EMA制劑成品生產(chǎn)指南-2023年(中英文)

EMA制劑成品生產(chǎn)指南-20234JJuly2023EMA/CHMP/QWP/245074/2023CommitteeforHumanMedicinalProducts(CHMP)Guidelineonmanufactureofthefinisheddosageform制劑成品生產(chǎn)指南Thisguidelinereplacesthe“NoteforGuidanceonManufactureoftheFinishedDosageForm”(CPMP/QWP/486/95)翻譯：王世華校對(duì)：OwenExecutivesummary綜述Thisguidelinereplacesthenoteforguidanceonthemanufactureofthefinisheddosageform(CPMP/QWP/486/95).ThenoteforguidancehasbeenupdatedtoreflecttherequirementsaslaiddowninthecurrentlegislationDirective2023/83/EC,andtofollowtheformatandcontentoftheCommonTechnicalDocument(CTD)Module3dossier.Italsoaddressescurrentmanufacturingpracticesintermsofcomplexsupplychainsandworldwidemanufacture.Inaddition,thecontentandprinciplesoftheICHQ8guideline(ref1)arealsotakenintoaccount.這份指南取代了制劑成品生產(chǎn)指南的條款〔CPMP/QWP/486/95〕，指南條款的更反映了當(dāng)前已提出的立法機(jī)構(gòu)指令2023/83/EC的要求，并且遵循通用技術(shù)文件模塊3文件的格式和內(nèi)容。從簡(jiǎn)單的供給鏈和世界范圍內(nèi)生產(chǎn)的方面看，她也代表了當(dāng)前的生產(chǎn)活動(dòng)。另外，也應(yīng)考慮ICHQ8指南的內(nèi)容和原則。Thisguidelinedoesnotintroducenewrequirementsonauthorisedmedicinalproductsforhumanuse.Howeverasstatedinarticle23ofDirective2023/83/EC,afteramarketingauthorisation(MA上市許可證)hasbeenapproved,theauthorisationholdershould,inrespectofthemethodsofmanufactureandcontroltakeaccountofscientificandtechnicalprogressandintroduceanychangesthatmayberequiredtoenablethemedicinalproducttobemanufacturedandcontrolledbymeansofgenerallyacceptedscientificmethods.這份指南沒(méi)有對(duì)已授權(quán)的人用藥品給出的要求，然而在指令2023/83/EC23來(lái)進(jìn)展藥品的生產(chǎn)和掌握。Introduction(background)介紹〔背景〕TheobjectiveoftheguidelineonthemanufactureofthefinisheddosageformistoprovideclarificationonthetypeandlevelofinformationthatshouldbeincludedintheCTDModule3ofthemarketingauthorisationapplication(MAA上市許可申請(qǐng))dossierwithrespecttothemanufacturingprocessdescription生產(chǎn)工藝描述.Thisdescriptionshouldincludeinformationaboutcriticalstepsandintermediatesandprovidesalinkbetweenthepharmaceuticaldevelopment,theproposedcontrolstrategyandprocessvalidation.Theguidelinealsoaddressesaspectsrelatedtooutsourcingandnewmanufacturingpracticessuchascomplexmanufacturingchainsorissueswithprolongedholdingtimesandtransportationconditions.Detailedinformationaboutrequirementsofthesterilisationprocessisprovidedinaseparateguideline.制劑成品生產(chǎn)指南的目的是為了在通用技術(shù)文件模塊3—上市許可申請(qǐng)文件中證之間的連接橋梁。這個(gè)指南同時(shí)也提到了關(guān)于外包和的生產(chǎn)活動(dòng)，比方簡(jiǎn)單一份單獨(dú)的指南中進(jìn)展供給。Scope范圍Thisguidelineisapplicabletothemanufactureofthefinisheddosageformofchemicalandherbalmedicinalproductsforhumanuseintendedformarketingauthorisation.ItalsoappliestovariationsforauthorisedproductsincaseswherechangestothemanufacturingprocessaffectingtheMAareproposed.這份指南適用于為取得上市許可證的人用化學(xué)藥品和植物藥品制劑成品生產(chǎn)。同時(shí)，它也適用于已經(jīng)批準(zhǔn)的產(chǎn)品在打算實(shí)施變更生產(chǎn)工藝影響MA的變更狀況。Theprinciplesdescribedareingeneralalsoapplicabletobiologicalmedicinalproducts.Whererelevant,theprinciplesofthisguidelinemayalsobeappliedtoradiopharmaceuticalsandtochemicalinvestigationalmedicinalproducts.陳述的原則根本上也適用于生物制品。如有相關(guān)，這個(gè)指導(dǎo)原則也適用于放射性藥品和化學(xué)試驗(yàn)藥品。Legalbasis法定根底ThisguidelineshouldbereadinconjunctionwithDirective2023/83/ECArticle8.3(d),asamendedwhereitisstatedthattheapplicationforamarketingauthorisationshallcontainadescriptionofthemanufacturingmethod.這個(gè)指南應(yīng)當(dāng)與2023/83/EC指令8.3(d)章((d)Descriptionofthemanufacturingmethod.)一起閱讀,在上市許可申請(qǐng)中應(yīng)當(dāng)包含一個(gè)生產(chǎn)方法的描述之處有所改進(jìn)。TherequirementsonthedescriptionofthemanufacturingmethodintheCTDModule3ofmarketingauthorisationdossieraredescribedinAnnex1,Part1(section3.2.2.3)tothisDirective.Furtherdetailsontheinformationtobeprovidedareoutlinedinthisguideline.在通用技術(shù)文件模塊3上市許可申請(qǐng)文件關(guān)于生產(chǎn)方法的描述要求在這份指令節(jié)〕有說(shuō)明。更多具體的信息在這份指南中有供給。Manufacture生產(chǎn)TheheadingsofthisguidelinefollowthestructureoftheCTDformatModule3,Section3.2.P.3Manufacture.這份指南的標(biāo)題遵循CTD模塊3下3.2.P.3節(jié)生產(chǎn)的構(gòu)造。OnlyproductspecificaspectsofmanufactureneedtobedescribedandincludedintheMAdossier;generalelementsofGoodManufacturingPractice(GMP),(ref.3)shouldnotbeincluded.只有生產(chǎn)的產(chǎn)品特性方面的描述需要包括在MA的文檔中，常規(guī)的GMP的要素不需要包括進(jìn)去。Manufacturer(s)生產(chǎn)商Foreachstageofthemanufacturingprocess,includingpackaging,detailsshouldbegivenofalltheindividualsitesinvolved(includingthosefromthesamecompany).生產(chǎn)工藝的每一步包括包裝，全部的細(xì)節(jié)都需要考慮到每一個(gè)包括在內(nèi)的單獨(dú)的產(chǎn)地〔包括來(lái)自同一家公司那些產(chǎn)地〕。Thename,addressandresponsibilityofeachmanufacturer,includingcontractors,shouldbeprovided.Thisappliesalsotoallqualitycontrolsites,includingon-goingstabilitytestingifdifferentfromthemanufacturingsite(s).每一家生包括正在進(jìn)展的穩(wěn)定性爭(zhēng)論場(chǎng)所，假設(shè)與生產(chǎn)地址不同的話。TheEUsiteresponsibleforbatchreleaseintheEUmarketshouldbespecified.要明確規(guī)定在歐盟市場(chǎng)上市產(chǎn)品由歐盟的公司負(fù)責(zé)批放行。BatchFormula批處方Thebatchformulafortheintendedbatchsizeshouldbestated.Incasearangeofbatchsizesisproposed,therangeshouldbestatedandthebatchformulashouldbeprovidedforatleastthelargestandsmallestbatchsizes.依據(jù)擬定批量的批處方應(yīng)當(dāng)說(shuō)明。假設(shè)擬定批量是一個(gè)范圍，則這個(gè)范圍應(yīng)當(dāng)說(shuō)明，應(yīng)供給至少最大批量和最小批量的批處方。Anapplicationforarangeofbatchsizesshouldbeadequatelyjustifiedasnotadverselyimpactingthecriticalqualityattributes(CQAs)ofthefinishedproductinaccordancewiththeguidelineonprocessvalidation(ref.4).對(duì)于批量為一個(gè)范圍的申請(qǐng)應(yīng)當(dāng)依據(jù)工藝驗(yàn)證指南被充分評(píng)估以防對(duì)成品的關(guān)鍵質(zhì)量屬性〔CQAs〕造成不利影響〔參見(jiàn)4〕。Ifthebulkproductisassembledintodifferentpresentationsorpacks,theproductionbatchsizeshouldbedefinedbythebulkbeforeanydivision.Whenthelengthofthesubsequentprocessesandassemblyisconsideredcritical(e.g.fillingtimeforasepticallymanufacturedproducts),theworst-casescenarioofthedivisionpattern(e.g.inrespectoftotalfillingtime)shouldbeindicated.假設(shè)散裝品被收集或包裝成不同的形式，則生產(chǎn)批量應(yīng)當(dāng)依據(jù)分裝之前的散裝品〔比方無(wú)菌產(chǎn)品的灌裝時(shí)間〕，最壞狀況的安排模式〔比方關(guān)于總的灌裝時(shí)間〕應(yīng)當(dāng)要說(shuō)明。Thebatchsizeforaproducttobemarketedshouldnormallybecompatiblewithproductionscaleequipment.Itshouldbesufficientlylargetoberepresentativeofcommercialmanufacturingtoenabledemonstrationofastateofcontrol.Forexample,acommercialbatchsizeforsolidoraldosageformsshouldbeatleast100,000unitsunlessjustificationisprovided(e.g.orphanmedicinalproducts)(ref.4).上市產(chǎn)品的批量通常應(yīng)當(dāng)與設(shè)備的生產(chǎn)力量相匹配。它應(yīng)當(dāng)充分地最大限度地代產(chǎn)批量至少在100,000個(gè)單位以上，除非供給正值理由〔比方孤兒藥品〕〔參4〕Ifsub-batchesarepreparedandcombinedforsubsequentprocessing,thisshouldbejustifiedasthefinalbatchisrequiredtobehomogeneous,theirformulaeandthenumberofsub-batchesperintendedbatchsizeshouldbestated.Inaddition,ifabatchissub-dividedtowardstheendoftheprocesstoreflectequipmentprocessingcapability,thisshouldbeclearlyindicated(e.g.soliddosageformmanufacturewheresublotsarerequiredduetoequipmentcapacity).Thenumberofsub-batchesperintendedbatchsizeshouldbestated.〔比方〕。每批預(yù)定批量中亞批的數(shù)量應(yīng)明確。Incaseofcontinuousmanufacture,theinformationaboutbatchsizeintraditionaltermsmightnotberelevant;however,informationastohowabatchisdefinedshouldbeprovided(e.g.expressedintermsofaperiodoftimeoraquantityofproduct,andmaybeexpressedasranges).當(dāng)連續(xù)生產(chǎn)，這個(gè)傳統(tǒng)意義上的批量信息似乎意義不大。然而，如何定義一批的〔比方批可以表達(dá)為一個(gè)時(shí)間段或者肯定數(shù)量的產(chǎn)品，也可以定義為某個(gè)范圍內(nèi)的產(chǎn)品〕Thenames,quantitiesandreferencetothequalitystandardsofallingredientsusedinthecourseofthemanufactureshouldbestated.Ingredientswhichareremovedfromtheproductduringtheproductionprocess,suchasgranulationliquids,solventsandgasesshouldbeincludedbuttheirquantitiesmaybeexpressedasranges.在生產(chǎn)過(guò)程中用到的全部的成分的名稱(chēng)、數(shù)量和參考的質(zhì)量標(biāo)準(zhǔn)需要說(shuō)明。在生他們的數(shù)量可以表示為一個(gè)范圍。Ingredientsthatareoptionallyused,suchasacidsandalkalisforpHadjustment,shouldalsobementioned.Formulaoveragesmustbeclearlyindicatedinquantitativetermsandjustifiedinthepharmaceuticaldevelopmentsectionofthedossier.Upperandloweracceptancelimitsfortheactualquantityofeachingredientmaybestatedinthebatchformula;however,theproposedacceptancelimitsshouldbejustified.Whenthequantityofanactiveingredienttobeusediscalculatedfromtheactualassayvalueofthebatchofthatactiveingredient(“factorisation“),thisshouldbestatedandjustified.Ifanotheringredientisusedtokeepthetotalmassperbatchequaltothequantityprovidedforinthebatchmanufacturingformula,thisshouldalsobeindicated.選擇性使用的成分，比方調(diào)整PH值的酸和堿，也應(yīng)當(dāng)要說(shuō)明，處方的過(guò)量投料可承受限度應(yīng)當(dāng)被評(píng)估。當(dāng)使用原料的數(shù)量是依據(jù)原料的實(shí)際含量計(jì)算出來(lái)的〕，這種狀況應(yīng)明確說(shuō)明和評(píng)估。如何讓其他的成分來(lái)保持與所供給批生產(chǎn)處方的每批總重量相平衡，這種狀況也應(yīng)明確。DescriptionofManufacturingProcessandProcessControls生產(chǎn)工藝和過(guò)程掌握Generalaspects一般考慮Anarrativedescriptionofthefullmanufacturingprocessshouldbeprovided,accompaniedbyaflowchartdescribingeachstepoftheprocessincludingin-processcontrolsandshowingateachstagewherematerialsentertheprocess.Incaseadesignspaceisproposed,thisshouldbeclearlyidentifiedanddescribed.應(yīng)供給全部的生產(chǎn)工藝過(guò)程描述，同時(shí)有一個(gè)流程圖描述每一步工藝過(guò)程，包括過(guò)程掌握和在每一個(gè)工序顯示物料從哪里進(jìn)入該流程。為了設(shè)計(jì)一個(gè)估量的構(gòu)造流程，這個(gè)需要被清楚地確認(rèn)和描述。Themanufacturingprocessdescriptionshouldbeadequatelyjustifiedin3.2.P.2bydevelopmentdata,inparticularasregardsanyprocessoperatingconditionsorranges.Thedescriptionofamanufacturingprocesswithwideranges(widerthanwouldnormallybeacceptedasnormaloperatingranges)ordescribedonlybyanupperorlowerlimit,generallyrequiresamorethoroughdiscussionand/orscientificrationaleinthemanufacturingprocessdevelopmentsection.生產(chǎn)工藝描述在3.2.P.2研發(fā)數(shù)據(jù)中應(yīng)當(dāng)被充分的評(píng)估，特別是關(guān)于任何工藝操〔比正?？沙惺懿僮鞣秶蟆郴蛘咧换蛘吖┙o細(xì)致嚴(yán)謹(jǐn)?shù)目茖W(xué)原理。Fullscalemanufacturingprocessvalidationisnotrequestedatthetimeofapplicationforcertaintypesofproducts(ref.4).Iftheresultofsuchfullscalestudyisnotavailableatthetimeofsubmission,itisexpectedthatprocessparameters”settingsidentifiedduringmanufacturingprocessdevelopmentarelaiddownintheprocessdescription.Intheeventthatanychangesarerequiredtotheregisteredprocessparametersasaresultoffullscaleprocessvalidationstudies,thesechangesshouldbeappliedforviapostapprovalvariation,inaccordancewiththevariationRegulation(ref.5,ref.6).大生產(chǎn)批量的生產(chǎn)工藝驗(yàn)證在產(chǎn)品申報(bào)階段是不要求的〔參考4〕。假設(shè)這種大變更治理要求執(zhí)行〔56〕.Wherespecificallyrelevantfortheproduct,anyrequiredenvironmentalconditionsduringmanufactureshouldbestatede.g.lowhumidityforaneffervescenttablet.當(dāng)對(duì)產(chǎn)品有特定價(jià)值，在生產(chǎn)過(guò)程中任何環(huán)境條件的要求都要說(shuō)明，比方易吸潮的片子需要低濕環(huán)境。Dependingonthenatureoftheprocessandtheproduct(e.g.sterileproducts),manufacturingdurationsofcriticalstepsandholdtimesshouldbestatedandjustified.依據(jù)工藝和產(chǎn)品的自然屬性〔比方無(wú)菌制劑〕，生產(chǎn)期間的關(guān)鍵步驟和存放時(shí)間需要明確和評(píng)估。Thestepsatwhichprocesscontrols,intermediatetestsorfinalproductcontrolsareconductedshouldbeidentified.在過(guò)程掌握的步驟如中間產(chǎn)品檢測(cè)或者最終的產(chǎn)品掌握需要指明并且要確認(rèn)。Considerationshouldbegivenin3.2.P.2towhatextenttheassuranceofqualityofthefinishedproductisfoundedonthemanufacturingprocessitself.Thesignificanceoftheprocessdescriptionandprocesscontrolsaspartoftheoverallcontrolstrategyshouldbeoutlinedbasedondevelopmentstudiesandevaluated.Indeed,everyfinishedproductmanufacturingprocessshouldhaveanassociatedcontrolstrategysuitableforitsintendedpurpose.Itisexpectedthatdifferentcontrolstrategiesmaybeutilisedincaserealtimereleasetesting(RTRT)(ref.7)isproposed,adesignspaceisclaimed(ref.1),acontinuousmanufactureorastandardmanufactureisperformed.在3.2.P.2中提到關(guān)于要保證成品的質(zhì)量到什么程度被覺(jué)察在于生產(chǎn)工藝本身。工藝流程的描述和過(guò)程掌握作為整個(gè)掌握策略的一局部應(yīng)當(dāng)基于爭(zhēng)論開(kāi)發(fā)和評(píng)標(biāo)。料想不同的掌握策略可能用于實(shí)時(shí)放行檢測(cè)是可以推舉的〔參考7〕，一個(gè)設(shè)計(jì)流程要求一個(gè)連續(xù)的生產(chǎn)或者一個(gè)標(biāo)準(zhǔn)的生產(chǎn)流程能執(zhí)行。Expectedlevelofdetailinthemanufacturingprocessdescription在生產(chǎn)工藝描述中預(yù)期的具體水平Althoughitisexpectedthattheprocessdescriptionisconsideredinrelationtothecontrolstrategy(ref.1),thereisaneedtodescribethemanufacturingprocessinrelevantdetailsinceconsistentqualityofaproductcannotbesafeguardedbyendproducttestingalone.雖然期望大家在工藝流程中考慮掌握策略〔參考1〕，但還是有必要對(duì)生產(chǎn)工藝進(jìn)展具體描述，由于始終如一的產(chǎn)品質(zhì)量不能只靠最終的檢測(cè)來(lái)保證。Itisimportantthattheprocessdescriptioniscomprehensive,includingprocessstepsinasequentialmannerwithbatchsize(s),operatingprincipleandequipmenttype(s)foreachunitoperation(merereferenceto“suitableequipment”isnotsufficient;conversely,detailssuchastheserialnumberandmodelarenotrequired).Equipmentworkingcapacityshouldbestatedwhereappropriate.Tomaketheprocessfullyunderstandableandtoallowassessmentofthevalidityoftheprocess,stepsintheprocessshouldhavethenecessarydetailintermsofappropriateprocessparametersalongwiththeirtargetvaluesorranges(merereferenceto“typical”setpointsisnotacceptable).Wherecriticalityisassignedtoprocessparameters,thedescriptionoftheprocessparametersshouldnotonlyberestrictedtoCPPs,butalsotothoseparametersimportantformanufacturingprocessconsistency.Non-criticalprocessparametersandalsoparametersforwhichtheimpactonqualityattributecannotberuledoutandwhichareconsideredtobeimportantfortheexecutionand/ortheconsistentperformanceofanyparticularprocessstep,andconsequentlyitsoutput,shouldbedescribedatanappropriatelevelofdetail.Awelldescribedmanufacturingprocessisessentialtounderstandwhatiscriticalandwhatissupportive.Anyinformationwhichisconsideredtobepurelysupportiveshouldbejustifiedandclearlyidentified.全面而具體的工藝描述是很重要的，包括以肯定批量的先后次序的工藝步驟和每一個(gè)單元操作的操作原理和設(shè)備型號(hào)〔“適宜的設(shè)備”是不夠的，相反地，一些細(xì)節(jié)比方編號(hào)和模型是沒(méi)有要求的〕。設(shè)備工作力量必要時(shí)應(yīng)當(dāng)說(shuō)明。為了使工藝充分被理解，允許做工藝合理性評(píng)估，關(guān)于適宜的工藝參數(shù)在工藝步驟中應(yīng)當(dāng)有必要的細(xì)節(jié)描述以為到達(dá)他們的目標(biāo)值或范圍〔僅僅參考“典型”設(shè)置掌握點(diǎn)是不被承受的〕。當(dāng)把關(guān)鍵性用于工藝參數(shù)時(shí)，工藝參數(shù)的描述應(yīng)當(dāng)不僅僅局經(jīng)過(guò)評(píng)估和明確說(shuō)明。Thesamerequirementsapplytothelevelofdetailinthemanufacturingprocessdescriptionirrespectiveofthedevelopmentapproach,i.e.iftheproducthasbeendevelopedbytheminimal(traditional)orenhancedapproach.同樣的要求也適用于生產(chǎn)工藝描述細(xì)節(jié)程度而不管它的研發(fā)方式，比方，不管這個(gè)產(chǎn)品是以小試驗(yàn)〔傳統(tǒng)的〕還是放大試驗(yàn)的方式。Incaseofcontinuousmanufacturing,thedescriptionofmanufacturingprocessisexpectedtobeprovidedinthesameway.假設(shè)是持續(xù)生產(chǎn)，生產(chǎn)工藝描述期望以同樣的方式供給。AnexampleofwhattypeofdetailsshouldbeincludedinthemanufacturingdetheAnnex.附件中供給了一個(gè)在生產(chǎn)工藝描述中應(yīng)當(dāng)包括什么類(lèi)型的細(xì)節(jié)的例如。Technicaladaptationsinthemanufacturingprocess生產(chǎn)工藝的技術(shù)調(diào)整Itwouldgenerallybeexpectedthat,regardlessofthenumberoffinishedproductmanufacturingsitesproposed,essentiallythesamemanufacturingprocessshouldbeappliedforaspecificmedicinalproduct.However,sometechnicaladaptationsmightbenecessaryifmorethanonemanufacturerormanufacturingsiteforthefinishedproductisforeseen.Technicaladaptationsareequallyacceptablewithinamanufacturer/manufacturingsitegivenappropriatejustification.Dependinguponequipmentavailability,differenttypesofequipmentcouldbeusedforthesamemanufacturingprocessingstep.通常狀況下，不管生產(chǎn)廠家打算生產(chǎn)的成品數(shù)量是多少，對(duì)于某一具體藥品，本工藝步驟。Wheretechnicaladaptationsareproposedinthemanufacturingprocess,theseadaptationsshouldbefullyjustifiedandsupportedbyevidence,showingthatallstepsproposedwillconsistentlyproduceanyintermediateandfinishedproductthatcomplywiththein-processcontrolsandtheproductspecifications.Irrespectiveofanydifferencesinthemanufacturingprocess,thefinishedproductshouldcomplywiththesamereleaseandshelf-lifespecifications.當(dāng)建議在生產(chǎn)工藝上做技術(shù)調(diào)整，這些調(diào)整應(yīng)當(dāng)被充分評(píng)估和有證據(jù)支持，顯示準(zhǔn)。Whererelevant,thejustifiedtechnicaladaptationsinvariousstepsofthemanufacturingprocessofoneormoremanufacturersandcorrespondingin-processcontrolsshouldalsobetransparentlyshowninseparateflow-charts.Onpresentationofseparateflow-chartsinadossierthedifferentmanufacturingstepsshouldbelistedandtheadaptationsshouldbecomparedtoeachotherbytheapplicant.Theapplicantshouldjustifythattheadaptation,onthebasisofusingdifferenttypesofequipment,doesnothaveanysignificantinfluenceonthefinishedproductqualityandthisshouldbesupportedbydata.Thein-processcontrolsandcorrespondingacceptancelimitsshouldalsobedescribed.Whereanytechnicaladaptationsareproposedatdifferentmanufacturingsites,theinformationshouldalwaysbepresentedinthesameModule3section,butifrequireddifferentiatedforeachmanufacturingsite.如有必要，在一個(gè)或多個(gè)生產(chǎn)商的各個(gè)的生產(chǎn)工藝步驟進(jìn)展合理的技術(shù)調(diào)整和相3節(jié)中呈現(xiàn)全都，但是假設(shè)要求的話，應(yīng)當(dāng)將每個(gè)生產(chǎn)地址的都區(qū)分開(kāi)。Thefollowingexamplesillustratethepossibleuseoftechnicaladaptationsfordifferentmanufacturingprocessingsteps.下面的例子說(shuō)明技術(shù)調(diào)整可能在不同生產(chǎn)工藝步驟中應(yīng)用Liquiddosageforms液體制劑Preparationofsolutionscanbeperformede.g.insimplestainlesssteeltanksequippedwithastirrerand/orhomogeniserorinadvancedmixing/homogenisingequipmentwhichcanberunundervacuum.溶液的配制可以這樣做，比方能運(yùn)轉(zhuǎn)混合或均質(zhì)的設(shè)備。Solidoraldosageforms口服固體制劑Differentequipmentcanbeusedfor:以下工序可以使用不同的設(shè)備Wetgranulation(wetgranulationbyhighshear,lowshearorfluidbedgranulation);濕法制?！哺咚偌羟袧穹ㄖ屏C(jī)、低速剪切濕法制粒機(jī)或者流化床噴霧制?！矴ranuledrying(e.g.fluidbed,traydrying,onepot(highsheargranulation/drying)systems);顆粒烘干〔比方流化床枯燥、托盤(pán)枯燥、一個(gè)容器〔/枯燥〕系統(tǒng)〕Drygranulation(rollercompactionorslugging);干法制粒〔滾壓法或直壓法〕Sizing/delumping(e.g.oscillating,rotatingorhammermill);篩分/過(guò)篩〔比方搖擺、旋轉(zhuǎn)或擠壓〕Coating(e.g.pan,fluidizedbedcoating);包衣〔比方平底鍋、流化床包衣〕Dryblending(e.g.highshearblender,IBCblender,conicalscrewblender,Vblender);干混〔IBC混合機(jī)〔自動(dòng)提升旋轉(zhuǎn)混合機(jī)〕，錐形混合機(jī)，V型混合機(jī)〕Tabletcompressiononafullyautomaticormanuallycontrolledtabletpress.在一個(gè)全自動(dòng)或手動(dòng)掌握的壓片機(jī)上壓片Incontrasttotechnicaladaptationsasdescribedabove,alternativemanufacturingprocesses,whichusedifferentprinciplesandmayormaynotleadtodifferencesinthein-processcontroland/orfinishedproductqualityarenotacceptable(e.g.usingdifferentsterilisationprocedures–terminalsterilisationofendproductvs.asepticmanufactureusingsterilefiltration–possiblytoreflecttheuseofdifferentcontainerswithdifferentheatresistanceproperties;orwetgranulationvs.drygranulation).相比于前面提到的技術(shù)調(diào)整，使用不同原理的可供替代的生產(chǎn)工藝可能會(huì)也可能不會(huì)導(dǎo)致過(guò)程掌握不同和成品質(zhì)量不能被承受〔比方使用不同的滅菌程序-最終產(chǎn)品的終端滅菌相對(duì)于無(wú)菌生產(chǎn)用的無(wú)菌過(guò)濾器-可能反映在使用不同的帶有不同加熱電阻特性的容器，或者濕法制粒相對(duì)于干法制?！场ontrolsofCriticalStepsandIntermediates關(guān)鍵步驟和中間產(chǎn)品的掌握Allcriticalstepsandintermediatesidentifiedduringthemanufactureofthefinishedproductshouldbelistedinthissectionincludinganyin-processcontrols,appliedtestmethodsandacceptancecriteria.全部的關(guān)鍵步驟和中間產(chǎn)品檢驗(yàn)在本節(jié)中成品生產(chǎn)過(guò)程要確認(rèn)，包括任何的過(guò)程掌握、應(yīng)用的檢驗(yàn)方法和可承受標(biāo)準(zhǔn)。Forcomplexcontrolstrategies(e.g.useofmodelsforprocesscontrol,continuousmanufacturing),emphasisshouldbegivenonthefrequencyofin-processcontrolsanditshouldbeclearlystatedhowreleasetestingandproductreleasedecisionsaremade.Informationofhowunexpecteddeviationsfromtheapprovedmanufacturingprocesswouldbedetectedandmanagedshouldbeprovidedtoassurethattheintendedqualityoftheproductisretained.對(duì)于簡(jiǎn)單的掌握環(huán)節(jié)〔比方應(yīng)用模型來(lái)過(guò)程掌握、連續(xù)生產(chǎn)〕，需要強(qiáng)調(diào)的是在過(guò)程掌握頻率上應(yīng)當(dāng)明確,應(yīng)明確說(shuō)明如何做放行檢測(cè)和產(chǎn)品放行打算。如何覺(jué)察的產(chǎn)品質(zhì)量。Thefactthataprocessparameterinamanufacturingstepiscontrolledandverifiedtobewithinarangethatdoesnotaffectacriticalqualityattribute(CQA)doesnotmakeitnon-criticalbydefault.Whiletheriskisreduced,monitoringwithestablishedacceptancecriteriashouldbeincludedinthedescriptiontoassureasufficientregulatoryoversight.Thejustificationfortheidentificationofstepsascriticalornon-criticalshouldbeprovided,includingalinktoexperimentaldatainthepharmaceuticaldevelopmentsection(e.g.riskassessmenttable),ifapplicable.一個(gè)被掌握和確認(rèn)在肯定范圍內(nèi)的且不會(huì)影響關(guān)鍵質(zhì)量屬性的生產(chǎn)步驟中的工個(gè)連接〔比方風(fēng)險(xiǎn)評(píng)估表〕，如適用。Storageofintermediateandbulkproducts中間產(chǎn)品和散裝品的儲(chǔ)存Anintermediateproductisdefinedaspartlyprocessedmaterialthatmustundergofurtherprocessingstepsbeforeitbecomesbulkproducte.g.solutionpriortofilling,granulates,uncoatedtabletsetc.中間產(chǎn)品定義為局部過(guò)程物料，在它成為散裝品之前仍需要做進(jìn)一步加工工序，比方灌裝前的溶液，未包衣的素片等。Abulkproductisdefinedasanyproductwhichhascompletedallprocessingsteps,uptobutnotincluding,finalpackaging.散裝品是指任何完成全部的加工工序?qū)⒁沁€沒(méi)有進(jìn)展最終包裝的產(chǎn)品。Amanufacturingprocessgenerallyinvolvesaseriesofunitoperations,whereintermediateproductisprocessedtobecomebulkproduct.一個(gè)生產(chǎn)工藝通常包括一系列的單元操作，就是將中間產(chǎn)品加工成散裝品的過(guò)程。Insomecases,theintermediatemaybestored,andifnecessary,transportedinasuitablecontainerbeforefurtherprocessing.Itmayalsobesubjecttoconfirmatorytestingpriortofurtherprocessingtoconfirmthatqualityattributeshavenotchangedandthereforeanyadditionaltestingdetailsshouldbeprovided.HoldtimevalidationforthestorageofintermediateproductisaGMPmatterandnormallyneednotbepresentedroutinelyintheapplicationforamarketingauthorisation.However,somespecifictypesofproducts(e.g.sterileproducts,biologicalproducts)mayrequirepresentationofdatarelevanttothetypeofproductandthisshouldbetakenintoconsiderationdependingonthecharacteristicsofthatparticularproduct.在某種狀況下，中間產(chǎn)品可以儲(chǔ)存，假設(shè)有必要的話，在進(jìn)展下一步工序之前放產(chǎn)品的存放時(shí)間驗(yàn)證是一項(xiàng)GMP問(wèn)題，通常不需要表達(dá)在MA申請(qǐng)資料中。然而，某些特別類(lèi)型的產(chǎn)品〔比方無(wú)菌制劑、生物制劑〕可能要求提交關(guān)于這類(lèi)產(chǎn)品的數(shù)據(jù)，這個(gè)應(yīng)當(dāng)依據(jù)特別的產(chǎn)品特性來(lái)考慮。Itshouldbestatedwhetherstorageisrequiredbeforefinalpackagingandifso,underwhattemperature,humidityorotherenvironmentalconditions.Thelevelofinformationtobeprovidedinthedocumentationisdependentonthenatureofthebulkproduct.應(yīng)當(dāng)說(shuō)明散裝品在最終包裝之前是否需要儲(chǔ)存，假設(shè)需要，在什么樣的溫度、濕度和其他環(huán)境條件下。這些基于散裝品的屬性存放條件的信息需要在文件中供給。Whererelevant,themaximumholdingtimesofthebulkproductor,alternatively,themaximumbatchmanufacturingtimefromstartofproductmanufacturetocompletionofpackagingintothefinalprimarycontainerformarketingshouldbestated,appropriatelyjustifiedandsupportedbydatainrelevantpartsofthedossier(e.g.challengingthemaximumholdtimeinprocessvalidationstudiesorprovidingdedicatedstabilitystudiesforthebulkstorage).如有必要，散裝品的最大存放時(shí)間或者從起始物料開(kāi)頭生產(chǎn)到完成包裝進(jìn)入最終〔比方在工藝驗(yàn)證爭(zhēng)論時(shí)做最長(zhǎng)存放時(shí)間挑戰(zhàn)試驗(yàn)或者供給散裝品專(zhuān)屬的穩(wěn)定性爭(zhēng)論資料〕Thereasonsforanyprolongedstorage/processingtimesshouldbestatedandbeconsistentwithGMP.Timelimitsforprocessingshouldbeminimisedandlimitsshouldbejustifiedandappropriatetoensureproductquality.Asageneralrule,prolongedstoragemeansmorethan30daysforsolidoraldosageformsandmorethan24hoursforsterileproducts.Whererelevant,stabilitydatatosupporttheholdingtimeshouldbeprovidedonatleasttwopilotscalebatches.Thestabilitystudiesshouldbeperformedatrelevanttemperatureandhumiditywithregardstotheexpectedbulkstorageconditions(ifrelevanttemperatureandhumidityduringstoragedoesnotcorrespondwithICHcondition,otherconditionsshouldbeused).任何延長(zhǎng)儲(chǔ)存或生產(chǎn)時(shí)間的狀況都要說(shuō)明理由，并且要符合GMP的要求。過(guò)程延期儲(chǔ)存意味著口服固體制劑超過(guò)30天、無(wú)菌產(chǎn)品超過(guò)24小時(shí)。如有必要，應(yīng)供給至少兩批試驗(yàn)批的存放時(shí)間穩(wěn)定性爭(zhēng)論數(shù)據(jù)。做穩(wěn)定性爭(zhēng)論的相關(guān)溫度和濕度條件應(yīng)考慮預(yù)期的散裝品存放條件〔假設(shè)儲(chǔ)存過(guò)程的相關(guān)的溫度和濕度與ICH規(guī)定的條件不全都，其他的條件也可以使用的?！砊heproductshelf-lifeshouldbecalculatedaccordingtotheNoteforGuidanceonthestartofshelf-lifeofthefinisheddosageform(ref.9).Ifotherapproachestocalculatethestartofshelflifeareproposed,theseshouldbedescribedandjustifiedbytheinclusionofsupportingdatafrombatchesthatrepresentthefullproposedholdingtimeofthebulkproduct(intermediate)inthefinishedproductstabilityprogram.產(chǎn)品有效期〔貨架期〕應(yīng)依據(jù)成品制劑起始有效期的指南的條款計(jì)算出來(lái)〔參考9〕。假設(shè)應(yīng)用其他的方法計(jì)算起始有效期，通過(guò)在成品穩(wěn)定性工程中代表散裝品的整個(gè)打算存放時(shí)間的批次的支持性數(shù)據(jù)來(lái)說(shuō)明和評(píng)估。Fortransportationofbulkproduct(intermediate)betweenmanufacturingsitesguidanceisgiveninGMPAnnex15onhowtransportshouldbetakenintoconsideration.Theimpactofshortorlongerexcursionsoutsideoftheoriginalstorageconditionsshouldbediscussed,wherenecessary,supportedbyacceleratedorrealtimestabilitydata.關(guān)于散裝品〔中間產(chǎn)品〕在生產(chǎn)地址間轉(zhuǎn)移的指南見(jiàn)GMP附錄15關(guān)于如何轉(zhuǎn)爭(zhēng)論，如有必要，通過(guò)加速或長(zhǎng)期穩(wěn)定性爭(zhēng)論來(lái)支持。Thesuitabilityoftheproposedbulkproduct(intermediate)containerclosuresystemforbulkstorage(andtransportifrelevant)shouldbejustifiedinrelevantpartsofthedossier.Thematerialsusedforthebulkcontainerclosuresystemshouldbedescribedalongwiththecontrolspecificationforprimarybulkpackaging.在文件的相關(guān)局部，預(yù)期的散裝品〔中間產(chǎn)品〕的容器密閉系統(tǒng)對(duì)于散裝品的儲(chǔ)〕的適應(yīng)性需要被評(píng)估。用于散裝品容器密閉系統(tǒng)的物料應(yīng)當(dāng)與散裝品內(nèi)包材的掌握標(biāo)準(zhǔn)要一道說(shuō)明。ProcessValidationand/orEvaluation工藝驗(yàn)證和評(píng)價(jià)Description,documentation,andresultsofthevalidationand/orevaluationstudiesshouldbeprovidedinthissection.FormoredetailsseeProcessValidationguideline(ref.4).工藝驗(yàn)證和評(píng)價(jià)爭(zhēng)論的描述、文件和結(jié)果應(yīng)當(dāng)在這節(jié)供給。更多具體內(nèi)容參見(jiàn)工藝驗(yàn)證指南〔參考4〕。Definitions定義ControlStrategy:掌握策略Aplannedsetofcontrols,derivedfromcurrentproductandprocessunderstandingthatensuresprocessperformanceandproductquality.Thecontrolscanincludeparametersandattributesrelatedtodrugsubstanceanddrugproductmaterialsandcomponents,facilityandequipmentoperatingconditions,in-processcontrols,finishedproductspecifications,andtheassociatedmethodsandfrequencyofmonitoringandcontrol(ref.8).一套打算掌握設(shè)置，是從當(dāng)前產(chǎn)品和工藝?yán)斫獾贸龅?，以保證過(guò)程表現(xiàn)和產(chǎn)品質(zhì)件、過(guò)程掌握、成品質(zhì)量標(biāo)準(zhǔn)和相關(guān)的方法和監(jiān)測(cè)和掌握的頻率〔8〕。CriticalProcessParameter(CPP):關(guān)鍵工藝參數(shù)Aprocessparameterwhosevariabilityhasanimpactonacriticalqualityattributeandthereforeshouldbemonitoredorcontrolledtoensuretheprocessproducesthedesiredquality(ref.1).保證過(guò)程產(chǎn)品符合預(yù)期的質(zhì)量〔1〕。CriticalQualityAttribute(CQA):關(guān)鍵質(zhì)量屬性Aphysical,chemical,biologicalormicrobiologicalpropertyorcharacteristicthatshouldbewithinanappropriatelimit,range,ordistributiontoensurethedesiredproductquality(ref.1).一個(gè)物理的、化學(xué)的、生物的或者微生物的性質(zhì)或特征應(yīng)當(dāng)在一個(gè)適宜的限度、范圍或者分布，以保證符合預(yù)期的產(chǎn)品質(zhì)量〔參考1〕。DesignSpace:設(shè)計(jì)范圍Themultidimensionalcombinationandinteractionofinputvariables(e.g.,materialattributes)andprocessparametersthathavebeendemonstratedtoprovideassuranceofquality.Workingwithinthedesignspaceisnotconsideredasachange.Movementoutofthedesignspaceisconsideredtobeachangeandwouldnormallyinitiatearegulatorypostapprovalchangeprocess.Designspaceisproposedbytheapplicantandissubjecttoregulatoryassessmentandapproval(ref.1).多重的結(jié)合體和輸入變量的相互作用〔比方物料屬性〕和工藝參數(shù)要被供給證明推舉的而且它是經(jīng)過(guò)正規(guī)的評(píng)估和批準(zhǔn)〔1〕。HoldTime:存放時(shí)間Holdtimecanbeconsideredastheestablishedtimeperiodforwhichmaterials(dispensedrawmaterials,intermediatesandbulkdosageformawaitingfinalpackaging)maybeheldunderspecifiedconditionsandwillremainwithinthedefinedspecifications(ref.11).存放時(shí)間可以被認(rèn)為是為物料〔稱(chēng)量后原輔料、中間產(chǎn)品和待最終包裝的散裝品〕確認(rèn)的時(shí)間周期，它可以在規(guī)定的條件下存放并且維持既定的標(biāo)準(zhǔn)。RealTimeReleaseTesting:實(shí)時(shí)放行測(cè)試Theabilitytoevaluateandensurethequalityofin-processand/orfinalproductbasedonprocessdata,whichtypicallyincludeavalidcombinationofmeasuredmaterialattributesandprocesscontrols(ref.1).評(píng)估和保證過(guò)程中或者最的結(jié)合體〔1〕。References參考文獻(xiàn)ICHQ8(R2)(Pharmaceuticaldevelopment),EMA/CHMP/ICH/167068/2023;Directive2023/83/EC