APIC原料药厂清洁验证指南(201405-中英文)

1/63APIC原料药厂清洁验证指南（201405中英文）ACTIVEPHARMACEUTICALINGREDIENTSCOMMITTEE(APIC)GUIDANCEONASPECTSOFCLEANINGVALIDATIONINACTIVEPHARMACEUTICALINGREDIENTPLANTSAPIC原料药工厂中清洁验证指南May2014TableofContents1.0FOREWORD前言2.0OBJECTIVE目的3.0SCOPE范围4.0ACCEPTANCECRITERIA可接受标准4.1Introduction介绍4.2MethodsofCalculatingAcceptanceCriteria可接受标准的计算方法4.2.1.Acceptancecriteriausinghealth-baseddata使用基于健康数据的可接受标准4.2.2AcceptancecriteriabasedonTherapeuticDailyDose基于日治疗剂量的可接受标准4.2.3.AcceptancecriteriabasedonLD50基于半数致死量的可接受标准4.2.4GeneralLimitasacceptancecriteria作为可接受标准的通用限度4.2.5SwabLimits擦拭限度4.2.6RinseLimits淋洗限度4.2.7Rationalefortheuseofdifferentlimitsinpharmaceuticalandchemicalproduction在药品和化学生产中使用不同限度的合理性5.0LEVELSOFCLEANING清洁级别5.1Introduction介绍5.2CleaningLevels清洁级别5.3CleaningVerification/Validation清洁验收/验证6.0CONTROLOFCLEANINGPROCESS清洁过程的控制7.0BRACKETINGANDWORSTCASERATING分类法和最差情况分级法7.1Introduction介绍2/637.2BracketingProcedure分类法程序7.3CleaningProcedures清洁程序7.4WorstCaseRating最差情况分级8.0DETERMINATIONOFTHEAMOUNTOFRESIDUE残留量检测8.1Introduction介绍8.2ValidationRequirements验证要求8.3SamplingMethods取样方法8.4AnalyticalMethods分析方法9.0CLEANINGVALIDATIONPROTOCOL清洁验证方案9.1Background背景9.2Purpose目的9.3Scope范围9.4Responsibility职责9.5SamplingProcedure取样程序9.6Testingprocedure分析方法9.7Acceptancecriteria可接受标准9.8Deviations偏差9.9Revalidation再验证10.0VALIDATIONQUESTIONS验证问题11.0REFERENCES参考文献12.0GLOSSARY词汇13.0COPYRIGHTANDDISCLAIMER版本及声明3/631.0FOREWORD前言TheoriginalversionofthisguidancedocumenthasnowbeenupdatedbytheAPICCleaningValidationTaskForceonbehalfoftheActivePharmaceuticalIngredientCommittee(APIC)ofCEFIC.本指南文件的原版本现已由APIC清洁验证工作组代表CEFIC的APIC委员会进行了更新。TheTaskForcemembersare:-以下是工作组的成员AnnickBonneure,APIC,BelgiumTomBuggy,DSMSinochemPharmaceuticals,TheNetherlandsPaulClingan,MacFarlanSmith,UKAnkeGrootaert,JanssenPharmaceutica,BelgiumPeterMungenast,MerckKGaA,Germany.LuisaPaulo,HovioneFarmaCienciaSA,PortugalFilipQuintiens,Genzyme,BelgiumClaudeVandenbossche,AjinomotoOmnichem,BelgiumJosvanderVen,AspenOssB.V.,TheNetherlandsStefanWienken,BASF,Germany.Withsupportandreviewfrom:-以下为提供支持和进行审核的人员PietervanderHoeven,APIC,BelgiumAnthonyStorey,Pfizer,U.K.RainerFendt,BASF,Germany.Thesubjectofcleaningvalidationinactivepharmaceuticalingredientmanufacturingplantshascontinuedtoreceivealargeamountofattentionfromregulators,companiesandcustomersalike.原料药生产工厂的清洁验证一直是法规人员、公司和客户等关注的问题。TheintegrationofCleaningValidationwithinaneffectiveQualitySystemsupportedbyQualityRiskManagementProcessesshouldgiveassurancethatAPIManufacturingOperationsareperformedinsuchawaythatRiskstopatientsrelatedtocleaningvalidationareunderstood,assessedforimpactandaremitigatedasnecessary.原料药生产企业应将清洁验证与有效的质量体系相结合，由质量风险管理来支持，了解与清洁验证相关的患者风险，评估其影响，并在必要时降低风险。Itisimportantthattherequirementsforthefinishedmanufacturingcompaniesarenottransferredbackintheprocesstoactivepharmaceuticalingredientmanufacturerswithoutconsiderationforthedifferentprocessesthattakeplaceatthisstage.重要的是，不能将对制剂生产企业的要求直接用于原料药生产商，而不考虑在此阶段所用生产工艺的差异。Forexample,higherlimitsmaybeacceptableinchemicalproductioncomparedtopharmaceuticalproductionbecausethecarry-overriskismuchlowerfortechnicalandchemicalmanufacturingreasons例如，与制剂生产相比，化学生产可以接受较高的残留限度，因为技术原因，化学生产所带入后续产品的残留风险会低很多。4/63ThedocumentreflectstheoutcomeofdiscussionsbetweenAPICmembercompaniesonhowcleaningvalidationrequirementscouldbefulfilledandimplementedaspartofroutineoperations.本文件反映了APIC成员公司之间关于如何满足清洁验证的要求及作为日常操作来实施的讨论结果。Inaddition,APICisaligningthisguidancewiththeISPERiskMaPPGuide1[1]thatfollowstheQualityRiskManagementProcessesasdescribedintheICHQ9GuidanceonQualityRiskManagement.另外，APIC将本指南与“ISPE基于风险的药品生产指南”保持一致，遵守“ICHQ9质量风险管理”中的“质量风险管理流程”。ThecriteriaofAcceptableDailyExposure(ADE)isnowrecommendedtobeusedbycompaniestodecideifDedicatedFacilitiesarerequiredornotandtodefinetheMaximumAcceptableCarryOver(MACO)ofAPI’sinparticular,inMulti-PurposeEquipment.目前推荐公司使用“可接受日暴露水平”标准来决定是否专用设施需要界定原料药“最大可接受残留MACO”，特别是针对多用途设备。AnewchapterisintroducedtodefinefactorsthatshouldbeconsideredinControlsofTheCleaningProcesstomanagetheRisksrelatedtopotentialchemicalormicrobiologicalcontamination.放入了一个新章节，对“清洁工艺的控制”中要考虑的因素进行了定义，以管理与潜在化学和微生物污染有关的风险。ThePDATechnicalReportNo.29–PointstoConsiderforCleaningValidation2[2]isalsorecommendedasavaluableguidancedocumentfromindustry.也推荐企业将“PDA第29号技术报告----清洁验证中应考虑的问题”作为有用的指南文件进行参考。ThefollowingtopicsarediscussedinthePDAdocument:Cleaningprocess(CIP/COP):designandqualification以下问题在PDA文件中进行了讨论：清洁工艺（CIP/COP）：设计和确认—Typesofresidues,settingacceptancecriteria,samplingandanalyticalmethods—残留类型、设定可接受标准、取样和分析方法—Maintenanceofthevalidatedstate:criticalparametersmeasurements,processalarms,changecontrol,trending&monitoring,trainingandperiodicreview—维护验证状态：关键参数测量、工艺警示、变更控制、趋势&监控、培训和周期性评审—Documentation—文件记录2.0Objective目的Thisdocumenthasbeenpreparedtoassistcompaniesintheformulationofcleaningvalidationprogrammesandshouldnotbeconsideredasatechnicalstandardbutastartingpointforinternaldiscussions.Thedocumentincludesexamplesonhowmembercompanieshavedealtwithspecificareasandissuesthatarisewhenperformingcleaningvalidation.1[1]ISPEBaseline?PharmaceuticalEngineer