EMA工藝驗(yàn)證指引

EMA工藝驗(yàn)證指南---EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev127February2014CommitteeforMedicinalProductsforHumanUse(CHMP)CommitteeforMedicinalProductsforVeterinaryUse(CVMP)Guidelineonprocessvalidationforfinishedproducts-informationanddatatobeprovidedinregulatorysubmissions制劑工藝驗(yàn)證指南---在法規(guī)提交中要提供的資料和數(shù)據(jù)DraftagreedbyCHMP/CVMPQualityWorkingParty2February2012由CHMP/CVMP質(zhì)量工作組通過草案2012年2月2日AdoptionbyCVMPforreleaseforconsultation8March2012CVMP同意公開征求意見2012年3月8日AdoptionbyCHMPforreleaseforconsultation15March2012CHMP同意公開征求意見2012年3月15日Endofconsultation(deadlineforcomments)31October2012征求意見結(jié)束（截止日期）2012年10月31日AgreedbyQWP8November2013由QWP通過2013年11月8日AgreedbyBWP13November2013由BWP通過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個(gè)月Thisguidelinereplacesthenoteforguidanceonprocessvalidation(CPMP/QWP/848/96,EMEA/CVMP/598/99)includingannexII-non-standardprocesses(CPMP/QWP/2054/03).本指南替代工藝驗(yàn)證注釋(CPMP/QWP/848/96,EMEA/CVMP/598/99)，包括附錄二----非標(biāo)準(zhǔn)工藝(CPMP/QWP/2054/03)。KeywordsProcessvalidation,continuousprocessverification,on-goingprocessverification,criticalprocessparameter,criticalqualityattribute,lifecycle,changecontrol關(guān)鍵詞工藝驗(yàn)證、持續(xù)工藝確認(rèn)、關(guān)鍵工藝參數(shù)、關(guān)鍵質(zhì)量屬性、生命周期、變更控制Tableofcontents目錄Executivesummary實(shí)施摘要1.Introduction(background)介紹（背景）2.Scope范圍3.Legalbasis法規(guī)依據(jù)4.Generalconsiderations一般考慮5.Processvalidation工藝驗(yàn)證5.1.Traditionalprocessvalidation傳統(tǒng)工藝驗(yàn)證5.2.Continuousprocessverification持續(xù)工藝確認(rèn)5.3.Hybridapproach混合方案5.4.Designspaceverification設(shè)計(jì)空間確認(rèn)6.Scale-up放大生產(chǎn)7.Postapprovalchangecontrol批準(zhǔn)后變更控制8.Standardvs.non-standardmethodsofmanufacture標(biāo)準(zhǔn)VS非標(biāo)準(zhǔn)生產(chǎn)方法Definitions定義References參考文獻(xiàn)AnnexI:Processvalidationscheme附錄I：工藝驗(yàn)證計(jì)劃AnnexII:Standard/non-standardprocesses附錄II：標(biāo)準(zhǔn)/非標(biāo)工藝Executivesummary實(shí)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藝驗(yàn)證指南解釋(CPMP/QWP/848/96,EMEA/CVMP/598/99)。本指南與ICHQ8,Q9和Q10文件相一致，提供在之前加入和鼓勵(lì)采用的傳統(tǒng)工藝驗(yàn)證這外，提供了使用持續(xù)工藝確認(rèn)的可能性。本指南對(duì)已批準(zhǔn)上市的藥品未引入新要求，但闡述了公司在ICHQ8,Q9和Q10中描述的有效質(zhì)量體系下，應(yīng)用強(qiáng)化工藝?yán)斫馀c風(fēng)險(xiǎn)管理工具時(shí)，如何抓住所給的新的可能性。Introduction(background)介紹(背景)Processvalidationcanbedefinedasdocumentedevidencethattheprocess,operatedwithinestablishedparameters,canperformeffectivelyandreproduciblytoproduceamedicinalproductmeetingitspredeterminedspecificationsandqualityattributes(ICHQ7).Continuousprocessverificationhasbeenintroducedtocoveranalternativeapproachtoprocessvalidationbasedonacontinuousmonitoringofmanufacturingperformance.Thisapproachisbasedontheknowledgefromproductandprocessdevelopmentstudiesand/orpreviousmanufacturingexperience.工藝可定義為證明在建立的參數(shù)范圍內(nèi)操作的工藝可以重復(fù)有效地生產(chǎn)出符合其預(yù)定質(zhì)量標(biāo)準(zhǔn)和質(zhì)量屬性的藥品的書面證據(jù)(ICHQ7)。持續(xù)工藝驗(yàn)證被引入替代基于對(duì)工藝性能持續(xù)監(jiān)測(cè)的工藝驗(yàn)證。這種方法是依據(jù)來自于產(chǎn)品和工藝研發(fā)和/或之前生產(chǎn)經(jīng)驗(yàn)的知識(shí)。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.持續(xù)工藝確認(rèn)既適用于傳統(tǒng)藥品研發(fā)方法，也適用于加強(qiáng)藥品研發(fā)方法。它采用廣泛的在線監(jiān)測(cè)和/或控制來評(píng)估工藝的性能。將研發(fā)藥物指南解釋(CPMP/QWP/155/96)、藥物研發(fā)指南解釋(ICHQ8R2)與本指南相結(jié)合，應(yīng)可以覆蓋人用藥法規(guī)申報(bào)文件所需包括的生產(chǎn)工藝的關(guān)鍵因素。對(duì)于獸藥產(chǎn)品，適用的指南為“獸藥研發(fā)指南解釋”(EMEA/CVMP/315/98)與本指南。盡管ICHQ8指南不適用獸藥產(chǎn)品，本指南中的原則可以應(yīng)用于獸藥產(chǎn)品，申請(qǐng)人應(yīng)選擇性采用更好的方法來進(jìn)行藥品研發(fā)和工藝驗(yàn)證。工藝驗(yàn)證不應(yīng)該作為是一次性的事情。工藝驗(yàn)證應(yīng)將產(chǎn)品生命周期結(jié)合工藝研發(fā)、商業(yè)生產(chǎn)工藝驗(yàn)證、在常規(guī)商業(yè)化生產(chǎn)中控制狀態(tài)的工藝維護(hù)相結(jié)合。Scope范圍Thisdocumentisintendedtoprovideguidanceontheprocessvalidationinformationanddatatobeprovidedinregulatorysubmissionsforthefinisheddosageformsofchemicalmedicinalproductsforhumanandveterinaryuse.Thegeneralprinciplesalsoapplytoactivesubstances.本文件意在提供關(guān)于人用和獸用化學(xué)藥品制劑的申報(bào)時(shí)所需提交的工藝驗(yàn)證資料和數(shù)據(jù)的指南。一般原則也適用于活性物質(zhì)。However,informationonvalidationofnon-sterileactivesubstancesisnotrequiredinthedossier.但是，在申報(bào)文件中并不要求提交非無菌原料藥的驗(yàn)證信息。Inaddition,expectationsforactivesubstancesarecontainedinICHQ11andsotheinformationisnotrepeatedinthisdocument.另外，ICHQ11中包括了對(duì)原料藥的建議，因此本文件中不再重復(fù)這些信息。Theprinciplesdescribedarealsoapplicabletobiologicalmedicinalproducts.However,theseshouldbeconsideredonacasebycasebasisinviewofthecomplexnatureandinherentvariabilityofthebiologicalsubstance.本文所述的原則也適用于生物制品。但是，生物制品的工藝驗(yàn)證應(yīng)根據(jù)其復(fù)雜性和內(nèi)在變因各案考查。Itisexpectedthattheinformation/datarequestedinthisguidelinebepresentinthedossieratthetimeofregulatorysubmission.在本指南中所要求的資料/數(shù)據(jù)應(yīng)該包括在法規(guī)申報(bào)的文件中。Thisdocumentprovidesguidanceonthevalidationofthemanufacturingprocess,whichcanbeconsideredasthesecondstageintheproductlifecycle.Thefirststage(processdesign)iscoveredinthenoteforguidanceonpharmaceuticaldevelopment(ICHQ8R2/EMEA/CVMP/315/98)andthethirdstage(on-goingprocessverification)iscoveredunderGMP(Annex15).本文件提供生產(chǎn)工藝驗(yàn)證指南，工藝驗(yàn)證可以當(dāng)作產(chǎn)品生命周期的第二階段。第一階段(工藝設(shè)計(jì))包括在藥物研發(fā)指南解釋(ICHQ8R2/EMEA/CVMP/315/98)中，第三階段(持續(xù)工藝確認(rèn))包括在GMP(附錄15)中。Legalbasis法律依據(jù)Thisguidelinehastobereadinconjunctionwiththeintroductionandgeneralprinciplessection(4)ofAnnexItoDirective2001/83/ECasamendedandtheintroductionandgeneralprinciplessection(2)ofAnnexItoDirective2001/82/ECasamended.本指南應(yīng)與指令2001/83/EC修訂版本附錄1第(4)部分中的介紹和一般原則，以及指令2001/82/EC修訂版附錄1第(2)部分中的介紹和一般原則一起解讀。Generalconsiderations一般考慮Irrespectiveofwhetheramedicinalproductisdevelopedbyatraditionalapproachoranenhancedapproach,themanufacturingprocessshouldbevalidatedbeforetheproductisplacedonthemarket.Inexceptionalcircumstancesconcurrentvalidationmaybeaccepted.PleaserefertoGMPAnnex15forfurtherguidance.Processvalidationshouldconfirmthatthecontrolstrategyisadequatetotheprocessdesignandthequalityoftheproduct.Thevalidationshouldcoverallmanufacturedstrengthsandallmanufacturingsitesusedforproductionofthemarketedproduct.Abracketingapproachmaybeacceptablefordifferentstrengths,batchsizesandpacksizes.However,validationmustcoverallproposedsites.Processvalidationdatashouldbegeneratedforallproductstodemonstratetheadequacyofthemanufacturingprocessateachsiteofmanufacture.ValidationshouldbecarriedoutinaccordancewithGMPanddatashouldbeheldatthemanufacturinglocationandmadeavailableforinspectionifnotrequiredinthedossier(seesection8).工藝驗(yàn)證應(yīng)確認(rèn)控制策略對(duì)于工藝設(shè)計(jì)和產(chǎn)品質(zhì)量來說已足夠。驗(yàn)證應(yīng)覆蓋生產(chǎn)上市產(chǎn)品的所有生產(chǎn)場(chǎng)所和所有劑量產(chǎn)品。不同劑量、不同批量和包裝規(guī)格可以括號(hào)法。但是，驗(yàn)證必須覆蓋所有擬生產(chǎn)的場(chǎng)所。每個(gè)生產(chǎn)場(chǎng)所所有產(chǎn)品均應(yīng)有工藝驗(yàn)證數(shù)據(jù)，以證明生產(chǎn)工藝的充分性。工藝驗(yàn)證應(yīng)符合GMP，數(shù)據(jù)應(yīng)保留在生產(chǎn)場(chǎng)所，如果申報(bào)文件中未要求(參見第8部分)則應(yīng)該在檢查過程中隨時(shí)可提供。Processvalidationcanbeperformedinatraditionalway,asdescribedbelow,regardlessoftheapproachtodevelopmenttaken.However,thereisalsothepossibilitytoimplementcontinuousprocessverificationifanenhancedapproachtodevelopmenthasbeenperformedorwhereasubstantialamountofproductandprocessknowledgeandunderstandinghasbeengainedthroughhistoricaldataandmanufacturingexperience.Acombinationoftraditionalprocessvalidationandcontinuousprocessverificationmaybeemployed.Thein-line,on-lineorat-linemonitoringthatisoftenutilisedforcontinuousprocessverification(discussedinsection5.2)providessubstantiallymoreinformationandknowledgeabouttheprocessandmightfacilitateprocessimprovements.如下所述，不管采用了什么研發(fā)方法，工藝驗(yàn)證都可以采用傳統(tǒng)方法。但是，如果已采用加強(qiáng)研發(fā)方法，或通過歷史數(shù)據(jù)和生產(chǎn)經(jīng)驗(yàn)已獲得大量產(chǎn)品和工藝知識(shí)和理解，也存在實(shí)施持續(xù)工藝確認(rèn)的可能性?？赡芤捎脗鹘y(tǒng)工藝驗(yàn)證和持續(xù)工藝確認(rèn)相結(jié)合的方法。在線監(jiān)控經(jīng)常用于持續(xù)工藝確認(rèn)(在第5.2部分中已討論)，提供大量的關(guān)于工藝的信息和知識(shí)，可能有利于工藝改進(jìn)。Processvalidation工藝驗(yàn)證Traditionalprocessvalidation傳統(tǒng)工藝驗(yàn)證Traditionalprocessvalidationisnormallyperformedwhenthepharmaceuticaldevelopmentand/orprocessdevelopmentisconcluded,afterscale-uptoproductionscaleandpriortomarketingofthefinishedproduct.Aspartoftheprocessvalidationlifecycle,someprocessvalidationstudiesmaybeconductedonpilotscalebatchesiftheprocesshasnotyetbeenscaleduptoproductionscale.傳統(tǒng)工藝驗(yàn)證一般在藥物研發(fā)和/或工藝研發(fā)結(jié)束后，在放大至生產(chǎn)規(guī)模后，成品上市前進(jìn)行。作為工藝驗(yàn)證生命周期的一部分，如果有些工藝還沒有放大到生產(chǎn)規(guī)模，部分工藝驗(yàn)證研究可能會(huì)在中試批次進(jìn)行。Itshouldbenotedthatpilotbatchsizeshouldcorrespondtoatleast10%oftheproductionscalebatch(i.e.suchthatthemultiplicationfactorforthescale-updoesnotexceed10).Forsolidoraldosageformsthissizeshouldgenerallybe10%ofthemaximumproductionscaleor100,000unitswhicheveristhegreater[1].Wheretheintendedbatchsizeislessthan100,000units,thepredictivevalueofthepilotbatchesmaybelimitedandajustifiedapproachshouldbefollowed.Forotherdosageformsthepilotbatchsizeshouldbejustifiedtakingintoaccountrisktothepatientoffailureofthedosageform.Sinceitisnotgenerallyconsideredusefultoconductfullvalidationstudiesonpilotscalebatches,theprocessvalidationschemeoutlinedinAnnexIofthisguidelineshouldbecompletedforeachproductforsubsequentexecutionatproductionscale;bracketingmaybeacceptable.Theprocessvalidationschemetobefollowedshouldbeincludedinthedossier.Theschemeshouldincludeadescriptionofthemanufacturingprocess,theteststobeperformedandacceptancecriteria,adescriptionoftheadditionalcontrolsinplaceandthedatatobecollected.AjustificationforthechosenprocessvalidationschemeshouldbepresentedinModule3andtheQualityOverallSummaryforhumanmedicinesandinPart2.BandthePharmaceuticalDetailedandCriticalSummaryforveterinarymedicines.要注意的是中試生產(chǎn)批應(yīng)至少對(duì)應(yīng)商業(yè)生產(chǎn)批量的10%(即，放大生產(chǎn)倍數(shù)不應(yīng)超過10)。該規(guī)模的固體口服劑型一般應(yīng)為最大生產(chǎn)批量的10%或10萬個(gè)單位劑量，取其中大者。如果要生產(chǎn)的批量小于10萬劑型單位，中試批次預(yù)期值可能受限，則需要采用經(jīng)過評(píng)估的方法。對(duì)于其它劑型，中試批量的論述要考慮劑型失敗給患者帶來的風(fēng)險(xiǎn)。由于一般認(rèn)為在中試規(guī)模批次進(jìn)行全驗(yàn)證研究是沒有用的，因此在本指南附錄1中列出的工藝驗(yàn)證計(jì)劃應(yīng)在之后的各產(chǎn)品生產(chǎn)規(guī)模時(shí)進(jìn)行完善，可以接受括號(hào)法。申報(bào)文件中應(yīng)包括要執(zhí)行的工藝驗(yàn)證計(jì)劃。計(jì)劃中應(yīng)包括工藝描述、要實(shí)施的測(cè)試和可接受標(biāo)準(zhǔn)、附加控制的描述和要收集的數(shù)據(jù)。要在人藥申報(bào)文件模塊3和質(zhì)量綜述、獸藥申報(bào)文件第2.B部分和藥品詳情和關(guān)鍵摘要中放入為什么選擇該工藝驗(yàn)證計(jì)劃的論述。Incertaincaseshowever,itisconsiderednecessarytoprovideproductionscalevalidationdatainthemarketingauthorisationdossieratthetimeofregulatorysubmission,forexamplewhentheproductisabiological/biotechproductorwheretheapplicantisproposinganon-standardmethodofmanufacture(seesection8andAnnexII).Inthesecases,datashouldbeprovidedinthedossieronanumberofconsecutivebatchesatproductionscalepriortoapproval.Thenumberofbatchesshouldbebasedonthevariabilityoftheprocess,thecomplexityoftheprocess/product,processknowledgegainedduringdevelopment,supportivedataatcommercialscaleduringtechnologytransferandtheoverallexperienceofthemanufacturer.Dataonaminimumof3productionscalebatchesshouldbesubmittedunlessotherwisejustified.Dataon1or2productionscalebatchesmaysufficewherethesearesupportedbypilotscalebatchesandajustificationashighlightedabove.在某些情況下，可能認(rèn)為有必要在上市許可申報(bào)資料中提交生產(chǎn)批量的驗(yàn)證數(shù)據(jù)，例如，如果產(chǎn)品是生物/生物技術(shù)制品，或者申請(qǐng)人所擬的工藝為非標(biāo)生產(chǎn)方法(參見第8部分和附錄二)。這種情況下，要在批準(zhǔn)前在申報(bào)資料中包括采用生產(chǎn)批量所獲得的連續(xù)批次數(shù)據(jù)。批次數(shù)應(yīng)基于工藝變動(dòng)情況、工藝/產(chǎn)品復(fù)雜程度、在研發(fā)階段所獲得的工藝知識(shí)、在技術(shù)轉(zhuǎn)移中所獲得的商業(yè)批量中的支持?jǐn)?shù)據(jù)，以及生產(chǎn)商的總體經(jīng)驗(yàn)。除非另有論述，否則至少需要提交3批生產(chǎn)批量的數(shù)據(jù)。如果另有中試批量數(shù)據(jù)支持，以及上述高亮顯示的論述提供，則僅提供1或2批生產(chǎn)批量數(shù)據(jù)也是可以的。譯者：未見哪里有高亮顯示的內(nèi)容。Thestudiesshouldaddresscriticalstepsofmanufacture,byconductingadditionaltestingasnecessary.研究應(yīng)說明關(guān)鍵生產(chǎn)工藝步驟，必要時(shí)增加檢測(cè)。Continuousprocessverification持續(xù)工藝確認(rèn)Continuousprocessverificationisanalternativeapproachtotraditionalprocessvalidationinwhichmanufacturingprocessperformanceiscontinuouslymonitoredandevaluated(ICHQ8).持續(xù)工藝確認(rèn)是傳統(tǒng)工藝驗(yàn)證的一種替代方式，是指生產(chǎn)工藝的性能被持續(xù)地監(jiān)控和評(píng)估(ICHQ8)。Continuousprocessverificationcanbeusedinadditionto,orinsteadof,traditionalprocessvalidation.持續(xù)工藝確認(rèn)可以用于補(bǔ)充，或替代傳統(tǒng)工藝驗(yàn)證。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.確認(rèn)和證明一個(gè)工藝如果在預(yù)定的特定參數(shù)范圍內(nèi)操作，即可以穩(wěn)定生產(chǎn)出符合所有CQA和控制策略要求的物料是一個(gè)科學(xué)并基于風(fēng)險(xiǎn)的實(shí)時(shí)方法。為了進(jìn)行持續(xù)工藝確認(rèn)，公司應(yīng)相應(yīng)地實(shí)施眾多的在線控制和工藝性能監(jiān)控，以及各批產(chǎn)品質(zhì)量監(jiān)控。應(yīng)收集進(jìn)廠物料或組件、制程中物料和成品的質(zhì)量屬性相關(guān)數(shù)據(jù)，還應(yīng)該包括對(duì)屬性、參數(shù)和終點(diǎn)，和CQA和CPP趨勢(shì)的評(píng)估。工藝分析技術(shù)PAT工具，如具有或不具有反饋回路的NIR光譜(例如，混合均一性終點(diǎn)測(cè)試，顆粒表面積測(cè)試，樣品量較大時(shí)含量均一性測(cè)試)，和多變量統(tǒng)計(jì)學(xué)工藝控制MSPC可以當(dāng)作持續(xù)工藝確認(rèn)的工具。Sufficientknowledgeandunderstandingoftheprocessisrequiredinordertosupportcontinuousprocessverification.However,thescopeandextentofcontinuousprocessverificationwillbeinfluencedbyanumberoffactorsincluding:為了支持持續(xù)工藝確認(rèn)，需要對(duì)工藝有足夠的知識(shí)和理解。但是，持續(xù)工藝確認(rèn)的程度會(huì)受到一些因素的影響，包括priordevelopmentandmanufacturingknowledgefromsimilarproductsand/orprocesses;從同類產(chǎn)品和/或工藝中獲得的研發(fā)生產(chǎn)前的知識(shí)theextentofprocessunderstandinggainedfromdevelopmentstudiesandcommercialmanufacturingexperience;在研發(fā)獲得的對(duì)工藝?yán)斫獾某潭?，以及商業(yè)生產(chǎn)經(jīng)驗(yàn)thecomplexityoftheproductand/ormanufacturingprocess;產(chǎn)品和/或生產(chǎn)工藝的復(fù)雜性thelevelofprocessautomationandanalyticaltechnologiesused;工藝自動(dòng)化水平和使用的分析技術(shù)水平—forlegacyproducts,withreferencetotheproductlifecycle,processrobustnessandmanufacturinghistorysincepointofcommercializationasappropriate.對(duì)于已有產(chǎn)品，參考產(chǎn)品生命周期、工藝耐用性和自從商業(yè)化以來的生產(chǎn)歷史(適用時(shí))Adiscussionontheappropriatenessandfeasibilityofthecontinuousprocessverificationstrategyshouldbeincludedinthedevelopmentsectionofthedossierandshouldbesupportedwithdatafromatleastlaboratoryorpilotscalebatches.Adescriptionofthecontinuousprocessverificationstrategyincludingtheprocessparametersandmaterialattributesthatwillbemonitored,aswellastheanalyticalmethodsthatwillbeemployed,shouldbeincludedasdescribedinAnnex1,withcross-referencetothevalidationsectionofthedossier.Actualdatageneratedduringcontinuousprocessverificationatproductionscaleshouldbeavailableatthesiteforinspection.Theapplicantshoulddefinethestageatwhichtheprocessisconsideredtobeundercontrolandthevalidationexercisecompletedpriortoreleaseoftheproducttothemarket,andthebasisonwhichthatdecisionwillbemade.Thediscussionshouldincludeajustificationforthenumberofbatchestobeusedbasedonthecomplexityandexpectedvariabilityoftheprocessandexistingmanufacturingexperienceofthemanufacturingsite.Continuousprocessverificationwouldbeconsideredthemostappropriatemethodforvalidatingcontinuousprocesses.在申報(bào)資料的研發(fā)部分，應(yīng)包括持續(xù)工藝確認(rèn)策略的適當(dāng)性和可行性討論，并使用至少是實(shí)驗(yàn)室規(guī)?；蛑性囈?guī)模批次的數(shù)據(jù)加以支持。持續(xù)工藝確認(rèn)策略的內(nèi)容應(yīng)包括：要監(jiān)控的工藝參數(shù)和物料屬性、要采用的分析方法，應(yīng)該如附錄1中所述，交叉引用至申報(bào)文件的驗(yàn)證部分。在生產(chǎn)規(guī)模持續(xù)工藝確認(rèn)中所產(chǎn)生的實(shí)際數(shù)據(jù)應(yīng)受檢查現(xiàn)場(chǎng)可以獲得。申請(qǐng)人應(yīng)定義工藝步驟受控起始點(diǎn)，和將產(chǎn)品放行上市銷售前所完成的驗(yàn)證工作，以及做出該決定的根據(jù)。討論應(yīng)包括根據(jù)工藝復(fù)雜性和預(yù)期變化，以及在生產(chǎn)場(chǎng)所內(nèi)已有生產(chǎn)經(jīng)驗(yàn)來決定批次數(shù)的論述。在驗(yàn)證連續(xù)生產(chǎn)的工藝時(shí)，持續(xù)工藝確認(rèn)被認(rèn)為是最適當(dāng)?shù)姆绞健ontinuousprocessverificationcanbeintroducedatanytimeinthelifecycleoftheproduct.Itcanbeusedfortheinitialcommercialproduction,tore-validatecommercialisedproductsaspartofprocesschangesortosupportcontinualimprovement.持續(xù)工藝確認(rèn)可以在產(chǎn)品生命周期的任何時(shí)間引入。它可以用于初始的商業(yè)化生產(chǎn)，作為工藝變更的一部分對(duì)商業(yè)產(chǎn)品進(jìn)行再驗(yàn)證，或用于支持持續(xù)改進(jìn)。ContinuousprocessverificationisdependentoncompliancewithGMPprinciplesandrequirements.持續(xù)工藝確認(rèn)是獨(dú)立于GMP原則和要求符合性的。Pharmaceuticalqualitysystems(PQS)asdescribedinICHQ10cancomplementGMPrequirements.However,GMPmattersandPQSshouldnotbeincludedinthesubmissionastheyareassessedandhandledbyGMPinspectorsasappropriate.在ICHQ10里所述藥品質(zhì)量體系PQS可以補(bǔ)充GMP要求，但是，GMP事宜和PQS不應(yīng)該包括在申報(bào)資料中，因?yàn)樗鼈兪怯蒅MP審計(jì)官在適當(dāng)時(shí)進(jìn)行評(píng)估的。Hybridapproach混合方案Itmaybenecessarytouseeitherthetraditionalprocessvalidationorthecontinuousprocessverificationapproachfordifferentstepswithinthemanufacturingprocess.Itshouldbeclearinthedossierwhichapproachtovalidationhasbeentakenforwhichstepsinthemanufacturingprocess.在生產(chǎn)工藝的不同步驟可能需要采用傳統(tǒng)工藝驗(yàn)證或持續(xù)工藝確認(rèn)方法。在文件中應(yīng)清楚說明生產(chǎn)工藝哪個(gè)步驟采用了哪種驗(yàn)證方法。Thevalidationrequirementsintermsofbatchsizeandnumberofbatcheswoulddependontheextenttowhichcontinuousprocessverificationhasbeenused.Fornon-standardprocesses(asdefinedinsection8)ifcontinuousprocessverificationdoesnotaddressthecriticalunitoperation(s)theprocessvalidationrequirementshighlightedinsection5.1shouldbeappliedunlessotherwisejustified.驗(yàn)證中關(guān)于批量和批次數(shù)的要求取決于所使用的持續(xù)工藝確認(rèn)的深度。對(duì)于非標(biāo)工藝(如第8部分所定義)，如果持續(xù)工藝確認(rèn)未包括對(duì)關(guān)鍵單元操作的確認(rèn)，如無其它論述，則適用第5.1部分中高亮顯示的工藝驗(yàn)證要求。Designspaceverification設(shè)計(jì)空間確認(rèn)Adesignspacewillnormallybedevelopedatlaboratoryorpilotscale.Duringscale-upthecommercialprocessisgenerallyconductedandvalidatedinaspecificareaofthedesignspace,definedasthetargetintervalorNormalOperatingRange(NOR).Duringtheproductlifecycle,movingfromoneareatoanotherwithinthedesignspace(i.e.changeintheNOR)mayrepresenthigherorunknownrisksnotpreviouslyidentifiedduringinitialestablishmentofthedesignspace.設(shè)計(jì)空間一般是在實(shí)驗(yàn)室或中試規(guī)模時(shí)建立的。在放大過程中，一般會(huì)實(shí)施商業(yè)化工藝，在設(shè)計(jì)空間的內(nèi)一個(gè)特定區(qū)域進(jìn)行驗(yàn)證，把它定義為目標(biāo)區(qū)間，或常規(guī)操作范圍NOR。在整個(gè)產(chǎn)品生命周期中，在設(shè)計(jì)空間內(nèi)從一個(gè)區(qū)間移動(dòng)至另一個(gè)區(qū)間(即NOR的變更)可能代表更高或未知風(fēng)險(xiǎn)，這些風(fēng)險(xiǎn)可能在初期設(shè)計(jì)空間建立期間并未能預(yù)先識(shí)別。Forthisreasonanddependingonhowthedesignspacewasoriginallyestablishedandhowtheprocesswasvalidated,therewillbesituationswhereitwillbenecessarytoconfirmthesuitabilityofthedesignspaceandverifythatallproductqualityattributesarestillbeingmetinthenewareaofoperationwithinthedesignspace.Thisistermed‘designspaceverification’.因?yàn)樯鲜鲈颍鶕?jù)設(shè)計(jì)空間初始建立情況，和工藝驗(yàn)證情況，會(huì)需要對(duì)設(shè)計(jì)空間的適當(dāng)性進(jìn)行確認(rèn)，對(duì)于在設(shè)計(jì)空間內(nèi)一個(gè)新的操作空間生產(chǎn)出的產(chǎn)品是否滿足所有質(zhì)量屬性應(yīng)進(jìn)行確認(rèn)。這稱為“設(shè)計(jì)空間確認(rèn)“。Iftheparametersinvestigatedduringdevelopmentofthedesignspacehavenotbeenshowntobescaleindependentandtheprocesshasbeenvalidatedusingtraditionalprocessvalidation,designspaceverificationwouldberequiredandaverificationprotocolshouldbeprovidedinthedossier.如果在設(shè)計(jì)空間發(fā)展階段所調(diào)查的參數(shù)并未顯出與放大不相關(guān)，且工藝采用了傳統(tǒng)工藝驗(yàn)證方法進(jìn)行驗(yàn)證，則需要對(duì)設(shè)計(jì)空間進(jìn)行確認(rèn)，并在文件中提供確認(rèn)方案。Ifcontinuousprocessverificationhasbeenutilised,thismaycontributetowardsensuringthevalidityofthedesignspacethroughouttheproductlifecycle.Inthiscase,adesignspaceverificationstrategyshouldbeincludedaspartofthecontinuousprocessverificationstrategy.如果采用了持續(xù)工藝確認(rèn)，則有助于保證在產(chǎn)品生命周期內(nèi)設(shè)計(jì)空間的有效性。這種情況下，設(shè)計(jì)空間確認(rèn)策略應(yīng)作為持續(xù)工藝確認(rèn)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.根據(jù)變更情況，以及在設(shè)計(jì)空間內(nèi)移動(dòng)程度()，確認(rèn)方案可能包括質(zhì)量屬性控制(QA)和工藝參數(shù)控制(PP)，這兩項(xiàng)并不包括在常規(guī)控制系統(tǒng)中(例如對(duì)不受放大和設(shè)施影響的QA和PP監(jiān)控和測(cè)試)。不需對(duì)設(shè)計(jì)空間的整個(gè)區(qū)間，或失效邊緣進(jìn)行確認(rèn)。原則上，應(yīng)該對(duì)設(shè)計(jì)空間內(nèi)不止一個(gè)區(qū)間進(jìn)行確認(rèn)，但在整個(gè)產(chǎn)品生命周期內(nèi)，由于會(huì)在批準(zhǔn)的設(shè)計(jì)空間對(duì)NOR進(jìn)行調(diào)整的需要，因而進(jìn)行分步確認(rèn)方式也是可以接受的。Scale-up放大生產(chǎn)Inordertoavoidtherepetitionoflengthyandcostlytests,itisnecessarytogatherinformationduringproperlydesigneddevelopmentandprocessoptimisationstudies,whenscalingupfromlaboratorythroughpilottoproductionscale.Suchinformationprovidesthebasisforjustificationthatscale-upcanbeachievedwithoutaconsequentlossinquality.Thosepartsoftheprocesslikelytobecriticalinscale-upshouldbeidentifiedinsection3.2.P.2(VeterinaryPart2.A.4)anddefinedinsection3.2.P.3(VeterinaryPart2.B)ofthedossier.在從化驗(yàn)室規(guī)模經(jīng)過試生產(chǎn)規(guī)模再放大至生產(chǎn)規(guī)模時(shí)，為了避免長(zhǎng)時(shí)間及昂貴的檢測(cè)，需要在適當(dāng)?shù)脑O(shè)計(jì)研發(fā)和工藝優(yōu)化研究過程中收集相關(guān)信息。這些信息是論述放大生產(chǎn)不會(huì)對(duì)質(zhì)量產(chǎn)生負(fù)面影響的基礎(chǔ)。在放大過程中可能比較關(guān)鍵的工藝部分應(yīng)在3.2.P.2(獸藥第2.A.4部分)和3.2.P.3(獸藥第2B部分)文件中識(shí)別。Whererangesofbatchsizesareproposed,itshouldbejustifiedthatvariationsinbatchsizewouldnotadverselyaltertheCQAsofthefinishedproduct.Itisenvisagedthatthoseparameterslistedintheprocessvalidationscheme(AnnexIofthisguideline)willneedtobere-validatedoncefurtherscale-upisproposedpost-authorisationunlesstheprocesshasbeenproventobescaleindependentorcontinuousprocessverificationisemployed.如果申請(qǐng)了批量范圍，應(yīng)論述批量變動(dòng)對(duì)制劑的CQA不會(huì)產(chǎn)生負(fù)面影響。除非已經(jīng)證明放大是獨(dú)立的，或者采用了持續(xù)工藝確認(rèn)方法，否則認(rèn)為這些列在工藝驗(yàn)證計(jì)劃中的參數(shù)(本指南附錄I)在獲得上市批準(zhǔn)后如果申請(qǐng)批量放大后即需要進(jìn)行再驗(yàn)證。Postapprovalchangecontrol批準(zhǔn)后變更控制Clearlydefinedproceduresareneededtocontrolchangesproposedinproductionprocesses.TheseproceduresarepartofGMPandwouldnotnormallybespecifiedinthedossier.Suchproceduresshouldcontrolplannedchanges,ensurethatsufficientsupportingdataaregeneratedtodemonstratethattherevisedprocesswillresultinaproductofthedesiredquality,consistentwiththeapprovedcontrolstrategyandensurethatallaspectsarethoroughlydocumentedandapprovedincludingwhetherregulatoryapprovalisneededbywayofvariation.需要清楚界定對(duì)生產(chǎn)工藝進(jìn)行變更控制要遵守的程序。這些程序是GMP的一部分，一般在文件里說明。這些程序應(yīng)對(duì)計(jì)劃變更進(jìn)行控制，保證會(huì)產(chǎn)生充分的支持性數(shù)據(jù)來證明修訂后的工藝會(huì)使用得產(chǎn)品具備所需的品質(zhì)，與所批準(zhǔn)的控制策略保持一致，保證所有事項(xiàng)均被完整記錄和批準(zhǔn)，包括是否需要提交變更申請(qǐng)獲得法規(guī)批準(zhǔn)。RefertotheEuropeanCommissionguidanceonTypeIandTypeIIvariations(Guidelinesonthedetailsofthevariouscategoriesofvariations,ontheoperationoftheprocedureslaiddowninChaptersII,IIa,IIIandIVofCommissionRegulation(EC)No.1234/2008of24November2008concerningtheexaminationofvariationstothetermsofmarketingauthorizationsformedicinalproductsforhumanuseandveterinarymedicinalproductsandonthedocumentationtobesubmittedpursuanttothoseprocedures)andRegulation712/2012/ECfordetailsonthechangeswhichwouldrequireavariation.參見歐洲委員會(huì)關(guān)于第I類和第II類變更指南(關(guān)于人用獸用藥品上市后變更檢查，及需要提交的文件規(guī)定，歐洲委員會(huì)法令EC1234/2008，2008年11月24日，第II章IIa節(jié)，第III章和第IV章中變更詳細(xì)分類)，及712/2012/EC法令關(guān)于申請(qǐng)變更的詳細(xì)要求。Standardvs.non-standardmethodsofmanufacture標(biāo)準(zhǔn)VS非標(biāo)準(zhǔn)生產(chǎn)方法Thissectionisonlyrelevantforprocesseswhichhavebeenvalidatedusingtraditionalprocessvalidation.Itisnotrelevantforthoseprocesseswherecontinuousprocessverificationisemployed(seesections5.1and5.2).Accordingtosection5.1,fullproduction-scaledatashouldbeprovidedinthedossierfornon-standardproductsorprocesseswhichwerevalidatedusingtraditionalprocessvalidation.Itispossiblefortheapplicanttojustifythattheproductprocesscanbeconsideredstandardforaparticularmanufacturer/sitetakingintoaccounttherisktothepatientoffailureoftheproductorprocess.Suchjustificationsareassessedonacasebycasebasis,buttheinformationprovidedbytheapplicant(foreachmanufacturingsite)shouldinclude:本部分僅與采用傳統(tǒng)工藝驗(yàn)證方法進(jìn)行驗(yàn)證的工藝相關(guān)，與采用持續(xù)工藝確認(rèn)的工藝不相關(guān)(參見第5.1和5.2部分）。根據(jù)第5.1部分，非標(biāo)工藝或采用傳統(tǒng)工藝驗(yàn)證方法進(jìn)行驗(yàn)證的工藝的申報(bào)資料需要提供生產(chǎn)規(guī)模的數(shù)據(jù)。申請(qǐng)人也可以對(duì)產(chǎn)品工藝進(jìn)行論述，證明考慮到產(chǎn)品或工藝失敗對(duì)患者的風(fēng)險(xiǎn)，該工藝對(duì)于一個(gè)特定的生產(chǎn)商/生產(chǎn)場(chǎng)所來說，可以作為標(biāo)準(zhǔn)工藝。這類論述應(yīng)是各案進(jìn)行評(píng)估，但由申請(qǐng)人（對(duì)每個(gè)生產(chǎn)場(chǎng)所）提供的資料應(yīng)包括：—experiencewiththesameoressentiallysimilarproductorprocess（numberofproductsauthorised/marketedintheEU/EEAandnumberofbatches（includinginformationonscale）manufactured）;—同樣或基本類似產(chǎn)品或工藝（在EU/EEA地區(qū)獲批準(zhǔn)/上市的產(chǎn)品數(shù)，及生產(chǎn)批數(shù)（包括規(guī)模信息））的經(jīng)驗(yàn)—?thenames/marketingauthorisationnumbersintherelevantEU/EEAmemberstateshouldbeprovided.—提供在相關(guān)EU/EEA成員國(guó)上市許可的名稱和數(shù)量—amountofknowledgegainedduringthedevelopmentoftheproduct（numberandscaleofbatchesmanufacturedateachmanufacturingsiteinvolved）;—在產(chǎn)品研發(fā)過程中獲得的知識(shí)量（各涉及的生產(chǎn)場(chǎng)所所生產(chǎn)的批數(shù)和規(guī)模）—historyofGMPcomplianceofmanufacturingsitesforthattypeofprocessTheapplicantshouldclearlystate（insection3.2.P.3.5ofthedossierforhumanmedicines,insection2.Bofthedossierforveterinarymedicines）whethertheyconsiderthemanufacturingprocesstobestandardornon-standardandthejustificationfortheirdecisionfornewmarketingauthorisationapplications.—該類工藝生產(chǎn)場(chǎng)所GMP符合性歷史。申請(qǐng)人應(yīng)清楚說明（在人用藥文件3.2.P.3.5部分，在獸藥文件2.B部分）其將生產(chǎn)工藝作為標(biāo)準(zhǔn)還是非標(biāo)準(zhǔn)工藝，其新上市許可申報(bào)決定的論述PleaseseeAnnexIIforfurtherinformationonproducts/processesconsideredtobenonstandard.關(guān)于作為非標(biāo)準(zhǔn)工藝/產(chǎn)品的詳細(xì)信息，參見附錄II。Definitions定義（翻譯略）At-line:在線Measurementwherethesampleisremoved,isolatedfrom,andanalysedincloseproximitytotheprocessstream.將樣品取出，具有獨(dú)立形態(tài)，在接近工藝流程場(chǎng)所對(duì)其進(jìn)行測(cè)試Bracketingapproach:括號(hào)法Avalidationscheme/protocoldesignedsuchthatonlybatchesontheextremesofcertainpredeterminedandjustifieddesignfactors,e.g.,strength,batchsize,packsizearetestedd