原料药GMP指南(中英文对照)

1、v1.0可编辑可修改12目录1. 简介目的法规的适用性范围2. 质量管理总则质量部门的责任生产作业的职责内部审计（自检）产品质量审核3. 人员3. 人员的资质人员卫生顾问4. 建筑和设施设计和结构of the Quality forUni t(s)Product ionQ7a （中英文对照）FDA原料药GMP指南Table of Contents1. INTRODUCTIONObjectiveRegulatory ApplicabilityScope2. QUALITY MANAGEMENTPrin ciplesResp on sibilitiesResp on sibilityActivit

2、iesInternal Audits (Self In spect ion)Product Quality Review3. PERSONNELPersonnel Qualificati onsPers onnel Hygie neCon sulta nts4. BUILDINGS AND FACILITIESDesig n and Con struct ionv1.0可编辑可修改UtilitiesWaterCon tai nmentLighti ngSewage and Refuse公用设施水限制照明排污和垃圾卫生和保养5. PROCESS EQUIPMENT5.工艺设备Desig n an

3、d Con struct ion设计和结构Equipme nt Maintenance and Clea ning设备保养和清洁Calibratio n校验Computerized Systems计算机控制系统6. DOCUMENTATION AND RECORDS6.文件和记录Docume ntati onSystemand 文件系统和质量标准San itati on and Maintenance23Specificati ons设备的清洁和使用记录Equipme nt clea ning and Use RecordRecordsof Raw Materials,原料、中间体、原料药的标

4、签和包装材料的In termediates,APILabel ingand 记录Packag ing MaterialsMaster Productio nIn structi ons(Master生产工艺规程（主生产和控制记录）（Batch批生产记录（批生产和控制记录）实验室控制记录批生产记录审核Product ion and Con trol Records)BatchProduct ionRecordsProduct ion and Con trol Records)Laboratory Con trol RecordsBatch Producti on Record Reviewv1.

5、0可编辑可修改7. MATERIALS MANAGEMENT7.物料管理Gen eral Con trols控制通则Receipt and Quara ntine接收和待验Sampli ngand Testi ngof Incoming进厂物料的取样与测试Product ion MaterialsStorage储存Re-evaluati on复验8. PRODUCTION AND IN-PROCESS CONTROLS 8.生产和过程控制Product ion Operati ons生产操作Time Limits时限In-process Sampli ng and Con trols工序取样和

6、控制Ble nding Batches of In termediatesor中间体或原料药的混批APIsCon tam in ati on Con trol污染控制9. PACKAGIN(ANDIDENTIFICATION LABELING9.原料药和中间体的包装和贴签OF APIs AND INTERMEDIATESGen eral总则Packaging Materials包装材料Label Issua nee and Con trol标签发放与控制Packagi ng and Labeli ng Operati ons包装和贴签操作10. STORAGE AND DISTRIBUTION

7、10.储存和分发Warehousi ng Procedures入库程序33v1.0可编辑可修改45Distributi on Procedures分发程序11. LABORATORY CONTROLS11.实验室控制Gen eral Con trols控制通则Testi ng of In termediates and APIs中间体和原料药的测试Validati on of An alytical Procedures分析方法的验证Certificates of An alysis分析报告单Stability Monitoring of APIs原料药的稳定性监测Expiry and Ret

8、est Dat ing有效期和复验期Reserve/Rete nti on Samples留样12. VALIDATION12.验证Validation Policy验证方针Validati on Docume ntati on验证文件Qualificatio n确认Approaches to Process Validati onProcess Validati on ProgramPeriodic Review of Validated SystemsClea ning Validati onValidation of An alytical Methods工艺验证的方法工艺验证的程序验证

9、系统的定期审核清洗验证分析方法的验证13.变更的控制13. CHANGE CONTROL14. REJECTION AND RE-USE OF MATERIALS 14.拒收和物料的再利用拒收返工Rejectio nReprocess ingv1.0可编辑可修改Reworki ngRecovery of Materials and SolventsReturns重新加工物料与溶剂的回收退货5515. COMPLAINTS AND RECALLS15.投诉与召回16. CONTRACTMANUFACTURERSNCLUDING 16.协议生产商（包括实验室）LABORATORIES）REPACK

10、ERS,AND包装者和重新贴签者17. AGENTS, BROKERS, TRADERS,DISTRIBUTORS,RELABELLERSApplicabilityTraceability of Distributed APIs andIn termediatesQuality Man ageme ntRepackaging, Relabeling, and Holding ofAPIs and In termediatesStabilityTran sfer of In formatio nHan dli ng of Complai nts and RecallsHan dli ng of

11、Retur ns18. Specific Guida nee for APIsManu facturedbyCellCulture/Ferme ntati on17. 代理商、经纪人、贸易商、经销商、重新适用性已分发的原料药和中间体的可追溯性质里官理原料药和中间体的重新包装、重新贴签和待检稳定性信息的传达投诉和召回的处理退货的处理18. 用细胞繁殖/发酵生产的原料药的特殊指南v1.0可编辑可修改Gen eral总则CellBank Maintenance and Record细胞库的维护和记录的保存Keep ingCell Culture/Ferme ntati on细胞繁殖/发酵Harves

12、ti ng,Isolati onand Purificati on收取、分离和精制Viral Removal/In activati on steps病毒的去除/灭活步骤19. APIs for Use in Clinical Trials19.用于临床研究的原料药Gen eral总则Quality质量Equipment and Facilities设备和设施Control of Raw Materials原料的控制Product ion生产Validati on验证Changes变更Laboratory Con trols实验室控制Docume ntati on文件20. Glossary2

13、0.术语66v1.0可编辑可修改Q7a GMP Guida nee for APIsQ7a原料药的GMpf南771. INTRODUCTIONObjectiveThis document is intended to provide guidanee regardinggood manufacturingpractice (GMP) for the manu facturi ng of active pharmaceutical in gredie nts (APIs) under an appropriate system for managing1.简介目的本文件旨在为在合适的质量管理体系

14、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。quality. It is also inten dedto helpensure that APIs meet the quality and purity characteristicsthat theypurport, or are represented, to possess.In this guidanee, the term manufacturing is defined to include all operations

15、of receipt of materials, producti on, packag ing, repackag ing,labeli ng,relabeli ng, qualitycon trol,release,storage and distribution of APIs and the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related con trols. In this guid

16、a nee, the 平的供选物来替代。本指南中的“现行优良v1.0可编辑可修改term should identifies recommendations生产管理规范（cGMp”和“优良生产管理规that,when followed, willensure范（GMp” 是等同的。complia neewith CGMPs. An alter nativeapproach may be used if such approachsatisfies therequireme ntsof theapplicable statues. For the purposes ofthis guidanee

17、, the terms currentgoodmanu facturi ngpractices and goodmanu facturi ng practicesare equivale nt.88The guida nee as a whole does not coversafety aspects for the personnel engagedin manufacturing,nor aspects related to本指南在总体上未涉及生产人员的安全冋题，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protect ingthe environment.

18、 These 的。con trols are in here nt resp on sibilitiesof the manu facturer and are gover ned by n atio nal laws.This guida nee is not inten ded to defi ne registration and/or filing requirements or modify pharmacopoeial requireme nts.This guidanee does not affect the ability of the resp on sible regul

19、atory age ncy to establish specificregistrati on /fili ngrequireme nts regard ing APIs within the con text ofmarket in g/ma nu facturi ng 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。v1.0可编辑可修改authorizations or drug applications.Allcommitme nts inregistra

20、ti on /fili ng法规的适用性may在世界范围内对原料药的法定定义是各不相 as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。docume nts should be met.Regulatory ApplicabilityWithin the world community, materials vary as to their legal classification an API. When a material is classified as an API in the regi on or country in which it

21、 is manufacturedor used in a drugproduct, it should be manu factured accord ing to this guida nee.范围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。ScopeThis guidanee applies to the manufacture of APIs for use in human drug (medicinal) products. It

22、applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs being rendered sterile. The sterilization and aseptic process ing of sterile APIs are not covered by this guidanee, but should be performed inaccordaneewith GMPguida nces for drug (medici nal) products as d

23、efined by local authorities.99v1.0可编辑可修改This guida nee covers APIs that are manu faeturedby chemicalsyn thesis,extract ion, cell culture/ferme ntatio n, recovery from naturalsources, or anycomb in ati on of these processes. Specific guida nee for APIs manu factured by cell culture/ferme ntati onis d

24、escribed inSection 18.This guida nee excludes all vacci nes, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fraction ati on), and gene therapy APIs.However, it does in clude APIs that are produced using blood or plasma as raw materials. Note that cell substrates (mammalia

25、n, pla nt, in sect or microbial cells, tissue or animal sources including transgenicanimals) and early processsteps may be subject to GMP but are not covered by this guida nee. In additi on, the guida nee does not apply to medical gases, bulk-packaged drug (medici nal) products ., tablets or capsule

26、s in bulk contain ers), or radiopharmaceuticals.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。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

27、（例如，散装的片剂和胶 囊）和放射性药物的生产。1010v1.0可编辑可修改Secti on 19 contains guida nee that only applies to the manufacture of APIs used in the product ionof drug (medici nal) 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。1111productsspecificallyfor clinicaltrials(in vestigati onalmedici nalproducts).An A

28、PI startingmaterialis a raw原料药的起始物料”是指一种原料、中间material, an in termediate,or an API that体或原料药，用来生产一种原料药，或者以is used in the producti on of an API andthat is incorporatedas a significantstructural fragment into the structure of the API. An API start ing material can be an article of commerce, a material

29、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。purchased from one or more suppliers un der con tract or commercial agreeme nt, or producedin-house.API start ingmaterialsno rmally have defi ned chemicalproperties and structure.The company should des

30、ignate and document the rati on alefor the point at whichproduct ion of the API beg ins. For synthetic processes, this is known as the point at which API starting materials are en tered into the process. For other 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

31、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v1.0可编辑可修改processes ., ferme ntati on, extracti on, purificati on), this rati on ale should be established on a case-by-case basis. Table 1 gives guida nee on the point at which the API starti ngmaterial isno rmally in troduced into the process.From this point on, ap

32、propriate GMP as defi ned in this guida nee should be applied to these in termediatean d/or APImanu facturi ng steps. This would in clude the validationof critical process stepsdeterm ined to impact the quality of theAPI. However, it should be no ted that the fact that a compa ny chooses to validate

33、 a process step does not necessarily define that steps as critical.The guidaneein thisdocument wouldnormally be applied to the steps shown in gray in Table 1. However, all steps shown may not be completed. The stri ngency of GMPn API manu facturi ngshould in creaseas the process proceeds from early

34、API steps to final steps, purification, and packag ing. Physical process ing of APIs,过程的指导原则。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。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，

35、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。1212v1.0可编辑可修改such as granulation,coating or physicalmanipulationof particle size ., milling,micronizing) should becon ductedaccord ing to this guida nee.1313This GMPguidanee does not apply to steps 本GMP旨南不适用于引入定义了的“原料药prior to the introduction

36、of the defined 的起始物料”以前的步骤。API starting material.Table 1: Application of this Guidance to API ManufacturingType ofManufacturingApplication of this guidance to steps (shown in gray) used in this type of manufacturingChemical manufacturingProduction of theAPI StartingmaterialIntroduction of theAPI sta

37、rting materialinto processProduction ofIntermediate(s)Isolation andpurificationPhysical processing, and packagingAPI derived fromCollection ofCutting, mixing,Introduction of theIsolation andPhysical processing, andanimal sourcesorgan, fluid, orand/or initialAPI starting materialpurificationpackaging

38、tissueprocessinginto processAPI extracted fromCollection of plantCutting and initialIntroduction of theIsolation andPhysical processing, andplant sourcesextraction(s)API starting materialpurificationpackaginginto processHerbal extractsCollection ofCutting and initialFurtherPhysical processing, andus

39、ed as APIplantsextracti onextractionpackagingAPI consisting ofCollection ofCutting/comminutingPhysical processing, andcomminuted orplants and/orpackagingpowdered herbscultivation andharvestingv1.0可编辑可修改Biotechnology:Establishment ofMaintenance ofCell culture and/orIsolation andPhysical processing, a

40、ndfermentation/cellmaster cell bank andworking cell bankfermentationpurificationpackagingcultureworking cell bank“Classical ”Establishment ofMaintenance of theIntroduction of theIsolation andPhysical processing, andfermentation tocell bankcell bankcells intopurificationpackagingproduce an APIferment

41、ation表1:本指南在原料药生产中的应用生产类型本指南在用于各类生产的工艺步骤（灰色背景）中的应用化学品的生产原料药起始物料的生产原料药起始物料引入工艺过程中间体的生产分离和纯化物理加工和包装动物源原料药器官、分泌物或组织切割、混合和/或初步加原料药起始物料引入工分离和纯化物理加工和包装的收集工艺过程从植物源提取的原料植物的收集切割和初步提取原料药起始物料引入工分离和纯化物理加工和包装药艺过程草药提取物用作原料植物的收集切割和初步提取进一步提取物理加工和包装药由粉碎的或粉末状草植物的收集和/或培切割/粉碎物理加工和包装药组成的原料药养和收获生物技术：发酵/细胞主细胞库和工作细胞工作细胞库的维

42、护细胞培养和/或发酵分离和纯化物理加工和包装培养库的建立“经典”发酵生产细胞库的建立细胞库的维护细胞引入发酵分离和纯化物理加工和包装原料药GMP的要求增加1414v1.0可编辑可修改2. QUALITY MANAGEMENTPrin ciplesQuality should be the resp on sibilities of all persons involved in manufacturing.Eachmanu facturershould establish,document, and implementan effectivesystem for managing qualit

43、y that involves the active participati on of man ageme nt and appropriatemanu facturi ng pers onn el.The system for man agi ng quality should en compass the orga ni zati onal structure, procedures, process and resources, as well as activities to en sure con fide nee that the API will meet itsintende

44、dspecifications for quality and purity.All quality-related activities should be defi ned and docume nted.There should be a quality un it(s) thatis independent of production and that fulfills both quality assuranee (QA and quality con trol (QC)resp on sibilities.2. 质量管理总则参与原料药生产的每一个人都应当对质量 负责。每一个生产商都

45、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。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。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。1515v1.0可编辑可修改The quality unit can be in the form of separate QA and QC unitsor a singlein divi

46、dual or group, depe nding upon the size and structure of the orga ni zati on.Thepers onsauthorized to release应当指定授权发放中间体和原料药的人员。in termediatesand APIs should be1616specified.All quality-related activities should所有有关质量的活动应当在其执行时就记be recordedat the time theyare 录。performed.Any deviati onfrom establish

47、ed任何偏离既定规程的情况都应当有文字记procedures shouldbe docume nted and录并加以解释。对于关键性偏差应当进行调expla in ed.Criticaldeviatio nsshould be 查，并记录调查经过及其结果。in vestigated, and the in vestigati on and its con clusi ons should be docume nted.No materials should be released or used before the satisfactory completion of evaluati o

48、n by the quality un it(s) uni ess there are appropriate systems in place toallow forsuch use ., releaseunderquara nti neas describedin Section10 orthe use ofraw materialsor in termediates在质量部门对物料完成满意的评价之前， 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）。v1.0可编辑可修改pending completi

49、on of evaluati on).1717Procedures should exist for no tify ingresponsiblemanagement in a timely mannerof regulatory in spect ions, serious GMPdeficie ncies,productdefectsandrelatedactions.,quality-related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。compla in ts,recalls, and

50、regulatoryactio ns).Resp on sibilitiesof the Quality Unit(s)质量部门的责任The quality un it(s) should be in volved in all quality-related matters.The quality un it(s) should review and approve all appropriate quality-related docume nts.质量部门应当参与所有与质量有关的事物。所有与质量有关的文件应当由质量部门审 核批准。The mainresp on sibilitiesof

51、theindependent quality unit(s) should not be delegated. These resp on sibilitiesshouldbe described in writi ng and should in clude, but not n ecessarily be limited to:1. Releas ingor rejecti ng all APIs.Releas ing or rejecti ng in termediates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

52、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;v1.0可编辑可修改for use outside the con trol of themanu facturi ng compa ny2. Establish ing a system to release or reject raw materials, in termediates, packag ing, and labeli ng materials3. Review ing completed batch product ionand laboratorycontro

53、lrecords ofcritical process steps before release of the API for distribution4. Making sure that critical deviati onsare in vestigated and resolved5. Approvi ngallspecificatio nsandmaster product ion in struct ions6. Approvi ngall proceduresaffect ingthe quality of in termediates or APIs7. Making sure that internal audits (self- in spect ions) are performed8. Approvi ngin termediate and APIcon tract manufacturers9. Approvingchanges that potentiallyaffect in termediate or API qual