ICH-Q9質(zhì)量風(fēng)險管理

______________________________________________________________________________________________________________精品資料INTERNATIONALCONFERENCEONHARMONISATIONOFTECHNICALREQUIREMENTSFORREGISTRATIONOFPHARMACEUTICALSFORHUMANUSE人用藥注冊技術(shù)要求國際協(xié)調(diào)會議ICHHarmonisedTripartiteGuideline人用藥注冊技術(shù)要求國際協(xié)調(diào)會議三方協(xié)調(diào)后的指南QualityRiskManagement質(zhì)量風(fēng)險管理CurrentStep4version現(xiàn)行第四步版本dated9November20052005年十一月9日ThisGuidelinehasbeendevelopedbytheappropriateICHExpertWorkingGroupandhasbeensubjecttoconsultationbytheregulatoryparties,inaccordancewiththeICHProcess.AtStep4oftheProcessthefinaldraftisrecommendedforadoptiontotheregulatorybodiesoftheEuropeanUnion,JapanandUSA.本指南由人用藥注冊技術(shù)要求國際協(xié)調(diào)會議專家工作組根據(jù)人用藥注冊技術(shù)要求國際協(xié)調(diào)會議程序開發(fā)并提交各方的藥政部門咨詢。根據(jù)人用藥注冊技術(shù)要求國際協(xié)調(diào)會議程序第四步，推薦給歐盟、日本和美國藥的政部門采用的最終文本。DocumentHistory文件歷史Codification最初編碼History歷史ApprovalbytheSteeringCommitteeunderStep2andreleaseforpublicconsultation.指導(dǎo)委員會批準(zhǔn)第二步文件并發(fā)放用于公開咨詢Date日期Q922March20052005/3/22ApprovalbytheSteeringCommitteeofPostStep2correction指導(dǎo)委員會在批準(zhǔn)第二步后的訂正文件15June20052005/6/15CurrentStep4version現(xiàn)行第四步版本ApprovalbytheSteeringCommitteeunderStep4andrecommendationforadoptiontothethreeICHregulatorybodies.指導(dǎo)委員會批準(zhǔn)第四步文件并推薦ICH三方藥政部門批準(zhǔn)9November20052005/11/9HavingreachedStep4oftheICHProcessattheICHSteeringCommitteemeetingon9November2005,thisguidelineisrecommendedforadoptiontothethreeregulatorypartiestoICH在2005年11月9日的人用藥注冊技術(shù)要求國際協(xié)調(diào)會議上，本指南已經(jīng)通過人用藥注冊技術(shù)要求國際協(xié)調(diào)會議第四步程序，本指南已經(jīng)推薦給人用藥注冊技術(shù)要求國際協(xié)調(diào)會議三方的藥政部門采用。

TABLEOFCONTENTS目錄1.INTRODUCTION簡介................................................................................12.SCOPE范圍............................................................................23.PRINCIPLESOFQUALITYRISKMANAGEMENT質(zhì)量風(fēng)險管理的原則............24.GENERALQUALITYRISKMANAGEMENTPROCESS常規(guī)質(zhì)量風(fēng)險管理程序.....24.1Responsibilities職責(zé).....................................................................................44.2InitiatingaQualityRiskManagementProcess啟動質(zhì)量風(fēng)險管理過程.......44.3RiskAssessment風(fēng)險評估...................................................................44.4RiskControl風(fēng)險控制....................................................................54.5RiskCommunication風(fēng)險溝通.....................................................................64.6RiskReview風(fēng)險評審..................................................................65.RISKMANAGEMENTMETHODOLOGY風(fēng)險管理方法學(xué)...................................76.INTEGRATIONOFQUALITYRISKMANAGEMENTINTOINDUSTRYANDREGULATORYOPERATIONS質(zhì)量風(fēng)險管理與業(yè)界及藥政運(yùn)行整合..................................................87.DEFINITIONS定義.........................................................................98.REFERENCES參考文獻(xiàn).................................................................11Annex附錄I:RiskManagementMethodsandTools風(fēng)險管理方法與工具...12I.1BasicRiskManagementFacilitationMethods基本風(fēng)險管理簡易方法.......12I.2FailureModeEffectsAnalysis故障模式效應(yīng)分析(FMEA)..........................12I.3FailureMode,EffectsandCriticalityAnalysis故障模式影響與嚴(yán)重性分析(FMECA)....................................................13I.4FaultTreeAnalysis故障樹分析(FTA)........................................13I.5HazardAnalysisandCriticalControlPoints危害分析關(guān)鍵控制點(diǎn)(HACCP)....................................................................14I.6HazardOperabilityAnalysis危害及可操作性分析(HAZOP)..................14I.7PreliminaryHazardAnalysis預(yù)先危險分析(PHA)...................................15I.8RiskRankingandFiltering風(fēng)險排序及過濾........................15I.9SupportingStatisticalTools輔助性統(tǒng)計(jì)工具............................................16Annex附錄II:PotentialApplicationsforQualityRiskManagement實(shí)施質(zhì)量風(fēng)險管理的潛在機(jī)會.......................................16II.1QualityRiskManagementasPartofIntegratedQualityManagement整合質(zhì)量管理部分的質(zhì)量風(fēng)險管理....................16II.2QualityRiskManagementasPartofRegulatoryOperations藥政操作部分的質(zhì)量風(fēng)險管理...........................................18II.3QualityRiskManagementasPartofdevelopment開發(fā)部分的質(zhì)量風(fēng)險管理..................................................................19II.4QualityRiskManagementforFacilities,EquipmentandUtilities廠房，設(shè)備和公用設(shè)施的質(zhì)量風(fēng)險管理..................19II.5QualityRiskManagementasPartofMaterialsManagement物料管理部分的質(zhì)量風(fēng)險管理..........................................21II.6QualityRiskManagementasPartofProduction生產(chǎn)部分的質(zhì)量風(fēng)險管理......................................................................21II.7QualityRiskManagementasPartofLaboratoryControlandStabilityStudies實(shí)驗(yàn)室控制和穩(wěn)定性研究部分的質(zhì)量QualityRiskManagement質(zhì)量風(fēng)險管理風(fēng)險管理....................................22II.8QualityRiskManagementasPartofPackagingandLabelling包裝和標(biāo)簽部分的質(zhì)量風(fēng)險管理...................................22

1.INTRODUCTION導(dǎo)言Riskmanagementprinciplesareeffectivelyutilizedinmanyareasofbusinessandgovernmentincludingfinance,insurance,occupationalsafety,publichealth,pharmacovigilance,andbyagenciesregulatingtheseindustries.Althoughtherearesomeexamplesoftheuseofqualityriskmanagementinthepharmaceuticalindustrytoday,theyarelimitedanddonotrepresentthefullcontributionsthatriskmanagementhastooffer.Inaddition,theimportanceofqualitysystemshasbeenrecognizedinthepharmaceuticalindustryanditisbecomingevidentthatqualityriskmanagementisavaluablecomponentofaneffectivequalitysystem.風(fēng)險管理原則被有效地應(yīng)用于許多商業(yè)和政府的領(lǐng)域，包括金融、保險、職業(yè)安全、公共健康、藥物預(yù)警，以及這些行業(yè)的主管部門。如今，盡管在制藥行業(yè)也有一些運(yùn)用質(zhì)量風(fēng)險管理的例子，但其非常有限，且沒有體現(xiàn)出風(fēng)險管理能提供的全部貢獻(xiàn)。另外，制藥行業(yè)已經(jīng)認(rèn)識到質(zhì)量體系的重要性，而且，質(zhì)量風(fēng)險管理對一個有效的質(zhì)量體系來說，是一個有價值的組成部分這一點(diǎn)越來越明顯。Itiscommonlyunderstoodthatriskisdefinedasthecombinationoftheprobabilityofoccurrenceofharmandtheseverityofthatharm.However,achievingasharedunderstandingoftheapplicationofriskmanagementamongdiversestakeholdersisdifficultbecauseeachstakeholdermightperceivedifferentpotentialharms,placeadifferentprobabilityoneachharmoccurringandattributedifferentseveritiestoeachharm.Inrelationtopharmaceuticals,althoughthereareavarietyofstakeholders,includingpatientsandmedicalpractitionersaswellasgovernmentandindustry,theprotectionofthepatientbymanagingtherisktoqualityshouldbeconsideredofprimeimportance.通常將風(fēng)險理解為，風(fēng)險是由傷害發(fā)生的概率及傷害嚴(yán)重性結(jié)合而成。然而，在不同的風(fēng)險涉眾中達(dá)成對風(fēng)險管理應(yīng)用共識仍是困難的，因?yàn)槊總€風(fēng)險涉眾可能感覺到不同的潛在傷害，對每個所發(fā)生的傷害設(shè)置不同的概率以及傷害不同的嚴(yán)重性屬性。對于藥品來說，盡管有多種的風(fēng)險涉眾，包括患者、醫(yī)療從業(yè)人員，以及政府和業(yè)界，運(yùn)用質(zhì)量風(fēng)險管理都應(yīng)該以保護(hù)病人為基本出發(fā)點(diǎn)。Themanufacturinganduseofadrug(medicinal)product,includingitscomponents,necessarilyentailsomedegreeofrisk.Therisktoitsqualityisjustonecomponentoftheoverallrisk.Itisimportanttounderstandthatproductqualityshouldbemaintainedthroughouttheproductlifecyclesuchthattheattributesthatareimportanttothequalityofthedrug(medicinal)productremainconsistentwiththoseusedintheclinicalstudies.Aneffectivequalityriskmanagementapproachcanfurtherensurethehighqualityofthedrug(medicinal)producttothepatientbyprovidingaproactivemeanstoidentifyandcontrolpotentialqualityissuesduringdevelopmentandmanufacturing.Additionally,useofqualityriskmanagementcanimprovethedecisionmakingifaqualityproblemarises.Effectivequalityriskmanagementcanfacilitatebetterandmoreinformeddecisions,canprovideregulatorswithgreaterassuranceofacompany’sabilitytodealwithpotentialrisksandcanbeneficiallyaffecttheextentandlevelofdirectregulatoryoversight.藥物(醫(yī)療)產(chǎn)品制造和使用，包括它的組份，必然要承擔(dān)一定程度的風(fēng)險。其質(zhì)量風(fēng)險僅是全部風(fēng)險中的一個。重要的是要了解到，產(chǎn)品質(zhì)量應(yīng)當(dāng)貫穿產(chǎn)品的生命周期，這個屬性對于藥物(醫(yī)療)產(chǎn)品保持與臨床研究時一致是非常重要的。通過前瞻意義上辨識與控制在研發(fā)與制造中的潛在質(zhì)量問題，一個有效的質(zhì)量風(fēng)險管理方法能進(jìn)一步給患者提供高質(zhì)量藥物(醫(yī)療)產(chǎn)品質(zhì)量的保證。另外，如果出現(xiàn)質(zhì)量問題，則采用質(zhì)量風(fēng)險管理可以改善決策。有效的質(zhì)量風(fēng)險管理可以促使做出更好，更基于可靠信息的決策，可以為業(yè)界藥政部門提供更強(qiáng)大應(yīng)對潛在風(fēng)險的能力的保證，并且會對藥政監(jiān)督的水平和范圍直接產(chǎn)生有利影響。Thepurposeofthisdocumentistoofferasystematicapproachtoqualityriskmanagement.Itservesasafoundationorresourcedocumentthatisindependentof,yetsupports,otherICHQualitydocumentsandcomplementsexistingqualitypractices,requirements,standards,andguidelineswithinthepharmaceuticalindustryandregulatoryenvironment.Itspecificallyprovidesguidanceontheprinciplesandsomeofthetoolsofqualityriskmanagementthatcanenablemoreeffectiveandconsistentriskbaseddecisions,bothbyregulatorsandindustry,regardingthequalityofdrugsubstancesanddrug(medicinal)productsacrosstheproductlifecycle.Itisnotintendedtocreateanynewexpectationsbeyondthecurrentregulatoryrequirements.本文件的目的是提供一個質(zhì)量風(fēng)險管理的綜合方法。其作為一個基礎(chǔ)的或資源性的文件，其獨(dú)立并支撐其它的ICH質(zhì)量文件，并對現(xiàn)有的質(zhì)量實(shí)踐、要求、標(biāo)準(zhǔn)以及制藥行業(yè)指南與藥政環(huán)境進(jìn)行補(bǔ)充。其將明確提供質(zhì)量風(fēng)險管理的原理，以及一些工具，其可以確保在藥政部門和業(yè)界在考慮到貫穿在整個產(chǎn)品生命周期的原料藥和藥物(醫(yī)療)產(chǎn)品質(zhì)量時，做出更有效與更一致的基于風(fēng)險的決策。其并未試圖建立任何超越當(dāng)前管理要求的新的要求。Itisneitheralwaysappropriatenoralwaysnecessarytouseaformalriskmanagementprocess(usingrecognizedtoolsand/orinternalprocedurese.g.,standardoperatingprocedures).Theuseofinformalriskmanagementprocesses(usingempiricaltoolsand/orinternalprocedures)canalsobeconsideredacceptable.Appropriateuseofqualityriskmanagementcanfacilitatebutdoesnotobviateindustry’sobligationtocomplywithregulatoryrequirementsanddoesnotreplaceappropriatecommunicationsbetweenindustryandregulators.使用一個正式的風(fēng)險管理過程(使用公認(rèn)的工具，和/或內(nèi)部程序，例如標(biāo)準(zhǔn)操作程序)既不總是恰當(dāng)?shù)?，也不總是必須的。采用非正式的風(fēng)險管理過程(使用經(jīng)驗(yàn)的工具，和/或內(nèi)部程序)也是可以考慮接受。恰當(dāng)運(yùn)用質(zhì)量風(fēng)險管理可以促進(jìn)，但并不能免除業(yè)界遵守藥政要求的責(zé)任，也不能取代業(yè)界和藥政部門之間適當(dāng)?shù)臏贤ā?.SCOPE范圍Thisguidelineprovidesprinciplesandexamplesoftoolsforqualityriskmanagementthatcanbeappliedtodifferentaspectsofpharmaceuticalquality.Theseaspectsincludedevelopment,manufacturing,distribution,andtheinspectionandsubmission/reviewprocessesthroughoutthelifecycleofdrugsubstances,drug(medicinal)products,biologicalandbiotechnologicalproducts(includingtheuseofrawmaterials,solvents,excipients,packagingandlabelingmaterialsindrug(medicinal)products,biologicalandbiotechnologicalproducts).本指南給出了質(zhì)量風(fēng)險管理的原理以及一些工具的例子，其可以應(yīng)用于藥品質(zhì)量的不同方面。這些方面包括開發(fā)、制造、分銷以及原料藥、藥物(醫(yī)療)產(chǎn)品、生物和生物技術(shù)產(chǎn)品(包括在藥物(醫(yī)療)產(chǎn)品、生物和生物技術(shù)產(chǎn)品中使用到的原料、溶劑、賦形劑、包裝和標(biāo)簽材料)整個生命周期的檢查和注冊/評審過程。3.PRINCIPLESOFQUALITYRISKMANAGEMENT質(zhì)量風(fēng)險管理的原則Twoprimaryprinciplesofqualityriskmanagementare:質(zhì)量風(fēng)險管理的兩個基本原則為：?Theevaluationoftherisktoqualityshouldbebasedonscientificknowledgeandultimatelylinktotheprotectionofthepatient;and應(yīng)該基于科學(xué)知識和最終與對患者的保護(hù)相關(guān)聯(lián)對質(zhì)量風(fēng)險進(jìn)行評價；以及?Thelevelofeffort,formalityanddocumentationofthequalityriskmanagementprocessshouldbecommensuratewiththelevelofrisk.質(zhì)量風(fēng)險管理過程的力度、正式程度和文件化程度都應(yīng)該與風(fēng)險水平相適應(yīng)。4.GENERALQUALITYRISKMANAGEMENTPROCESS常規(guī)質(zhì)量風(fēng)險管理程序Qualityriskmanagementisasystematicprocessfortheassessment,control,communicationandreviewofriskstothequalityofthedrug(medicinal)productacrosstheproductlifecycle.Amodelforqualityriskmanagementisoutlinedinthediagram(Figure1).Othermodelscouldbeused.Theemphasisoneachcomponentoftheframeworkmightdifferfromcasetocasebutarobustprocesswillincorporateconsiderationofalltheelementsatalevelofdetailthatiscommensuratewiththespecificrisk.質(zhì)量風(fēng)險管理指的是對貫穿于藥物(醫(yī)療)產(chǎn)品生產(chǎn)周期中的風(fēng)險進(jìn)行評估、控制、溝通及評審的系統(tǒng)過程。圖中概括了質(zhì)量風(fēng)險管理模式(圖1)。也可以使用其他模式。所強(qiáng)調(diào)的構(gòu)架中每個組成，可依不同情況而有所不同的，但一個完善的過程會更加詳細(xì)地整合考慮到所有因素，其與具體的風(fēng)險有相同的水平。Figure1:Overviewofatypicalqualityriskmanagementprocess圖1：典型的質(zhì)量風(fēng)險管理過程概述unacceptableunacceptable不接受RiskReview風(fēng)險評審RiskControl風(fēng)險控制InitiateQualityRiskManagementProcess啟動風(fēng)險管理過程風(fēng)險控制RiskReduction風(fēng)險降低RiskAcceptance接受風(fēng)險Output/ResultoftheQualityRiskManagementProcess質(zhì)量風(fēng)險管理程序的輸出/結(jié)果風(fēng)險控制ReviewEvents事件評審RiskCommunication風(fēng)險溝通RiskManagementtools風(fēng)險管理工具RiskAssessment風(fēng)險評估RiskIdentification風(fēng)險辯識AnalysisRisk風(fēng)險分析RiskEvaluationun風(fēng)險評價Decisionnodesarenotshowninthediagramabovebecausedecisionscanoccuratanypointintheprocess.Thesedecisionsmightbetoreturntothepreviousstepandseekfurtherinformation,toadjusttheriskmodelsoreventoterminatetheriskmanagementprocessbaseduponinformationthatsupportssuchadecision.Note:“unacceptable”intheflowchartdoesnotonlyrefertostatutory,legislativeorregulatoryrequirements,butalsototheneedtorevisittheriskassessmentprocess.在上圖中并未標(biāo)明判斷結(jié)點(diǎn)，因?yàn)榕袛嗫沙霈F(xiàn)在這個過程中的任何一個點(diǎn)。這些判斷將會退回到前一步，并尋求進(jìn)一步的信息以調(diào)整風(fēng)險模型，甚至根據(jù)支持這個判斷的信息來終止風(fēng)險管理過程。（注：在流程圖中的“不接受”不僅僅是依據(jù)法定、立法或藥政要求，同樣也需要返回風(fēng)險評估過程。）4.1Responsibilities職責(zé)Qualityriskmanagementactivitiesareusually,butnotalways,undertakenbyinterdisciplinaryteams.Whenteamsareformed,theyshouldincludeexpertsfromtheappropriateareas(e.g.,qualityunit,businessdevelopment,engineering,regulatoryaffairs,productionoperations,salesandmarketing,legal,statisticsandclinical)inadditiontoindividualswhoareknowledgeableaboutthequalityriskmanagementprocess.風(fēng)險管理活動通常，但并不總是，需要多學(xué)科的團(tuán)隊(duì)參與。當(dāng)形成一個團(tuán)隊(duì)時，應(yīng)當(dāng)要包括適當(dāng)領(lǐng)域的專家(例如，質(zhì)量部門、商業(yè)開發(fā)、工程、藥政、生產(chǎn)運(yùn)行、銷售和市場、法律和臨床)，及精通質(zhì)量風(fēng)險管理過程的個人。Decisionmakersshould決策者應(yīng)當(dāng)：?takeresponsibilityforcoordinatingqualityriskmanagementacrossvariousfunctionsanddepartmentsoftheirorganization;and負(fù)責(zé)在其組織內(nèi)各職能部門間協(xié)調(diào)質(zhì)量風(fēng)險管理；以及，?assurethataqualityriskmanagementprocessisdefined,deployedandreviewedandthatadequateresourcesareavailable.確保明確，開展與評審了質(zhì)量風(fēng)險管理過程，并有適當(dāng)?shù)馁Y源。4.2InitiatingaQualityRiskManagementProcess啟動質(zhì)量風(fēng)險管理過程Qualityriskmanagementshouldincludesystematicprocessesdesignedtocoordinate,facilitateandimprovescience-baseddecisionmakingwithrespecttorisk.Possiblestepsusedtoinitiateandplanaqualityriskmanagementprocessmightincludethefollowing:質(zhì)量風(fēng)險管理包括那些用于協(xié)調(diào)、促進(jìn)和改善做出與風(fēng)險相關(guān)的基于科學(xué)的決策系統(tǒng)過程?？赡苡糜趩雍筒邉澮粋€質(zhì)量風(fēng)險管理過程的步驟可能包括以下幾點(diǎn)：?Definetheproblemand/orriskquestion,includingpertinentassumptionsidentifyingthepotentialforrisk;明確問題和/或風(fēng)險問題，包括辨識潛在風(fēng)險相關(guān)假設(shè)；?Assemblebackgroundinformationand/ordataonthepotentialhazard,harmorhumanhealthimpactrelevanttotheriskassessment;收集與風(fēng)險評估相關(guān)的潛在危險、傷害或影響人體健康的背景信息和資料和/或數(shù)據(jù)；?Identifyaleaderandnecessaryresources;辯識領(lǐng)導(dǎo)與必要的資源；?Specifyatimeline,deliverablesandappropriatelevelofdecisionmakingfortheriskmanagementprocess.指定風(fēng)險管理程序的時限、交付日期與決策水平。4.3RiskAssessment風(fēng)險評估Riskassessment:consistsoftheidentificationofhazardsandtheanalysisandevaluationofrisksassociatedwithexposuretothosehazards(asdefinedbelow).Qualityriskassessmentsbeginwithawell-definedproblemdescriptionorriskquestion.Whentheriskinquestioniswelldefined,anappropriateriskmanagementtool(seeexamplesinsection5)andthetypesofinformationneededtoaddresstheriskquestionwillbemorereadilyidentifiable.Asanaidtoclearlydefiningtherisk(s)forriskassessmentpurposes,threefundamentalquestionsareoftenhelpful:風(fēng)險評估：其包括辨識危險因素與暴露在這些危險因素(定義于后)相關(guān)風(fēng)險的分析和評估。質(zhì)量風(fēng)險評估開始于一個明確的問題或風(fēng)險問題。當(dāng)被討論的風(fēng)險被明確定義后，則將會很容易確定適當(dāng)?shù)娘L(fēng)險管理工具(見第5節(jié)中的例子)和需要用于風(fēng)險問題說明的資料類型。在風(fēng)險評估時，作為明確定義風(fēng)險的輔助工具，通常如下這三個基本問題是非常有用的：1.Whatmightgowrong?什么可能出錯?2.Whatisthelikelihood(probability)itwillgowrong?會出錯的可能性(概率)是什么?3.Whataretheconsequences(severity)?結(jié)果(嚴(yán)重性)是什么?Riskidentification:isasystematicuseofinformationtoidentifyhazardsreferringtotheriskquestionorproblemdescription.Informationcanincludehistoricaldata,theoreticalanalysis,informedopinions,andtheconcernsofstakeholders.Riskidentificationaddressesthe“Whatmightgowrong?”question,includingidentifyingthepossibleconsequences.Thisprovidesthebasisforfurtherstepsinthequalityriskmanagementprocess.風(fēng)險辨識：其是指參照風(fēng)險問題或問題描述，系統(tǒng)地運(yùn)用信息來辨識危險因素。這些信息可能包括歷史數(shù)據(jù)、理論分析、意見以及風(fēng)險涉眾的考慮。風(fēng)險辨識關(guān)注“什么可能出錯?”這個問題，包括辨識可能的結(jié)果。這為進(jìn)一步的質(zhì)量風(fēng)險管理過程奠定了基礎(chǔ)。Riskanalysis:istheestimationoftheriskassociatedwiththeidentifiedhazards.Itisthequalitativeorquantitativeprocessoflinkingthelikelihoodofoccurrenceandseverityofharms.Insomeriskmanagementtools,theabilitytodetecttheharm(detectability)alsofactorsintheestimationofrisk.風(fēng)險分析：其是對風(fēng)險所關(guān)聯(lián)已經(jīng)辨識了的危險因素進(jìn)行估計(jì)。它是對發(fā)生事件可能性與及災(zāi)害嚴(yán)重性進(jìn)行定量或定性過程。在一些風(fēng)險管理工具中，探測傷害的能力(可檢測性)同樣是在估計(jì)風(fēng)險中的因素。Riskevaluation:comparestheidentifiedandanalyzedriskagainstgivenriskcriteria.Riskevaluationsconsiderthestrengthofevidenceforallthreeofthefundamentalquestions.風(fēng)險評價：其是比較已經(jīng)辨識和分析的風(fēng)險與給定的風(fēng)險標(biāo)準(zhǔn)進(jìn)行比較。風(fēng)險評價考慮到了所有這三個基本問題的證據(jù)強(qiáng)度。Indoinganeffectiveriskassessment,therobustnessofthedatasetisimportantbecauseitdeterminesthequalityoftheoutput.Revealingassumptionsandreasonablesourcesofuncertaintywillenhanceconfidenceinthisoutputand/orhelpidentifyitslimitations.Uncertaintyisduetocombinationofincompleteknowledgeaboutaprocessanditsexpectedorunexpectedvariability.Typicalsourcesofuncertaintyincludegapsinknowledgegapsinpharmaceuticalscienceandprocessunderstanding,sourcesofharm(e.g.,failuremodesofaprocess,sourcesofvariability),andprobabilityofdetectionofproblems.在進(jìn)行一個有效的風(fēng)險評估時，數(shù)據(jù)集的完美性很重要，因?yàn)樗鼪Q定了輸出的質(zhì)量。顯示假設(shè)及合理資源不確定性將會加強(qiáng)輸出的可靠性，并且/或有助于辨識其限度。不確定性是由于關(guān)于過程不完整的知識以及其期望的或非期望的變異性綜合造成。典型的不確定來源包括制藥科學(xué)知識差距、對過程理解差距、傷害來源(如一個過程的失效模式，變異行來源)以及發(fā)現(xiàn)問題概率。Theoutputofariskassessmentiseitheraquantitativeestimateofriskoraqualitativedescriptionofarangeofrisk.Whenriskisexpressedquantitatively,anumericalprobabilityisused.Alternatively,riskcanbeexpressedusingqualitativedescriptors,suchas“high”,“medium”,or“l(fā)ow”,whichshouldbedefinedinasmuchdetailaspossible.Sometimesa"riskscore"isusedtofurtherdefinedescriptorsinriskranking.Inquantitativeriskassessments,ariskestimateprovidesthelikelihoodofaspecificconsequence,givenasetofrisk-generatingcircumstances.Thus,quantitativeriskestimationisusefulforoneparticularconsequenceatatime.Alternatively,someriskmanagementtoolsusearelativeriskmeasuretocombinemultiplelevelsofseverityandprobabilityintoanoverallestimateofrelativerisk.Theintermediatestepswithinascoringprocesscansometimesemployquantitativeriskestimation.風(fēng)險評估的輸出既是一個對風(fēng)險定量估計(jì)也是一個對風(fēng)險范圍的定性描述。當(dāng)風(fēng)險被定量地表達(dá)，則運(yùn)用數(shù)值表達(dá)它的概率。另外，風(fēng)險還可以運(yùn)用如“高”、“中”或“低”等定性描述詞來表達(dá)，對其應(yīng)該盡可能詳細(xì)地確定。一些時候，使用“風(fēng)險記分”來進(jìn)一步確定描述風(fēng)險的排列。在定量風(fēng)險評估中，對一個風(fēng)險估計(jì)能提供一個特定結(jié)果的可能性，給出一系列產(chǎn)生風(fēng)險狀況。因此，定量風(fēng)險評估對于在某個時間的特定后果非常有用。另外，一些風(fēng)險管理工具采用了相對的風(fēng)險度量將多種級別的嚴(yán)重性和概率合并到一個完整的相對風(fēng)險估計(jì)中。在一個記分過程的中間步驟有時候可以使用定量風(fēng)險評估。4.4RiskControl風(fēng)險控制Riskcontrol:includesdecisionmakingtoreduceand/oracceptrisks.Thepurposeofriskcontrolistoreducetherisktoanacceptablelevel.Theamountofeffortusedforriskcontrolshouldbeproportionaltothesignificanceoftherisk.Decisionmakersmightusedifferentprocesses,includingbenefit-costanalysis,forunderstandingtheoptimallevelofriskcontrol.風(fēng)險控制：其包括做出的降低和/或接受風(fēng)險的決定。風(fēng)險控制的目的是降低風(fēng)險到一個可接受的水平。用于風(fēng)險控制所作工作量應(yīng)該與風(fēng)險的顯著性相稱。決策者可能會采用不同的過程，包括收益成本分析，來了解最佳的風(fēng)險控制水平。Riskcontrolmightfocusonthefollowingquestions:風(fēng)險控制可能會集中在下列問題：?Istheriskaboveanacceptablelevel?是否風(fēng)險超過了一個可接受的水平??Whatcanbedonetoreduceoreliminaterisks?什么方法可以用來降低或消除風(fēng)險??Whatistheappropriatebalanceamongbenefits,risksandresources?效益、風(fēng)險和資源之間的恰當(dāng)?shù)钠胶恻c(diǎn)是什么??Arenewrisksintroducedasaresultoftheidentifiedrisksbeingcontrolled?控制已經(jīng)所辨識的風(fēng)險是否引入新的風(fēng)險?Riskreduction:focusesonprocessesformitigationoravoidanceofqualityriskwhenitexceedsaspecified(acceptable)level(seeFig.1).Riskreductionmightincludeactionstakentomitigatetheseverityandprobabilityofharm.Processesthatimprovethedetectabilityofhazardsandqualityrisksmightalsobeusedaspartofariskcontrolstrategy.Theimplementationofriskreductionmeasurescanintroducenewrisksintothesystemorincreasethesignificanceofotherexistingrisks.Hence,itmightbeappropriatetorevisittheriskassessmenttoidentifyandevaluateanypossiblechangeinriskafterimplementingariskreductionprocess.風(fēng)險降低：其是著眼于當(dāng)風(fēng)險超過了某個特定(可接受)水平(見圖1)后緩和或避免質(zhì)量風(fēng)險的過程。風(fēng)險降低可能包括用于減緩傷害的嚴(yán)重性和概率所采取的行動。改善危險因素和質(zhì)量風(fēng)險可檢測性的過程也可能作為一個風(fēng)險控制策略中的一個部分。通過實(shí)施風(fēng)險降低措施，新的風(fēng)險可能被引入到系統(tǒng)中或者顯著增加其它已經(jīng)存在的風(fēng)險。因此，在實(shí)施風(fēng)險降低過程后，可能會適當(dāng)?shù)胤祷氐斤L(fēng)險評估中對風(fēng)險中任何可能的改變進(jìn)行辯識和評價。Riskacceptance:isadecisiontoacceptrisk.Riskacceptancecanbeaformaldecisiontoaccepttheresidualriskoritcanbeapassivedecisioninwhichresidualrisksarenotspecified.Forsometypesofharms,eventhebestqualityriskmanagementpracticesmightnotentirelyeliminaterisk.Inthesecircumstances,itmightbeagreedthatanappropriatequalityriskmanagementstrategyhasbeenappliedandthatqualityriskisreducedtoaspecified(acceptable)level.This(specified)acceptablelevelwilldependonmanyparametersandshouldbedecidedonacase-by-casebasis.接受風(fēng)險：其是一個接受風(fēng)險的決定。風(fēng)險接受可以是一個接受剩余風(fēng)險的正式?jīng)Q定或者是當(dāng)剩余風(fēng)險不具體時的被動接受。對于一些類型的傷害，甚至最好的質(zhì)量風(fēng)險實(shí)踐也未必能全部消除風(fēng)險。這些情況下，可以認(rèn)為已應(yīng)用了恰當(dāng)?shù)馁|(zhì)量風(fēng)險管理策略，并且質(zhì)量風(fēng)險已降低到一個特定(可接受)的水平。這個(特定)可接受的水平將會取決于許多參數(shù)，并且具體情況具體判斷定。4.5RiskCommunication風(fēng)險溝通Riskcommunication:isthesharingofinformationaboutriskandriskmanagementbetweenthedecisionmakersandothers.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.風(fēng)險溝通：是在決策者和其它人員之間分享有關(guān)風(fēng)險和風(fēng)險管理的信息。各方之間可以在任何風(fēng)險管理過程階段進(jìn)行溝通(見圖1的點(diǎn)劃線箭頭)。質(zhì)量風(fēng)險管理過程的輸出/結(jié)果應(yīng)當(dāng)進(jìn)行適當(dāng)?shù)臏贤ê痛鏅n(見圖1的實(shí)線箭頭)。溝通有可能包括這些相關(guān)方，例如，藥政與業(yè)界、業(yè)界與患者、在一個公司、業(yè)界或藥政當(dāng)局內(nèi)部等。所包括的信息應(yīng)該與質(zhì)量風(fēng)險的存在性、性質(zhì)、形式、概率、嚴(yán)重性、可接受性、控制、處理、可檢測性或其它有關(guān)方面。溝通不需要對每個風(fēng)險接受都進(jìn)行。如果在業(yè)界和藥政當(dāng)局之間，就可能受影響進(jìn)行質(zhì)量風(fēng)險管理決策溝通，則這些溝通可能通過現(xiàn)有的規(guī)章或指南中所說明的渠道來進(jìn)行。4.6RiskReview風(fēng)險評審Riskmanagementshouldbeanongoingpartofthequalitymanagementprocess.Amechanismtoreviewormonitoreventsshouldbeimplemented.質(zhì)量風(fēng)險管理應(yīng)當(dāng)是質(zhì)量管理過程中的一個進(jìn)行部分。應(yīng)當(dāng)實(shí)施一個評審或?qū)κ录M(jìn)行監(jiān)控的機(jī)制。Theoutput/resultsoftheriskmanagementprocessshouldbereviewedtotakeintoaccountnewknowledgeandexperience.Onceaqualityriskmanagementprocesshasbeeninitiated,thatprocessshouldcontinuetobeutilizedforeventsthatmightimpacttheoriginalqualityriskmanagementdecision,whethertheseeventsareplanned(e.g.,resultsofproductreview,inspections,audits,changecontrol)orunplanned(e.g.,rootcausefromfailureinvestigations,recall).Thefrequencyofanyreviewshouldbebaseduponthelevelofrisk.Riskreviewmightincludereconsiderationofriskacceptancedecisions(section4.4).對風(fēng)險管理過程輸出/結(jié)果進(jìn)行評審應(yīng)當(dāng)考慮采用新的知識和經(jīng)驗(yàn)。一旦開始了某個質(zhì)量風(fēng)險管理過程，則該過程應(yīng)該一直應(yīng)用于可能影響初始質(zhì)量風(fēng)險管理決策的事件，而不管那些事件是已被計(jì)劃的(如產(chǎn)品評審、檢查、審計(jì)、變更控制結(jié)果)或未計(jì)劃的(如從失敗調(diào)查的根本原因、檢查、召回)。評審頻率應(yīng)該取決于風(fēng)險水平。風(fēng)險評審可能包括對風(fēng)險接受決策重新考慮(4.4節(jié))。5.RISKMANAGEMENTMETHODOLOGY風(fēng)險管理方法學(xué)Qualityriskmanagementsupportsascientificandpracticalapproachtodecision-making.Itprovidesdocumented,transparentandreproduciblemethodstoaccomplishstepsofthequalityriskmanagementprocessbasedoncurrentknowledgeaboutassessingtheprobability,severityandsometimesdetectabilityoftherisk.質(zhì)量風(fēng)險管理支持科學(xué)和實(shí)際方法來進(jìn)行決策。在現(xiàn)有關(guān)于風(fēng)險概率，嚴(yán)重性和一些事件的可檢測性評估知識的基礎(chǔ)上，其提供文件的，透明的和可重復(fù)的方法來實(shí)現(xiàn)質(zhì)量風(fēng)險管理程序的步驟。Traditionally,riskstoqualityhavebeenassessedandmanagedinavarietyofinformalways(empiricaland/orinternalprocedures)basedon,forexample,compilationofobservations,trendsandotherinformation.Suchapproachescontinuetoprovideusefulinformationthatmightsupporttopicssuchashandlingofcomplaints,qualitydefects,deviationsandallocationofresources.傳統(tǒng)上，對于質(zhì)量的風(fēng)險的評估和管理是基于多種非正式的方式(經(jīng)驗(yàn)的，和/或，內(nèi)部程序)，例如，現(xiàn)象匯總、趨勢和其它資料。此類方法繼續(xù)提供有用的信息，這些信息可以支持諸如處理投訴、質(zhì)量缺陷、偏差與資源分配。Additionally,thepharmaceuticalindustryandregulatorscanassessandmanageriskusingrecognizedriskmanagementtoolsand/orinternalprocedures(e.g.,standardoperatingprocedures).Belowisanon-exhaustivelistofsomeofthesetools(furtherdetailsinAnnex1andchapter8):此外，制藥業(yè)界與藥政可以使用公認(rèn)的風(fēng)險管理工具，和/或，內(nèi)部程序(例如，標(biāo)準(zhǔn)操作程序)來評估和管理風(fēng)險。以下并非是這些工具的一個詳盡的列表(詳細(xì)在附件1和第8章)：?Basicriskmanagementfacilitationmethods(flowcharts,checksheetsetc.);基本風(fēng)險管理簡易方法(流程圖，核對單等)；?FailureModeEffectsAnalysis(FMEA);故障模式效應(yīng)分析(FMEA)；?FailureMode,EffectsandCriticalityAnalysis(FMECA);故障模式影響與嚴(yán)重性分析(FMECA)；?FaultTreeAnalysis(FTA);故障樹分析(FTA)；?HazardAnalysisandCriticalControlPoints(HACCP);危害分析關(guān)鍵控制點(diǎn)(HACCP)；?HazardOperabilityAnalysis(HAZOP);危害及可操作性分析(HAZOP)；?PreliminaryHazardAnalysis(PHA);預(yù)先危險分析(PHA)；?Riskrankingandfiltering;風(fēng)險排行與過濾；?Supportingstatisticaltools.輔助性統(tǒng)計(jì)工具。Itmightbeappropriatetoadaptthesetoolsforuseinspecificareaspertainingtodrugsubstanceanddrug(medicinal)productquality.Qualityriskmanagementmethodsandthesupportingstatisticaltoolscanbeusedincombination(e.g.,ProbabilisticRiskAssessment).Combineduseprovidesflexibilitythatcanfacilitatetheapplicationofqualityriskmanagementprinciples.在原料藥和藥物(醫(yī)療)產(chǎn)品質(zhì)量的特定領(lǐng)域運(yùn)用這些工具可能是恰當(dāng)?shù)?。質(zhì)量風(fēng)險管理方法以及輔助統(tǒng)計(jì)工具可以聯(lián)合使用(如，概率性風(fēng)險評估)。聯(lián)合使用提供了靈活性，而這種靈活性可以促進(jìn)質(zhì)量風(fēng)險管理原則的應(yīng)用。Thedegreeofrigorandformalityofqualityriskmanagementshouldreflectavailableknowledgeandbecommensuratewiththecomplexityand/orcriticalityoftheissuetobeaddressed.質(zhì)量風(fēng)險管理的嚴(yán)格程度與和形式應(yīng)當(dāng)反映可利用的知識和所關(guān)注問題的復(fù)雜性，和/或嚴(yán)重性相當(dāng)。6.INTEGRATIONOFQUALITYRISKMANAGEMENTINTOINDUSTRYANDREGULATORYOPERATIONS質(zhì)量風(fēng)險管理與業(yè)界及藥政運(yùn)行整合Qualityriskmanagementisaprocessthatsupportsscience-basedandpracticaldecisionswhenintegratedintoqualitysystems(seeAnnexII).Asoutlinedintheintroduction,appropriateuseofqualityriskmanagementdoesnotobviateindustry’sobligationtocomplywithregulatoryrequirements.However,effectivequalityriskmanagementcanfacilitatebetterandmoreinformeddecisions,canprovideregulatorswithgreaterassuranceofacompany’sabilitytodealwithpotentialrisks,andmightaffecttheextentandlevelofdirectregulatoryoversight.Inaddition,qualityriskmanagementcanfacilitatebetteruseofresourcesbyallparties.質(zhì)量風(fēng)險管理是一個過程，當(dāng)將其整合到質(zhì)量體系中時(見附錄II)可以支持基于科學(xué)和實(shí)踐的決策。正如在簡介中所簡述的，恰當(dāng)?shù)剡\(yùn)用質(zhì)量風(fēng)險管理并不能免除業(yè)界遵守藥政的要求。然而，有效的質(zhì)量風(fēng)險管理可以促使做出更好和更有遠(yuǎn)見的決策，它可以為管理者提供業(yè)界更多的應(yīng)對潛在風(fēng)險能力的保證并且可能會影響直接監(jiān)管的范圍和水平。另外，質(zhì)量風(fēng)險管理可以促使資源能被所有部門更好地運(yùn)用。Trainingofbothindustryandregulatorypersonnelinqualityriskmanagementprocessesprovidesforgreaterunderstandingofdecision-makingprocessesandbuildsconfidenceinqualityriskmanagementoutcomes.對業(yè)界以及藥政人員進(jìn)行質(zhì)量風(fēng)險管理的培訓(xùn)可以更好地了解決策過程，并且對質(zhì)量風(fēng)險管理的結(jié)果建立信心。Qualityriskmanagementshouldbeintegratedintoexistingoperationsanddocumentedappropriately.AnnexIIprovidesexamplesofsituation