0731欧盟APIGMP中英文对照CX0112最新整理阿拉蕾

1、european commission 欧盟委员会enterprise and industry directorate-general 企业与工业管理局consumer goods 消费品pharmaceuticals 药品brussels, 03 february 2010 布鲁塞尔 2010.02.03entr/f/2/am/an d(2010) 3374eudralex（european union law on drug regulatory affairs） 欧盟药品法规the rules governing medicinal products in the european u

2、nion欧盟医药产品管理规则volume 4卷4good manufacturing practice良好生产规范medicinal products for human and veterinary use人用和兽用医药产品part ii: basic requirements for active substances used as starting materials第二部分：作为起始物料的原料药的基本要求document history 文件历史an amendment is made to part ii of the gmp guide to incorporate对gmp指南第

3、二部分的修订是为了纳入与ich q9关于质量风险principles of quality risk management in line with the ich q9管理的指南一致的质量风险管理原则。guideline on quality risk management. amendments correspond to对指南第一部分第一章有过类似的修订并在2008年2月公布过。similar changes made to part i chapter 1 of the guide and publishedin february 2008. a new section on qual

4、ity risk management is本版本新增加了2.19节，一个关于质量风险管理的新章节。introduced as section 2.19. the remaining sections of chapter 2 are第二章节其余部分进行了重新编号。2.21节进行了一个微小的变更，renumbered. a minor change is made to section 2.21. no other除此以外，没有其它的变更。changes have been made.september 20072007年9月public consultation 公开咨询 april 200

5、8 until october 20082008年4月至2008年10月adopted by the european commission 欧盟委员会通过31 january 20102010年1月31日deadline for coming into operation 生效日期31 july 20102010年7月31日table of contents 目录 1 introduction 1简介 1.1 objective 1.1目的 1.2 regulatory applicability 1.2法规适用性1.3 scope 1.3范围2 quality management 2质量

6、管理2.1 principles 2.1原则 2.2 quality risk management2.2质量风险管理2.3 responsibilities of the quality unit(s)2.3质量部门的职责2.4 responsibility for production activities2.4生产活动的职责2.5 internal audits (self-inspection)2.5内部审计（自检）2.6 product quality review 2.6产品质量回顾3 personnel 3 人员3.1 personnel qualifications3.1 人员

7、资质3.2 personnel hygiene3.2 人员卫生3.3 consultants 3.3 顾问4 buildings and facilities 4 厂房设施4.1 design and construction 4.1 设计和建造4.2 utilities 4.2 公用工程4.3 water 4.3 水4.4 containment 4.4 限制4.5 lighting 4.5 照明4.6 sewage and refuse 4.6 废水废物4.7 sanitation and maintenance 4.7 公共卫生及保养 5 process equipment 5 工艺设备

8、5.1 design and construction 5.1 设计和建造5.2 equipment maintenance and cleaning 5.2 设备的保养和清洁5.3 calibration 5.3 校验5.4 computerized systems 5.4 计算机系统6 documentation and records 6 文件和记录6.1 documentation system and specifications 6.1 文件系统与规格标准6.2 equipment cleaning and use record 6.2 设备清洁和使用记录6.3 records o

9、f raw materials, intermediates, api labelling and packaging materials6.3 原料、中间产品、原料药的标签和包装材料的记录6.4 master production instructions (master production and control records)6.4 生产指令（生产和控制记录）6.5 batch production records (batch production and control records)6.5批生产记录（批生产和控制记录）6.6 laboratory control record

10、s6.6 实验室控制记录（批检验记录）6.7 batch production record review6.7 批生产记录审核7 materials management7 物料管理7.1 general controls7.1 控制通则7.2 receipt and quarantine7.2 接受和待检7.3 sampling and testing of incoming production materials7.3 到货物料的取样和检测7.4 storage7.4 贮存7.5 re-evaluation7.5 再评估8 production and in-process contr

11、ols8 生产和过程控制8.1 production operations8.1 生产操作8.2 time limits8.2 时间限制8.3 in-process sampling and controls8.3 中控取样和控制8.4 blending batches of intermediates or apis8.4 中间产品和原料药的混批8.5 contamination control8.5 污染控制9 packaging and identification labelling of apis and intermediates9 中间产品和原料药的包装和贴签9.1 genera

12、l9.1 总则9.2 packaging materials9.2 包装材料9.3 label issuance and control9.3 标签放行和控制9.4 packaging and labelling operations9.4 包装和贴签操作10 storage and distribution10 贮存和销售10.1 warehousing procedures10.1 入库程序10.2 distribution procedures10.2 销售程序11 laboratory controls11 实验室控制11.1 general controls11.1 控制通则11.2

13、 testing of intermediates and apis11.2 中间产品和原料药的检测11.3 validation of analytical procedures11.3 分析方法的验证11.4 certificates of analysis11.4 分析报告11.5 stability monitoring of apis11.5 原料药的稳定性监测11.6 expiry and retest dating11.6 失效和复检日期11.7 reserve/retention samples11.7 留样12 validation12 验证12.1 validation p

14、olicy12.1 验证方针12.2 validation documentation12.2 验证文件12.3 qualification12.3 确认12.4 approaches to process validation12.4 工艺验证方法12.5 process validation program12.5 工艺验证计划12.6 periodic review of validated systems12.6 验证系统的定期审核12.7 cleaning validation12.7 清洁验证12.8 validation of analytical methods12.8 分析方

15、法验证13 change control13 变更控制14 rejection and reuse of materials14 物料的拒收和再利用14.1 rejection14.1 拒收14.2 reprocessing14.2 返工14.3 reworking14.3 重新加工14.4 recovery of materials and solvents14.4 物料和溶剂的回收利用14.5 returns14.5 退回15 complaints and recalls15 投诉和召回16 contract manufacturers (including laboratories)16

16、 合同生产企业（包含实验室）17 agents, brokers, traders, distributors, repackers, and relabellers17 代理商、经纪商、贸易商、经销商、重新包装商和重新贴签商17.1 applicability17.1 适用性17.2 traceability of distributed apis and intermediates17.2 已销售中间产品和原料药的追踪17.3 quality management17.3 质量管理17.4 repackaging, relabelling and holding of apis and i

17、ntermediates17.4 中间产品和原料药的重新包装、重新贴签和处理17.5 stability17.5 稳定性17.6 transfer of information17.6 信息的传输17.7 handling of complaints and recalls17.7 投诉和召回的处理17.8 handling of returns17.8 退货的处理18 specific guidance for apis manufactured by cell culture/fermentation18 用于细胞培养/发酵而得原料药的特殊指南18.1 general18.1 总则18.2

18、 cell bank maintenance and recordkeeping18.2 细胞库的维护和记录保存18.3 cell culture/fermentation18.3 细胞培养/发酵18.4 harvesting, isolation, and purification18.4 收获、分离和精制18.5 viral removal/inactivation steps18.5 病毒除去/灭火步骤19 apis for use in clinical trials19 用于临床试验的原料药19.1 general19.1 总则19.2 quality19.2 质量19.3 equi

19、pment and facilities19.3 设备设施19.4 control of raw materials19.4 原料的控制19.5 production19.5 生产19.6 validation19.6 验证19.7 changes19.7 变更19.8 laboratory controls19.8 实验室控制19.9 documentation19.9 文件20 glossary20 词汇表1 introduction1 介绍this guideline was published in november 2000 as annex 18 to the gmp guider

20、eflecting the eus agreement to ich q7a and has been used by manufacturers andgmp inspectorates on a voluntary basis. article 46 (f) of directive 2001/83/ec andarticle 50 (f) of directive 2001/82/ec; as amended by directives 2004/27/ec and2004/28/ec respectively, place new obligations on manufacturin

21、g authorisation holders to use only active substances that have been manufactured in accordance with good manufacturing practice for starting materials. the directives go on to say that the principles of good manufacturing practice for active substances are to be adopted as detailed guidelines. memb

22、er states have agreed that the text of former annex 18 should form the basis of the detailed guidelines to create part ii of the gmp guide.本指南已经在2000年11月以gmp指南附录18的形式公布过，它反应了欧盟对ich q7a的认可以，该指南已经被生产商和gmp检查员在自愿的原则下所使用。法令2001/83/ec的第46条和法令2001/82/ec的第50条分别修订为法令2004/27/ec和2004/28/ec，赋予了生产许可证持有人新的责任，即药品生

23、产企业只能使用按照gmp要求生产的原料药作为起始物料。这些法令还指出将制定gmp的细则。会员国认为原来的附录18已构成详细指南的基础，可以作为gmp指南的第二部分。1.1 objective1.1 目的these guidelines are intended to provide guidance regarding good manufacturingpractice (gmp) for the manufacture of active substances under an appropriate system for managing quality. it is also inte

24、nded to help ensure that active substances meet therequirements for quality and purity that they purport or are represented to possess.in these guidelines “manufacturing” includes all operations of receipt of materials,production, packaging, repackaging, labeling, relabelling, quality control, relea

25、se,storage and distribution of active substances and the related controls. the term “should” indicates recommendations that are expected to apply unless shown to beinapplicable, modified in any relevant annexes to the gmp guide, or replaced by analternative demonstrated to provide at least an equiva

26、lent level of quality assurance.the gmp guide as a whole does not cover safety aspects for the personnel engaged in manufacture, nor aspects of protection of the environment. these controls are inherent responsibilities of the manufacturer and are governed by other parts of the legislation .these gu

27、idelines are not intended to define registration requirements or modify pharmacopoeial requirements and do not affect the ability of the responsiblecompetent authority to establish specific registration requirements regarding activesubstances within the context of marketing/manufacturing authorisati

28、ons. allcommitments in registration documents must be met.这些指南准备在适当的质量管理体系下为原料药生产提供关于药品生产质量管理规范的指导。这也是为了帮助确保原料药符合他们所声称和拥有的质量和纯度的要求。在这些指南中“生产”包含所有关于原料药的物料的接受、生产、包装、重新包装、贴签、重新贴签、质量控制、放行、贮存和销售的操作以及相关的控制。 “should”一词表示对预期应用的建议，除非表明不适用，或者是可以由提供同等质量水平的其它方法所替代。gmp指南整体上不涉及生产人员安全方面的内容，也不设计环境保护方面。这些是生产者固有的责任，并

29、由其它法规管理。这些指南没有定义注册方面的要求或修订药典的要求，本指南不影响主管机关在原料药销售/生产范围内制定特殊注册要求。所有在注册文件中的承诺必须得到满足。1.2 scope1.2 范围these guidelines apply to the manufacture of active substances for medicinal productsfor both human and veterinary use. they apply to the manufacture of sterile activesubstances only up to the point immed

30、iately prior to the active substance being rendered sterile. the sterilisation and aseptic processing of sterile active substances are not covered, but should be performed in accordance with the principles and guidelines of gmp as laid down in directive 2003/94/ec and interpreted in the gmp guide in

31、cluding its annex 1.这些指南适用于人用和兽用药品中使用到的原料药的生产。也适用于无菌api的生产，仅到api刚刚被灭菌前的那个时间点上为止。原料药的灭菌和无菌处理不包含在本指南中，但是应该按照法令2003/94/ec和gmp指南附件1的方针和指导执行。in the case of ectoparasiticides for veterinary use, other standards than theseguidelines, that ensure that the material is of appropriate quality, may be used.对于兽用

32、外用杀虫剂，除了这些指南以外的标准如果能确保物料具有合适的质量，那么也是可以采用的。these guidelines exclude, whole blood and plasma, as directive 2002/98/ec and thetechnical requirements supporting that directive lay down the detailed requirements for the collection and testing of blood, however, it does include active substances that are

33、produced using blood or plasma as raw materials. finally, these guidelines do not apply to bulk-packaged medicinal products. they apply to all other active starting materials subject to any derogations described in the annexes to the gmp guide, in particular annexes 2 to 7 where supplementary guidan

34、ce for certain types of active substance may be found. the annexes will consequently undergo a review but in the meantime and only until this review is complete, manufacturers may choose to continue to use part i of the basic requirements and the relevant annexes for products covered by those annexe

35、s, or may already apply part ii.这些指南不包含全血和血浆，法令2002/98/ec以及配套的技术要求对血液的收集和检测做出了详细的规定，但是本指南包含以血液和血浆为原料生产的原料药。另外，本指南不适用于散装药品。本指南适用于gmp指南附录中所有其它易降解的原料药的生产，尤其是能找到某些类型原料药的补充指南的附录2至附录7。这些附录将因此进行审核,但在完成审核前的时间内,药品生产企业可以继续采用其基本要求第i 部分与覆盖相关产品的附录,或可以已经采用的第ii 部分。section 19 contains guidance that only applies to

36、the manufacture of active substancesused in the production of investigational medicinal products although it should be noted that its application in this case, although recommended, is not required by community legislation.指南第19 节只适用于用生产临床试验用药原料药的生产,请注意,这一节尽管是建议,但尚不是欧盟法规要求。an “active substance start

37、ing material” is a raw material, intermediate, or an activesubstance that is used in the production of an active substance and that is incorporated as a significant structural fragment into the structure of the active substance. an active substance starting material can be an article of commerce, a

38、material purchased from one or more suppliers under contract or commercial agreement, or produced in-house."活性起始物料(原料药)"系指原料,中间体或用来生产某一原料药的某一活性原料,该活性原料的关键结构将进入原料药中。原料药的起始物料可以是市售的,按合同或商业协议从一个或数个供货商处购得的,也可以是企业自行生产的。active substance starting materials normally have defined chemical properties

39、 andstructure.一般说来,原料药的起始物料具有确定的化学性质和结构。the manufacturer should designate and document the rationale for the point at whichproduction of the active substance begins. for synthetic processes, this is known as the point at which "active substance starting materials" are entered into the proc

40、ess. for other processes (e.g. fermentation, extraction, purification, etc), this rationale should be established on a case-by-case basis. table 1 gives guidance on the point at which the active substance starting material is normally introduced into the process. from this point on, appropriate gmp

41、as defined in these guidelines should be applied to these intermediate and/or active substance manufacturing steps. this would include the validation of critical process steps determined to impact the quality of the activesubstance. however, it should be noted that the fact that a manufacturer choos

42、es tovalidate a process step does not necessarily define that step as critical. the guidance in this document would normally be applied to the steps shown in grey in table 1. it does not imply that all steps shown should be completed. the stringency of gmp in active substance manufacturing should in

43、crease as the process proceeds from early steps to final steps, purification, and packaging. physical processing of active substances, such as granulation, coating or physical manipulation of particle size (e.g. milling, micronising),should be conducted at least to the standards of these guidelines.

44、 these guidelines do not apply to steps prior to the first introduction of the defined "active substance starting material".生产企业应当有文件说明原料药生产的起点并阐明确定起点的理由。对于合成工艺而言,它即是"原料药起始物料"开始加工的那一点。对其他工艺(如,发酵,提取,精制等),应根据具体情况具体分析的原则确定。表1 给出了原料药起始物料的进入工艺过程的指南。从这一步开始,中间体和/或原料药生产的各步操作,应当符合本gmp指南的相

45、关要求。它包括对原料药质量有影响的关键工艺步骤进行验证。但是,应当注意一个事实,一个生产企业选择某一步骤进行验证,并不一定意味着将该步定义为关键步骤。本指南通常适用于表1 中的灰色区域的步骤,但,表中所列操作可能尚不完善。原料药生产中的gmp 要求应随着工艺步骤向前进行,从原料药生产的前几步到最后几步,精制和包装,越来越严格。制粒,包衣或粉碎(如,磨粉,微粉化)等原料药的物理加工,均应至少遵循这些指南的标准。这些指南不适用于原料药起始物料最早引入点以前的各步操作。in the remainder of this guideline the term active pharmaceutical

46、ingredient (api) isused repeatedly and should be considered interchangeable with the term “activesubstance”. the glossary in section 20 of part ii should only be applied in the contextof part ii. some of the same terms are already defined in part i of the gmp guide andthese therefore should only be

47、applied in the context of part i.本指南中其它部分中药物活性成分(api)一词将反复使用,其与活性物质(activesubstance)应是可以互换的。第ii 部分的第20 节中的术语只适用于第ii 部分的文本。一些同一术语在gmp 指南的第一部分中已经定义,它们只适用于第i 部分的文本。table 1: application of this guide to api manufacturing2 quality management质量管理2.1 principles原则2.10 quality should be the responsibility of

48、 all persons involved in manufacturing.2.10 参与生产的所有人员都必须对质量负责。2.11 each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management andappropriate manufacturing personnel.2.11 每一个生产企业都应当制订,记录,并且实施一个有管理人员和生产人员积极参

49、与的,有效的质量管理体系。2.12 the system for managing quality should encompass the organisational structure,procedures, processes and resources, as well as activities necessary to ensure confidence that the api will meet its intended specifications for quality and purity. all quality related activities should b

50、e defined and documented.2.12质量管理体系应当包含组织结构,程序,工艺和资源,以及确保原料药达到预期质量与纯度要求所必需活动。所有的与质量相关的活动应当定义并记录。2.13 there should be a quality unit(s) that is independent of production and that fulfills both quality assurance (qa) and quality control (qc) responsibilities. this can be in the form of separate qa and

51、 qc units or a single individual or group, depending upon the size and structure of the organization.2.13应当有一个独立于生产之外,来同时履行质量保证(qa)和质量控制(qc)职责的质量部门(qu)。它可以是分开的质量保证或质量控制部门,或一个人或组,这取决于组织的大小和结构。2.14 the persons authorised to release intermediates and apis should be specified.2.14应当具体指定授权放行中间体或原料药的人员。2.

52、15 all quality related activities should be recorded at the time they are performed.2.15 所有与质量相关的活动都应该在执行的时候记录。2.16 any deviation from established procedures should be documented and explained.critical deviations should be investigated, and the investigation and its conclusionsshould be documented.2

53、.16 任何与已经制订了的程序相偏离的偏差都应当进行记录并且加以解释。对于关键性偏差,应当进行调查,并记录调查过程和结论。2.17 no materials should be released or used before the satisfactory completion ofevaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g. release under quarantine as described in section

54、10.20 or the use of raw materials or intermediates pending completion of evaluation).2.17在质量部门没有作出满意完整评估之前,任何物料不能被放行或被使用,除非有恰当的在线系统允许此种使用(即在第10.20 节所描述待检的状态下放行,或原料或中间体在未完成评估前使用)。2.18 procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious gm

55、p deficiencies, product defects and related actions (e.g. quality related complaints, recalls, regulatory actions, etc.).2.18应当有一个程序来及时地通知有关的管理部门有关药政检查,严重的药品生产质量管理规范方面缺陷,产品缺陷或相关的活动(即,与质量相关的投诉,召回,药政活动等)。2.19 to achieve the quality objective reliably there must be a comprehensively designed and correc

56、tly implemented quality system incorporating good manufacturing practice, quality control and quality risk management.2.19 为了达到可靠的质量目的，必须有一个经过全面设计和正确执行的包含gmp、质量控制和质量风险管理的质量体系。2.2 quality risk management2.2 质量风险管理2.20 quality risk management is a systematic process for the assessment, control,communication and review of risks to the quality of the active