欧盟GMP附录15：确认与验证

EUROPEANCOMMISSIONENTERPRISEDIRECTORATE-GENERALSinglemarket,regulatoryenvironment,industriesunderverticallegislationPharmaceuticalsandcosmeticsBrussels,30March2015EudraLex欧盟药品管理法Volume4EUGuidelinesforGoodManufacturingPracticeforMedicinalProductsforHumanandVeterinaryUse第四卷欧盟人用和兽用药品GMP指南Annex15:QualificationandValidation附录15:确认和验证Legalbasisforpublishingthedetailedguidelines:Article47ofDirective2001/83/EContheCommunitycoderelatingtomedicinalproductsforhumanuseandArticle51ofDirective2001/82/EContheCommunitycoderelatingtoveterinarymedicinalproducts.Thisdocumentprovidesguidancefortheinterpretationoftheprinciplesandguidelinesofgoodmanufacturingpractice(GMP)formedicinalproductsaslaiddowninDirective2003/94/ECformedicinalproductsforhumanuseandDirective91/412/EECforveterinaryuse.发布该细化指南的法律依据:人用药物欧共体法案指令2001/83/EC第47章和兽用药物欧共体法案指令2001/82/EC第51章。本文件为人药GMP指令2003/94/EC以及兽药GMP指令91/412/EEC的原则和指南提供诠释。Statusofthedocument:Revision文件状态：修订版Reasonsforchanges:SinceAnnex15waspublishedin2001themanufacturingandregulatoryenvironmenthaschangedsignificantlyandanupdateisrequiredtothisAnnextoreflectthischangedenvironment.ThisrevisiontoAnnex15takesintoaccountchangestoothersectionsoftheEudraLex,Volume4,PartI,relationshiptoPartII,Annex11,ICHQ8,Q9,Q10andQ11,QWPguidaneeonprocessvalidation,andchangesinmanufacturingtechnology.变更原因：从2001年附录15发布以后，制药生产和法规环境都有了显著变化，需要相应的更新来反映变化的环境。本文对附录15所做的修订考虑了欧盟法规第四卷第一部分质量管理和第二部分活性物质作起始物料以及附录11计算机化系统的验证、CHQ8药物研发、ICHQ9质量风向管理、ICHQ11药物研发和生产、质量工作组的工艺验证指南和生产技术的变化。Deadlineforcomingintooperation:1October2015最终实施日期：2015年10月1日目录TOC\o"1-5"\h\z原则2概述3确认和验证的组织和计划3文件，包括验证主计划5设备、设施、公用工程和系统的确认阶段75.工艺验证106.运输确认197.包装验证208.公用工程的确认209.检验方法验证2110.清洁验证2111.变更控制2512.词汇表26PrincipleThisAnnexdescribestheprinciplesofqualificationandvalidationwhichareapplicabletothefacilities,equipment,utilitiesandprocessesusedforthemanufactureofmedicinalproductsandmayalsobeusedassupplementaryoptionalguidaneeforactivesubstanceswithoutintroductionofadditionalrequirementstoEudraLex,Volume4,PartII.ItisaGMPrequirementthatmanufacturerscontrolthecriticalaspectsoftheirparticularoperationsthroughqualificationandvalidationoverthelifecycleoftheproductandprocess.Anyplannedchangestothefacilities,equipment,utilitiesandprocesses,whichmayaffectthequalityoftheproduct,shouldbeformallydocumentedandtheimpactonthevalidatedstatusorcontrolstrategyassessed.ComputerisedsystemsusedforthemanufactureofmedicinalproductsshouldalsobevalidatedaccordingtotherequirementsofAnnex11.TherelevantconceptsandguidaneepresentedinICHQ8,Q9,Q10andQ11shouldalsobetakenintoaccount.原则本附录描述了确认与验证的基本原则，适用于药品生产中的设施、设备、公用系统及工艺,也可以用于第四卷第二部分《活性物质作起始物料》的附加要求中没有介绍部分的补充性、选择性指南。GMP要求生产商应通过确认和验证对整个生命周期内的产品和工艺涉及的关键操作中的关键因素来进行控制。所有影响产品质量的计划性变更（含设施、设备、工艺系统和工艺），都应当有正式文件或记录，并评估其对验证状态或是控制策略的影响。用于药品生产的计算机化系统也应根据附录11的要求进行验证。同时，应当考虑现行的ICHQ8、Q9、Q10、Q11中的相关理念和指南要求。GeneralAqualityriskmanagementapproachshouldbeappliedthroughoutthelifecycleofamedicinalproduct.Aspartofaqualityriskmanagementsystem,decisionsonthescopeandextentofqualificationandvalidationshouldbebasedonajustifiedanddocumentedriskassessmentofthefacilities,equipment,utilitiesandprocesses.Retrospectivevalidationisnolongerconsideredanacceptableapproach.Datasupportingqualificationand/orvalidationstudieswhichwereobtainedfromsourcesoutsideofthemanufacturersownprogrammesmaybeusedprovidedthatthisapproachhasbeenjustifiedandthatthereisadequateassuraneethatcontrolswereinplacethroughouttheacquisitionofsuchdata.概述质量风险管理的方法应作为质量风险管理系统的一部分贯穿于药品的整个生命周期，应基于对设施、设备、公用系统和工艺的论证和书面风险评估决定确认和验证的范围和程度。回顾性验证不再被认为是可接受的方式。如果方法经过论证，并且获取数据的整个过程中有足够的保证性控制措施，也可以使用从生产商自身程序以外获得的用于支持确认和/或验证研究的数据。ORGANISINGANDPLANNINGFORQUALIFICATIONANDVALIDATION确认和验证的组织和计划AIIqualificationandvalidationactivitiesshouldbeplannedandtakethelifecycleoffacilities,equipment,utilities,processandproductintoconsideration.所有的确认和验证都应当被计划，并考虑到设施、设备、公用系统、工艺和产品的生命周期。Qualificationandvalidationactivitiesshouldonlybeperformedbysuitablytrainedpersonnelwhofollowapprovedprocedures.确认和验证活动应只能由经过培训合格的人员严格按照批准的程序实施。Qualification/validationpersonnelshouldreportasdefinedinthepharmaceuticalqualitysystemalthoughthismaynotnecessarilybetoaqualitymanagementoraqualityassuraneefunction.However,thereshouldbeappropriatequalityoversightoverthewholevalidationlifecycle.确认或验证人员应按照药品质量体系中指定要求进行 报告 软件系统测试报告下载sgs报告如何下载关于路面塌陷情况报告535n,sgs报告怎么下载竣工报告下载 ，尽管并不一定是报告给质量管理或质量保证部门。然而，对于整个验证生命周期来说，应当有合适的质量监督。Thekeyelementsofthesitequalificationandvalidationprogrammeshouldbeclearlydefinedanddocumentedinavalidationmasterplan(VMP)orequivalentdocument.应当在验证主计划（VMP）或其等同文件中，清晰地界定和记录现场确认与验证程序的关键性要素。TheVMPorequivalentdocumentshoulddefinethequalification/validationsystemandincludeorreferenceinformationonatleastthefollowing:验证主计划或其等同文件中应定义确认/验证体系，至少包括如下信息：QualificationandValidationpolicy;确认与验证的方针政策。Theorganisationalstructureincludingrolesandresponsibilitiesforqualificationandvalidationactivities;在确认和验证活动中的组织结构，包括分工和 职责 岗位职责下载项目部各岗位职责下载项目部各岗位职责下载建筑公司岗位职责下载社工督导职责.docx 。Summaryofthefacilities,equipment,systems,processesonsiteandthequalificationandvalidationstatus;现场设施、设备、系统、工艺汇总表及其确认和验证状态。Changecontrolanddeviationmanagementforqualificationandvalidation;确认与验证活动的变更控制和偏差管理。Guidanceondevelopingacceptancecriteria;开发可接受 标准 excel标准偏差excel标准偏差函数exl标准差函数国标检验抽样标准表免费下载红头文件格式标准下载 的指南。Referencestoexistingdocuments;现有文件的参考资料。Thequalificationandvalidationstrategy,includingrequalification,whereapplicable.确认与验证的策略，适当时应包括再确认。Forlargeandcomplexprojects,planningtakesonaddedimportanceandseparatevalidationplansmayenhanceclarity对于大型和复杂的项目，增加计划重点和独立的验证计划将有助于明晰要做的工作。Aqualityriskmanagementapproachshouldbeusedforqualificationandvalidationactivities.Inlightofincreasedknowledgeandunderstandingfromanychangesduringtheprojectphaseorduringcommercialproduction,theriskassessmentsshouldberepeated,asrequired.Thewayinwhichriskassessmentsareusedtosupportqualificationandvalidationactivitiesshouldbeclearlydocumented.在确认与验证活动中应使用质量风险管理的方法，随着在项目开展或者商业化生产的过程中的知识积累及理解加深，应当根据需要对风险进行不断地重复评估，并清楚地记录确认与验证的风险评估所采用的方法。Appropriatechecksshouldbeincorporatedintoqualificationandvalidationworktoensuretheintegrityofalldataobtained.1.8.应将适当的检查加入到确认和验证工作中，以保证所获得的数据的完整性。DOCUMENTATION,INCLUDINGVMP文件，包括验证主计划Gooddocumentationpracticesareimportanttosupportknowledgemanagementthroughouttheproductlifecycle.1.在产品的生命周期中，良好的文件管理对于知识管理而言是非常重要的。Alldocumentsgeneratedduringqualificationandvalidationshouldbeapprovedandauthorisedbyappropriatepersonnelasdefinedinthepharmaceuticalqualitysystem.确认与验证产生的所有文件都应当由药品质量管理体系规定的人批准和授权。Theinter-relationshipbetweendocumentsincomplexvalidationprojectsshouldbeclearlydefined.2.3.在复杂的验证项目中，应清楚地说明文件之间的内在关系。24Validationprotocolsshouldbepreparedwhichdefinesthecriticalsystems,attributesandparametersandtheassociatedacceptaneecriteria.制定验证 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 的时候，应当定义关键系统、属性、参数及相关的可接受标准。Qualificationdocumentsmaybecombinedtogether,whereappropriate,e.g.installationqualification(IQ)andoperationalqualification(OQ).确认文件适当的时候可以合并，例如IQ和OQ的文件可以合并在一起。Wherevalidationprotocolsandotherdocumentationaresuppliedbyathirdpartyprovidingvalidationservices,appropriatepersonnelatthemanufacturingsiteshouldconfirmsuitabilityandcompliancewithinternalproceduresbeforeapproval.Vendorprotocolsmaybesupplementedbyadditionaldocumentation/testprotocolsbeforeuse.如果验证方案和其它文件记录由验证服务第三方提供，应当由企业内部的合适人员确认其适用性，满足内部规定后方可批准。在使用之前，可由附加的文件或测试对供应商提供的方案进行补充。Anysignificantchangestotheapprovedprotocolduringexecution,e.g.acceptaneecriteria,operatingparametersetc.,shouldbedocumentedasadeviationandbescientificallyjustified.在执行期间，对已批准方案的任何重大变更，如可接受标准、操作参数等，均需按照偏差记录在册，并进行科学合理的评判。Resultswhichfailtomeetthepre-definedacceptancecriteriashouldberecordedasadeviationandbefullyinvestigatedaccordingtolocalprocedures.Anyimplicationsforthevalidationshouldbediscussedinthereport。若验证结果不符合预定的可接受标准需作为偏差处理，并按照内部规程进行全面调查。任何与偏差关联的东西都应当在验证报告中进行讨论。Thereviewandconclusionsofthevalidationshouldbereportedandtheresultsobtainedsummarisedagainsttheacceptaneecriteria.Anysubsequentchangestoacceptancecriteriashouldbescientificallyjustifiedandafinalrecommendationmadeastotheoutcomeofthevalidation.验证的评价和结论都应当被报告，且结果应与可接受标准比对，对可接受标准的任何后期变更都应当进行科学的评判，并在验证结果中做出最终建议。Aformalreleaseforthenextstageinthequalificationandvalidationprocessshouldbeauthorisedbytherelevantresponsiblepersonneleitheraspartofthevalidationreportapprovalorasaseparatesummarydocument.Conditionalapprovaltoproceedtothenextqualificationstagecanbegivenwherecertainacceptancecriteriaordeviationshavenotbeenfullyaddressedandthereisadocumentedassessmentthatthereisnosignificantimpactonthenextactivity.由相关的负责人对确认与验证过程中的阶段性放行，既可以作为验证报告批准的一部分，也可以是单独的总结文件。因某个可接受标准未达到或偏差未关闭，并通过评估确定对下一阶段活动无显著影响，可以有条件的放行进入下一阶段。QUALIFICATIONSTAGESFOREQUIPMENT,FACILITIES,UTILITIESANDSYSTEMS.设备、设施、公用工程和系统的确认阶段Qualificationactivitiesshouldconsiderallstagesfrominitialdevelopmentoftheuserrequirementsspecificationthroughtotheendofuseoftheequipment,facility,utilityorsystem.Themainstagesandsomesuggestedcriteria(althoughthisdependsonindividualprojectcircumstancesandmaybedifferent)whichcouldbeincludedineachstageareindicatedbelow:1.设备、设施、公用工程或系统的确认活动应当贯穿其用户需求说明书的制定到使用的各个阶段，主要阶段及其要求如下：Userrequirementsspecification(URS)用户需求说明(URS)Thespecificationforequipment,facilities,utilitiesorsystemsshouldbedefinedinaURSand/orafunctionalspecification.TheessentialelementsofqualityneedtobebuiltinatthisstageandanyGMPrisksmitigatedtoanacceptablelevel.TheURSshouldbeapointofrefereneethroughoutthevalidationlifecycle.设备、设施、公用工程或系统的说明应当在URS文件和/或功能说明中定义，应考虑质量的关键性因素，并把GMP风险降低到可接受水平。URS应该是整个验证生命周期中的参照。Designqualification(DQ)设计确认Thenextelementinthequalificationofequipment,facilities,utilities,orsystemsisDQwherethecomplianceofthedesignwithGMPshouldbedemonstratedanddocumented.Therequirementsoftheuserrequirementsspecificationshouldbeverifiedduringthedesignqualification.33确认活动的第二阶段就是设计确认，这里应当用文件证明其符合GMP要求，还应当对用户需求说明中的要求进行确认。Factoryacceptancetesting(FAT)/Siteacceptancetesting(SAT)工厂验收测试(FAT)/现场验收测试(SAT)34Equipment,especiallyifincorporatingnovelorcomplextechnology,maybeevaluated,ifapplicable,atthevendorpriortodelivery.如果需要的话，设备(尤其是新型或复杂的设备)在供应商发货前应在其产地被充分的评估。Priortoinstallation,equipmentshouldbeconfirmedtocomplywiththeURS/functionalspecificationatthevendorsite,ifapplicable.如果需要的话，在供应商的现场，设备应在安装之前被确认是否符合URS或功能说明的要求。Whereappropriateandjustified,documentationreviewandsometestscouldbeperformedattheFATorotherstageswithouttheneedtorepeatonsiteatIQ/OQifitcanbeshownthatthefunctionalityisnotaffectedbythetransportandinstallation.合适的话，经过评估，文件审核和部分测试可以在FAT时或其他阶段进行，如果能够证明其功能在运输和安装中未受影响，就不需要在IQ/OQ时重复进行已经做过的审核和测试了。FATmaybesupplementedbytheexecutionofaSATfollowingthereceiptofequipmentatthemanufacturingsite.在药品生产场地收到设备后，可以紧接着做SAT作为FAT的补充。Installationqualification(IQ)安装确认(IQ)IQshouldbeperformedonequipment,facilities,utilities,orsystems.设备、设施、公用工程或系统应进行安装确认。IQshouldinclude,butisnotlimitedtothefollowing:安装确认包括但不限于以下内容：Verificationofthecorrectinstallationofcomponents,instrumentation,equipment,pipeworkandservicesagainsttheengineeringdrawingsandspecifications;对照设计图纸和说明书，对组件、仪表、设备、管道和服务的安装正确性进行确认。Verificationofthecorrectinstallationagainstpre-definedcriteria;按照预先设定的标准对安装正确性进行确认。Collectionandcollationofsupplieroperatingandworkinginstructionsandmaintenancerequirements;收集并核对供应商操作、工作指令和维护要求。Calibrationofinstrumentation;仪表校准。Verificationofthematerialsofconstruction.核对部件的材质。Operationalqualification(OQ)运行确认(OQ)OQnormallyfollowsIQbutdependingonthecomplexityoftheequipment,itmaybeperformedasacombinedInstallation/OperationQualification(IOQ).OQ一般紧跟着IQ,但是根据设备的复杂情况，OQ也可以合并在安装/运行方案中执行(IOQ)。OQshouldincludebutisnotlimitedtothefollowing:运行确认包括但不限于以下内容：Teststhathavebeendevelopedfromtheknowledgeofprocesses,systemsandequipmenttoensurethesystemisoperatingasdesigned;根据工艺、系统和设备的相关知识开展测试，以确保其可以像设计的那样运行。Teststoconfirmupperandloweroperatinglimits,and/or“worstcase”conditions.对其上下操作线或最差工况进行测试。ThecompletionofasuccessfulOQshouldallowthefinalisationofstandardoperatingandcleaningprocedures,operatortrainingandpreventativemaintenancerequirements.成功的完成OQ后，就可以进行标准 操作规程 操作规程下载怎么下载操作规程眼科护理技术滚筒筛操作规程中医护理技术操作规程 、清洁规程、员工培训、预防性维护的最终定稿。Performancequalification(PQ)性能确认(PQ)PQshouldnormallyfollowthesuccessfulcompletionofIQandOQ.However,itmayinsomecasesbeappropriatetoperformitinconjunctionwithOQorProcessValidation.性能确认一般是在安装确认和运行确认成功完成之后。但是，在有些情况下，也可以将其与运行确认或工艺验证合并进行。PQshouldinclude,butisnotlimitedtothefollowing:性能确认包括但不限于以下内容：Tests,usingproductonmaterials,qualifiedsubstitutesorsimulatedproductproventohaveequivalentbehaviourundernormaloperatingconditionswithworstcasebatchsizes.Thefrequencyofsamplingusedtoconfirmprocesscontrolshouldbejustified;设备使用生产物料、合格替代物或模拟产品在最差批量工况的正常操作条件下进行测试，被证明具有等同表现。工艺控制的取样频次应当经过充分证明。Testsshouldcovertheoperatingrangeoftheintendedprocess,uniessdocumentedevideneefromthedevelopmentphasesconfirmingtheoperationalrangesisavailable.测试应覆盖预期工艺的操作范围，除非有文件证明在研发阶段确认过操作范围。RE-QUALIFICATION4.再确认Equipment,facilities,utilitiesandsystemsshouldbeevaluatedatanappropriatefrequencytoconfirmthattheyremaininastateofcontrol.1.应当对设备、设施、公用工程和系统保持合适的评估频率，以确保其依然在受控状态。Wherere-qualificationisnecessaryandperformedataspecifictimeperiod,theperiodshouldbejustifiedandthecriteriaforevaluationdefined.Furthermore,thepossibilityofsmallchangesovertimeshouldbeassessed.4.2.如果需要在一个特定时间周期内进行再验证，则应对该时间周期进行论证，并确定评估的标准。此外，应评估随着时间推移产生小变更的可能性。PROCESSVALIDATION5.工艺验证General通则Therequirementsandprinciplesoutlinedinthissectionareapplicabletothemanufactureofallpharmaceuticaldosageforms.Theycovertheinitialvalidationofnewprocesses,subsequentvalidationofmodifiedprocesses,sitetransfersandongoingprocessverification.Itisimplicitinthisannexthatarobustproductdevelopmentprocessisinplacetoenablesuccessfulprocessvalidation.1.本节提出的要求和原则适用于所有药品剂型，包括新工艺的初次验证、工艺变更后的验证、现场转移及持续的工艺验证。本附录认为一个成熟稳定的研发工艺有助于确保工艺验证的成功。Section5shouldbeusedinconjunctionwiththecurrentEMAguidelineonProcessValidation.第五节应该和现行的欧洲药品局关于工艺验证的指南联合使用。TheguidelineonProcessValidationisintendedtoprovideguidaneeontheinformationanddatatobeprovidedintheregulatorysubmissiononly.HoweverGMPrequirementsforprocessvalidationcontinuethroughoutthelifecycleoftheprocess本工艺验证指南仅仅为提交给药政当局的相关信息和数据提供指导。然而，GMP对工艺验证的要求依然是贯穿于工艺的整个生命周期。Thisapproachshouldbeappliedtolinkproductandprocessdevelopment.Itwillensurevalidationofthecommercialmanufacturingprocessandmaintenanceoftheprocessinastateofcontrolduringroutinecommercialproduction.本方法适用于关联产品和工艺开发，它可以确保商业化的生产工艺和工艺维护在商业化生产期间处于受控状态。53Manufacturingprocessesmaybedevelopedusingatraditionalapproachoracontinuousverificationapproach.However,irrespectiveoftheapproachused,processesmustbeshowntoberobustandensureconsistentproductqualitybeforeanyproductisreleasedtothemarket.Manufacturingprocessesusingthetraditionalapproachshouldundergoaprospectivevalidationprogramme,whereverpossible,priortocertificationoftheproduct.Retrospectivevalidationisnolongeranacceptableapproach.何种方法，工艺都必须是成熟稳定的，并确保在产品上市之前其质量的一致性。使用传统方法开发的生产工艺在产品放行前都应当经过前验证。回顾性验证不再是可接受的方式。Processvalidationofnewproductsshouldcoverallintendedmarketedstrengthsandsitesofmanufacture.Bracketingcouldbejustifiedfornewproductsbasedonextensiveprocessknowledgefromthedevelopmentstageinconjunctionwithanappropriateongoingverificationprogramme.新产品的工艺验证应当包括所有计划上市的规格和生产场所。基于开发阶段大量的工艺知识，结合适当的正在进行中的验证程序，新产品可以经过论证采用界定法。Forprocessvalidationofproductswhicharetransferredfromonesitetoanotherorwithinthesamesite,thenumberofvalidationbatchescouldbereducedbytheuseofabracketingapproach.However,existingproductknowledge,includingthecontentofthepreviousvalidation,shouldbeavailable.Differentstrengths,batchsizesandpacksizes/containertypesmayalsouseabracketingapproach,ifjustified.对于同一地点内或者两个不同地点之间的场地转移的工艺验证，可以使用界定法减少验证批次。但是，必须保证现有的产品知识（包括上一次的验证内容）可用。不同之处在于，可以使用界定法决定批量、包装规格、包装容器类型。Forthesitetransferoflegacyproducts,themanufacturingprocessandcontrolsmustcomplywiththemarketingauthorisationandmeetcurrentstandardsformarketingauthorisationforthatproducttype.Ifnecessary,variationstothemarketingauthorisationshouldbesubmitted.对于老产品的生产地址转移,生产工艺和控制应符合上市监督管理要求，产品类型应符合相应的现行上市标准。必要的时候还应当提交上市许可的变更。Processvalidationshouldestablishwhetherallqualityattributesandprocessparameters,whichareconsideredimportantforensuringthevalidatedstateandacceptableproductquality,canbeconsistentlymetbytheprocess.Thebasisbywhichprocessparametersandqualityattributeswereidentifiedasbeingcriticalornon-criticalshouldbeclearlydocumented,takingintoaccounttheresultsofanyriskassessmentactivities.工艺验证应当证明是否所有的质量属性和工艺参数（被认为可以确保验证状态和产品质量的重要项目）能够与工艺持续相符。应当根据风险评估的结果，在文件中明确哪些工艺参数和质量属性是关键的或者不关键的。NormallybatchesmanufacturedforprocessvalidationshouldbethesamesizeastheintendedcommercialscalebatchesandtheuseofanyotherbatchsizesshouldbejustifiedorspecifiedinothersectionsofEudraLex,Volume4.工艺验证批次与计划商业化生产的上市批次的批量应保持一致，使用其他批量应按照第四卷其他部分相关的要求进行评估和说明。Equipment,facilities,utilitiesandsystemsusedforprocessvalidationshouldbequalified.Testmethodsshouldbevalidatedfortheirintendeduse.设备、设施、公用工程和系统在工艺验证前应经过确认，预定用途的检验方法应经过验证。Forallproductsirrespectiveoftheapproachused,processknowledgefromdevelopmentstudiesorothersourcesshouldbeaccessibletothemanufacturingsite,unlessotherwisejustified,andbethebasisforvalidationactivities.与所使用的方法无关，除非经过其他评估，所有产品在研发阶段或者其它来源的工艺知识应当被生产工厂做接收，并作为验证活动开展的基础。Forprocessvalidationbatches,production,development,orothersitetransferpersonnelmaybeinvolved.BatchesshouldonlybemanufacturedbytrainedpersonnelinaccordaneewithGMPusingapproveddocumentation.Itisexpectedthatproductionpersonnelareinvolvedinthemanufactureofvalidationbatchestofacilitateproductunderstanding.对于工艺验证批而言，生产、研发或者其他现场转移的人员均需要参加。验证批次必须由按照GMP文件规定培训合格的人员进行生产，这样有助于生产人员通过工艺验证批次生产加深对工艺的理解。Thesuppliersofcriticalstartingandpackagingmaterialsshouldbequalifiedpriortothemanufactureofvalidationbatches;otherwiseajustificationbasedontheapplicationofqualityriskmanagementprinciplesshouldbedocumented.在工艺验证开始之前，应审核起始物料、包装材料的供应商，以确定其资质。否则，应当根据风险管理的原则来证明不这样做的理由。Itisespeciallyimportantthattheunderlyingprocessknowledgeforthedesignspacejustification(ifused)andfordevelopmentofanymathematicalmodels(ifused)toconfirmaprocesscontrolstrategyshouldbeavailable.需要特别强调的是，基于设计空间(如有使用)和工艺开发数学模型(如有使用)的基础知识确定的工艺控制策略是可接受的。Wherevalidationbatchesarereleasedtothemarket,thisshouldbepre-defined.TheconditionsunderwhichtheyareproducedshouldfullycomplywithGMP,withthevalidationacceptaneecriteria,withanycontinuousprocessverificationcriteria(ifused)andwiththemarketingauthorisationorclinicaltrialauthorisation.验证批上市之前，应确定产品的生产环境应完全符合GMP、验证可接受标准、持续工艺确认标准(如有使用)，并获得上市许可或临床许可。Fortheprocessvalidationofinvestigationalmedicinalproducts(IMP),pleaserefertoAnnex13.临床试验用药品(IMP)的工艺验证，参见附录13。Concurrentvalidation同步验证Inexceptionalcircumstances,wherethereisastrongbenefit-riskratioforthepatient,itmaybeacceptablenottocompleteavalidationprogrammebeforeroutineproductionstartsandconcurrentvalidationcouldbeused.However,thedecisiontocarryoutconcurrentvalidationmustbejustified,documentedintheVMPforvisibilityandapprovedbyauthorisedpersonnel.在特殊情况下，如果对患者利益明显大于风险，允许在常规商业化生产前没有完成验证程序而使用同步验证。然而，进行同步验证的决定必须进行论证，并在验证主计划中明确，且经被授权的人批准。Whereaconcurrentvalidationapproachhasbeenadopted,thereshouldbesufficientdatatosupportaconclusionthatanygivenbatchofproductisuniformandmeetsthedefinedacceptaneecriteria.TheresultsandconclusionshouldbeformallydocumentedandavailabletotheQualifiedPersonpriortocertificationofthebatch.当采用同步验证的时候，应有足够数据支持做出“批次间产品是均一的且符合预定可接受标准”的结论。结果和结论应进行正式记录，并在批放行前通过质量授权人审核。Traditionalprocessvalidation传统工艺验证Inthetraditionalapproach,anumberofbatchesofthefinishedproductaremanufacturedunderroutineconditionstoconfirmreproducibility.在传统方式中，需要在正常条件下生产出很多批成品才能确认其重现性。Thenumberofbatchesmanufacturedandthenumberofsamplestakenshouldbebasedonqualityriskmanagementprinciples,allowthenormalrangeofvariationandtrendstobeestablishedandprovidesufficientdataforevaluation.Eachmanufacturermustdetermineandjustifythenumberofbatchesnecessarytodemonstrateahighlevelofassurancethattheprocessiscapableofconsistentlydeliveringqualityproduct.生产批次数和取样样品数量都应基于质量风险管理的原则，如果能够提供足够的数据进行评估，允许规定变动和趋势的范围。生产商需要确定和交代必须生产多少批次才可以表明工艺能够持续生产出优质产品的高水平保证度。Withoutprejudiceto5.19,itisgenerallyconsideredacceptablethataminimumofthreeconsecutivebatchesmanufacturedunderroutineconditionscouldconstituteavalidationoftheprocess.Analternativenumberofbatchesmaybejustifiedtakingintoaccountwhetherstandardmethodsofmanufactureareusedandwhethersimilarproductsorprocessesarealreadyusedatthesite.Aninitialvalidationexercisewiththreebatchesmayneedtobesupplementedwithfurtherdataobtainedfromsubsequentbatchesaspartofanon-goingprocessverificationexercise.一般来说，在不违背5.19的情况下，正常生产条件下至少连续生产三个批次可被认为满足工艺验证要求。若使