ICH 指导原则 Q11原料药的开发和生产(化学实体和生物技术生物实体)

GMPMay2011EMA/CHMP/ICH/425213/2011ICH/Committeeformedicinalproductsforhumanuse(CHMP)ICHguidelineQ11ondevelopmentandmanufactureofdrugsubstances(chemicalentitiesandbiotechnological/biologicalentities)ICH指导原则Q11 原料药的开发和生产(化学实体和生物技术/生物实体)Step3翻译/审核：谢永/ChankTransmissiontoCHMPAdoptionbyCHMPforreleaseforconsultationEndofconsultationn(deadlineforcomments)May2011May2011September2011CommentsShouldbeprovidedusingthistemplate.TheCompletedcommentsformshouldbesenttoICH@ema.europa.eu7WestferryCircus●CanaryWharf●LondonE144HB●UnitedKingdomTelephone+44(0)2074188400Facsimile+44(0)2074188416E-mailich@ema.europa.euWebsitewww.ema.europa.euAnagencyoftheEuropeanUnion©EuropeanMedicinesAgency,2011.Reproductionisauthorisedprovidedthesourceisacknowledged.ICHguidelineQ11ondevelopmentandmanufactureofdrugsubstances(chemicalentitiesandbiotechnological/biologicalentities)TABLEOFCONTENTS目录1.INTRODUCTION介绍.................................................................................................................42.SCOPE范围...............................................................................................................................................43.MANUFACTURINGPROCESSDEVELOPMENT制造工艺开发....................................................................53.1.GeneralPrinciples总则...................................................................................................................................................53.1.1.DrugSubstanceQualityLinktoDrugProduct 将原料药质量与制剂药品联系起来..............53.1.2.ProcessDevelopmentTools工艺开发工具...........................................................................53.1.3.ApproachestoDevelopment开发的方法.............................................................................63.1.4.DrugSubstanceCriticalQualityAttributes原料药的关键质量属性（CQA）....................73.1.5.LinkingMaterialAttributesandProcessParameterstoDrugSubstanceCQAs将物料属性和工艺参数与原料药的关键质量属性相关联..............................................................................................83.1.6.DesignSpace设计空间.......................................................................................................93.2.SubmissionofManufacturingProcessDevelopmentInformation制造工艺开发信息的注册递交.........103.2.1.OverallProcessDevelopmentSummary全面的工艺开发 总结 初级经济法重点总结下载党员个人总结TXt高中句型全总结.doc高中句型全总结.doc理论力学知识点总结pdf .........................................103.2.2.DrugSubstanceCQAs原料药的CQAs.................................................................................113.2.3.ManufacturingProcessHistory制造工艺历史......................................................................113.2.4.ManufacturingDevelopmentalStudies制造开发研究...........................................................124.DESCRIPTIONOFMANUFACTURINGPROCESSANDPROCESSCONTROLS制造工艺描述和工艺控制.125.SELECTIONOFSTARTINGMATERIALSANDSOURCEMATERIALS起始物料和源物料的选择.......135.1.GeneralPrinciples通则.................................................................................................................................................135.1.1.SelectionofStartingMaterialsforSyntheticDrugSubstances化学合成原料药的起始物料的选择.......................................................................................................................135.1.2.SelectionofStartingMaterialsforSemi-syntheticDrugSubstances半合成原料药的起始物料的选择.....................................................................................................................................................145.1.3.SelectionofSourceMaterialsforBiotechnological/BiologicalProducts生物产品的起始物料的选择.................................................................................................................................................................155.2.SubmissionofInformationforStartingMaterialorSourceMaterial起始物料或源物料的信息申报.....155.2.1.JustificationofStartingMaterialSelectionforSyntheticDrugSubstances合成原料药的起始物料的选择的合理解释.................................................................................................................................155.2.2.JustificationofStartingMaterialSelectionforSemi-SyntheticDrugSubstances半合成原料药的起2/ 37ICHguidelineQ11ondevelopmentandmanufactureofdrugsubstances(chemicalentitiesandbiotechnological/biologicalentities)始原料选择的合理解释.....................................................................................................................165.2.3.QualificationofSourceMaterialsforBiotechnological/BiologicalProducts生物产品源物料的确认.................................................................................................................................................................166.CONTROLSTRATEGY 控制策略.............................................................................................................166.1.GeneralPrinciples通则.................................................................................................................................................166.1.1.ApproachestoDevelopingaControlStrategy开发控制策略的方法.............................................176.1.2.ConsiderationsinDevelopingaControlStrategy开发控制策略中的考虑....................................176.2.SubmissionofControlStrategyInformation控制策略信息的注册申报.........................................................187.PROCESSVALIDATION/EVALUATION 工艺验证/评估.............................................................................197.1.GeneralPrinciples一般原则........................................................................................................................................197.2.PrinciplesSpecifictoBiotechnological/BiologicalProducts生物制品的特殊原则.....................................208.SUBMISSIONOFMANUFACTURINGPROCESSDEVELOPMENTANDRELATEDINFORMATIONINCOMMONTECHNICALDOCUMENTS(CTD)FORMAT 生产工艺开发及相关信息在CTD格式的递交....................218.1.QualityRiskManagementandProcessDevelopment质量风险管理和工艺开发........................................218.2.CriticalQualityAttributes(CQAs)关键质量属性（CQAs）............................................................................218.3.DesignSpace设计空间................................................................................................................................................218.4.ControlStrategy控制策略...........................................................................................................................................229.LIFECYCLEMANAGEMENT生命周期管理............................................................................................2210.IllustrativeExamples实例..................................................................................................................2310.1.Example1:LinkingMaterialAttributesandProcessParameterstoDrugSubstanceCQAs-ChemicalEntity将物料属性和工艺参数与原料药的关键质量属性（CQA）相关联—化学药部分............................2310.2.Example2:UseofQualityRiskManagementtoSupportLifecycleManagementofProcessParameters使用质量风险管理支持工艺参数的生命周期管理......................................................................................................2710.3.Example3:PresentationofaDesignSpaceforaBiotechnologicalProductUnitOperation例3：生物产品单元操作设计空间的介绍...............................................................................................................................................2810.4.Example4:SelectinganAppropriateStartingMaterial例4：选择一个恰当的起始物料.......................3010.5.Example5:SummaryofControlElementsforselectCQAs选择CQA的控制要素的小结...................3111.GLOSSARY 术语....................................................................................................................................353/ 37ICHguidelineQ11ondevelopmentandmanufactureofdrugsubstances(chemicalentitiesandbiotechnological/biologicalentities)1.INTRODUCTION介绍ThisguidelinedescribesapproachestodevelopingprocessanddrugsubstanceunderstandingandalsoprovidesguidanceonwhatinformationshouldbeprovidedinCTDsections3.2.S.2.2¨C3.2.S.2.6.ItprovidesfurtherclarificationontheprinciplesandconceptsdescribedinICHguidelinesonPharmaceuticalDevelopment(Q8),QualityRiskManagement(Q9)andPharmaceuticalQualitySystems(Q10)astheypertaintothedevelopmentandmanufactureofdrugsubstance.此指南描述了开发原料药工艺及理解的方法，也提供了那些信息需要在CTD章节3.2.S.2.2和3.2.S.2.6中提供的指南。并提供对在ICHQ8（药物开发）、Q9（质量风险管理）和Q10（药物质量系统）中提到的关于原料药开发和生产的原则和理念的进一步的说明。Acompanycanchoosetofollowdifferentapproachesindevelopingadrugsubstance.Forthepurposeofthisguideline,theterms“traditional”and“enhanced”areusedtodifferentiatetwopossibleapproaches.Inatraditionalapproach,setpointsandoperatingrangesforprocessparametersaredefinedandthedrugsubstancecontrolstrategyistypicallybasedondemonstrationofprocessreproducibilityandtestingtomeetestablishedacceptancecriteria.Inanenhancedapproach,riskmanagementandmoreextensivescientificknowledgeareusedtoselectprocessparametersandunitoperationsthatimpactcriticalqualityattributes(CQAs)forevaluationinfurtherstudiestoestablishanydesignspace(s)andcontrolstrategiesapplicableoverthelifecycleofthedrugsubstance.AsdiscussedinICHQ8fordrugproduct,agreaterunderstandingofthedrugsubstanceanditsmanufacturingprocesscancreatethebasisformoreflexibleregulatoryapproaches.Thedegreeofregulatoryflexibilityisgenerallypredicatedonthelevelofrelevantscientificknowledgeprovidedintheapplicationformarketingauthorization.各个公司可以选择按照不同的方法去开发原料药。在本指南中，用术语“传统方法”和“改进方法”来区别两种可能不同的原料药开发方法。在传统方法中，工艺参数的设定点及操作范围是确认好的，典型的原料药的控制策略是证明工艺的可重复性以及测试产品是否符合已建立的可接受的规格标准。在改进方法中，风险管理和更广泛的科学知识被用来选择可能影响关键质量属性的工艺参数和单元操作，并在进一步研究中对其评估，以建立在整个原料药生命周期中都可应用的设计空间和控制策略。如ICHQ8中制剂产品一样，，对原料药及其生产工艺的更多的理解可以成为搭建一个更加灵活的药政监管方法的基础。药政监管方法的灵活程度通常取决于提供在为上市递交的申报文件中的相关科学知识的水平。Traditionalandenhancedapproachesarenotmutuallyexclusive.Acompanycanuseeitheratraditionalapproachoranenhancedapproachtodrugsubstancedevelopment,oracombinationofboth.传统的和改进的方法互相并不排斥。一个公司可以使用传统的或者改进的方法或者同时使用两种方法来开发原料药。2.SCOPE范围ThisguidelineisapplicabletodrugsubstancesasdefinedintheScopesectionsofICHGuidelinesQ6AandQ6B,butmightalsobeappropriateforothertypesofproductsfollowingconsultationwiththeappropriateregulatoryauthorities.Itisparticularlyrelevanttothepreparationandorganizationofthecontentsofsections3.2.S.2.2¨C3.2.S.2.6ofModule3oftheCommonTechnicalDocument(ICHM4Q).Theguidelinedoesnotapplytocontentsofsubmissionsduringtheclinicalresearchstagesofdrugdevelopment.Nevertheless,thedevelopmentprinciplespresentedinthisguidelineareimportanttoconsiderduringtheinvestigationalstages.此指导原则适用于ICHQ6A和Q6B指南的范围章节中定义的原料药，但是也可与合适的药政当局咨询后用于其它类型的产品开发。本指南主要规范了ICHM4Q中模块3中的章节3.2.S.2.2到章节3.2.S.2.6相关内容4/ 37ICHguidelineQ11ondevelopmentandmanufactureofdrugsubstances(chemicalentitiesandbiotechnological/biologicalentities)的准备和组织。此指南不适用于新药物开发阶段的临床研究状态的注册递交的内容。然而此指南中的开发原则对于在临床研究阶段的新药开发是重要的。Regionalrequirementsforpost-approvalchangesarenotcoveredbythisguideline.各个药政当局对于产品批准后变更的相关要求并不涵盖于本指南。3.MANUFACTURINGPROCESSDEVELOPMENT制造工艺开发3.1.GeneralPrinciples总则Thegoalofmanufacturingprocessdevelopmentforthedrugsubstanceistoestablishacommercialmanufacturingprocesscapableofconsistentlyproducingdrugsubstanceoftheintendedquality.原料药制造工艺开发的目的是建立一个能够始终如一地生产预期质量的原料药的商业化制造工艺。3.1.1.DrugSubstanceQualityLinktoDrugProduct将原料药质量与制剂产品联系起来Theintendedqualityofthedrugsubstanceshouldbedeterminedthroughconsiderationofitsuseinthedrugproductaswellasfromknowledgeandunderstandingofitsphysical,chemical,biological,andmicrobiologicalpropertiesorcharacteristics,whichcaninfluencethedevelopmentofthedrugproduct(e.g.,thesolubilityofthedrugsubstancecanaffectthechoiceofdosageform).TheQualityTargetProductProfile(QTPP)andpotentialCQAsofthedrugproduct(asdefinedinICHQ8)canhelpidentifypotentialCQAsofthedrugsubstance.KnowledgeandunderstandingoftheCQAscanevolveduringthecourseofdevelopment.原料药的预期质量应该通过考虑其在制剂中的用途及其对制剂开发的潜在影响（例如，原料药的溶解性可能影响剂型的选择），并结合原料药的物理、化学、生物和微生物属性或特性的知识和理解来定义。制剂的质量目标产品档案（QTPP）和潜在关键质量属性CQA（QTPP和CQA的定义请参见ICHQ8）可以有助于识别原料药的潜在关键质量属性。关键质量属性(CQA)的知识和对CQA的理解可以在开发的过程中不断发展。3.1.2.ProcessDevelopmentTools工艺开发工具QualityRiskManagement(QRM,asdescribedinICHQ9)canbeusedinavarietyofactivitiesincludingassessingoptionsforthedesignofthemanufacturingprocess,assessingqualityattributesandmanufacturingprocessparameters,andincreasingtheassuranceofroutinelyachievingacceptablequalityresults.Riskassessmentscanbecarriedoutearlyinthedevelopmentprocessandrepeatedasgreaterknowledgeandunderstandingbecomeavailable.Itisneitheralwaysappropriatenoralwaysnecessarytouseaformalriskmanagementprocess(usingrecognizedtoolsand/orinternalprocedures,e.g.,standardoperatingprocedures).Theuseofinformalriskmanagementprocesses(usingempiricaltoolsand/orinternalprocedures)canalsobeconsideredacceptable.质量风险管理（QRM,定义请参见ICHQ9）可以用在各种活动中，包括为制造工艺的设计评估可选项、评估质量属性和生产工艺参数，增加日常获得可接受质量结果的保证。风险评估可以在开发工艺的早期就展开，当可以得到更多的知识和理解时可以重复进行。并不要求一定或必须使用正式的风险管理程序（指的是使用公认的工具和/或内部的程序，例如，SOP）。使用非正式风险管理程序（使用经验工具和/或内部程序）的也是可接受的。Knowledgemanagement(asdescribedinICHQ10)canalsofacilitatemanufacturingprocessdevelopment.Inthiscontext,potentialsourcesofinformationcanincludepriorknowledgeanddevelopmentstudies.Priorknowledgecanincludeestablishedbiological,chemicalandengineeringprinciplesandappliedmanufacturingexperience.Dataderivedfromrelevantpriorknowledge,includingplatformmanufacturing(seeglossary)canbeleveragedtosupportdevelopmentofthecommercialprocessandexpeditescientificunderstanding.5/ 37ICHguidelineQ11ondevelopmentandmanufactureofdrugsubstances(chemicalentitiesandbiotechnological/biologicalentities)知识管理（定义参见ICHQ10）也可促进制造工艺开发。在此环境下，信息的潜在来源可以包括先前的知识和开发研究。先前的知识可以包括已经建立的生物学、化学和工程学的原理和已经应用了的制造经验。来源于有关的先前知识包括平台生产（见术语）可以用于支持商业化工艺的开发和加快科学理解。3.1.3.ApproachestoDevelopment开发的方法ICHQ8recognizesthat“Strategiesforproductdevelopmentsvaryfromcompanytocompanyandfromproducttoproduct.Theapproachto,andextentof,developmentcanalsovaryandshouldbeoutlinedinthesubmission”.Theseconceptsapplyequallytothedevelopmentofthedrugsubstancemanufacturingprocess.Anapplicantcanchooseeitheratraditionalapproachoranenhancedapproachtodrugsubstancedevelopment,oracombinationofboth.ICHQ8 提到“产品开发策略因不同公司和不同产品而不同。开发的方法和范围也可以改变，应该在申报递交中概述”。这些理念同样应用于原料药制造工艺的开发。申请者可以选择传统方法或改进方法，或两者结合的方法来做原料药的开发。Manufacturingprocessdevelopmentshouldinclude,ataminimum,thefollowingelements:制造工艺开发应该包括以下要素（至少涵盖但不限于）： IdentifyingpotentialCQAsassociatedwiththedrugsubstancesothatthosecharacteristicshavinganimpactonproductqualitycanbestudiedandcontrolled;识别与原料药有关的潜在CQAs以便这些对于产品质量有影响的特性能够被研究和控制。 Defininganappropriatemanufacturingprocess;定义一个适当的制造工艺。 Definingacontrolstrategytoensureprocessperformanceanddrugsubstancequality(seeSection6onControlStrategy).定义一个控制策略确保工艺性能和原料药质量（见章节6，控制策略）Anenhancedapproachtomanufacturingprocessdevelopmentwouldadditionallyincludethefollowingelements:一个生产工艺开发的改进方法将增加以下的要素： Asystematicevaluation,understandingandrefiningofthemanufacturingprocess,including;对制造工艺的系统的评估、理解和细化，包括： Identifying,throughe.g.priorknowledge,experimentationandriskassessment,thematerialattributesandprocessparametersthatcanhaveaneffectondrugsubstanceCQAs;通过先前的知识、试验和风险评估来识别可能对原料药关键质量属性（CQA）有影响的物料属性和工艺参数。 DeterminingthefunctionalrelationshipsthatlinkmaterialattributesandprocessparameterstodrugsubstanceCQAs;定义联系物料属性和工艺参数和原料药关键质量属性CQA之间的效应关系。UsingtheenhancedapproachincombinationwithQRMtoestablishanappropriatecontrolstrategywhichcan,forexample,includeaproposalforadesignspace(s)and/orreal-timereleasetesting(RTRT).用改进方法结合QRM（质量风险管理）去建立一个合适的控制策略，例如提出设计空间和/或实时放行测试6/ 37ICHguidelineQ11ondevelopmentandmanufactureofdrugsubstances(chemicalentitiesandbiotechnological/biologicalentities)（RTRT）之类的控制 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 。Theincreasedknowledgeandunderstandingobtainedfromtakinganenhancedapproachcouldfacilitatecontinualimprovementandinnovationthroughouttheproductlifecycle(seeICHQ10).从实施改进方法获得的增加的知识和理解可以促进持续改进和贯穿整个产品生命周期的创新。3.1.4.DrugSubstanceCriticalQualityAttributes原料药的关键质量属性（CQA）ACQAisaphysical,chemical,biological,ormicrobiologicalpropertyorcharacteristicthatshouldbewithinanappropriatelimit,range,ordistributiontoensurethedesiredproductquality.PotentialdrugsubstanceCQAsareusedtoguideprocessdevelopment.ThelistofpotentialCQAscanbemodifiedasdrugsubstanceknowledgeandprocessunderstandingincrease.关键质量属性（CQA）是物理的、化学的、生物学的或微生物学的属性或特性，且必须在一定合适的限度、范围或分布内以确保产品质量符合要求。潜在原料药CQA用来指导工艺开发。当原料药知识和工艺理解增加时潜在CQA可以被修正。DrugsubstanceCQAstypicallyincludesthosepropertiesorcharacteristicsthataffectidentity,purity,biologicalactivityandstability.Whenphysicalpropertiesareimportantwithrespecttoinvivoperformanceordrugproductmanufacture,thesecanbedesignatedasCQAs.Inthecaseofbiotechnological/biologicalproducts,mostoftheCQAsofthedrugproductareassociatedwiththedrugsubstanceandthusareadirectresultofthedesignofthedrugsubstanceoritsmanufacturingprocess.原料药的CQAs 一般包括哪些影响鉴别、纯度、生物活性和稳定性的属性或特性。当物理属性对于产品在人体内的活性或制剂产品生产过程非常重要时，也可以指定为CQAs。至于生物技术或生物制剂产品，他们的CQAs大多都是与原料药相关的，既是原料药或其生产工艺的设计的直接结果。ImpuritiesareanimportantclassofpotentialdrugsubstanceCQAsbecauseoftheirpotentialimpactondrugproductsafety.Forchemicalentities,impuritiescanincludeorganicimpurities(includingpotentialgenotoxicimpurities),inorganicimpurities,forexamplemetalresidues,andresidualsolvents(seeICHQ6A,Q3A,andQ3C).Forbiotechnological/biologicalproducts,impuritiesmaybeprocess-relatedorproduct-related(seeICHQ6B).Process-relatedimpuritiesinclude:cellsubstrate-derivedimpurities(e.g.,HostCellProteinsandDNA);cellculture-derivedimpurities(e.g.，mediacomponents);anddownstream-derivedimpurities(e.g.,columnleachable).CQAsforbiotechnology/biologicalproductsshouldalsoincludeconsiderationofcontaminants,asdefinedinQ6B,includingalladventitiouslyintroducedmaterialsnotintendedtobepartofthemanufacturingprocess(e.g.,adventitiousviral,bacterial,ormycoplasmacontamination).杂质是一类重要的潜在的原料药CQAs 因为他们对药品安全的潜在影响。对与化学分子实体，杂质可能包括有机杂质（包括潜在基因毒性杂质）、无机杂质，例如金属残留物和残留溶剂（参见ICHQ6A,Q3A和Q3C）。对于生物技术/生物制剂产品，杂质可能是工艺相关或产品相关的（参见ICHQ6B）。工艺杂质相关杂质包括：细胞基质源杂质（如宿主细胞蛋白质和DNA）；细胞培养源杂质（如培养基组分）和后续工艺源杂质（如柱滤出物）。生物技术/生物制剂杂质相关的CQAs也包括在Q6B中定义的对污染的考虑，包括所有不是制造工艺一部分的偶然引入的物质（如外来病毒、细菌或支原体污染物）。TheidentificationofCQAsforcomplexproductscanbechallenging.Biotechnological/biologicalproducts,forexample,typicallypossesssuchalargenumberofqualityattributesthatitmightnotbepossibletofullyevaluatetheimpactonsafetyandefficacyofeachone.Riskassessmentscanbeperformedtorankorprioritizequalityattributes.Priorknowledgecanbeusedatthebeginningofdevelopmentandassessmentscanbeiterativelyupdatedwithdevelopmentdata(includingdatafromnon-clinicalandclinicalstudies)duringthelifecycle.Knowledgeregardingmechanismofactionandbiologicalcharacterization,suchasstudiesevaluatingstructure-function7/ 37ICHguidelineQ11ondevelopmentandmanufactureofdrugsubstances(chemicalentitiesandbiotechnological/biologicalentities)relationships,cancontributetotheassessmentofriskforsomeproductattributes.复杂产品的CQAs的辨识可能是具有挑战性的。例如对于生物技术/生物制剂产品而言，对如此众多的质量属性逐一完整的评估其对产品安全性和有效性的影响是不现实的。风险评估可能被用于进行质量属性的分级和优先级。先前的知识可以用在开发的开始，评估可以根据生命周期中的开发数据（包括从非临床和临床数据）反复的更新。有关作用机理和生物特性描述的知识，比如评估构效关系的研究，可以有助于某些产品属性的风险评估。3.1.5.LinkingMaterialAttributesandProcessParameterstoDrugSubstanceCQAs将物料属性和工艺参数与原料药的关键质量属性相关联Themanufacturingprocessdevelopmentprogramshouldidentifywhichmaterialattributes(e.g.,ofrawmaterials,startingmaterials,reagents,solvents,processaids,intermediates)andprocessparametersshouldbecontrolled.RiskassessmentcanhelpidentifythematerialattributesandprocessparameterswiththepotentialforhavinganeffectondrugsubstanceCQAs.Thosematerialattributesandprocessparametersthatarefoundtobeimportanttodrugsubstancequalityshouldbeaddressedbythecontrolstrategy.制造工艺的开发 计划 项目进度计划表范例计划下载计划下载计划下载课程教学计划下载 应该识别哪些物料属性（如原料、起始物料、试剂、溶剂、工艺助剂、中间体）和工艺参数应该被控制。风险评估可以帮助识别那些对原料药CQAs有潜在影响的物料属性和工艺参数。被发现的对原料药质量很关键的那些物料属性和工艺参数应该通过控制策略来处理。Theriskassessmenttodefinethecontrolstrategyofmaterialsupstreamfromthedrugsubstancecanincludeanassessmentofmanufacturingprocesscapability,attributedetectability,andseverityofimpactastheyrelatetodrugsubstancequality.Forexample,whenassessingthelinkbetweenanimpurityinarawmaterialorintermediateanddrugsubstanceCQAs,theabilityofthedrugsubstancemanufacturingprocesstoremovethatimpurityshouldbeconsideredintheassessment.Theriskrelatedtoimpuritiescanusuallybecontrolledbyspecificationsforrawmaterial/intermediatesand/orrobustpurificationcapabilityindownstreamsteps.Theriskassessmentcanalsoidentifymaterialattributesforwhichthereareinherentlimitationsindetectability(e.g.,viralsafety)orinadequatepurificationcapability.Inthesecases,suchupstreammaterialattributesshouldbeconsidereddrugsubstanceCQAs.用于定义原料药上游物料的控制策略的风险评估可以包括生产工