EMA工藝驗證指引

EMA工藝驗證指南---EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev127February2014CommitteeforMedicinalProductsforHumanUse(CHMP)CommitteeforMedicinalProductsforVeterinaryUse(CVMP)Guidelineonprocessvalidationforfinishedproducts-informationanddatatobeprovidedinregulatorysubmissions制劑工藝驗證指南---在法規(guī)提交中要提供的資料和數據DraftagreedbyCHMP/CVMPQualityWorkingParty2February2012由CHMP/CVMP質量工作組通過草案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).本指南替代工藝驗證注釋(CPMP/QWP/848/96,EMEA/CVMP/598/99)，包括附錄二----非標準工藝(CPMP/QWP/2054/03)。KeywordsProcessvalidation,continuousprocessverification,on-goingprocessverification,criticalprocessparameter,criticalqualityattribute,lifecycle,changecontrol關鍵詞工藝驗證、持續(xù)工藝確認、關鍵工藝參數、關鍵質量屬性、生命周期、變更控制Tableofcontents目錄Executivesummary實施摘要1.Introduction(background)介紹（背景）2.Scope范圍3.Legalbasis法規(guī)依據4.Generalconsiderations一般考慮5.Processvalidation工藝驗證5.1.Traditionalprocessvalidation傳統(tǒng)工藝驗證5.2.Continuousprocessverification持續(xù)工藝確認5.3.Hybridapproach混合方案5.4.Designspaceverification設計空間確認6.Scale-up放大生產7.Postapprovalchangecontrol批準后變更控制8.Standardvs.non-standardmethodsofmanufacture標準VS非標準生產方法Definitions定義References參考文獻AnnexI:Processvalidationscheme附錄I：工藝驗證計劃AnnexII:Standard/non-standardprocesses附錄II：標準/非標工藝Executivesummary實施摘要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采用的傳統(tǒng)工藝驗證這外，提供了使用持續(xù)工藝確認的可能性。本指南對已批準上市的藥品未引入新要求，但闡述了公司在ICHQ8,Q9和Q10中描述的有效質量體系下，應用強化工藝理解與風險管理工具時，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范圍內操作的工藝可以重復有效地生產出符合其預定質量標準和質量屬性的藥品的書面證據(ICHQ7)。持續(xù)工藝驗證被引入替代基于對工藝性能持續(xù)監(jiān)測的工藝驗證。這種方法是依據來自于產品和工藝研發(fā)和/或之前生產經驗的知識。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)工藝確認既適用于傳統(tǒng)藥品研發(fā)方法，也適用于加強藥品研發(fā)方法。它采用廣泛的在線監(jiān)測和/或控制來評估工藝的性能。將研發(fā)藥物指南解釋(CPMP/QWP/155/96)、藥物研發(fā)指南解釋(ICHQ8R2)與本指南相結合，應可以覆蓋人用藥法規(guī)申報文件所需包括的生產工藝的關鍵因素。對于獸藥產品，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指南不適用獸藥產品，本指南中的原則可以應用于獸藥產品，申請人應選擇性采用更好的方法來進行藥品研發(fā)和工藝驗證。工藝驗證不應該作為是一次性的事情。工藝驗證應將產品生命周期結合工藝研發(fā)、商業(yè)生產工藝驗證、在常規(guī)商業(yè)化生產中控制狀態(tài)的工藝維護相結合。Scope范圍Thisdocumentisintendedtoprovideguidanceontheprocessvalidationinformationanddatatobeprovidedinregulatorysubmissionsforthefinisheddosageformsofchemicalmedicinalproductsforhumanandveterinaryuse.Thegeneralprinciplesalsoapplytoactivesubstances.本文件意在提供關于人用和獸用化學藥品制劑的申報時所需提交的工藝驗證資料和數據的指南。一般原則也適用于活性物質。However,informationonvalidationofnon-sterileactivesubstancesisnotrequiredinthedossier.但是，在申報文件中并不要求提交非無菌原料藥的驗證信息。Inaddition,expectationsforactivesubstancesarecontainedinICHQ11andsotheinformationisnotrepeatedinthisdocument.另外，ICHQ11中包括了對原料藥的建議，因此本文件中不再重復這些信息。Theprinciplesdescribedarealsoapplicabletobiologicalmedicinalproducts.However,theseshouldbeconsideredonacasebycasebasisinviewofthecomplexnatureandinherentvariabilityofthebiologicalsubstance.本文所述的原則也適用于生物制品。但是，生物制品的工藝驗證應根據其復雜性和內在變因各案考查。Itisexpectedthattheinformation/datarequestedinthisguidelinebepresentinthedossieratthetimeofregulatorysubmission.在本指南中所要求的資料/數據應該包括在法規(guī)申報的文件中。Thisdocumentprovidesguidanceonthevalidationofthemanufacturingprocess,whichcanbeconsideredasthesecondstageintheproductlifecycle.Thefirststage(processdesign)iscoveredinthenoteforguidanceonpharmaceuticaldevelopment(ICHQ8R2/EMEA/CVMP/315/98)andthethirdstage(on-goingprocessverification)iscoveredunderGMP(Annex15).本文件提供生產工藝驗證指南，工藝驗證可以當作產品生命周期的第二階段。第一階段(工藝設計)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)包括在GMP(附錄15)中。Legalbasis法律依據Thisguidelinehastobereadinconjunctionwiththeintroductionandgeneralprinciplessection(4)ofAnnexItoDirective2001/83/ECasamendedandtheintroductionandgeneralprinciplessection(2)ofAnnexItoDirective2001/82/ECasamended.本指南應與指令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).工藝驗證應確認控制策略對于工藝設計和產品質量來說已足夠。驗證應覆蓋生產上市產品的所有生產場所和所有劑量產品。不同劑量、不同批量和包裝規(guī)格可以括號法。但是，驗證必須覆蓋所有擬生產的場所。每個生產場所所有產品均應有工藝驗證數據，以證明生產工藝的充分性。工藝驗證應符合GMP，數據應保留在生產場所，如果申報文件中未要求(參見第8部分)則應該在檢查過程中隨時可提供。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，工藝驗證都可以采用傳統(tǒng)方法。但是，如果已采用加強研發(fā)方法，或通過歷史數據和生產經驗已獲得大量產品和工藝知識和理解，也存在實施持續(xù)工藝確認的可能性。可能要采用傳統(tǒng)工藝驗證和持續(xù)工藝確認相結合的方法。在線監(jiān)控經常用于持續(xù)工藝確認(在第5.2部分中已討論)，提供大量的關于工藝的信息和知識，可能有利于工藝改進。Processvalidation工藝驗證Traditionalprocessvalidation傳統(tǒng)工藝驗證Traditionalprocessvalidationisnormallyperformedwhenthepharmaceuticaldevelopmentand/orprocessdevelopmentisconcluded,afterscale-uptoproductionscaleandpriortomarketingofthefinishedproduct.Aspartoftheprocessvalidationlifecycle,someprocessvalidationstudiesmaybeconductedonpilotscalebatchesiftheprocesshasnotyetbeenscaleduptoproductionscale.傳統(tǒng)工藝驗證一般在藥物研發(fā)和/或工藝研發(fā)結束后，在放大至生產規(guī)模后，成品上市前進行。作為工藝驗證生命周期的一部分，如果有些工藝還沒有放大到生產規(guī)模，部分工藝驗證研究可能會在中試批次進行。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批應至少對應商業(yè)生產批量的10%(即，放大生產倍數不應超過10)。該規(guī)模的固體口服劑型一般應為最大生產批量的10%或10萬個單位劑量，取其中大者。如果要生產的批量小于10萬劑型單位，中試批次預期值可能受限，則需要采用經過評估的方法。對于其它劑型，中試批量的論述要考慮劑型失敗給患者帶來的風險。由于一般認為在中試規(guī)模批次進行全驗證研究是沒有用的，因此在本指南附錄1中列出的工藝驗證計劃應在之后的各產品生產規(guī)模時進行完善，可以接受括號法。申報文件中應包括要執(zhí)行的工藝驗證計劃。計劃中應包括工藝描述、要實施的測試和可接受標準、附加控制的描述和要收集的數據。要在人藥申報文件模塊3和質量綜述、獸藥申報文件第2.B部分和藥品詳情和關鍵摘要中放入為什么選擇該工藝驗證計劃的論述。Incertaincaseshowever,itisconsiderednecessarytoprovideproductionscalevalidationdatainthemarketingauthorisationdossieratthetimeofregulatorysubmission,forexamplewhentheproductisabiological/biotechproductorwheretheapplicantisproposinganon-standardmethodofmanufacture(seesection8andAnnexII).Inthesecases,datashouldbeprovidedinthedossieronanumberofconsecutivebatchesatproductionscalepriortoapproval.Thenumberofbatchesshouldbebasedonthevariabilityoftheprocess,thecomplexityoftheprocess/product,processknowledgegainedduringdevelopment,supportivedataatcommercialscaleduringtechnologytransferandtheoverallexperienceofthemanufacturer.Dataonaminimumof3productionscalebatchesshouldbesubmittedunlessotherwisejustified.Dataon1or2productionscalebatchesmaysufficewherethesearesupportedbypilotscalebatchesandajustificationashighlightedabove.在某些情況下，可能認為有必要在上市許可申報資料中提交生產批量的驗證數據，例如，如果產品是生物/生物技術制品，或者申請人所擬的工藝為非標生產方法(參見第8部分和附錄二)。這種情況下，要在批準前在申報資料中包括采用生產批量所獲得的連續(xù)批次數據。批次數應基于工藝變動情況、工藝/產品復雜程度、在研發(fā)階段所獲得的工藝知識、在技術轉移中所獲得的商業(yè)批量中的支持數據，以及生產商的總體經驗。除非另有論述，否則至少需要提交3批生產批量的數據。如果另有中試批量數據支持，以及上述高亮顯示的論述提供，則僅提供1或2批生產批量數據也是可以的。譯者：未見哪里有高亮顯示的內容。Thestudiesshouldaddresscriticalstepsofmanufacture,byconductingadditionaltestingasnecessary.研究應說明關鍵生產工藝步驟，必要時增加檢測。Continuousprocessverification持續(xù)工藝確認Continuousprocessverificationisanalternativeapproachtotraditionalprocessvalidationinwhichmanufacturingprocessperformanceiscontinuouslymonitoredandevaluated(ICHQ8).持續(xù)工藝確認是傳統(tǒng)工藝驗證的一種替代方式，是指生產工藝的性能被持續(xù)地監(jiān)控和評估(ICHQ8)。Continuousprocessverificationcanbeusedinadditionto,orinsteadof,traditionalprocessvalidation.持續(xù)工藝確認可以用于補充，或替代傳統(tǒng)工藝驗證。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.確認和證明一個工藝如果在預定的特定參數范圍內操作，即可以穩(wěn)定生產出符合所有CQA和控制策略要求的物料是一個科學并基于風險的實時方法。為了進行持續(xù)工藝確認，公司應相應地實施眾多的在線控制和工藝性能監(jiān)控，以及各批產品質量監(jiān)控。應收集進廠物料或組件、制程中物料和成品的質量屬性相關數據，還應該包括對屬性、參數和終點，和CQA和CPP趨勢的評估。工藝分析技術PAT工具，如具有或不具有反饋回路的NIR光譜(例如，混合均一性終點測試，顆粒表面積測試，樣品量較大時含量均一性測試)，和多變量統(tǒng)計學工藝控制MSPC可以當作持續(xù)工藝確認的工具。Sufficientknowledgeandunderstandingoftheprocessisrequiredinordertosupportcontinuousprocessverification.However,thescopeandextentofcontinuousprocessverificationwillbeinfluencedbyanumberoffactorsincluding:為了支持持續(xù)工藝確認，需要對工藝有足夠的知識和理解。但是，持續(xù)工藝確認的程度會受到一些因素的影響，包括priordevelopmentandmanufacturingknowledgefromsimilarproductsand/orprocesses;從同類產品和/或工藝中獲得的研發(fā)生產前的知識theextentofprocessunderstandinggainedfromdevelopmentstudiesandcommercialmanufacturingexperience;在研發(fā)獲得的對工藝理解的程度，以及商業(yè)生產經驗thecomplexityoftheproductand/ormanufacturingprocess;產品和/或生產工藝的復雜性thelevelofprocessautomationandanalyticaltechnologiesused;工藝自動化水平和使用的分析技術水平—forlegacyproducts,withreferencetotheproductlifecycle,processrobustnessandmanufacturinghistorysincepointofcommercializationasappropriate.對于已有產品，參考產品生命周期、工藝耐用性和自從商業(yè)化以來的生產歷史(適用時)Adiscussionontheappropriatenessandfeasibilityofthecontinuousprocessverificationstrategyshouldbeincludedinthedevelopmentsectionofthedossierandshouldbesupportedwithdatafromatleastlaboratoryorpilotscalebatches.Adescriptionofthecontinuousprocessverificationstrategyincludingtheprocessparametersandmaterialattributesthatwillbemonitored,aswellastheanalyticalmethodsthatwillbeemployed,shouldbeincludedasdescribedinAnnex1,withcross-referencetothevalidationsectionofthedossier.Actualdatageneratedduringcontinuousprocessverificationatproductionscaleshouldbeavailableatthesiteforinspection.Theapplicantshoulddefinethestageatwhichtheprocessisconsideredtobeundercontrolandthevalidationexercisecompletedpriortoreleaseoftheproducttothemarket,andthebasisonwhichthatdecisionwillbemade.Thediscussionshouldincludeajustificationforthenumberofbatchestobeusedbasedonthecomplexityandexpectedvariabilityoftheprocessandexistingmanufacturingexperienceofthemanufacturingsite.Continuousprocessverificationwouldbeconsideredthemostappropriatemethodforvalidatingcontinuousprocesses.在申報資料的研發(fā)部分，應包括持續(xù)工藝確認策略的適當性和可行性討論，并使用至少是實驗室規(guī)模或中試規(guī)模批次的數據加以支持。持續(xù)工藝確認策略的內容應包括：要監(jiān)控的工藝參數和物料屬性、要采用的分析方法，應該如附錄1中所述，交叉引用至申報文件的驗證部分。在生產規(guī)模持續(xù)工藝確認中所產生的實際數據應受檢查現場可以獲得。申請人應定義工藝步驟受控起始點，和將產品放行上市銷售前所完成的驗證工作，以及做出該決定的根據。討論應包括根據工藝復雜性和預期變化，以及在生產場所內已有生產經驗來決定批次數的論述。在驗證連續(xù)生產的工藝時，持續(xù)工藝確認被認為是最適當的方式。Continuousprocessverificationcanbeintroducedatanytimeinthelifecycleoftheproduct.Itcanbeusedfortheinitialcommercialproduction,tore-validatecommercialisedproductsaspartofprocesschangesortosupportcontinualimprovement.持續(xù)工藝確認可以在產品生命周期的任何時間引入。它可以用于初始的商業(yè)化生產，作為工藝變更的一部分對商業(yè)產品進行再驗證，或用于支持持續(xù)改進。ContinuousprocessverificationisdependentoncompliancewithGMPprinciplesandrequirements.持續(xù)工藝確認是獨立于GMP原則和要求符合性的。Pharmaceuticalqualitysystems(PQS)asdescribedinICHQ10cancomplementGMPrequirements.However,GMPmattersandPQSshouldnotbeincludedinthesubmissionastheyareassessedandhandledbyGMPinspectorsasappropriate.在ICHQ10里所述藥品質量體系PQS可以補充GMP要求，但是，GMP事宜和PQS不應該包括在申報資料中，因為它們是由GMP審計官在適當時進行評估的。Hybridapproach混合方案Itmaybenecessarytouseeitherthetraditionalprocessvalidationorthecontinuousprocessverificationapproachfordifferentstepswithinthemanufacturingprocess.Itshouldbeclearinthedossierwhichapproachtovalidationhasbeentakenforwhichstepsinthemanufacturingprocess.在生產工藝的不同步驟可能需要采用傳統(tǒng)工藝驗證或持續(xù)工藝確認方法。在文件中應清楚說明生產工藝哪個步驟采用了哪種驗證方法。Thevalidationrequirementsintermsofbatchsizeandnumberofbatcheswoulddependontheextenttowhichcontinuousprocessverificationhasbeenused.Fornon-standardprocesses(asdefinedinsection8)ifcontinuousprocessverificationdoesnotaddressthecriticalunitoperation(s)theprocessvalidationrequirementshighlightedinsection5.1shouldbeappliedunlessotherwisejustified.驗證中關于批量和批次數的要求取決于所使用的持續(xù)工藝確認的深度。對于非標工藝(如第8部分所定義)，如果持續(xù)工藝確認未包括對關鍵單元操作的確認，如無其它論述，則適用第5.1部分中高亮顯示的工藝驗證要求。Designspaceverification設計空間確認Adesignspacewillnormallybedevelopedatlaboratoryorpilotscale.Duringscale-upthecommercialprocessisgenerallyconductedandvalidatedinaspecificareaofthedesignspace,definedasthetargetintervalorNormalOperatingRange(NOR).Duringtheproductlifecycle,movingfromoneareatoanotherwithinthedesignspace(i.e.changeintheNOR)mayrepresenthigherorunknownrisksnotpreviouslyidentifiedduringinitialestablishmentofthedesignspace.設計空間一般是在實驗室或中試規(guī)模時建立的。在放大過程中，一般會實施商業(yè)化工藝，在設計空間的內一個特定區(qū)域進行驗證，把它定義為目標區(qū)間，或常規(guī)操作范圍NOR。在整個產品生命周期中，在設計空間內從一個區(qū)間移動至另一個區(qū)間(即NOR的變更)可能代表更高或未知風險，這些風險可能在初期設計空間建立期間并未能預先識別。Forthisreasonanddependingonhowthedesignspacewasoriginallyestablishedandhowtheprocesswasvalidated,therewillbesituationswhereitwillbenecessarytoconfirmthesuitabilityofthedesignspaceandverifythatallproductqualityattributesarestillbeingmetinthenewareaofoperationwithinthedesignspace.Thisistermed‘designspaceverification’.因為上述原因，根據設計空間初始建立情況，和工藝驗證情況，會需要對設計空間的適當性進行確認，對于在設計空間內一個新的操作空間生產出的產品是否滿足所有質量屬性應進行確認。這稱為“設計空間確認“。Iftheparametersinvestigatedduringdevelopmentofthedesignspacehavenotbeenshowntobescaleindependentandtheprocesshasbeenvalidatedusingtraditionalprocessvalidation,designspaceverificationwouldberequiredandaverificationprotocolshouldbeprovidedinthedossier.如果在設計空間發(fā)展階段所調查的參數并未顯出與放大不相關，且工藝采用了傳統(tǒng)工藝驗證方法進行驗證，則需要對設計空間進行確認，并在文件中提供確認方案。Ifcontinuousprocessverificationhasbeenutilised,thismaycontributetowardsensuringthevalidityofthedesignspacethroughouttheproductlifecycle.Inthiscase,adesignspaceverificationstrategyshouldbeincludedaspartofthecontinuousprocessverificationstrategy.如果采用了持續(xù)工藝確認，則有助于保證在產品生命周期內設計空間的有效性。這種情況下，設計空間確認策略應作為持續(xù)工藝確認策略的一部分。Dependingonthechangeandtheextentofmovementwithinthedesignspace(i.e.distancefromvalidatedtarget/NORornewareaofdesignspacewithhigherorunknownrisk)protocolsforverificationmayincludecontrolsofqualityattributes(QA's)andprocessparameters(PP's)notincludedintheroutinecontrolsystem(e.g.monitoringortestingofQA,sandPP,sthatareexpectedtobescaledependantandwhenapplicable,equipmentdependant).ItisnotnecessarytoverifyentireareasoftheDesignSpaceortheedgeoffailure.InprinciplemorethanoneareaofthedesignspaceshouldbeverifiedbutastepwiseapproachtakingintoconsiderationtheneedtoadjusttheNORwithintheapproveddesignspaceduringproductlifecycleisacceptable.根據變更情況，以及在設計空間內移動程度()，確認方案可能包括質量屬性控制(QA)和工藝參數控制(PP)，這兩項并不包括在常規(guī)控制系統(tǒng)中(例如對不受放大和設施影響的QA和PP監(jiān)控和測試)。不需對設計空間的整個區(qū)間，或失效邊緣進行確認。原則上，應該對設計空間內不止一個區(qū)間進行確認，但在整個產品生命周期內，由于會在批準的設計空間對NOR進行調整的需要，因而進行分步確認方式也是可以接受的。Scale-up放大生產Inordertoavoidtherepetitionoflengthyandcostlytests,itisnecessarytogatherinformationduringproperlydesigneddevelopmentandprocessoptimisationstudies,whenscalingupfromlaboratorythroughpilottoproductionscale.Suchinformationprovidesthebasisforjustificationthatscale-upcanbeachievedwithoutaconsequentlossinquality.Thosepartsoftheprocesslikelytobecriticalinscale-upshouldbeidentifiedinsection3.2.P.2(VeterinaryPart2.A.4)anddefinedinsection3.2.P.3(VeterinaryPart2.B)ofthedossier.在從化驗室規(guī)模經過試生產規(guī)模再放大至生產規(guī)模時，為了避免長時間及昂貴的檢測，需要在適當的設計研發(fā)和工藝優(yōu)化研究過程中收集相關信息。這些信息是論述放大生產不會對質量產生負面影響的基礎。在放大過程中可能比較關鍵的工藝部分應在3.2.P.2(獸藥第2.A.4部分)和3.2.P.3(獸藥第2B部分)文件中識別。Whererangesofbatchsizesareproposed,itshouldbejustifiedthatvariationsinbatchsizewouldnotadverselyaltertheCQAsofthefinishedproduct.Itisenvisagedthatthoseparameterslistedintheprocessvalidationscheme(AnnexIofthisguideline)willneedtobere-validatedoncefurtherscale-upisproposedpost-authorisationunlesstheprocesshasbeenproventobescaleindependentorcontinuousprocessverificationisemployed.如果申請了批量范圍，應論述批量變動對制劑的CQA不會產生負面影響。除非已經證明放大是獨立的，或者采用了持續(xù)工藝確認方法，否則認為這些列在工藝驗證計劃中的參數(本指南附錄I)在獲得上市批準后如果申請批量放大后即需要進行再驗證。Postapprovalchangecontrol批準后變更控制Clearlydefinedproceduresareneededtocontrolchangesproposedinproductionprocesses.TheseproceduresarepartofGMPandwouldnotnormallybespecifiedinthedossier.Suchproceduresshouldcontrolplannedchanges,ensurethatsufficientsupportingdataaregeneratedtodemonstratethattherevisedprocesswillresultinaproductofthedesiredquality,consistentwiththeapprovedcontrolstrategyandensurethatallaspectsarethoroughlydocumentedandapprovedincludingwhetherregulatoryapprovalisneededbywayofvariation.需要清楚界定對生產工藝進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。這些程序應對計劃變更進行控制，保證會產生充分的支持性數據來證明修訂后的工藝會使用得產品具備所需的品質，與所批準的控制策略保持一致，保證所有事項均被完整記錄和批準，包括是否需要提交變更申請獲得法規(guī)批準。RefertotheEuropeanCommissionguidanceonTypeIandTypeIIvariations(Guidelinesonthedetailsofthevariouscategoriesofvariations,ontheoperationoftheprocedureslaiddowninChaptersII,IIa,IIIandIVofCommissionRegulation(EC)No.1234/2008of24November2008concerningtheexaminationofvariationstothetermsofmarketingauthorizationsformedicinalproductsforhumanuseandveterinarymedicinalproductsandonthedocumentationtobesubmittedpursuanttothoseprocedures)andRegulation712/2012/ECfordetailsonthechangeswhichwouldrequireavariation.參見歐洲委員會關于第I類和第II類變更指南(關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章中變更詳細分類)，及712/2012/EC法令關于申請變更的詳細要求。Standardvs.non-standardmethodsofmanufacture標準VS非標準生產方法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)工藝驗證方法進行驗證的工藝相關，與采用持續(xù)工藝確認的工藝不相關(參見第5.1和5.2部分）。根據第5.1部分，非標工藝或采用傳統(tǒng)工藝驗證方法進行驗證的工藝的申報資料需要提供生產規(guī)模的數據。申請人也可以對產品工藝進行論述，證明考慮到產品或工藝失敗對患者的風險，該工藝對于一個特定的生產商/生產場所來說，可以作為標準工藝。這類論述應是各案進行評估，但由申請人（對每個生產場所）提供的資料應包括：—experiencewiththesameoressentiallysimilarproductorprocess（numberofproductsauthorised/marketedintheEU/EEAandnumberofbatches（includinginformationonscale）manufactured）;—同樣或基本類似產品或工藝（在EU/EEA地區(qū)獲批準/上市的產品數，及生產批數（包括規(guī)模信息））的經驗—?thenames/marketingauthorisationnumbersintherelevantEU/EEAmemberstateshouldbeprovided.—提供在相關EU/EEA成員國上市許可的名稱和數量—amountofknowledgegainedduringthedevelopmentoftheproduct（numberandscaleofbatchesmanufacturedateachmanufacturingsiteinvolved）;—在產品研發(fā)過程中獲得的知識量（各涉及的生產場所所生產的批數和規(guī)模）—historyofGMPcomplianceofmanufacturingsitesforthattypeofprocessTheapplicantshouldclearlystate（insection3.2.P.3.5ofthedossierforhumanmedicines,insection2.Bofthedossierforveterinarymedicines）whethertheyconsiderthemanufacturingprocesstobestandardornon-standardandthejustificationfortheirdecisionfornewmarketingauthorisationapplications.—該類工藝生產場所GMP符合性歷史。申請人應清楚說明（在人用藥文件3.2.P.3.5部分，在獸藥文件2.B部分）其將生產工藝作為標準還是非標準工藝，其新上市許可申報決定的論述PleaseseeAnnexIIforfurtherinformationonproducts/processesconsideredtobenonstandard.關于作為非標準工藝/產品的詳細信息，參見附錄II。Definitions定義（翻譯略）At-line:在線Measurementwherethesampleisremoved,isolatedfrom,andanalysedincloseproximitytotheprocessstream.將樣品取出，具有獨立形態(tài)，在接近工藝流程場所對其進行測試Bracketingapproach:括號法Avalidationscheme/protocoldesignedsuchthatonlybatchesontheextremesofcertainpredeterminedandjustifieddesignfactors,e.g.,strength,batchsize,packsizearetestedd