美国FDA原料药生产质量管理规范(-中英文).doc

DIRECTIONOFGMP(GOODMANUFACTURINGPRACTICE)OFRAWMATERIALSBYFDA美国FDA原料药生产质量管理规范（?中英文）TableofContents?目录1.INTRODUCTION?简介1.1Objective?目的1.2RegulatoryApplicability法规的适用性1.3Scope?范围2.QUALITYMANAGEMENT?.质量管理2.1Principles?总则2.2ResponsibilitiesoftheQualityUnit(s)?质量部门的责任2.3ResponsibilityforProductionActivities?生产作业的职责2.4InternalAudits(SelfInspection)?内部审计（自检）2.5ProductQualityReview?产品质量审核3.PERSONNEL?人员3.1PersonnelQualifications?人员的资质3.2PersonnelHygiene?人员卫生3.3Consultants?顾问4.BUILDINGSANDFACILITIES?建筑和设施4.1DesignandConstruction?设计和结构4.2Utilities?公用设施4.3Water?水4.4Containment?限制4.5Lighting?照明4.6SewageandRefuse?排污和垃圾4.7SanitationandMaintenance?卫生和保养5.PROCESSEQUIPMENT?工艺设备5.1DesignandConstruction?设计和结构5.2EquipmentMaintenanceandCleaning?设备保养和清洁5.3Calibration.校验5.4ComputerizedSystems?计算机控制系统6.DOCUMENTATIONANDRECORDS文件和记录6.1DocumentationSystemandSpecifications?文件系统和质量标准6.2EquipmentcleaningandUseRecord?设备的清洁和使用记录6.3RecordsofRawMaterials,Intermediates,APILabelingandPackagingMaterials?原料、中间体、原料药的标签和包装材料的记录6.4MasterProductionInstructions(MasterProductionandControlRecords)?生产工艺规程（主生产和控制记录）6.5BatchProductionRecords(BatchProductionandControlRecords)?批生产记录（批生产和控制记录）6.6LaboratoryControlRecords?实验室控制记录6.7BatchProductionRecordReview?批生产记录审核7.MATERIALSMANAGEMENT?物料管理7.1GeneralControls?控制通则7.2ReceiptandQuarantine?接收和待验7.3SamplingandTestingofIncomingProductionMaterials进厂物料的取样与测试7.4Storage?储存7.5Re-evaluation?复验8.PRODUCTIONANDIN-PROCESSCONTROLS?生产和过程控制8.1ProductionOperations?生产操作8.2TimeLimits?时限8.3In-processSamplingandControls?工序取样和控制8.4BlendingBatchesofIntermediatesorAPIs?中间体或原料药的混批8.5ContaminationControl?污染控制9.PACKAGINGANDIDENTIFICATIONLABELINGOFAPIsANDINTERMEDIATES?原料药和中间体的包装和贴签9.1General?总则9.2PackagingMaterials包装材料9.3LabelIssuanceandControl?标签发放与控制9.4PackagingandLabelingOperations包装和贴签操作10.STORAGEANDDISTRIBUTION.储存和分发10.1WarehousingProcedures入库程序10.2DistributionProcedures分发程序11.LABORATORYCONTROLS?实验室控制11.1GeneralControls?控制通则11.2TestingofIntermediatesandAPIs中间体和原料药的测试11.3ValidationofAnalyticalProcedures?分析方法的验证11.4CertificatesofAnalysis分析报告单11.5StabilityMonitoringofAPIs原料药的稳定性监测11.6ExpiryandRetestDating?有效期和复验期11.7Reserve/RetentionSamples?留样12.VALIDATION?.验证12.1ValidationPolicy?验证方针12.2ValidationDocumentation?验证文件12.3Qualification?确认12.4ApproachestoProcessValidation?工艺验证的方法12.5ProcessValidationProgram?工艺验证的程序12.6PeriodicReviewofValidatedSystems?验证系统的定期审核12.7CleaningValidation?清洗验证12.8ValidationofAnalyticalMethods分析方法的验证13.CHANGECONTROL?变更的控制14.REJECTIONANDRE-USEOFMATERIALS.拒收和物料的再利用14.1Rejection拒收14.2Reprocessing?返工14.3Reworking?重新加工14.4RecoveryofMaterialsandSolvents?物料与溶剂的回收14.5Returns?退货15.COMPLAINTSANDRECALLS?投诉与召回16.CONTRACTMANUFACTURERS(INCLUDINGLABORATORIES)协议生产商（包括实验室）17.AGENTS,BROKERS,TRADERS,DISTRIBUTORS,REPACKERS,ANDRELABELLERS?代理商、经纪人、贸易商、经销商、重新包装者和重新贴签者17.1Applicability?适用性17.2TraceabilityofDistributedAPIsandIntermediates已分发的原料药和中间体的可追溯性17.3QualityManagement?质量管理17.4Repackaging,Relabeling,andHoldingofAPIsandIntermediates原料药和中间体的重新包装、重新贴签和待检17.5Stability?稳定性17.6TransferofInformation信息的传达17.7HandlingofComplaintsandRecalls?投诉和召回的处理17.8HandlingofReturns?退货的处理18.SpecificGuidanceforAPIsManufacturedbyCellCulture/Fermentation?用细胞繁殖/发酵生产的原料药的特殊指南18.1General?总则18.2CellBankMaintenanceandRecordKeeping?细胞库的维护和记录的保存18.3CellCulture/Fermentation?细胞繁殖/发酵18.4Harvesting,IsolationandPurification?收取、分离和精制18.5ViralRemoval/Inactivationsteps?病毒的去除/灭活步骤19.APIsforUseinClinicalTrials用于临床研究的原料药19.1General?总则19.2Quality?质量19.3EquipmentandFacilities设备和设施19.4ControlofRawMaterials原料的控制19.5Production?生产19.6Validation?验证19.7Changes?变更19.8LaboratoryControls?实验室控制19.9Documentation?文件20.Glossary?术语1.INTRODUCTION?1.简介1.1Objective?1.1目的Thisdocumentisintendedtoprovideguidanceregardinggoodmanufacturingpractice(GMP)forthemanufacturingofactivepharmaceuticalingredients(APIs)underanappropriatesystemformanagingquality.ItisalsointendedtohelpensurethatAPIsmeetthequalityandpuritycharacteristicsthattheypurport,orarerepresented,topossess.?本文件旨在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.Inthisguidance,thetermshouldidentifiesrecommendationsthat,whenfollowed,willensurecompliancewithCGMPs.Analternativeapproachmaybeusedifsuchapproachsatisfiestherequirementsoftheapplicablestatues.Forthepurposesofthisguidance,thetermscurrentgoodmanufacturingpracticesandgoodmanufacturingpracticesareequivalent.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.Thesecontrolsareinherentresponsibilitiesofthemanufacturerandaregovernedbynationallaws.?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.Thisguidancedoesnotaffecttheabilityoftheresponsibleregulatoryagencytoestablishspecificregistration/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。1.2RegulatoryApplicability?1.2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，就应该按照本指南进行生产。1.3Scope?1.3范围ThisguidanceappliestothemanufactureofAPIsforuseinhumandrug(medicinal)products.ItappliestothemanufactureofsterileAPIsonlyuptothepointimmediatelypriortotheAPIsbeingrenderedsterile.ThesterilizationandasepticprocessingofsterileAPIsarenotcoveredbythisguidance,butshouldbeperformedinaccordancewithGMPguidancesfordrug(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,oranycombinationoftheseprocesses.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),andgenetherapyAPIs.However,itdoesincludeAPIsthatareproducedusingbloodorplasmaasrawmaterials.Notethatcellsubstrates(mammalian,plant,insectormicrobialcells,tissueoranimalsourcesincludingtransgenicanimals)andearlyprocessstepsmaybesubjecttoGMPbutarenotcoveredbythisguidance.Inaddition,theguidancedoesnotapplytomedicalgases,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,oranAPIthatisusedintheproductionofanAPIandthatisincorporatedasasignificantstructuralfragmentintothestructureoftheAPI.AnAPIstartingmaterialcanbeanarticleofcommerce,amaterialpurchasedfromoneormoresuppliersundercontractorcommercialagreement,orproducedin-house.APIstartingmaterialsnormallyhavedefinedchemicalpropertiesandstructure.?“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,thisisknownasthepointatwhichAPIstartingmaterialsareenteredintotheprocess.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,itshouldbenotedthatthefactthatacompanychoosestovalidateaprocessstepdoesnotnecessarilydefinethatstepsascritical.?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.ThestringencyofGMPinAPImanufacturingshouldincreaseastheprocessproceedsfromearlyAPIstepstofinalsteps,purification,andpackaging.PhysicalprocessingofAPIs,suchasgranulation,coatingorphysicalmanipulationofparticlesize(e.g.,milling,micronizing)shouldbeconductedaccordingtothisguidance.?本文件的指南通常适用于表1中的灰色步骤。但在表中体现的所有步骤并不是将应用GMP管理的所有步骤全部体现出来了。原料药生产中的GMP要求应当随着工艺的进行，从原料药的前几步到最后几步，精制和包装，越来越严格。原料药的物理加工，如制粒、包衣或颗粒度的物理处理（例如制粉、微粉化）应当按本指南的标准进行。ThisGMPguidancedoesnotapplytostepspriortotheintroductionofthedefinedAPIstartingmaterial.本GMP指南不适用于引入定义了的“原料药的起始物料”以前的步骤。2.QUALITYMANAGEMENT?2质量管理2.1Principles?2.1总则2.10Qualityshouldbetheresponsibilitiesofallpersonsinvolvedinmanufacturing.?参与原料药生产的每一个人都应当对质量负责。2.11Eachmanufacturershouldestablish,document,andimplementaneffectivesystemformanagingqualitythatinvolvestheactiveparticipationofmanagementandappropriatemanufacturingpersonnel.?每一个生产商都应当建立并执行一套有管理人员和有关员工积极参与的有效的质量管理体系，并使其文件化。2.12Thesystemformanagingqualityshouldencompasstheorganizationalstructure,procedures,processandresources,aswellasactivitiestoensureconfidencethattheAPIwillmeetitsintendedspecificationsforqualityandpurity.Allquality-relatedactivitiesshouldbedefinedanddocumented.?质量管理体系应当包括组织机构、规程、工艺和资源，以及确保原料药会符合其预期的质量与纯度要求所必需的活动。所有涉及质量管理的活动都应当明确规定，并使其文件化。2.13Thereshouldbeaqualityunit(s)thatisindependentofproductionandthatfulfillsbothqualityassurance(QA)andqualitycontrol(QC)responsibilities.ThequalityunitcanbeintheformofseparateQAandQCunitsorasingleindividualorgroup,dependinguponthesizeandstructureoftheorganization.?2.13应当设立一个独立于生产部门的质量部门，同时履行质量保证(QA)和质量控制(QC)的职责。依照组织机构的大小，可以是分开的QA和QC部门，或者只是一个人或小组。2.14ThepersonsauthorizedtoreleaseintermediatesandAPIsshouldbespecified.?2.14应当指定授权发放中间体和原料药的人员。2.15Allquality-relatedactivitiesshouldberecordedatthetimetheyareperformed.?2.15所有有关质量的活动应当在其执行时就记录。2.16Anydeviationfromestablishedproceduresshouldbedocumentedandexplained.Criticaldeviationsshouldbeinvestigated,andtheinvestigationanditsconclusionsshouldbedocumented.2.16任何偏离既定规程的情况都应当有文字记录并加以解释。对于关键性偏差应当进行调查，并记录调查经过及其结果。2.17Nomaterialsshouldbereleasedorusedbeforethesatisfactorycompletionofevaluationbythequalityunit(s)unlessthereareappropriatesystemsinplacetoallowforsuchuse(e.g.,releaseunderquarantineasdescribedinSection10ortheuseofrawmaterialsorintermediatespendingcompletionofevaluation).?2.17在质量部门对物料完成满意的评价之前，任何物料都不应当发放或使用，除非有合适的系统允许此类使用（如10.20条款所述的待检情况下的使用，或是原料或中间体在等待评价结束时的使用）。2.18Proceduresshouldexistfornotifyingresponsiblemanagementinatimelymannerofregulatoryinspections,seriousGMPdeficiencies,productdefectsandrelatedactions(e.g.,quality-relatedcomplaints,recalls,andregulatoryactions).2.18应当有规程能确保公司的责任管理部门能及时得到有关药政检查、严重的GMP缺陷、产品缺陷及其相关活动（如质量投诉，召回，药政活动等）的通知。2.2ResponsibilitiesoftheQualityUnit(s)?2.2质量部门的责任2.20Thequalityunit(s)shouldbeinvolvedinallquality-relatedmatters.?2.20质量部门应当参与所有与质量有关的事物。2.21Thequalityunit(s)shouldreviewandapproveallappropriatequality-relateddocuments.2.21所有与质量有关的文件应当由质量部门审核批准。2.22Themainresponsibilitiesoftheindependentqualityunit(s)shouldnotbedelegated.Theseresponsibilitiesshouldbedescribedinwritingandshouldinclude,butnotnecessarilybelimitedto:1.?ReleasingorrejectingallAPIs.Releasingorrejectingintermediatesforuseoutsidethecontrolofthemanufacturingcompany2.?Establishingasystemtoreleaseorrejectrawmaterials,intermediates,packaging,andlabelingmaterials3.?ReviewingcompletedbatchproductionandlaboratorycontrolrecordsofcriticalprocessstepsbeforereleaseoftheAPIfordistribution4.?Makingsurethatcriticaldeviationsareinvestigatedandresolved5.?Approvingallspecificationsandmasterproductioninstructions6.?ApprovingallproceduresaffectingthequalityofintermediatesorAPIs7.?Makingsurethatinternalaudits(self-inspections)areperformed8.?ApprovingintermediateandAPIcontractmanufacturers9.?ApprovingchangesthatpotentiallyaffectintermediateorAPIquality10.?Reviewingandapprovingvalidationprotocolsandreports11.?Makingsurethatquality-relatedcomplaintsareinvestigatedandresolved12.?Makingsurethateffectivesystemsareusedformaintainingandcalibratingcriticalequipment13.?Makingsurethatmaterialsareappropriatelytestedandtheresultsarereported14.?MakingsurethatthereisstabilitydatatosupportretestorexpirydatesandstorageconditionsonAPIsand/orintermediates,whereappropriate15.?Performingproductqualityreviews(asdefinedinSection2.5)?2.22独立的质量部门的主要职责不应当委派给他人。这些责任应当以文字形式加以说明，而且应当包括，但不限于：1.?所有原料药的放行与否。用于生产商控制范围以外的中间体的放行与否；2.?建立一个放行与拒收原材料、中间体、包装材料和标签的系统；3.?在供销售的原料药放行前，审核已完成的关键步骤的批生产记录和实验室检验记录；4.?确保已对重大偏差进行了调查并已解决；5.?批准所有的规格标准和主生产指令；6.?批准所有可能影响原料药和中间体质量的规程；7.?确保进行内部审计（自检）；8.?批准中间体或原料药的委托生产商；9.?批准可能影响到中间体或原料药质量的变更；10.?审核并批准验证方案和报告；11.?确保调查并解决质量问题的投诉；12.?确保用有效的体系来维护和校验关键设备；13.?确保物料都经过了适当的检验并报告结果；14.?确保有稳定性数据支持中间体或原料药的复验期或有效期和储存条件；15.?开展产品质量审核（详见2.5节）。2.3ResponsibilityforProductionActivities?2.3生产作业的职责Theresponsibilityforproductionactivitiesshouldbedescribedinwritingandshouldinclude,butnotnecessarilybelimitedto:1.?Preparing,reviewing,approving,anddistributingtheinstructionsfortheproductionofintermediatesorAPIsaccordingtowrittenprocedures2.?ProducingAPIsand,whenappropriate,intermediatesaccordingtopre-approvedinstructions3.?Reviewingallproductionbatchrecordsandensuringthatthesearecompletedandsigned4.?Makingsurethatallproductiondeviationsarereportedandevaluatedandthatcriticaldeviationsareinvestigatedandthecon