EMA工艺验证指引

EMA工艺验证指南---EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev127February2014CommitteeforMedicinalProductsforHumanUse(CHMP)CommitteeforMedicinalProductsforVeterinaryUse(CVMP)Guidelineonprocessvalidationforfinishedproducts-informationanddatatobeprovidedinregulatorysubmissions制剂工艺验证指南---在法规提交中要提供的资料和数据DraftagreedbyCHMP/CVMPQualityWorkingParty2February2012由CHMP/CVMP质量工作组通过草案2012年2月2日AdoptionbyCVMPforreleaseforconsultation8March2012CVMP同意公开征求意见2012年3月8日AdoptionbyCHMPforreleaseforconsultation15March2012CHMP同意公开征求意见2012年3月15日Endofconsultation(deadlineforcomments)31October2012征求意见结束（截止日期）2012年10月31日AgreedbyQWP8November2013由QWP通过2013年11月8日AgreedbyBWP13November2013由BWP通过2013年11月13日AdoptionbyCHMP19December2013由CHMP采用2013年12月19日AdoptionbyCVMP15January2014由CVMP采用2014年1月15日Dateforcomingintoeffect6monthsafterpublication生效日期公布后6个月Thisguidelinereplacesthenoteforguidanceonprocessvalidation(CPMP/QWP/848/96,EMEA/CVMP/598/99)includingannexII-non-standardprocesses(CPMP/QWP/2054/03).本指南替代工艺验证注释(CPMP/QWP/848/96,EMEA/CVMP/598/99)，包括附录二----非标准工艺(CPMP/QWP/2054/03)。KeywordsProcessvalidation,continuousprocessverification,on-goingprocessverification,criticalprocessparameter,criticalqualityattribute,lifecycle,changecontrol关键词工艺验证、持续工艺确认、关键工艺参数、关键质量属性、生命周期、变更控制Tableofcontents目录Executivesummary实施摘要1.Introduction(background)介绍（背景）2.Scope范围3.Legalbasis法规依据4.Generalconsiderations一般考虑5.Processvalidation工艺验证5.1.Traditionalprocessvalidation传统工艺验证5.2.Continuousprocessverification持续工艺确认5.3.Hybridapproach混合方案5.4.Designspaceverification设计空间确认6.Scale-up放大生产7.Postapprovalchangecontrol批准后变更控制8.Standardvs.non-standardmethodsofmanufacture标准VS非标准生产方法Definitions定义References参考文献AnnexI:Processvalidationscheme附录I：工艺验证计划AnnexII:Standard/non-standardprocesses附录II：标准/非标工艺Executivesummary实施摘要Thisguidelinereplacesthepreviousnoteforguidanceonprocessvalidation(CPMP/QWP/848/96,EMEA/CVMP/598/99).TheguidelineisbroughtintolinewithICHQ8,Q9andQ10documentsandthepossibilitytousecontinuousprocessverificationinadditionto,orinsteadof,traditionalprocessvalidationdescribedinthepreviousguidelinehasbeenaddedandisencouraged.Thisguidelinedoesnotintroducenewrequirementsonmedicinalproductsalreadyauthorisedandonthemarket,butclarifieshowcompaniescantakeadvantageofthenewpossibilitiesgivenwhenapplyingenhancedprocessunderstandingcoupledwithriskmanagementtoolsunderanefficientqualitysystemasdescribedbyICHQ8,Q9andQ10.本指南替代之前的工艺验证指南解释(CPMP/QWP/848/96,EMEA/CVMP/598/99)。本指南与ICHQ8,Q9和Q10文件相一致，提供在之前加入和鼓励采用的传统工艺验证这外，提供了使用持续工艺确认的可能性。本指南对已批准上市的药品未引入新要求，但阐述了公司在ICHQ8,Q9和Q10中描述的有效质量体系下，应用强化工艺理解与风险管理工具时，如何抓住所给的新的可能性。Introduction(background)介绍(背景)Processvalidationcanbedefinedasdocumentedevidencethattheprocess,operatedwithinestablishedparameters,canperformeffectivelyandreproduciblytoproduceamedicinalproductmeetingitspredeterminedspecificationsandqualityattributes(ICHQ7).Continuousprocessverificationhasbeenintroducedtocoveranalternativeapproachtoprocessvalidationbasedonacontinuousmonitoringofmanufacturingperformance.Thisapproachisbasedontheknowledgefromproductandprocessdevelopmentstudiesand/orpreviousmanufacturingexperience.工艺可定义为证明在建立的参数范围内操作的工艺可以重复有效地生产出符合其预定质量标准和质量属性的药品的书面证据(ICHQ7)。持续工艺验证被引入替代基于对工艺性能持续监测的工艺验证。这种方法是依据来自于产品和工艺研发和/或之前生产经验的知识。Continuousprocessverificationmaybeapplicabletobothatraditionalandenhancedapproachtopharmaceuticaldevelopment.Itmayuseextensivein-line,on-lineorat-linemonitoringand/orcontrolstoevaluateprocessperformance.ItisintendedthatthecombinationoftheadviceprovidedintheNoteforGuidanceonDevelopmentPharmaceutics(CPMP/QWP/155/96)andtheNoteforGuidanceonPharmaceuticalDevelopment(ICHQ8R2)togetherwiththisguidelineshouldcoverallofthecriticalelementsinmanufacturingprocessforinclusioninthedossierforregulatorysubmissionforapharmaceuticalproductforhumanuse.Forveterinarymedicinalproducts,theapplicableguidanceisthatprovidedintheNoteforGuidanceonDevelopmentPharmaceuticsforVeterinaryMedicinalProducts(EMEA/CVMP/315/98)togetherwiththisguideline.AlthoughtheICHQ8guidelineisnotapplicabletoveterinarymedicinalproductstheprinciplesdetailedinthisguidelinemaybeappliedtoveterinarymedicinalproductsshouldanapplicantchoosetoapplyanenhancedapproachtopharmaceuticaldevelopmentandprocessvalidation.Processvalidationshouldnotbeviewedasaone-offevent.Processvalidationincorporatesalifecycleapproachlinkingproductandprocessdevelopment,validationofthecommercialmanufacturingprocessandmaintenanceoftheprocessinastateofcontrolduringroutinecommercialproduction.持续工艺确认既适用于传统药品研发方法，也适用于加强药品研发方法。它采用广泛的在线监测和/或控制来评估工艺的性能。将研发药物指南解释(CPMP/QWP/155/96)、药物研发指南解释(ICHQ8R2)与本指南相结合，应可以覆盖人用药法规申报文件所需包括的生产工艺的关键因素。对于兽药产品，适用的指南为“兽药研发指南解释”(EMEA/CVMP/315/98)与本指南。尽管ICHQ8指南不适用兽药产品，本指南中的原则可以应用于兽药产品，申请人应选择性采用更好的方法来进行药品研发和工艺验证。工艺验证不应该作为是一次性的事情。工艺验证应将产品生命周期结合工艺研发、商业生产工艺验证、在常规商业化生产中控制状态的工艺维护相结合。Scope范围Thisdocumentisintendedtoprovideguidanceontheprocessvalidationinformationanddatatobeprovidedinregulatorysubmissionsforthefinisheddosageformsofchemicalmedicinalproductsforhumanandveterinaryuse.Thegeneralprinciplesalsoapplytoactivesubstances.本文件意在提供关于人用和兽用化学药品制剂的申报时所需提交的工艺验证资料和数据的指南。一般原则也适用于活性物质。However,informationonvalidationofnon-sterileactivesubstancesisnotrequiredinthedossier.但是，在申报文件中并不要求提交非无菌原料药的验证信息。Inaddition,expectationsforactivesubstancesarecontainedinICHQ11andsotheinformationisnotrepeatedinthisdocument.另外，ICHQ11中包括了对原料药的建议，因此本文件中不再重复这些信息。Theprinciplesdescribedarealsoapplicabletobiologicalmedicinalproducts.However,theseshouldbeconsideredonacasebycasebasisinviewofthecomplexnatureandinherentvariabilityofthebiologicalsubstance.本文所述的原则也适用于生物制品。但是，生物制品的工艺验证应根据其复杂性和内在变因各案考查。Itisexpectedthattheinformation/datarequestedinthisguidelinebepresentinthedossieratthetimeofregulatorysubmission.在本指南中所要求的资料/数据应该包括在法规申报的文件中。Thisdocumentprovidesguidanceonthevalidationofthemanufacturingprocess,whichcanbeconsideredasthesecondstageintheproductlifecycle.Thefirststage(processdesign)iscoveredinthenoteforguidanceonpharmaceuticaldevelopment(ICHQ8R2/EMEA/CVMP/315/98)andthethirdstage(on-goingprocessverification)iscoveredunderGMP(Annex15).本文件提供生产工艺验证指南，工艺验证可以当作产品生命周期的第二阶段。第一阶段(工艺设计)包括在药物研发指南解释(ICHQ8R2/EMEA/CVMP/315/98)中，第三阶段(持续工艺确认)包括在GMP(附录15)中。Legalbasis法律依据Thisguidelinehastobereadinconjunctionwiththeintroductionandgeneralprinciplessection(4)ofAnnexItoDirective2001/83/ECasamendedandtheintroductionandgeneralprinciplessection(2)ofAnnexItoDirective2001/82/ECasamended.本指南应与指令2001/83/EC修订版本附录1第(4)部分中的介绍和一般原则，以及指令2001/82/EC修订版附录1第(2)部分中的介绍和一般原则一起解读。Generalconsiderations一般考虑Irrespectiveofwhetheramedicinalproductisdevelopedbyatraditionalapproachoranenhancedapproach,themanufacturingprocessshouldbevalidatedbeforetheproductisplacedonthemarket.Inexceptionalcircumstancesconcurrentvalidationmaybeaccepted.PleaserefertoGMPAnnex15forfurtherguidance.Processvalidationshouldconfirmthatthecontrolstrategyisadequatetotheprocessdesignandthequalityoftheproduct.Thevalidationshouldcoverallmanufacturedstrengthsandallmanufacturingsitesusedforproductionofthemarketedproduct.Abracketingapproachmaybeacceptablefordifferentstrengths,batchsizesandpacksizes.However,validationmustcoverallproposedsites.Processvalidationdatashouldbegeneratedforallproductstodemonstratetheadequacyofthemanufacturingprocessateachsiteofmanufacture.ValidationshouldbecarriedoutinaccordancewithGMPanddatashouldbeheldatthemanufacturinglocationandmadeavailableforinspectionifnotrequiredinthedossier(seesection8).工艺验证应确认控制策略对于工艺设计和产品质量来说已足够。验证应覆盖生产上市产品的所有生产场所和所有剂量产品。不同剂量、不同批量和包装规格可以括号法。但是，验证必须覆盖所有拟生产的场所。每个生产场所所有产品均应有工艺验证数据，以证明生产工艺的充分性。工艺验证应符合GMP，数据应保留在生产场所，如果申报文件中未要求(参见第8部分)则应该在检查过程中随时可提供。Processvalidationcanbeperformedinatraditionalway,asdescribedbelow,regardlessoftheapproachtodevelopmenttaken.However,thereisalsothepossibilitytoimplementcontinuousprocessverificationifanenhancedapproachtodevelopmenthasbeenperformedorwhereasubstantialamountofproductandprocessknowledgeandunderstandinghasbeengainedthroughhistoricaldataandmanufacturingexperience.Acombinationoftraditionalprocessvalidationandcontinuousprocessverificationmaybeemployed.Thein-line,on-lineorat-linemonitoringthatisoftenutilisedforcontinuousprocessverification(discussedinsection5.2)providessubstantiallymoreinformationandknowledgeabouttheprocessandmightfacilitateprocessimprovements.如下所述，不管采用了什么研发方法，工艺验证都可以采用传统方法。但是，如果已采用加强研发方法，或通过历史数据和生产经验已获得大量产品和工艺知识和理解，也存在实施持续工艺确认的可能性。可能要采用传统工艺验证和持续工艺确认相结合的方法。在线监控经常用于持续工艺确认(在第5.2部分中已讨论)，提供大量的关于工艺的信息和知识，可能有利于工艺改进。Processvalidation工艺验证Traditionalprocessvalidation传统工艺验证Traditionalprocessvalidationisnormallyperformedwhenthepharmaceuticaldevelopmentand/orprocessdevelopmentisconcluded,afterscale-uptoproductionscaleandpriortomarketingofthefinishedproduct.Aspartoftheprocessvalidationlifecycle,someprocessvalidationstudiesmaybeconductedonpilotscalebatchesiftheprocesshasnotyetbeenscaleduptoproductionscale.传统工艺验证一般在药物研发和/或工艺研发结束后，在放大至生产规模后，成品上市前进行。作为工艺验证生命周期的一部分，如果有些工艺还没有放大到生产规模，部分工艺验证研究可能会在中试批次进行。Itshouldbenotedthatpilotbatchsizeshouldcorrespondtoatleast10%oftheproductionscalebatch(i.e.suchthatthemultiplicationfactorforthescale-updoesnotexceed10).Forsolidoraldosageformsthissizeshouldgenerallybe10%ofthemaximumproductionscaleor100,000unitswhicheveristhegreater[1].Wheretheintendedbatchsizeislessthan100,000units,thepredictivevalueofthepilotbatchesmaybelimitedandajustifiedapproachshouldbefollowed.Forotherdosageformsthepilotbatchsizeshouldbejustifiedtakingintoaccountrisktothepatientoffailureofthedosageform.Sinceitisnotgenerallyconsideredusefultoconductfullvalidationstudiesonpilotscalebatches,theprocessvalidationschemeoutlinedinAnnexIofthisguidelineshouldbecompletedforeachproductforsubsequentexecutionatproductionscale;bracketingmaybeacceptable.Theprocessvalidationschemetobefollowedshouldbeincludedinthedossier.Theschemeshouldincludeadescriptionofthemanufacturingprocess,theteststobeperformedandacceptancecriteria,adescriptionoftheadditionalcontrolsinplaceandthedatatobecollected.AjustificationforthechosenprocessvalidationschemeshouldbepresentedinModule3andtheQualityOverallSummaryforhumanmedicinesandinPart2.BandthePharmaceuticalDetailedandCriticalSummaryforveterinarymedicines.要注意的是中试生产批应至少对应商业生产批量的10%(即，放大生产倍数不应超过10)。该规模的固体口服剂型一般应为最大生产批量的10%或10万个单位剂量，取其中大者。如果要生产的批量小于10万剂型单位，中试批次预期值可能受限，则需要采用经过评估的方法。对于其它剂型，中试批量的论述要考虑剂型失败给患者带来的风险。由于一般认为在中试规模批次进行全验证研究是没有用的，因此在本指南附录1中列出的工艺验证计划应在之后的各产品生产规模时进行完善，可以接受括号法。申报文件中应包括要执行的工艺验证计划。计划中应包括工艺描述、要实施的测试和可接受标准、附加控制的描述和要收集的数据。要在人药申报文件模块3和质量综述、兽药申报文件第2.B部分和药品详情和关键摘要中放入为什么选择该工艺验证计划的论述。Incertaincaseshowever,itisconsiderednecessarytoprovideproductionscalevalidationdatainthemarketingauthorisationdossieratthetimeofregulatorysubmission,forexamplewhentheproductisabiological/biotechproductorwheretheapplicantisproposinganon-standardmethodofmanufacture(seesection8andAnnexII).Inthesecases,datashouldbeprovidedinthedossieronanumberofconsecutivebatchesatproductionscalepriortoapproval.Thenumberofbatchesshouldbebasedonthevariabilityoftheprocess,thecomplexityoftheprocess/product,processknowledgegainedduringdevelopment,supportivedataatcommercialscaleduringtechnologytransferandtheoverallexperienceofthemanufacturer.Dataonaminimumof3productionscalebatchesshouldbesubmittedunlessotherwisejustified.Dataon1or2productionscalebatchesmaysufficewherethesearesupportedbypilotscalebatchesandajustificationashighlightedabove.在某些情况下，可能认为有必要在上市许可申报资料中提交生产批量的验证数据，例如，如果产品是生物/生物技术制品，或者申请人所拟的工艺为非标生产方法(参见第8部分和附录二)。这种情况下，要在批准前在申报资料中包括采用生产批量所获得的连续批次数据。批次数应基于工艺变动情况、工艺/产品复杂程度、在研发阶段所获得的工艺知识、在技术转移中所获得的商业批量中的支持数据，以及生产商的总体经验。除非另有论述，否则至少需要提交3批生产批量的数据。如果另有中试批量数据支持，以及上述高亮显示的论述提供，则仅提供1或2批生产批量数据也是可以的。译者：未见哪里有高亮显示的内容。Thestudiesshouldaddresscriticalstepsofmanufacture,byconductingadditionaltestingasnecessary.研究应说明关键生产工艺步骤，必要时增加检测。Continuousprocessverification持续工艺确认Continuousprocessverificationisanalternativeapproachtotraditionalprocessvalidationinwhichmanufacturingprocessperformanceiscontinuouslymonitoredandevaluated(ICHQ8).持续工艺确认是传统工艺验证的一种替代方式，是指生产工艺的性能被持续地监控和评估(ICHQ8)。Continuousprocessverificationcanbeusedinadditionto,orinsteadof,traditionalprocessvalidation.持续工艺确认可以用于补充，或替代传统工艺验证。Itisascienceandrisk-basedreal-timeapproachtoverifyanddemonstratethataprocessthatoperateswithinthepredefinedspecifiedparametersconsistentlyproducesmaterialwhichmeetsallitscriticalqualityattributes(CQAs)andcontrolstrategyrequirements.Inordertoenablecontinuousprocessverification,companiesshouldperform,asrelevant,extensivein-line,on-lineorat-linecontrolsandmonitorprocessperformanceandproductqualityoneachbatch.Relevantdataonqualityattributesofincomingmaterialsorcomponents,in-processmaterialandfinishedproductsshouldbecollected.Thisshouldincludetheverificationofattributes,parametersandendpoints,andassessmentofCQAandcriticalprocessparameter(CPP)trends.Processanalyticaltechnology(PAT)applicationssuchasNIRspectroscopywithorwithoutfeedbackloop(e.g.endpointdeterminationofblendhomogeneity,determinationofgranulessurfacearea,determinationofcontentuniformitywithlargesamplesize)andMultivariateStatisticalProcessControl(MSPC)canbeviewedasenablersforcontinuousprocessverification.确认和证明一个工艺如果在预定的特定参数范围内操作，即可以稳定生产出符合所有CQA和控制策略要求的物料是一个科学并基于风险的实时方法。为了进行持续工艺确认，公司应相应地实施众多的在线控制和工艺性能监控，以及各批产品质量监控。应收集进厂物料或组件、制程中物料和成品的质量属性相关数据，还应该包括对属性、参数和终点，和CQA和CPP趋势的评估。工艺分析技术PAT工具，如具有或不具有反馈回路的NIR光谱(例如，混合均一性终点测试，颗粒表面积测试，样品量较大时含量均一性测试)，和多变量统计学工艺控制MSPC可以当作持续工艺确认的工具。Sufficientknowledgeandunderstandingoftheprocessisrequiredinordertosupportcontinuousprocessverification.However,thescopeandextentofcontinuousprocessverificationwillbeinfluencedbyanumberoffactorsincluding:为了支持持续工艺确认，需要对工艺有足够的知识和理解。但是，持续工艺确认的程度会受到一些因素的影响，包括priordevelopmentandmanufacturingknowledgefromsimilarproductsand/orprocesses;从同类产品和/或工艺中获得的研发生产前的知识theextentofprocessunderstandinggainedfromdevelopmentstudiesandcommercialmanufacturingexperience;在研发获得的对工艺理解的程度，以及商业生产经验thecomplexityoftheproductand/ormanufacturingprocess;产品和/或生产工艺的复杂性thelevelofprocessautomationandanalyticaltechnologiesused;工艺自动化水平和使用的分析技术水平—forlegacyproducts,withreferencetotheproductlifecycle,processrobustnessandmanufacturinghistorysincepointofcommercializationasappropriate.对于已有产品，参考产品生命周期、工艺耐用性和自从商业化以来的生产历史(适用时)Adiscussionontheappropriatenessandfeasibilityofthecontinuousprocessverificationstrategyshouldbeincludedinthedevelopmentsectionofthedossierandshouldbesupportedwithdatafromatleastlaboratoryorpilotscalebatches.Adescriptionofthecontinuousprocessverificationstrategyincludingtheprocessparametersandmaterialattributesthatwillbemonitored,aswellastheanalyticalmethodsthatwillbeemployed,shouldbeincludedasdescribedinAnnex1,withcross-referencetothevalidationsectionofthedossier.Actualdatageneratedduringcontinuousprocessverificationatproductionscaleshouldbeavailableatthesiteforinspection.Theapplicantshoulddefinethestageatwhichtheprocessisconsideredtobeundercontrolandthevalidationexercisecompletedpriortoreleaseoftheproducttothemarket,andthebasisonwhichthatdecisionwillbemade.Thediscussionshouldincludeajustificationforthenumberofbatchestobeusedbasedonthecomplexityandexpectedvariabilityoftheprocessandexistingmanufacturingexperienceofthemanufacturingsite.Continuousprocessverificationwouldbeconsideredthemostappropriatemethodforvalidatingcontinuousprocesses.在申报资料的研发部分，应包括持续工艺确认策略的适当性和可行性讨论，并使用至少是实验室规模或中试规模批次的数据加以支持。持续工艺确认策略的内容应包括：要监控的工艺参数和物料属性、要采用的分析方法，应该如附录1中所述，交叉引用至申报文件的验证部分。在生产规模持续工艺确认中所产生的实际数据应受检查现场可以获得。申请人应定义工艺步骤受控起始点，和将产品放行上市销售前所完成的验证工作，以及做出该决定的根据。讨论应包括根据工艺复杂性和预期变化，以及在生产场所内已有生产经验来决定批次数的论述。在验证连续生产的工艺时，持续工艺确认被认为是最适当的方式。Continuousprocessverificationcanbeintroducedatanytimeinthelifecycleoftheproduct.Itcanbeusedfortheinitialcommercialproduction,tore-validatecommercialisedproductsaspartofprocesschangesortosupportcontinualimprovement.持续工艺确认可以在产品生命周期的任何时间引入。它可以用于初始的商业化生产，作为工艺变更的一部分对商业产品进行再验证，或用于支持持续改进。ContinuousprocessverificationisdependentoncompliancewithGMPprinciplesandrequirements.持续工艺确认是独立于GMP原则和要求符合性的。Pharmaceuticalqualitysystems(PQS)asdescribedinICHQ10cancomplementGMPrequirements.However,GMPmattersandPQSshouldnotbeincludedinthesubmissionastheyareassessedandhandledbyGMPinspectorsasappropriate.在ICHQ10里所述药品质量体系PQS可以补充GMP要求，但是，GMP事宜和PQS不应该包括在申报资料中，因为它们是由GMP审计官在适当时进行评估的。Hybridapproach混合方案Itmaybenecessarytouseeitherthetraditionalprocessvalidationorthecontinuousprocessverificationapproachfordifferentstepswithinthemanufacturingprocess.Itshouldbeclearinthedossierwhichapproachtovalidationhasbeentakenforwhichstepsinthemanufacturingprocess.在生产工艺的不同步骤可能需要采用传统工艺验证或持续工艺确认方法。在文件中应清楚说明生产工艺哪个步骤采用了哪种验证方法。Thevalidationrequirementsintermsofbatchsizeandnumberofbatcheswoulddependontheextenttowhichcontinuousprocessverificationhasbeenused.Fornon-standardprocesses(asdefinedinsection8)ifcontinuousprocessverificationdoesnotaddressthecriticalunitoperation(s)theprocessvalidationrequirementshighlightedinsection5.1shouldbeappliedunlessotherwisejustified.验证中关于批量和批次数的要求取决于所使用的持续工艺确认的深度。对于非标工艺(如第8部分所定义)，如果持续工艺确认未包括对关键单元操作的确认，如无其它论述，则适用第5.1部分中高亮显示的工艺验证要求。Designspaceverification设计空间确认Adesignspacewillnormallybedevelopedatlaboratoryorpilotscale.Duringscale-upthecommercialprocessisgenerallyconductedandvalidatedinaspecificareaofthedesignspace,definedasthetargetintervalorNormalOperatingRange(NOR).Duringtheproductlifecycle,movingfromoneareatoanotherwithinthedesignspace(i.e.changeintheNOR)mayrepresenthigherorunknownrisksnotpreviouslyidentifiedduringinitialestablishmentofthedesignspace.设计空间一般是在实验室或中试规模时建立的。在放大过程中，一般会实施商业化工艺，在设计空间的内一个特定区域进行验证，把它定义为目标区间，或常规操作范围NOR。在整个产品生命周期中，在设计空间内从一个区间移动至另一个区间(即NOR的变更)可能代表更高或未知风险，这些风险可能在初期设计空间建立期间并未能预先识别。Forthisreasonanddependingonhowthedesignspacewasoriginallyestablishedandhowtheprocesswasvalidated,therewillbesituationswhereitwillbenecessarytoconfirmthesuitabilityofthedesignspaceandverifythatallproductqualityattributesarestillbeingmetinthenewareaofoperationwithinthedesignspace.Thisistermed‘designspaceverification’.因为上述原因，根据设计空间初始建立情况，和工艺验证情况，会需要对设计空间的适当性进行确认，对于在设计空间内一个新的操作空间生产出的产品是否满足所有质量属性应进行确认。这称为“设计空间确认“。Iftheparametersinvestigatedduringdevelopmentofthedesignspacehavenotbeenshowntobescaleindependentandtheprocesshasbeenvalidatedusingtraditionalprocessvalidation,designspaceverificationwouldberequiredandaverificationprotocolshouldbeprovidedinthedossier.如果在设计空间发展阶段所调查的参数并未显出与放大不相关，且工艺采用了传统工艺验证方法进行验证，则需要对设计空间进行确认，并在文件中提供确认方案。Ifcontinuousprocessverificationhasbeenutilised,thismaycontributetowardsensuringthevalidityofthedesignspacethroughouttheproductlifecycle.Inthiscase,adesignspaceverificationstrategyshouldbeincludedaspartofthecontinuousprocessverificationstrategy.如果采用了持续工艺确认，则有助于保证在产品生命周期内设计空间的有效性。这种情况下，设计空间确认策略应作为持续工艺确认策略的一部分。Dependingonthechangeandtheextentofmovementwithinthedesignspace(i.e.distancefromvalidatedtarget/NORornewareaofdesignspacewithhigherorunknownrisk)protocolsforverificationmayincludecontrolsofqualityattributes(QA's)andprocessparameters(PP's)notincludedintheroutinecontrolsystem(e.g.monitoringortestingofQA,sandPP,sthatareexpectedtobescaledependantandwhenapplicable,equipmentdependant).ItisnotnecessarytoverifyentireareasoftheDesignSpaceortheedgeoffailure.InprinciplemorethanoneareaofthedesignspaceshouldbeverifiedbutastepwiseapproachtakingintoconsiderationtheneedtoadjusttheNORwithintheapproveddesignspaceduringproductlifecycleisacceptable.根据变更情况，以及在设计空间内移动程度()，确认方案可能包括质量属性控制(QA)和工艺参数控制(PP)，这两项并不包括在常规控制系统中(例如对不受放大和设施影响的QA和PP监控和测试)。不需对设计空间的整个区间，或失效边缘进行确认。原则上，应该对设计空间内不止一个区间进行确认，但在整个产品生命周期内，由于会在批准的设计空间对NOR进行调整的需要，因而进行分步确认方式也是可以接受的。Scale-up放大生产Inordertoavoidtherepetitionoflengthyandcostlytests,itisnecessarytogatherinformationduringproperlydesigneddevelopmentandprocessoptimisationstudies,whenscalingupfromlaboratorythroughpilottoproductionscale.Suchinformationprovidesthebasisforjustificationthatscale-upcanbeachievedwithoutaconsequentlossinquality.Thosepartsoftheprocesslikelytobecriticalinscale-upshouldbeidentifiedinsection3.2.P.2(VeterinaryPart2.A.4)anddefinedinsection3.2.P.3(VeterinaryPart2.B)ofthedossier.在从化验室规模经过试生产规模再放大至生产规模时，为了避免长时间及昂贵的检测，需要在适当的设计研发和工艺优化研究过程中收集相关信息。这些信息是论述放大生产不会对质量产生负面影响的基础。在放大过程中可能比较关键的工艺部分应在3.2.P.2(兽药第2.A.4部分)和3.2.P.3(兽药第2B部分)文件中识别。Whererangesofbatchsizesareproposed,itshouldbejustifiedthatvariationsinbatchsizewouldnotadverselyaltertheCQAsofthefinishedproduct.Itisenvisagedthatthoseparameterslistedintheprocessvalidationscheme(AnnexIofthisguideline)willneedtobere-validatedoncefurtherscale-upisproposedpost-authorisationunlesstheprocesshasbeenproventobescaleindependentorcontinuousprocessverificationisemployed.如果申请了批量范围，应论述批量变动对制剂的CQA不会产生负面影响。除非已经证明放大是独立的，或者采用了持续工艺确认方法，否则认为这些列在工艺验证计划中的参数(本指南附录I)在获得上市批准后如果申请批量放大后即需要进行再验证。Postapprovalchangecontrol批准后变更控制Clearlydefinedproceduresareneededtocontrolchangesproposedinproductionprocesses.TheseproceduresarepartofGMPandwouldnotnormallybespecifiedinthedossier.Suchproceduresshouldcontrolplannedchanges,ensurethatsufficientsupportingdataaregeneratedtodemonstratethattherevisedprocesswillresultinaproductofthedesiredquality,consistentwiththeapprovedcontrolstrategyandensurethatallaspectsarethoroughlydocumentedandapprovedincludingwhetherregulatoryapprovalisneededbywayofvariation.需要清楚界定对生产工艺进行变更控制要遵守的程序。这些程序是GMP的一部分，一般在文件里说明。这些程序应对计划变更进行控制，保证会产生充分的支持性数据来证明修订后的工艺会使用得产品具备所需的品质，与所批准的控制策略保持一致，保证所有事项均被完整记录和批准，包括是否需要提交变更申请获得法规批准。RefertotheEuropeanCommissionguidanceonTypeIandTypeIIvariations(Guidelinesonthedetailsofthevariouscategoriesofvariations,ontheoperationoftheprocedureslaiddowninChaptersII,IIa,IIIandIVofCommissionRegulation(EC)No.1234/2008of24November2008concerningtheexaminationofvariationstothetermsofmarketingauthorizationsformedicinalproductsforhumanuseandveterinarymedicinalproductsandonthedocumentationtobesubmittedpursuanttothoseprocedures)andRegulation712/2012/ECfordetailsonthechangeswhichwouldrequireavariation.参见欧洲委员会关于第I类和第II类变更指南(关于人用兽用药品上市后变更检查，及需要提交的文件规定，欧洲委员会法令EC1234/2008，2008年11月24日，第II章IIa节，第III章和第IV章中变更详细分类)，及712/2012/EC法令关于申请变更的详细要求。Standardvs.non-standardmethodsofmanufacture标准VS非标准生产方法Thissectionisonlyrelevantforprocesseswhichhavebeenvalidatedusingtraditionalprocessvalidation.Itisnotrelevantforthoseprocesseswherecontinuousprocessverificationisemployed(seesections5.1and5.2).Accordingtosection5.1,fullproduction-scaledatashouldbeprovidedinthedossierfornon-standardproductsorprocesseswhichwerevalidatedusingtraditionalprocessvalidation.Itispossiblefortheapplicanttojustifythattheproductprocesscanbeconsideredstandardforaparticularmanufacturer/sitetakingintoaccounttherisktothepatientoffailureoftheproductorprocess.Suchjustificationsareassessedonacasebycasebasis,buttheinformationprovidedbytheapplicant(foreachmanufacturingsite)shouldinclude:本部分仅与采用传统工艺验证方法进行验证的工艺相关，与采用持续工艺确认的工艺不相关(参见第5.1和5.2部分）。根据第5.1部分，非标工艺或采用传统工艺验证方法进行验证的工艺的申报资料需要提供生产规模的数据。申请人也可以对产品工艺进行论述，证明考虑到产品或工艺失败对患者的风险，该工艺对于一个特定的生产商/生产场所来说，可以作为标准工艺。这类论述应是各案进行评估，但由申请人（对每个生产场所）提供的资料应包括：—experiencewiththesameoressentiallysimilarproductorprocess（numberofproductsauthorised/marketedintheEU/EEAandnumberofbatches（includinginformationonscale）manufactured）;—同样或基本类似产品或工艺（在EU/EEA地区获批准/上市的产品数，及生产批数（包括规模信息））的经验—?thenames/marketingauthorisationnumbersintherelevantEU/EEAmemberstateshouldbeprovided.—提供在相关EU/EEA成员国上市许可的名称和数量—amountofknowledgegainedduringthedevelopmentoftheproduct（numberandscaleofbatchesmanufacturedateachmanufacturingsiteinvolved）;—在产品研发过程中获得的知识量（各涉及的生产场所所生产的批数和规模）—historyofGMPcomplianceofmanufacturingsitesforthattypeofprocessTheapplicantshouldclearlystate（insection3.2.P.3.5ofthedossierforhumanmedicines,insection2.Bofthedossierforveterinarymedicines）whethertheyconsiderthemanufacturingprocesstobestandardornon-standardandthejustificationfortheirdecisionfornewmarketingauthorisationapplications.—该类工艺生产场所GMP符合性历史。申请人应清楚说明（在人用药文件3.2.P.3.5部分，在兽药文件2.B部分）其将生产工艺作为标准还是非标准工艺，其新上市许可申报决定的论述PleaseseeAnnexIIforfurtherinformationonproducts/processesconsideredtobenonstandard.关于作为非标准工艺/产品的详细信息，参见附录II。Definitions定义（翻译略）At-line:在线Measurementwherethesampleisremoved,isolatedfrom,andanalysedincloseproximitytotheprocessstream.将样品取出，具有独立形态，在接近工艺流程场所对其进行测试Bracketingapproach:括号法Avalidationscheme/protocoldesignedsuchthatonlybatchesontheextremesofcertainpredeterminedandjustifieddesignfactors,e.g.,strength,batchsize,packsizearetestedd