who验证指南2016年版

1、INTRODUCTION简介Validationisanessentialpartofgoodpracticesincludinggoodmanufacturingpractices(GMP)(4)andgoodclinicalpractices(GCP).Itisthereforeanelementofthepharmaceuticalqualitysystem.Validation,asaconcept,incorporatesqualificationandshouldbeappliedoverthelifecycleof,e.g.theapplicableproduct,process

2、,system,equipmentorutility.验证是包括GMP和GCP在内的良好规范的必要部分。因此是制药质量体系的组成部分。验证这个概念包括确认并且应该在产品、工艺、系统、设备或设施的整个生命周期中被使用。Theseguidelinescoverthegeneralprinciplesofvalidationandqualification.Inadditiontothemainpart,appendicesonvalidationandqualification(e.g.cleaning,computerandcomputerizedsystems,equipment,utilit

3、iesandsystems,andanalyticalmethods)areincluded.这个指南包括验证和确认的一般原则。除了主体部分外，还包括确认和验证附件(如清洁、计算机和计算机化系统、设备、设施和系统以及分析方法。Thefollowingprinciplesapply:适用的原则如下：theexecutionofvalidationshouldbeincompliancewithregulatoryexpectations;验证的执行应该符合监管预期quality,safetyandefficacymustbedesignedandbuiltintotheproduct;质量、安全

4、和效力应该被设计和构建到产品中qualitycannotbeinspectedortestedintotheproduct;质量不能通过检查或测试赋予产品qualityriskmanagementprinciplesshouldbeappliedindeterminingtheneed,scopeandextentofvalidation;应该应用质量风险管理规则来决定验证的需求、范围和程度ongoingreviewshouldtakeplacetoensurethatthevalidatedstateismaintainedandopportunitiesforcontinuingimpro

5、vementareidentified.应该进行持续的回顾来确保维持验证状态并识别持续改进的机会Theimplementationofvalidationworkrequiresconsiderableresourcessuchas:验证工作的完成需要大量资源，例如time:generallyvalidationworkissubjecttorigoroustimeschedules;时间：一般验证工作需要有一个严密的时间表financial:validationoftenrequiresthetimeofspecializedpersonnelandexpensivetechnology.资

6、金：验证经常需要专业人员和昂贵的技术human:validationrequiresthecollaborationofexpertsfromvariousdisciplines(e.g.amultidisciplinaryteam,comprisingqualityassurance,engineering,informationtechnology,manufacturingandotherdisciplines,asappropriate.).人员：验证需要不同学科专家的协作(例如一个多学科小组，视情况可能包括QA、工程、信息技术、生产以及其他学科人员)SCOPE范围Theseguide

7、linesfocusmainlyontheoverallconceptofvalidationandarenotintendedtobeprescriptiveinspecificvalidationrequirements.Thisdocumentservesasgeneralguidanceonlyandtheprinciplesmaybeconsideredusefulinitsapplicationinthemanufactureandcontrolofstartingmaterialsandfinishedpharmaceuticalproducts(FPPs),aswellasot

8、herareas.Validationofspecificprocessesandsystems,forexample,insterileproductmanufacture,requiresmuchmoreconsiderationandadetailedapproachthatisbeyondthescopeofthisdocument.这些指南主要关注验证的整体概念，无意规定具体的验证要求。用作GMP检查官和生产商的基本指南，本文件仅作为一个一般指南，其原则在其应用于起始物料及制剂的生产和控制时会比较有用，也应用于其他领域。特定工艺和产品的验证，例如无菌产品生产，需要考虑更多内容，和更详

9、细的方法，不在本文件范围之内。Therearemanyfactorsaffectingthedifferenttypesofvalidationanditis,therefore,notintendedtodefineandaddressallaspectsrelatedtooneparticulartypeofvalidationhere.有很多因素会对不同类型的验证产生影响，因此，这里不会对某个特定类型的验证相关的所有方面进行定义和说明。Thegeneraltextinthemainpartoftheseguidelinesmaybeapplicabletovalidationandqua

10、lificationofpremises,equipment,utilities,systems,processesandprocedures.这些指南的主体部分的一般内容可能适用于设施、设备、公用设施和系统、工艺和程序的验证和确认。GLOSSARY术语Thedefinitionsgivenbelowapplytothetermsusedintheseguidelines.Theymayhavedifferentmeaningsinothercontexts.本指南使用的术语定义如下。它们在其它环境中可能有不同的含义calibration.Thesetofoperationsthatestab

11、lish,underspecifiedconditions,therelationshipbetweenvaluesindicatedbyaninstrumentorsystemformeasuring(forexample,weight,temperatureandpH),recording,andcontrolling,orthevaluesrepresentedbyamaterialmeasure,andthecorrespondingknownvaluesofareferencestandard.Limitsforacceptanceoftheresultsofmeasuringsho

12、uldbeestablished.校准：changecontrol(includingchangemanagement).Aformalsystembywhichqualifiedrepresentativesofappropriatedisciplinesreviewproposedoractualchangesthatmightaffectavalidatedstatus.Theintentistodeterminetheneedforactionthatwouldensurethatthesystemismaintainedinavalidatedstate(referenceworki

13、ngdocumentQAS/15.639/Rev.1-unpublished).变更控制(包括变更管理)cleaningvalidation.Documentedevidencetoestablishthatcleaningproceduresareremovingresiduestopredeterminedlevelsofacceptability,takingintoconsiderationfactorssuchasbatchsize,dosing,toxicologyandequipmentsize.清洁验证commissioning.Thesettingup,adjustmenta

14、ndtestingofequipmentorasystemtoensurethatitmeetsalltherequirements,asspecifiedintheuserrequirementspecification,andcapacitiesasspecifiedbythedesignerordeveloper.Commissioningiscarriedoutbeforequalificationandvalidation.试车computervalidation(includingcomputerizedsystemvalidation).Confirmationbyexamina

15、tionandprovisionofobjectivedocumentedevidencethatcomputerizedsystemspecificationsconformtouserneedsandintendeduses,andthatallrequirementscanbeconsistentlyfulfilled.计算机验证(包括计算机化系统验证)concurrentvalidation.Validationcarriedoutduringroutineproductionofproductsintendedforsale.同步验证designqualification.Docum

16、entedverificationthattheproposeddesignoffacilities,systemsandequipmentissuitablefortheintendedpurpose.设计确认goodengineeringpractices.Establishedengineeringmethodsandstandardsthatareappliedthroughouttheprojectlife-cycletodeliverappropriate,cost-effectivesolutions.良好工程规范installationqualification.Documen

17、tedverificationthattheinstallations(suchasmachines,computersystemcomponents,measuringdevices,utilitiesandmanufacturingareas)usedinaprocessorsystemareappropriatelyselectedandcorrectlyinstalledinaccordancewithestablishedspecifications.安装确认operationalqualification.Documentedverificationthatthesystemors

18、ubsystemoperatesasintendedoverallanticipatedoperatingranges.运行确认performancequalification.Documentedverificationthattheequipmentorsystemperformsconsistentlyandreproduciblywithindefinedspecificationsandparametersinitsnormaloperatingenvironment(heproductionenvironment).(Inthecontextofsystems,theterm“pr

19、ocessvalidation”mayalsobeused.)性能确认processvalidation.Thecollectionandevaluationofdata,throughouttheproductlifecycle,whichprovidesdocumentedscientificevidencethataprocessiscapableofconsistentlydeliveringqualityproducts.工艺验证prospectivevalidation.Validationcarriedoutduringthedevelopmentstageonthebasiso

20、fariskanalysisoftheproductionprocess,whichisbrokendownintoindividualsteps;thesearethenevaluatedonthebasisofpastexperiencetodeterminewhethertheymayleadtocriticalsituations.前验证qualification.Documentedevidencethatpremises,systemsorequipmentareabletoachievethepredeterminedspecificationsproperlyinstalled

21、,and/orworkcorrectlyandleadtotheexpectedresults.Qualificationisoftenapart(theinitialstage)ofvalidation,buttheindividualqualificationstepsalonedonotconstituteprocessvalidation.确认revalidation.Repeatedvalidationofapreviouslyvalidatedsystem(orapartthereof)toensurecontinuedcompliancewithestablishedrequir

22、ements.再验证：对先前已验证的系统(或它的一部分)的重复验证来确保持续符合既定标准。standardoperatingprocedure.Anauthorizedwrittenproceduregivinginstructionsforperformingoperationsnotnecessarilyspecifictoagivenproductormaterialbutofamoregeneralnature(e.g.equipmentoperation,maintenanceandcleaning;validation;cleaningofpremisesandenvironmen

23、talcontrol;samplingandinspection).Certainstandardoperatingproceduresmaybeusedtosupplementproduct-specificmasterbatchproductiondocumentation.标准操作规程validation.Actionofprovinganddocumentingthatanyprocess,procedureormethodactuallyandconsistentlyleadstotheexpectedresults.验证validationmasterplan.Thevalidat

24、ionmasterplanisahigh-leveldocumentthatestablishesanumbrellavalidationplanfortheentireprojectandsummarizesthemanufacturersoverallphilosophyandapproach,tobeusedforestablishingperformanceadequacy.Itprovidesinformationonthemanufacturersvalidationworkprogrammeanddefinesdetailsofandtimescalesforthevalidat

25、ionworktobeperformed,includingastatementoftheresponsibilitiesofthoseimplementingtheplan.验证主计划validationprotocol.Adocumentdescribingtheactivitiestobeperformedduringavalidation,includingtheacceptancecriteriafortheapprovalofaprocessorsystemorapartthereofforintendeduse.验证方案validationreport.Adocumentinwh

26、ichtherecords,resultsandevaluationofvalidationareassembledandsummarized.Itmayalsocontainproposalsfortheimprovementofprocessesand/orsystemsand/orequipment.验证报告verification.Theapplicationofmethods,procedures,testsandotherevaluations,inadditiontomonitoring,todeterminecompliancewithestablishedrequiremen

27、tsandspecifications.核实worstcase.Aconditionorsetofconditionsencompassingtheupperandlowerprocessinglimitsforoperatingparametersandcircumstances,withinSOPs,whichposethegreatestchanceofproductorprocessfailurewhencomparedtoidealconditions.Suchconditionsdonotnecessarilyincludeproductorprocessfailure.最差条件R

28、ELATIONSHIPBETWEENVALIDATIONANDQUALIFICATION验证与确认的关系Qualificationandvalidationareessentiallythesame.Thetermqualificationisnormallyusedforequipmentandutilities,andvalidationforsystemsandprocesses.Inthissense,qualificationcanbeseenaspartofvalidation.确认和验证本质上是一样的。确认通常用于设备和设施，而验证则用于系统和工艺。在这层意义上，确认可以被看做是

29、验证的一部分。Wheretheterm“validation”isusedinthedocument,thesameprinciplesmaybeapplicablefor“qualification在文件中使用术语“验证”的规则同样适用于“确认”VALIDATION验证Approachestovalidation验证的方法Manufacturersshouldorganizeandplanvalidationinamannerthatwillensureproductquality,safetyandefficacythroughoutitslifecycle.生产商应该组织和计划验证以保证

30、产品在其生命周期内的质量、安全和有效。Thescopeandextentofqualificationandvalidationshouldbebasedonriskmanagementprinciples.确认和验证的范围和程度应该基于风险管理规则。Statisticalcalculationsshouldbeapplied,whereappropriate,andprovidescientificevidencethattheprocess,systemorotherrelatedaspectisappropriatelyvalidated.适当时，应该使用统计学计算并提供工艺、系统或其它

31、相关方面有效的科学证据Qualificationandvalidationshouldbedoneinaccordancewithpredeterminedprotocols,andtheresultsappropriatelydocumented,e.g.inreports.确认和验证应该按照预定的方案执行并且结果应被适当的记录，如在报告中。Thereshouldbeanappropriateandeffectivequalitysystemensuringtheorganizationandmanagementofvalidation.应有适当的和有效的质量体系来保证验证的组织和管理。Se

32、niormanagementshouldensurethattherearesufficientresourcestoperformvalidationinatimelymanner.Managementandpersonsresponsibleforqualityassuranceshouldbeactivelyinvolvedintheprocessandauthorizationofprotocolsandreports.高级管理层应该确保充分的资源来及时地执行验证。管理层和质量保证负责人应该积极参与方案和报告的批准活动中。Personnelwithappropriatequalific

33、ationandexperienceshouldberesponsibleforperformingvalidation.有适当资质和经验的人员应该对验证的执行负责。Thereshouldbeaspecificprogrammeorscheduletosupportplanningandexecutionofvalidationactivities.应有专门的计划或时间表来支持计划和执行验证活动。Validationshouldbeperformedinastructuredwayaccordingtothedocumentedprotocolsandprocedures.验证应该按照文件化的

34、方案和规程以一种有组织的方式执行。Qualificationandvalidationshouldbeperformed:确认和验证应该被执行：-fornewpremises,equipment,utilitiesandsystems,andprocessesandprocedures;新设施、设备、公用设施和系统，以及新的工艺和程序；-whenchangesaremade,dependingontheoutcomeofriskassessment;当发生变更时，根据风险评估的结果；-wherenecessaryorindicatedbasedontheoutcomeofperiodicrev

35、iew.基于定期回顾的结果表明需要的5.11Awrittenreportontheoutcomeofthevalidationshouldbeprepared.应该对验证的结果准备一份书面报告。5.12Thescopeandextentofvalidationshouldbebasedonknowledgeandexperience,andtheoutcomeofqualityriskmanagementprinciplesasdescribedintheWorldHealthOrganization(WHO)guidelinesonqualityriskmanagement.Wherenec

36、essaryworst-casesituationsorspecificchallengetestsshouldbeconsideredforinclusioninthevalidation,forexample,stressloadandvolumeverificationincomputersystemvalidation.验证的范围和程度应该基于知识和经验，以及描述于WHO质量风险管理指南中的质量风险管理管理规则的结果来决定。DOCUMENTATION文件-Qualificationandvalidationshouldbedoneaccordingtowrittenprocedures

37、.确认和验证应该按照书面程序执行6.2Documentsassociatedwithqualificationandvalidationinclude:与确认和验证相关的文件包括：-validationmasterplan(VMP);验证主计划(VMP)-standardoperatingprocedures(SOPs);标准操作规程(SOP)specifications;规范protocolsandreports;方案和报告riskassessmentoutcomes;风险管理结果processflowcharts;工艺流程图operatormanuals;操作手册trainingrecor

38、ds;培训记录calibrationproceduresandrecords;校准规程和记录samplingplans;取样计划testingplansandmethods;测试计划和方法statisticalmethodsandresults;统计学方法和结果historyofqualificationorvalidation;确认或验证历史planforensuringreviewofvalidationstatus;确保回顾验证状态的计划planforensuringmaintainingavalidatedstate.确保维持验证状态的计划VALIDATIONMASTERPLAN验证主

39、计划AmanufacturershouldhaveaVMPwhichreflectsthekeyelementsofvalidation.Itshouldbeconciseandclearandcontainatleastthefollowing:生产商应有一份VMP反映验证的关键要素。它应该简洁清晰并至少包括：-titlepageandauthorization(approvalsignaturesanddates);书名页和批准(批准签名和日期)tableofcontents;目录abbreviationsandglossary;缩写和术语validationpolicy;验证方针phil

40、osophy,intentionandapproachtovalidation;验证的原理、目的和方法rolesandresponsibilitiesofrelevantpersonnel;相关人员的角色和责任resourcestoensurevalidationisdone;确保验证执行的资源-outsourcedservices(selection,qualification,managementthroughlifecycle);外包服务(选择、确认和生命周期管理)-deviationmanagementinvalidation;验证偏差管理changecontrolinvalidati

41、on;验证变更控制-riskmanagementprinciplesinvalidation;验证风险管理规则training;培训scopeofvalidation;验证的范围documentationrequiredinqualificationandvalidationsuchasprocedures,certificates,protocolsandreports;确认和验证所需的文件，如规程、证书、方案和报告premisesqualification;设施确认utilitiesqualification;公用设施确认-equipmentqualification;设备确认proces

42、svalidation;工艺验证cleaningvalidation;清洁验证-personnelqualificationsuchasanalystqualification;人员确认例如分析人员确认analyticalmethodvalidation;分析方法验证computerizedsystemvalidation;计算机化系统验证establishingacceptancecriteria;建立接受标准life-cyclemanagementincludingretirementpolicy;生命周期管理包括退役的方针requalificationandrevalidation;再确

43、认和再验证relationshipwithotherqualitymanagementelements;与其他质量管理要素的关系validationmatrix;验证矩阵references.参考文献TheVMPshouldbereviewedatregularintervalsandkeptuptodateaccordingtocurrentGMP.VMP应该每隔一段时间回顾并保持持续符合现行GMPQUALIFICATIONANDVALIDATIONPROTOCOLS确认和验证方案Thereshouldbequalificationandvalidationprotocolsdescribi

44、ngthequalificationandvalidationtobeperformed.应有确认和验证方案描述所要执行的确认和验证。Asaminimumtheprotocolsshouldincludethefollowingsignificantbackgroundinformation:方案应该至少包括下列重要的背景信息：theobjectives;目的thesite;场所theresponsiblepersonnel负责的人员-descriptionofthestandardoperatingprocedures（SOPs）tobefollowed;所遵循的标准操作规程描述equipm

45、entorinstrumentstobeused;所使用的设备或仪器standardsandcriteriaasappropriate;适当的标准-thestageofvalidationorqualification;验证或确认的阶段theprocessesand/orparameters;工艺和/或参数-sampling,testingandmonitoringrequirements;取样，测试和监测需求-stresstestingwhereappropriate;压力测试（如适用）calibrationrequirements;校准需求-predeterminedacceptancec

46、riteriafordrawingconclusions;预定的用于下定结论的接受标准-reviewandinterpretationofresults;结果的审核和分析changecontrol,deviations;变更控制、偏差archivingandretention.归档和保留8.3Thereshouldbeadescriptionofthewayinwhichtheresultswillbeanalysed,includingstatisticalanalysiswhereappropriate.应有一个结果分析方法，包括统计学分析（如使用）的描述Theprotocolshould

47、beapprovedpriortouse.Anychangestoaprotocolshouldbeapprovedpriortoimplementationofthechange.方案应该在使用前被批准。方案的任何变更应在实施前被批准。QUALIFICATIONANDVALIDATIONREPORTS确认和验证报告Thereshouldbewrittenreportsonthequalificationandvalidationperformed.应有所执行的确认和验证的书面报告Reportsshouldreflecttheprotocolsandproceduresfollowedandi

48、ncludeatleastthetitleandobjectiveofthestudy;makereferencetotheprotocol;referencetotheappropriateriskassessment;detailsofmaterials,equipment,programmesandcyclesused;proceduresandtestmethodswithappropriatetraceability.报告应该反映所遵循的方案和规程并至少包括题目和目的；方案的参考；适当的风险评估的参考；所使用的材料、设备、计划和周期的描述；适当的规程和测试方法追溯Resultssho

49、uldberecordedandbeincompliancewithgooddataandrecordmanagementpractices.应该记录结果并符合良好数据和记录管理规范。Resultsshouldbereviewed,analysedandcomparedagainstthejustifiedpredeterminedacceptancecriteria,interpretedandstatisticallyanalysedwhereappropriate.结果应该被回顾、分析并与预定的接受标准比较，解释和统计学分析（如适用）Resultsshouldmeettheaccepta

50、ncecriteria.Deviations,out-of-specificationandout-of-limitresultsshouldbedocumentedandinvestigatedaccordingtoappropriateprocedures.Ifthesedeviationsareaccepted,thisshouldbejustified.Wherenecessary,furtherstudiesshouldbeperformed.结果应该符合接受标准。偏差、OOS和超限结果应该按照适当的程序记录和调查。如接受这些偏差，应有正当理由。必要时，应进行更进一步的研究。Thec

51、onclusionofthereportshouldstatewhetherornottheoutcomeofthequalificationand/orvalidationwasconsideredsuccessful,andshouldmakerecommendationsforfuturemonitoringandsettingofalertandactionlimitswhereapplicable.报告的结论应声明确认和/或验证的结果是否被认为是成功的，并应该对下一步的监测和设置警戒限、行动限（如适用）提供建议Thedepartmentsresponsibleforthequalif

52、icationandvalidationworkshouldapprovethecompletedreport.确认和验证工作的责任部门应该批准完成报告Thequalityassurancedepartmentshouldapprovethereportafterthefinalreview.Thecriteriaforapprovalshouldbeinaccordancewiththecompanysqualityassurancesystem.质量保证部门应该在最终审核后批准报告。批准的标准应该符合公司的质量保证体系。Anydeviationsfoundduringthevalidati

53、onprocessshouldbemanagedanddocumented.Correctiveactionsshouldbeconsidered.在验证过程中发生的任何偏差应该被管理和记录，应该考虑纠正措施。QUALIFICATION确认Therearedifferentapproachesinqualificationandvalidation.Themanufacturershouldselectanappropriateapproachfortheconductthereof.确认和验证有不同的方法，生产者应该在其中选择适用的方法。Figure1.TheV-modelasanexamp

54、leofanapproachtoqualificationandvalidation.图一一个确认和验证的V模型举例*Note.Seetextbelowforclarificationontermsandstages备注：术语和阶段描述见下列文本AllrelevantSOPsforoperation,maintenanceandcalibrationshouldbepreparedduringqualification.所有运行、维护和校准相关的SOP应该在确认期间被准备妥当Trainingshouldbeprovidedtooperatorsandtrainingrecordsshouldb

55、emaintained.培训应该被提供给操作者并且应有培训记录Normally,qualificationshouldbecompletedbeforeprocessvalidationisperformed.通常地，确认应该在执行工艺验证前完成Theprocessofqualificationshouldbealogical,systematicprocessandshouldfollowalogicalflowfromthepremises,followedbyutilities,equipment,toproceduresandprocesses.确认的过程应该符合逻辑、有条理和应该遵循

56、从前提，然后公用设施、设备到程序和工艺的逻辑流程Stagesofqualificationshouldnormallystartwiththepreparationofuserrequirementspecifications(URS).Dependingonthefunctionandoperationoftheutility,equipmentorsystem,thisisfollowedby,asappropriate,differentstagesinqualificationsuchasafactoryacceptancetest(FAT),siteacceptancetest(SA

57、T),designqualification(DQ),installationqualification(IQ),operationalqualification(OQ)andperformancequalification(PQ).通常地，确认的阶段应该从用户需求规范(URS)的准备开始。然后根据设施、设备或者系统的功能和操作特点，选择不同的确认阶段，如工厂验收测试(FAT),现场验收测试(SAT),设计确认(DQ)、安装确认(IQ)、运行确认(0Q)和性能确认(PQ)。Onestageofqualificationshouldbesuccessfullycompletedbeforethe

58、nextstageisinitiated,e.g.fromIQtoOQ.确认时，一个阶段在开始下一个阶段前被成功地完成，例如，从IQ到OQ。Insomecases,onlyIQandOQmayberequired,asthecorrectoperationoftheequipment,utilityorsystemcouldbeconsideredtobeasufficientindicatorofitsperformance.在某些情况下，只需要进行IQ和0Q,设备、设施或系统的正确操作就可以被认为它的性能的一个充分的指标了。Majorequipmentandcriticalutilitie

59、sandsystems,however,mayrequireURS,DQ,IQ,OQandPQ.主要设备和关键设施和系统则可能需要URS、DQ、IQ、OQ和PQComputerizedsystems,includingequipmentwithsoftwarecomponent(s),requireuserandfunctionalrequirementsspecifications,designandconfigurationspecifications,developmentofSOPs,trainingprogrammesforsystemuseandadministration,and

60、anappropriatelevelofIQ,OQandPQverificationtesting.Thisincludestestssuchasstress,load,volumeandotherperformanceverificationteststhatmimictheliveproductionenvironment.ItalsoincludesuseracceptancetestingaccordingtodraftSOPsandtrainingaswellasend-to-endbusinessprocessesforintendeduse.计算机化系统，包括有软件构件的设备，需