeEffectsAnalysis(FMEA)I.2失误模式影响分析(FMEA)I.3FailureMode,EffectsandCriticalityAnalysis(FMECA)I.3失误模式影响及危险程度分析(FMECA)I.4FaultTreeAnalysis(FTA)I.4故障树型分析(FTA)I.5HazardAnalysisandCriticalControlPoints(HACCP)I.5危害分析及关键控制点(HACCP)I.6HazardOperabilityAnalysis(HAZOP)I.6危害可操作性分析(HAZOP)I.7PreliminaryHazardAnalysis(PHA)I.7初步危害分析(PHA)I.8RiskRankingandFilteringI.8风险排序及滤除I.9SupportingStatisticalToolsI.9辅助统计工具AnnexII:PotentialApplicationsforQualityRiskManagement附件II:质量风险管理潜在应用前景.II.1QualityRiskManagementasPartofIntegratedII.1综合质量管理中的质量风险管理

QualityManagementII・2QualityRiskManagementasPartofRegulatoryOperationsII.2操作优化中的应用II・3QualityRiskManagementasPartofdevelopmentII.3研发中的应用II.4QualityRiskManagementforFacilities,EquipmentandUtilitiesn.4对工具、设备和设施的质量风险管理II・5QualityRiskManagementasPartofMaterialsManagementII.5物料管理中的应用II・6QualityRiskManagementasPartofProductionII.6生产中的应用II.7QualityRiskManagementasPartofLaboratoryControlandStabilityStudiesII.7实验室控制及稳定性研究中的应用II.8QualityRiskManagementasPartofPackagingandLabellingII.8标签及包装中的应用1・INTRODUCTIONRiskmanagementprinciplesareeffectivelyutilizedinmanyareasofbusinessandgovernmentincludingfinance,insurance,occupationalsafety,publichealth,pharmacovigilance,andbyagenciesregulatingtheseindustries.Althoughtherearesomeexamplesoftheuseofqualityriskmanagementinthepharmaceuticalindustrytoday,theyarelimitedanddonotrepresentthefullcontributionsthatriskmanagementhastooffer.Inaddition,theimportanceofqualitysystemshasbeenrecognizedinthepharmaceuticalindustryanditisbecomingevidentthatqualityriskmanagementisavaluablecomponentofaneffectivequalitysystem.Itiscommonlyunderstoodthatriskisdefinedasthecombinationoftheprobabilityofoccurrenceofharmandtheseverityofthatharm.However,achievingasharedunderstandingoftheapplicationofriskmanagementamongdiversestakeholdersisdifficultbecauseeachstakeholdermightperceivedifferentpotentialharms,placeadifferentprobabilityoneachharmoccurringandattributedifferentseveritiestoeachharm.Inrelationtopharmaceuticals,althoughthereareavarietyofstakeholders,includingpatientsandmedicalpractitionersaswellasgovernmentandindustry,theprotectionofthepatientbymanagingtherisktoqualityshouldbeconsideredofprimeimportance.引言风险管理原理在商业和政府的许多领域都得到了有效应用，如：金融、保险、职业安全、公共卫生、药物监测及相应的监管部门。如今质量风险管理在药企中虽有应用，但范围有限，并没有发挥出它的全部效用。药企已经意识到了质量体系的重要性，而质量风险管理越来越明显地成为有效质量体系的重要组分。Themanufacturinganduseofadrug(medicinal)药品生产、使用过程，包括药品的成分，都会不可避根据常规理解，风险被定义为伤害发生的可能性及严重程度。然而，要在不同利益集团之间寻求风险管理应用方面的共同认识是相当困难的，因为他们认识到的潜在危害、各危害发生的可能性及严重程度都不同。药品相关的利益集团很多，如病人、医疗人员和政府企业，但是质量风险管理的首要目的是保护病人。Themanufacturinganduseofadrug(medicinal)药品生产、使用过程，包括药品的成分，都会不可避ContainsNonbindingRecommendationsContainsNonbindingRecommendationsproduct,includingitscomponents,necessarilyentailsomedegreeofrisk.Therisktoitsqualityisjustonecomponentoftheoverallrisk.Itisimportanttounderstandthatproductqualityshouldbemaintainedthroughouttheproductlifecyclesuchthattheattributesthatareimportanttothequalityofthedrug(medicinal)productremainconsistentwiththoseusedintheclinicalstudies.Aneffectivequalityriskmanagementapproachcanfurtherensurethehighqualityofthedrug(medicinal)producttothepatientbyprovidingaproactivemeanstoidentifyandcontrolpotentialqualityissuesduringdevelopmentandmanufacturing.Additionally,useofqualityriskmanagementcanimprovethedecisionmakingifaqualityproblemarises.Effectivequalityriskmanagementcanfacilitatebetterandmoreinformeddecisions,canprovideregulatorswithgreaterassuranceofacompany'sabilitywithpotentialrisksandcanbeneficiallyaffecttheextentandlevelofdirectregulatoryoversight.Thepurposeofthisdocumentistoofferasystematicapproachtoqualityriskmanagement.Itservesasafoundationorresourcedocumentthatisindependentof,yetsupports,otherICHQualitydocumentsandcomplementsexistingqualitypractices,requirements,standards,andguidelineswithinthepharmaceuticalindustryandregulatoryenvironment.Itspecificallyprovidesguidanceontheprinciplesandsomeofthetoolsofqualityriskmanagementthatcanenablemore免地引入一定的风险。质量风险只是其中的一部分。在产品整个生命周期中，确保产品的质量，使得药品质量方面的重要性质与临床研究中的一致，做到这些是非常重要的。一个有效的质量风险管理方法能通过提供前摄措施，确定控制研发和生产中潜在的质量问题，来进一步确保药品质量。当质量问题出现时，应用质量风险管理还能改善决策过程。有效进行质量风险管理能促使产生更好更正式决策，增强监控者对公司处理潜在风险能力的信心，积极影响直接监理的程度和水平。todeal此文件的目的是提供质量风险管理方面的系统方法。作为一个基础性、资源性的文件，它独立于却又支持其它ICH质量文件，补充药企和监管机构内已有的质量措施、要求、标准和指南。特别是它提供了一些质量风险管理工具的原理指南，这些工具能促使监管者和企业考虑整个产品周期中药用物质和药品的质量，做出更有效、更连续的基于风险的决策，并不想在现有法规之外提出新的期望。effectiveandconsistentriskbaseddecisions,bothbyregulatorsandindustry,regardingthequalityofdrugsubstancesanddrug(medicinal)productsacrosstheproductlifecycle.Itisnotintendedtocreateanynewexpectationsbeyondthecurrentregulatoryrequirements.Itisneitheralwaysappropriatenoralwaysnecessaryto应用正式的风险管理程序并非总是合适的或必要的useaformalriskmanagementprocess(using（用已承认的工具或内部程序，如标准操作规程）。recognizedtoolsand/orinternalprocedurese.g.,有时也允许使用非正式的风险管理程序（用经验工具standardoperatingprocedures).Theuseofinformalrisk或内部程序）。恰当运用风险管理能方便但不消除企managementprocesses(usingempiricaltoolsand/or业遵守法规要求的责任，也不能取代企业和监管者之internalprocedures)canalsobeconsideredacceptable.间必要的沟通交流。Appropriateuseofqualityriskmanagementcanfacilitatebutdoesnotobviateindustry'sobligationtocomplywithregulatoryrequirementsanddoesnotreplaceappropriatecommunicationsbetweenindustryandregulators.2.SCOPE2.范围Thisguidelineprovidesprinciplesandexamplesof本指南给出了质量风险管理工具的原理和应用实例，toolsforqualityriskmanagementthatcanbeappliedto这些工具可用于药品质量各方面，即药用物质、药品differentaspectsofpharmaceuticalquality.These生物和生物技术产品（包括药品中用到的原料、溶剂aspectsincludedevelopment,manufacturing,赋形剂、包装标签材料等）生命周期中的研发、生产distribution,andtheinspectionandsubmission/review销售、检察、提交和复审各过程。processesthroughoutthelifecycleofdrugsubstances,drug(medicinal)products,biologicalandbiotechnologicalproducts(includingtheuseofrawmaterials,solvents,excipients,packagingandlabelingmaterialsindrug(medicinal)products,biologicalandbiotechnologicalproducts).PRINCIPLESOFQUALITYRISKMANAGEMENTTwoprimaryprinciplesofqualityriskmanagementare:Theevaluationoftherisktoqualityshouldbebasedonscientificknowledgeandultimatelylinktotheprotectionofthepatient;andThelevelofeffort,formalityanddocumentationofthequalityriskmanagementprocessshouldbecommensuratewiththelevelofrisk.质量风险管理原理质量风险管理的两条基本原理是：评估质量风险应基于科学知识并最终同对病人的保护联系起来。投入的努力程度、管理的正式程度及文件管理水平应与风险水平相适应。GENERALQUALITYRISKMANAGEMENTPROCESSQualityriskmanagementisasystematicprocessfortheassessment,control,communicationandreviewofriskstothequalityofthedrug(medicinal)productacrosstheproductlifecycle.Amodelforqualityriskmanagementisoutlinedinthediagram(Figure1).Othermodelscouldbeused.Theemphasisoneachcomponentoftheframeworkmightdifferfromcasetocasebutarobustprocesswillincorporateconsiderationofalltheelementsatalevelofdetailthatiscommensuratewiththespecificrisk.质量风险管理基本过程质量风险管理是对药品质量风险进行评估，控制，交流和审查的系统过程，这一过程贯穿药品整个生命周期。图1给出了这方面的一个模型，其他模型也有应用。具体情况不同，框架中各组分受重视水平会各有差别，可是一个有效的管理过程会将所有因素纳入考虑，各因素受关注程度会因风险的特异而各有区别。ContainsNonbindingRecommendationsContainsNonbindingRecommendationsprocessFigure1:Overviewof5爲z杳n“«!■HimTffftuRiskAssessmentiRiskIdsntifjcati-DnVRiskAnalysisJRiskEvaluationRiskControlrRiskReductioHiIRiskAcceptanceFigure1:典型质量风险管理过程简介ContainsNonbindingRecommendationsContainsNonbindingRecommendations风险管理工具风险交流Decisionnodesarenotshowninthediagramabovebecausedecisionscanoccuratanypointintheprocess.Thesedecisionsmightbetoreturntothepreviousstepandseekfurtherinformation,toadjusttheriskmodels由于决策行为随时都可能发生，上图就没有显示决策点。这些决策有可能被反馈到上一步以寻求更多信息，这些信息可用于调整风险模型；也可能用于管理过程的终止。注解：图中的“不可接受”项不仅指违oreventoterminatetheriskmanagementprocessbaseduponinformationthatsupportssuchadecision.Note:背了法令法规要求，也表示风险管理过程需要重头再来。“unacceptable"intheflowchartdoesnotonlyrefertostatutory,legislativeorregulatoryrequirements,butalsototheneedtorevisittheriskassessmentprocess.

4.1Responsibilities4.1.职责分配Qualityriskmanagementactivitiesareusually,butnotalways,undertakenbyinterdisciplinaryteams.Whenteamsareformed,theyshouldincludeexpertsfromtheappropriateareas(e.g.,qualityunit,businessdevelopment,engineering,regulatoryaffairs,productionoperations,salesandmarketing,legal,statisticsandclinical)inadditiontoindividualswhoareknowledgeableaboutthequalityriskmanagementprocess.Decisionmakershouldtakeresponsibilityforcoordinatingqualityriskmanagementacrossvariousfunctionsanddepartmentsoftheirorganization;andassurethataqualityriskmanagementprocessisdefined,deployedandreviewedandthatadequateresourcesareavailable.质量风险管理经常是但也不总是由交叉学科团队执行。除了要有风险管理方面的经验人士，团队还应包括相关领域的专家（例如：质量小组、事业发展、工程、管理，生产、行销、法律、统计和临床方面等。决策者必须负责组织协调各部门之间的关系，保障团队各项功能的有效发挥，确保整个管理过程得以合理展开、不断完善、反复审查，保障有足够的资源供团队使用。4.2InitiatingaQualityRiskManagementProcess4.2质量风险管理的启动Qualityriskmanagementshouldincludesystematicprocessesdesignedtocoordinate,facilitateandimprovescience-baseddecisionmakingwithrespecttorisk.Possiblestepsusedtoinitiateandplanaqualityriskmanagementprocessmightincludethefollowing:Definetheproblemand/orriskquestion,includingpertinentassumptionsidentifyingthepotentialforrisk;Assemblebackgroundinformationand/ordataonthepotentialhazard,harmorhumanhealthimpactrelevanttotheriskassessment;质量风险管理应包括这样一些系统程序，这些设计好的程序用来协调，推动和改善那些风险方面基于科学认识的决定。一项管理程序的发起和设计可能要经过如下步骤：•定义存在的难题和风险问题，包括识别潜在风险的相关假设；•收集风险评估相关的关于潜在危险、危害或人体健康影响的背景信息和数据；•确定领导人和重要资源；•详细说明决策的时间表，可交付性和适当的标准。

Identifyaleaderandnecessaryresources;Specifyatimeline,deliverablesandappropriatelevelofdecisionmakingfortheriskmanagementprocess.4.3RiskAssessment4.3风险评估Riskassessmentconsistsoftheidentificationofhazards风险评估：此过程进行危险确认并对接触这些危险所andtheanalysisandevaluationofrisksassociatedwith带来的风险进行分析评价。它以一个定义明确的难点exposuretothosehazards(asdefinedbelow).Quality描叙或风险问题开始，当风险明确后，选择合适而有riskassessmentsbeginwithawell-definedproblem针对性的管理工具和信息类型将会变得更容易。以下descriptionorriskquestion.Whentheriskinquestionis三个基本问题将有助于给出风险的清晰定义。welldefined,anappropriateriskmanagementtool(see1.什么可能会出错？examplesinsection5)andthetypesofinformation2.出错的可能性有多大？neededtoaddresstheriskquestionwillbemorereadily3.出错的后果和严重性有哪些？identifiable.Asanaidtoclearlydefiningtherisk(s)forriskassessmentpurposes,threefundamentalquestionsareoftenhelpful:Whatmightgowrong?Whatisthelikelihood(probability)itwillgowrong?Whataretheconsequences(severity)?Riskidentificationisasystematicuseofinformationto风险鉴定：参照风险问题或难点描叙，系统利用已有identifyhazardsreferringtotheriskquestionor信息去鉴定危险。这些信息包括历史数据、理论分析、problemdescription.Informationcanincludehistorical多方面观点和风险承担人的意见。风险鉴定时提出data,theoreticalanalysis,informedopinions,andthe“什么会出错”这一问题，同时还确定可能答案。这concernsofstakeholders.Riskidentificationaddresses一过程为后续步骤奠定了基础。the“Whatmightgowrong?"question,includingidentifyingthepossibleconsequences.Thisprovidesthebasisforfurtherstepsinthequalityriskmanagementprocess.Riskanalysisistheestimationoftheriskassociatedwiththeidentifiedhazards.Itisthequalitativeorquantitativeprocessoflinkingthelikelihoodofoccurrenceandseverityofharms.Insomeriskmanagementtools,theabilitytodetecttheharm(detectability)alsofactorsintheestimationofrisk.

风险分析：估计与已确认危险相联系的风险，这是对危害发生的可能性和严重程度进行定性和定量分析的过程。风险评价中同样也应用到某些管理工具检测危害的能力（检测能力）。Riskevaluationcomparestheidentifiedandanalyzedriskagainstgivenriskcriteria.Riskevaluationsconsiderthestrengthofevidenceforallthreeofthefundamentalquestions.Indoinganeffectiveriskassessment,therobustnessofthedatasetisimportantbecauseitdeterminesthequalityoftheoutput.RevealingassumptionsandreasonablesourcesofuncertaintywillenhanceTOC\o"1-5"\h\zconfidenceinthisoutputand/orhelpidentifyitslimitations.Uncertaintyisduetocombinationofincompleteknowledgeaboutaprocessanditsexpectedorunexpectedvariability.Typicalsourcesofuncertaintyincludegapsinknowledgegapsinpharmaceuticalscienceandprocessunderstanding,sourcesofharm(e.g.,failuremodesofaprocess,sourcesofvariability),andprobabilityofdetectionofproblems.Theoutputofariskassessmentiseitheraquantitativeestimateofriskoraqualitativedescriptionofarangeofrisk.Whenriskisexpressedquantitatively,anumerical

风险评估:将经过分析和鉴定的风险同给定标准作比较，考虑三个基本问题的证据力。风险评估中，数据的有效性决定了评估结果的质量。揭示、设想、分析不确定性的来源将有助于增强对结果的信心、识别结果的局限性。对过程了解不充分、过程中可预见及不可预见变动的发生，都将导致不确定性的发生。知识结构的不完整，有限的药学发展水平、不充分的过程理解、危险来源（不成功的过程模式、变动的来源）及问题被发现的可能性都是不确定性的典型来源。评估结果可以是对风险的定量表示，也可以是对分险程度的定性描述。定量表示时可用数值表示可能性，用高、中、低来给风险排序时，各个词的适用范围都要详细规定，有时候还用到风险评分来进一步定义。定量评估能对给定的风险衍生环境中特定结果发生的可能性做出判断。因此，定量评估一次只能评判一个特定结果。于是一些管理工具用到相对衡量尺度，将多重水平的严重性和可能性结合起来，以完成对相对风险的整体评估。评分过程的中间步骤有时也用到定量风险估计方法。probabilityisused.Alternatively,riskcanbeexpressedusingqualitativedescriptors,suchas“high",“medium",or“low",whichshouldbedefinedinasmuchdetailaspossible.Sometimesa"riskscore"isusedtofurtherdefinedescriptorsinriskranking.Inquantitativeriskassessments,ariskestimateprovidesthelikelihoodofaspecificconsequence,givenasetofrisk-generatingcircumstances.Thus,quantitativeriskestimationisusefulforoneparticularconsequenceatatime.Alternatively,someriskmanagementtoolsusearelativeriskmeasuretocombinemultiplelevelsofseverityandprobabilityintoanoverallestimateofrelativerisk.Theintermediatestepswithinascoringprocesscansometimesemployquantitativeriskestimation.4.4RiskControl4.4风险控制Riskcontrolincludesdecisionmakingtoreduceand/or风险控制包括风险抑低和风险接受两方面的决朿过acceptrisks.Thepurposeofriskcontrolistoreducethe程，进行控制的目的是将风险降低到可接受水平，risktoanacceptablelevel.Theamountofeffortusedforriskcontrolshouldbeproportionaltothesignificanceoftherisk.Decisionmakersmightuse投入努力量应与风险的严重程度相衬。决策者应用包括效益-耗费比分析在内的不同的程序去理解风险控制的最佳水平。differentprocesses,includingbenefit-costanalysis,for风险控制过程中以下问题会受到关注：understandingtheoptimallevelofriskcontrol.风险水平是否咼于可接受水平之上？Riskcontrolmightfocusonthefollowingquestions:怎样做才能降低乃至消除风险？•Istheriskaboveanacceptablelevel?如何寻求效益、风险和资源之间的合适平衡？Whatcanbedonetoreduceoreliminaterisks?Whatistheappropriatebalanceamongbenefits,risks对已确定风险进行控制时是否会引入新的风险？andresources?Arenewrisksintroducedasarestihetidentifiedrisksbeingcontrolled?Riskreductionfocusesonprocessesformitigationoravoidanceofqualityriskwhenitexceedsaspecified(acceptable)level(seeFig.1).Riskreductionmightincludeactionstakentomitigatetheseverityandprobabilityofharm.Processesthatimprovethedetectabilityofhazardsandqualityrisksmightalsobeusedaspartofariskcontrolstrategy.Theimplementationofriskreductionmeasurescanintroducenewrisksintothesystemorincreasethesignificanceofotherexistingrisks.Hence,itmightbeappropriatetorevisittheriskassessmenttoidentifyandevaluateanypossiblechangeinriskafterimplementingariskreductionprocess.

风险抑低：此过程着力于减轻或避免超过一定水平（可接受水平）的质量风险，包括为减轻危害严重性和发生可能性而采取的一系列措施，还包括一些致力于改善危险及质量风险可检测性的程序。风险抑低过程可能会给系统带入新的风险，其他业已存在的风险的严重程度也可能增加。因此，完成风险抑低程序后,有必要再重复一下质量评估过程，来识别和评价风险系统的可能变化。Riskacceptanceisadecisiontoacceptrisk.Riskacceptancecanbeaformaldecisiontoaccepttheresidualriskoritcanbeapassivedecisioninwhichresidualrisksarenotspecified.Forsometypesofharms,eventhebestqualityriskmanagementpracticesmightnotentirelyeliminaterisk.Inthesecircumstances,itmightbeagreedthatanappropriatequalityriskmanagementstrategyhasbeenappliedandthatqualityriskisreducedtoaspecified(acceptable)level.This(specified)acceptablelevelwilldependon

风险接受：就是接受风险的决定。它可能为接受残留风险的正式决定，也可以是忽略剩余风险的消极决定。有些类型的风险，即使用最好的质量风险管理手段，也不能完全清除。在这种情形下，应确认使用了合适的风险管理策略，且风险已被降至特定水平（可接受水平）。这个可接受水平由很多参数和各例具体情况来确定。manyparametersandshouldbedecidedonacase-by-casebasis.4.5RiskCommunication4.5风险沟通Riskcommunicationisthesharingofinformation风险沟通：决朿者和其他人就风险和风险管理方面的aboutriskandriskmanagementbetweenthedecision信息进行沟通、交流，各利益集团间的交流在风险管makersandothers.Partiescancommunicateatanystageoftheriskmanagementprocess(seeFig.1:dashedarrows).Theoutput/resultofthequalityriskmanagementprocessshouldbeappropriatelycommunicatedanddocumented(seeFig.1:solidarrows).Communicationsmightincludethoseamonginterestedparties;e.g.,regulatorsandindustry,industryandthepatient,withinacompany,industryorregulatoryauthority,etc.Theincludedinformationmightrelatetotheexistence,nature,form,probability,severity,acceptability,control,treatment,detectabilityorotheraspectsofriskstoquality.Communicationneednotbecarriedoutforeachandeveryriskacceptance.Betweentheindustryandregulatoryauthorities,communicationconcerningqualityriskmanagementdecisionsmightbeeffectedthroughexistingchannelsasspecifiedinregulationsandguidances.理的任意阶段都可以进行（见图1虚线部分）。质量风险管理过程的产出和结果应得到合理沟通并存档。（见图1实线部分）各利益团体间（如监管者同企业之间，企业和患者之间，公司、企业、监管机构内部），就质量风险的存在、性质、形式、可能性、严重程度、可接受度、控制、处理、可检测度及其他方面的信息进行交流。不需要就每个风险承担都进行风险交流。企业和监管机构之间关于质量风险管理方面的沟通交流可以通过规则、指导中给定的渠道来实现。4.6RiskReview4.6风险回顾Riskmanagementshouldbeanongoingpartofthequalitymanagementprocess.Amechanismtoreviewormonitoreventsshouldbeimplemented.风险管理伴随着质量管理过程的全程,应当引入审查和监控机制。在审查风险管理过程的结果时要将新的知识和经验纳入考虑范围。一旦一个质量风险管理过Theoutput/resultsoftheriskmanagementprocessshouldbereviewedtotakeintoaccountnewknowledgeandexperience.Onceaqualityriskmanagementprocesshasbeeninitiated,thatprocessshouldcontinuetobeutilizedforeventsthatmightimpacttheoriginalqualityriskmanagementdecision,whethertheseeventsareplanned(e.g.,resultsofproductreview,inspections,audits,changecontrol)orunplanned(e.g.,rootcausefromfailureinvestigations,recall).Thefrequencyofanyreviewshouldbebaseduponthelevelofrisk.Riskreviewmightincludereconsiderationofriskacceptancedecisions(section4.4).RISKMANAGEMENTMETHODOLOGYQualityriskmanagementsupportsascientificandpracticalapproachtodecision-making.Itprovidesdocumented,transparentandreproduciblemethodstoaccomplishstepsofthequalityriskmanagementprocessbasedoncurrentknowledgeaboutassessingtheprobability,severityandsometimesdetectabilityoftherisk.Traditionally,riskstoqualityhavebeenassessedandmanagedinavarietyofinformalways(empiricaland/orinternalprocedures)basedon,forexample,compilationofobservations,trendsandotherinformation.Suchapproachescontinuetoprovideusefulinformationthatmightsupporttopicssuchashandlingofcomplaints,qualitydefects,deviationsandallocationofresources.程开始启动，它便用于管理那些可能会影响最初质量风险管理决策的事件，不管这些事件是计划中的（产品回顾结果，自检、审计和变更控制管理）还是计划外的（如失败调查的根由，召回）。任何回顾的进行频率都应基于风险水平，风险回顾还可能包括对风险接受决定的再审议。质量管理方法学质量风险管理中的决策过程用到了一种科学而实用的方法，它根据现有的关于估计风险可能性、严重程度和可检测性方面的知识，提供一些已形成文件的、透明的和可再生的方法，来完成质量风险管理各步骤。质量风险传统上是用一系列非正规方法来进行评估和控制的，这些方法基于观测报告，风险趋势以及一些其它信息，在处理投诉，质量缺陷，偏差和资源配置方面仍能提供有用的资料。同样，药品厂家和管理者也可用已承认的工具和内部程序来进行评估和控制，以下就是这样一些工具（Annex1andsectionVIII中更有详叙）：基本风险管理简易方法（流程图，对账单等）失败模式影响分析失败模式，影响，和重要性分析（FMECA）错误树形分析（FTA）Additionally,thepharmaceuticalindustryandregulatorscanassessandmanageriskusingrecognizedriskmanagementtoolsand/orinternalprocedures(e.g.,standardoperatingprocedures).Belowisanon-exhaustivelistofsomeofthesetools(furtherdetailsinAnnex1andchapter8):•Basicriskmanagementfacilitationmethods(flowcharts,checksheetsetc.);FailureModeEffectsAnalysis(FMEA);FailureMode,EffectsandCriticalityAnalysis(FMECA);FaultTreeAnalysis(FTA);HazardAnalysisandCriticalControlPoints(HACCP);HazardOperabilityAnalysis(HAZOP);PreliminaryHazardAnalysis(PHA);Riskrankingandfiltering;Supportingstatisticaltools.Itmightbeappropriatetoadaptthesetoolsforuseinspecificareaspertainingtodrugsubstanceanddrug(medicinal)productquality.Qualityriskmanagementmethodsandthesupportingstatisticaltoolscanbeusedincombination(e.g.,ProbabilisticRiskAssessment).Combineduseprovidesflexibilitythatcanfacilitatetheapplicationofqualityriskmanagementprinciples.Thedegreeofrigorandformalityofqualityriskmanagementshouldreflectavailableknowledgeandbecommensuratewiththecomplexityand/orcriticalityoftheissuetobeaddressed.危害分析和关键监控点(HACCP)危害可操作性分析(HAZ0P)危害预分析(PHA)风险排序及滤除辅助统计工具将以上方法加以适当改进，就可用于药物、药品质量相关的一些特殊领域。方法同辅助统计工具结合，带来的灵活性能为质量风险管理原则的应用提供便利。质量风险管理的正式程度及精确程度应该反映可用到的知识，并与要反映问题的复杂性、重要程度相适应。INTEGRATIONOFQUALITYRISKMANAGEMENTINTOINDUSTRYANDREGULATORYOPERATIONS行业与监管同质量风险管理的综合Qualityriskmanagementisaprocessthatsupportsscience-basedandpracticaldecisionswhenintegratedintoqualitysystems(seeAnnexII).Asoutlinedintheintroduction,appropriateuseofqualityriskmanagementdoesnotobviateindustry'sobligationtocomplywithregulatoryrequirements.However,effectivequalityriskmanagementcanfacilitatebetterandmoreinformeddecisions,canprovideregulatorswithgreaterassuranceofacompany'sabilitytodealwithpotentialrisks,andmightaffecttheextentandlevelofdirectregulatoryoversight.Inaddition,qualityriskmanagementcanfacilitatebetteruseofresourcesbyallparties.Trainingofbothindustryandregulatorypersonnelinqualityriskmanagementprocessesprovidesforgreaterunderstandingofdecision-makingprocessesandbuildsconfidenceinqualityriskmanagementoutcomes.Qualityriskmanagementshouldbeintegratedintoexistingoperationsanddocumentedappropriately.AnnexIIprovidesexamplesofsituationsinwhichtheuseofthequalityriskmanagementprocessmightprovideinformationthatcouldthenbeusedinavarietyofpharmaceuticaloperations.Theseexamplesareprovidedforillustrativepurposesonlyand质量风险管理与质量体系结合后，它能支持基于科学研究和实际情况的决策。(seeAnnexII).正如引言中所述，恰当地运用质量风险管理虽不能免除企业遵守法规要求的义务，却能推动更好、更合情合理决策的产生，还能增强监管当局对企业处理潜在风险能力的信心，影响直接监管造成的疏忽的程度和水平，促进各方对资源的优化利用。对企业职工和监管人员进行质量风险管理方面的培训，能使他们更好的理解决策行为，树立对管理结果的信心。应该将质量风险管理同已有的工作结合起来,并建立妥善的文档保管。附件2列举了应用此方法为药品各种生产步骤提供信息的几种情形。列出这些例子只是用于说明的目的，并不能视作是详尽而确定的，也不在现有法规的要求之外提出新的期望。・企业运营和活动中的质量管理实例(seeAnnexII):shouldnotbeconsideredadefinitiveorexhaustivelist.Theseexamplesarenotintendedtocreateanynewexpectationsbeyondtherequirementslaidoutinthecurrentregulations.Examplesforindustryandregulatoryoperations(seeAnnexII):Qualitymanagement.Examplesforindustryoperationsandactivities(seeAnnexII):Development;Facility,equipmentandutilities;Materialsmanagement;Production;Laboratorycontrolandstabilitytesting;Packagingandlabeling.Examplesforregulatoryoperations(seeAnnexII):Inspectionandassessmentactivities.・研发・工具，设备和设施・物料管理・生产・实验室控制和稳定性检测・包装和标签・监管实例(seeAnnexII):・检查和评估活动Whileregulatorydecisionswillcontinuetobetakenonaregionalbasis,acommonunderstandingandapplicationofqualityriskmanagementprinciplescouldfacilitatemutualconfidenceandpromotemoreconsistentdecisionsamongregulatorsonthebasisofthesameinformation.Thiscollaborationcouldbeimportantinthedevelopmentofpoliciesandguidelinesthatintegrateandsupportqualityriskmanagementpractices.尽管监管决策依旧是被区域性的采纳,但对质量风险管理原则的普遍理解和应用能增进监管者同企业之间的相互信任，促使监管者基于同样的信息做出更易于让企业接受的决策。这种合作在发展整合支持质量风险管理的政策、指导原则方面非常重要。DEFINITIONSDecisionMaker(s):Person(s)withthecompetenceandauthoritytomakeappropriateandtimelyqualityriskmanagementdecisions.

定义决策者：有能力和权力在质量风险管理中做出适当及及时决策的人员Detectability:Theabilitytodiscoverordeterminetheexistence,presence,orfactofahazard.

探测能力：发现并确定危害存在事实的能力Harm:Damagetohealth,includingthedamagethatcanoccurfromlossofproductqualityoravailability.

损伤:产品质量及有效性降低引起对健康的损害Hazard:Thepotentialsourceofharm(ISO/IECGuide51).

危险：危害的可能来源(ISO/IECGuide51).ProductLifecycle:Allphasesinthelifeoftheproductfromtheinitialdevelopmentthroughmarketinguntiltheproduct'sdiscontinuation.Quality:Thedegreetowhichasetofinherentpropertiesofaproduct,systemorprocessfulfillsrequirements(seeICHQ6Adefinitionspecificallyfor"quality"ofdrugsubstanceanddrug(medicinal)products.)

产品生命周期：产品从最初的开发到销售，直至最终停产的各个阶段质量：产品、系统和过程的一整套内在性质与已有规定、要求的符合程度。(seeICHQ6Adefinitionspecificallyforqualityofdrugsubstanceanddrugproducts).QualityRiskManagement:

质量风险管理：在产品生命周期中，系统地对产品质Asystematicprocessfortheassessment,control,communicationandreviewofriskstothequalityofthedrug(medicinal)productacrosstheproductlifecycle.量相关的风险进彳丁评估、控制、父流及审查。QualitySystem:Thesumofallaspectsofasystemthatimplementsqualitypolicyandensuresthatqualityobjectivesaremet.质量体系：一个能贯彻质量方针并确保质量目标的达到的体系各方面的总和Requirements:Theexplicitorimplicitneedsorexpectationsofthepatientsortheirsurrogates(e.g.,healthcareprofessionals,regulatorsandlegislators).Inthisdocument,“requirements"refersnotonlytostatutory,legislative,orregulatoryrequirements,butalsotosuchneedsandexpectations.要求：病人及他们的代理人(卫生从业人员，管理者，立法者)的明晰或隐性要求、期望。此文件中，要求不仅是法定和规定的要求，还包括这些需要和期望Risk:Thecombinationoftheprobabilityofoccurrenceofharmandtheseverityofthatharm(ISO/IECGuide51).风险:损害发生的可能性及其可能严重程度(IS0/IECGuide51).RiskAcceptance:Thedecisiontoacceptrisk(ISOGuide73).风险承担：决定承担风险(ISOGuide73).RiskAnalysis:Theestimationoftheriskassociatedwiththeidentifiedhazards.风险分析：对与已确定危险相联系的风险进行评估RiskAssessment:Asystematicprocessoforganizinginformationto风险评估：系统地组织信息以支持风险管理过程中做出的决策。这一过程包括对危害的辨别，及分析、

supportariskdecisiontobemadewithinariskmanagementprocess.Itconsistsoftheidentificationofhazardsandtheanalysisandevaluationofrisksassociatedwithexposuretothosehazards.评估接触这些危害所带来的风险。RiskCommunication:Thesharingofinformationaboutriskandriskmanagementbetweenthedecisionmakerandotherstakeholders.风险沟通：决策者冋其他风险承担人就风险和风险管理方面的信息进行父流。RiskControl:Actionsimplementingriskmanagementdecisions(ISOGuide73).风险控制：贯彻执行风险管理决策(ISOGuide73).RiskEvaluation:Thecomparisonoftheestimatedrisktogivenriskcriteriausingaquantitativeorqualitativescaletodeterminethesignificanceoftherisk.风险评价：用定量或是定性方法，将预计风险冋已有风险标准进行比较，以判定风险的大小程度。RiskIdentification:Thesystematicuseofinformationtoidentifypotentialsourcesofharm(hazards)referringtotheriskquestionorproblemdescription.风险鉴定：参考风险问题及问题描述,系统地运用其提供的信息来判定危害(危险)来源。RiskManagement:Thesystematicapplicationofqualitymanagementpolicies,procedures,andpracticestothetasksofassessing,controlling,communicatingandreviewingrisk.风险管理：系统地运用质量管理方针，程序，实践，来进行风险评估，控制，交流及审查。

RiskReduction:Actionstakentolessentheprobabilityofoccurrenceofharmandtheseverityofthatharm.风险抑减：米取措施来减少风险带来的危害及降低危害的严重性。RiskReview:Reviewormonitoringofoutput/resultsoftheriskmanagementprocessconsidering(ifappropriate)newknowledgeandexperienceabouttherisk.风险审核：借鉴风险方面的新知识和经验，对风险管理结果进行审核和跟踪监测Severity:Ameasureofthepossibleconsequencesofahazard.严重性：度量危害后果可能程度的尺度Stakeholder:Anyindividual,groupororganizationthatcanaffect,beaffectedby,orperceiveitselftobeaffectedbyarisk.Decisionmakersmightalsobestakeholders.Forthepurposesofthisguideline,theprimarystakeholdersarethepatient,healthcareprofessional,regulatoryauthority,andindustry.风险承担者：风险波及或能感受到奉献影响的个人，集体，或组织。决策者可被称为风险承担者。再此指南中，风险承担者主要是指病人，卫生事业从业人员，管理机构和工业。Trend:Astatisticaltermreferringtothedirectionorrateofchangeofavariable(s).趋势：一个关于各种变化的方向和频率的统计学术语。8.REFERENCESICHQ8PharmaceuticalDevelopment.ISO/IECGuide73:2002-RiskManagement-Vocabulary-GuidelinesforuseinStandards.ISO/IECGuide51:1999-SafetyAspects-Guidelinefortheirinclusioninstandards.

ProcessMappingbytheAmericanProductivity&QualityCenter,2002,ISBN1928593739.IEC61025-FaultTreeAnalysis(FTA).IEC60812AnalysisTechniquesforsystemreliability—Proceduresforfailuremodeandeffectsanalysis(FMEA).FailureModeandEffectAnalysis,FMEAfromTheorytoExecution,2ndEdition2003,D.H.Stamatis,ISBN0873895983.GuidelinesforFailureModesandEffectsAnalysis(FMEA)forMedicalDevices,2003DyademPress,ISBN0849319102.TheBasicsofFMEA,RobinMcDermott,RaymondJ.Mikulak,MichaelR.Beauregard1996,ISBN0527763209.WHOTechnicalReportSeriesNo908,2003,Annex7ApplicationofHazardAnalysisandCriticalControlPoint(HACCP)methodologytopharmaceuticals.IEC61882-HazardOperabilityAnalysis(HAZOP).ISO14971:2000-ApplicationofRiskManagementtoMedicalDevices.ISO7870:1993-ControlCharts.ISO7871:1997-CumulativeSumCharts.ISO7966:1993-AcceptanceControlCharts.ISO8258:1991-ShewhartControlCharts.WhatisTotalQualityControl?;TheJapaneseWay,KaoruIshikawa(TranslatedbyDavidJ.Liu),1985,ISBN0139524339.AnnexI:RiskManagemen