ICHQa原料药的GMP指南中英对照.docx

1、ICHQa原料药的GMP指南中英对照Q7a（中英文对照）FDA原料药GMP指南TableofContents1.INTRODUCTION1.简介1.1Objective1.1目的1.2RegulatoryApplicability1.2法规的适用性1.3Scope1.3范围2.QUALITYMANAGEMENT2.质量管理2.1Principles2.1总则2.2ResponsibilitiesoftheQualityUnit(s)2.2质量部门的责任2.3ResponsibilityforProductionActivities2.3生产作业的职责2.4InternalAudits(Self

2、Inspection)2.4内部审计（自检）2.5ProductQualityReview2.5产品质量审核3.PERSONNEL3.人员3.1PersonnelQualifications3.人员的资质3.2PersonnelHygiene3.2人员卫生3.3Consultants3.3顾问4.BUILDINGSANDFACILITIES4.建筑和设施4.1DesignandConstruction4.1设计和结构4.2Utilities4.2公用设施4.3Water4.3水4.4Containment4.4限制4.5Lighting4.5照明4.6SewageandRefuse4.6排污和

3、垃圾4.7SanitationandMaintenance4.7卫生和保养5.PROCESSEQUIPMENT5.工艺设备5.1DesignandConstruction5.1设计和结构5.2EquipmentMaintenanceandCleaning5.2设备保养和清洁5.3Calibration5.3校验5.4ComputerizedSystems5.4计算机控制系统6.DOCUMENTATIONANDRECORDS6.文件和记录6.1DocumentationSystemandSpecifications6.1文件系统和质量标准6.2EquipmentcleaningandUseRec

4、ord6.2设备的清洁和使用记录6.3RecordsofRawMaterials,Intermediates,APILabelingandPackagingMaterials6.3原料、中间体、原料药的标签和包装材料的记录6.4MasterProductionInstructions(MasterProductionandControlRecords)6.4生产工艺规程（主生产和控制记录）6.5BatchProductionRecords(BatchProductionandControlRecords)6.5批生产记录（批生产和控制记录）6.6LaboratoryControlRecords

5、6.6实验室控制记录6.7BatchProductionRecordReview6.7批生产记录审核7.MATERIALSMANAGEMENT7.物料管理7.1GeneralControls7.1控制通则7.2ReceiptandQuarantine7.2接收和待验7.3SamplingandTestingofIncomingProductionMaterials7.3进厂物料的取样与测试7.4Storage7.4储存7.5Re-evaluation7.5复验8.PRODUCTIONANDIN-PROCESSCONTROLS8.生产和过程控制8.1ProductionOperations8.1

6、生产操作8.2TimeLimits8.2时限8.3 In-processSamplingandControls8.3工序取样和控制8.4BlendingBatchesofIntermediatesorAPIs8.4中间体或原料药的混批8.5ContaminationControl8.5污染控制9.PACKAGINGANDIDENTIFICATIONLABELINGOFAPIsANDINTERMEDIATES9.原料药和中间体的包装和贴签9.1General9.1总则9.2PackagingMaterials9.2包装材料9.3LabelIssuanceandControl9.3标签发放与控制9

7、.4PackagingandLabelingOperations9.4包装和贴签操作10.STORAGEANDDISTRIBUTION10.储存和分发10.1WarehousingProcedures10.1入库程序10.2DistributionProcedures10.2分发程序11.LABORATORYCONTROLS11.实验室控制11.1GeneralControls11.1控制通则11.2TestingofIntermediatesandAPIs11.2中间体和原料药的测试11.3ValidationofAnalyticalProcedures11.3分析方法的验证11.4Cert

8、ificatesofAnalysis11.4分析报告单11.5StabilityMonitoringofAPIs11.5原料药的稳定性监测11.6ExpiryandRetestDating11.6有效期和复验期11.7Reserve/RetentionSamples11.7留样12.VALIDATION12.验证12.1ValidationPolicy12.1验证方针12.2ValidationDocumentation12.2验证文件12.3Qualification12.3确认12.4ApproachestoProcessValidation12.4工艺验证的方法12.5ProcessVa

9、lidationProgram12.5工艺验证的程序12.6PeriodicReviewofValidatedSystems12.6验证系统的定期审核12.7CleaningValidation12.7清洗验证12.8ValidationofAnalyticalMethods12.8分析方法的验证13.CHANGECONTROL13.变更的控制14.REJECTIONANDRE-USEOFMATERIALS14.拒收和物料的再利用14.1Rejection14.1拒收14.2Reprocessing14.2返工14.3Reworking14.3重新加工14.4RecoveryofMateria

10、lsandSolvents14.4物料与溶剂的回收14.5Returns14.5退货15.COMPLAINTSANDRECALLS15.投诉与召回16.CONTRACTMANUFACTURERS(INCLUDINGLABORATORIES)16.协议生产商（包括实验室）17.AGENTS,BROKERS,TRADERS,DISTRIBUTORS,REPACKERS,ANDRELABELLERS17.代理商、经纪人、贸易商、经销商、重新包装者和重新贴签者17.1Applicability17.1适用性17.2TraceabilityofDistributedAPIsandIntermediate

11、s17.2已分发的原料药和中间体的可追溯性17.3QualityManagement17.3质量管理17.4Repackaging,Relabeling,andHoldingofAPIsandIntermediates17.4原料药和中间体的重新包装、重新贴签和待检17.5Stability17.5稳定性17.6TransferofInformation17.6信息的传达17.7HandlingofComplaintsandRecalls17.7投诉和召回的处理17.8HandlingofReturns17.8退货的处理18.SpecificGuidanceforAPIsManufacture

12、dbyCellCulture/Fermentation18.用细胞繁殖/发酵生产的原料药的特殊指南18.1General18.1总则18.2CellBankMaintenanceandRecordKeeping18.2细胞库的维护和记录的保存18.3CellCulture/Fermentation18.3细胞繁殖/发酵18.4Harvesting,IsolationandPurification18.4收取、分离和精制18.5ViralRemoval/Inactivationsteps18.5病毒的去除/灭活步骤19.APIsforUseinClinicalTrials19.用于临床研究的原料

13、药19.1General19.1总则19.2Quality19.2质量19.3EquipmentandFacilities19.3设备和设施19.4ControlofRawMaterials19.4原料的控制19.5Production19.5生产19.6Validation19.6验证19.7Changes19.7变更19.8LaboratoryControls19.8实验室控制19.9Documentation19.9文件20.Glossary20.术语Q7aGMPGuidanceforAPIsQ7a原料药的GMP指南1.INTRODUCTION1.简介1.1Objective1.1目的T

14、hisdocumentisintendedtoprovideguidanceregardinggoodmanufacturingpractice(GMP)forthemanufacturingofactivepharmaceuticalingredients(APIs)underanappropriatesystemformanagingquality.ItisalsointendedtohelpensurethatAPIsmeetthequalityandpuritycharacteristicsthattheypurport,orarerepresented,topossess.本文件旨在

15、为在合适的质量管理体系下制造活性药用成分（以下称原料药）提供有关优良药品生产管理规范（GMP）提供指南。它也着眼于帮助确保原料药符合其旨在达到或表明拥有的质量与纯度要求。Inthisguidance,thetermmanufacturingisdefinedtoincludealloperationsofreceiptofmaterials,production,packaging,repackaging,labeling,relabeling,qualitycontrol,release,storageanddistributionofAPIsandtherelatedcontrols.In

16、thisguidance,thetermshouldidentifiesrecommendationsthat,whenfollowed,willensurecompliancewithCGMPs.Analternativeapproachmaybeusedifsuchapproachsatisfiestherequirementsoftheapplicablestatues.Forthepurposesofthisguidance,thetermscurrentgoodmanufacturingpracticesandgoodmanufacturingpracticesareequivale

17、nt.本指南中所指的“制造”包括物料接收、生产、包装、重新包装、贴签、重新贴签、质量控制、放行、原料药的储存和分发及其相关控制的所有操作。本指南中，“应当”一词表示希望采用的建议，除非证明其不适用或者可用一种已证明有同等或更高质量保证水平的供选物来替代。本指南中的“现行优良生产管理规范（cGMP）”和“优良生产管理规范（GMP）”是等同的。Theguidanceasawholedoesnotcoversafetyaspectsforthepersonnelengagedinmanufacturing,noraspectsrelatedtoprotectingtheenvironment.The

18、secontrolsareinherentresponsibilitiesofthemanufacturerandaregovernedbynationallaws.本指南在总体上未涉及生产人员的安全问题，亦不包括环保方面的内容。这方面的管理是生产者固有的责任，也是国家法律规定的。Thisguidanceisnotintendedtodefineregistrationand/orfilingrequirementsormodifypharmacopoeialrequirements.Thisguidancedoesnotaffecttheabilityoftheresponsibleregu

19、latoryagencytoestablishspecificregistration/filingrequirementsregardingAPIswithinthecontextofmarketing/manufacturingauthorizationsordrugapplications.Allcommitmentsinregistration/filingdocumentsshouldbemet.本指南未规定注册/归档的要求、或修改药典的要求。本指南不影响负责药政审理部门在原料药上市/制造授权或药品申请方面建立特定注册/归档要求的能力。注册/归档的所有承诺必须做到。1.2Regula

20、toryApplicability1.2法规的适用性Withintheworldcommunity,materialsmayvaryastotheirlegalclassificationasanAPI.WhenamaterialisclassifiedasanAPIintheregionorcountryinwhichitismanufacturedorusedinadrugproduct,itshouldbemanufacturedaccordingtothisguidance.在世界范围内对原料药的法定定义是各不相同的。当某种物料在其制造或用于药品的地区或国家被称为原料药，就应该按照本指

21、南进行生产。1.3Scope1.3范围ThisguidanceappliestothemanufactureofAPIsforuseinhumandrug(medicinal)products.ItappliestothemanufactureofsterileAPIsonlyuptothepointimmediatelypriortotheAPIsbeingrenderedsterile.ThesterilizationandasepticprocessingofsterileAPIsarenotcoveredbythisguidance,butshouldbeperformedinacco

22、rdancewithGMPguidancesfordrug(medicinal)productsasdefinedbylocalauthorities.本文件适用于人用药品（医疗用品）所含原料药的生产。它适用于无菌原料药在灭菌前的步骤。本指南不包括无菌原料药的消毒和灭菌工艺，但是，应当符合地方当局所规定的药品（医疗用品）生产的GMP指南。ThisguidancecoversAPIsthataremanufacturedbychemicalsynthesis,extraction,cellculture/fermentation,recoveryfromnaturalsources,oranyc

23、ombinationoftheseprocesses.SpecificguidanceforAPIsmanufacturedbycellculture/fermentationisdescribedinSection18.本文件适用于通过化学合成、提取、细胞培养/发酵，通过从自然资源回收，或通过这些工艺的结合而得到的原料药。通过细胞培养/发酵生产的原料药的特殊指南则在第18章论述。Thisguidanceexcludesallvaccines,wholecells,wholebloodandplasma,bloodandplasmaderivatives(plasmafractionation

24、),andgenetherapyAPIs.However,itdoesincludeAPIsthatareproducedusingbloodorplasmaasrawmaterials.Notethatcellsubstrates(mammalian,plant,insectormicrobialcells,tissueoranimalsourcesincludingtransgenicanimals)andearlyprocessstepsmaybesubjecttoGMPbutarenotcoveredbythisguidance.Inaddition,theguidancedoesno

25、tapplytomedicalgases,bulk-packageddrug(medicinal)products(e.g.,tabletsorcapsulesinbulkcontainers),orradiopharmaceuticals.本指南不包括所有疫苗、完整细胞、全血和血浆、全血和血浆的衍生物（血浆成分）和基因治疗的原料药。但是却包括以血或血浆为原材料生产的原料药。值得注意的是细胞培养基（哺乳动物、植物、昆虫或微生物的细胞、组织或动物源包括转基因动物）和前期生产可能应遵循GMP规范，但不包括在本指南之内。另外，本指南不适用于医用气体、散装的制剂药（例如，散装的片剂和胶囊）和放射性药物

26、的生产。Section19containsguidancethatonlyappliestothemanufactureofAPIsusedintheproductionofdrug(medicinal)productsspecificallyforclinicaltrials(investigationalmedicinalproducts).第19章的指南只适用于用在药品（医疗用品）生产中的原料药制造，特别是临床实验用药（研究用医疗产品）的原料药制造。AnAPIstartingmaterialisarawmaterial,anintermediate,oranAPIthatisusedin

27、theproductionofanAPIandthatisincorporatedasasignificantstructuralfragmentintothestructureoftheAPI.AnAPIstartingmaterialcanbeanarticleofcommerce,amaterialpurchasedfromoneormoresuppliersundercontractorcommercialagreement,orproducedin-house.APIstartingmaterialsnormallyhavedefinedchemicalpropertiesandst

28、ructure.“原料药的起始物料”是指一种原料、中间体或原料药，用来生产一种原料药，或者以主要结构单元的形式被结合进原料药结构中。原料药的起始物料可能是在市场上有售、能够通过合同或商业协议从一个或多个供应商处购得，或由生产厂家自制。原料药的起始物料一般来说有特定的化学特性和结构。ThecompanyshoulddesignateanddocumenttherationaleforthepointatwhichproductionoftheAPIbegins.Forsyntheticprocesses,thisisknownasthepointatwhichAPIstartingmateria

29、lsareenteredintotheprocess.Forotherprocesses(e.g.,fermentation,extraction,purification),thisrationaleshouldbeestablishedonacase-by-casebasis.Table1givesguidanceonthepointatwhichtheAPIstartingmaterialisnormallyintroducedintotheprocess.生产厂商要指定并用书面文件说明原料药的生产从何处开始的理论依据。对于合成工艺而言，就是“原料药的起始物料”进入工艺的那一点。对其他工

30、艺（如：发酵，提取，纯化等）可能需要具体问题具体对待。表1给出了原料药的起始物料从哪一点引入工艺过程的指导原则。Fromthispointon,appropriateGMPasdefinedinthisguidanceshouldbeappliedtotheseintermediateand/orAPImanufacturingsteps.ThiswouldincludethevalidationofcriticalprocessstepsdeterminedtoimpactthequalityoftheAPI.However,itshouldbenotedthatthefactthataco

31、mpanychoosestovalidateaprocessstepdoesnotnecessarilydefinethatstepsascritical.从这步开始，本指南中的有关GMP规范应当应用在这些中间体和/或原料药的制造中。这包括对原料药质量有影响的关键工艺步骤的验证。但是，值得注意的是厂商选择某一步骤进行验证，并不一定将该步骤定为关键步骤。TheguidanceinthisdocumentwouldnormallybeappliedtothestepsshowningrayinTable1.However,allstepsshownmaynotbecompleted.ThestringencyofGMPinAPImanufacturingshouldinc