ICH-Q7a原料药地GMP指南设计(中英对照)

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1、word Q7a〔中英文对照〕 FDA原料药GMP指南 Table of Contents 目录 1. INTRODUCTION 1. 简介 1.1 Objective 1.2 Regulatory Applicability 1.3 Scope 2. QUALITY MANAGEMENT 2.1 Principles 2.2 Responsibilities of the Quality Unit(s) 2.3 Responsibility for Production Activities 2.4 Internal Aud

2、its (Self Inspection) 2.4内部审计〔自检〕 2.5 Product Quality Review 3. PERSONNEL 3. 人员 3.1 Personnel Qualifications 3.2 Personnel Hygiene 3.2 人员卫生 3.3 Consultants 3.3 顾问 4. BUILDINGS AND FACILITIES 4. 建筑和设施 4.1 Design and Construction 4.1 设计和结构 4.2 Utilities 4.2 公用设施 4.3 Water

3、4.3 水 4.4 Containment 4.4 限制 4.5 Lighting 4.5 照明 4.6 Sewage and Refuse 4.6 排污和垃圾 4.7 Sanitation and Maintenance 4.7 卫生和保养 5. PROCESS EQUIPMENT 5. 工艺设备 5.1 Design and Construction 5.1 设计和结构 5.2 Equipment Maintenance and Cleaning 5.2 设备保养和清洁 5.3 Calibration 5.3 校验 5.4 puterized Sy

4、stems 5.4 计算机控制系统 6. DOCUMENTATION AND RECORDS 6. 文件和记录 6.1 Documentation System and Specifications 6.1 文件系统和质量标准 6.2 Equipment cleaning and Use Record 6.2 设备的清洁和使用记录 6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials 6.3 原料、中间体、原料药的标签和包装材料的记录 6.4 Master

5、Production Instructions (Master Production and Control Records) 6.4 生产工艺规程〔主生产和控制记录〕 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 Records 6.6 实验室控制记录 6.7 Batch Production Record Review 7. MATERIALS MANAGEMENT 7. 物料管理 7.

6、1 General Controls 7.1 控制通如此 7.2 Receipt and Quarantine 7.3 Sampling and Testing of Ining Production Materials 7.3 进厂物料的取样与测试 7.4 Storage 7.5 Re-evaluation 8. PRODUCTION AND IN-PROCESS CONTROLS 8. 生产和过程控制 8.1 Production Operations 8.1 生产操作 8.2 Time Limits 8.2 时限 8.3 In-proces

7、s Sampling and Controls 8.3 工序取样和控制 8.4 Blending Batches of Intermediates or APIs 8.4 中间体或原料药的混批 8.5 Contamination Control 8.5 污染控制 9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES 9. 原料药和中间体的包装和贴签 9.1 General 9.1 总如此 9.2 Packaging Materials 9.2 包装材料 9.3 Label Issua

8、nce and Control 9.3 标签发放与控制 9.4 Packaging and Labeling Operations 9.4 包装和贴签操作 10. STORAGE AND DISTRIBUTION 10.1 Warehousing Procedures 10.1 入库程序 10.2 Distribution Procedures 10.2 分发程序 11. LABORATORY CONTROLS 11.1 General Controls 11.1 控制通如此 11.2 Testing of Intermediates and A

9、PIs 11.2 中间体和原料药的测试 11.3 Validation of Analytical Procedures 11.3 分析方法的验证 11.4 Certificates of Analysis 11.4 分析报告单 11.5 Stability Monitoring of APIs 11.5 原料药的稳定性监测 11.6 Expiry and Retest Dating 11.6 有效期和复验期 11.7 Reserve/Retention Samples 11.7 留样 12. VALIDATION 12.1 Validation Poli

10、cy 12.1 验证方针 12.2 Validation Documentation 12.2 验证文件 12.3 Qualification 12.3 确认 12.4 Approaches to Process Validation 12.4 工艺验证的方法 12.5 Process Validation Program 12.5 工艺验证的程序 12.6 Periodic Review of Validated Systems 12.7 Cleaning Validation 12.7 清洗验证 12.8 Validation of Analytical Me

11、thods 12.8 分析方法的验证 13. CHANGE CONTROL 14. REJECTION AND RE-USE OF MATERIALS 14.1 Rejection 14.1 拒收 14.2 Reprocessing 14.2 返工 14.3 Reworking 14.3 重新加工 14.4 Recovery of Materials and Solvents 14.4 物料与溶剂的回收 14.5 Returns 14.5 退货 15. PLAINTS AND RECALLS 16. CONTRACT M

12、ANUFACTURERS (INCLUDING LABORATORIES) 16.协议生产商〔包括实验室〕 17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS 17.代理商、经纪人、贸易商、经销商、重新包装者和重新贴签者 17.1 Applicability 17.2 Traceability of Distributed APIs and Intermediates 17.3 Quality Management 17.4 Repackaging, Relabeling

13、, and Holding of APIs and Intermediates 17.4原料药和中间体的重新包装、重新贴签和待检 17.5 Stability 17.6 Transfer of Information 17.6 信息的传达 17.7 Handling of plaints and Recalls 17.7 投诉和召回的处理 17.8 Handling of Returns 17.8 退货的处理 18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18.

14、用细胞繁殖/发酵生产的原料药的特殊指南 18.1 General 18.1 总如此 18.2 Cell Bank Maintenance and Record Keeping 18.3 Cell Culture/Fermentation /发酵 18.4 Harvesting, Isolation and Purification 18.4收取、别离和精制 18.5 Viral Removal/Inactivation steps 18.5 病毒的去除/灭活步骤 19. APIs for Use in Clinical Trials 19.用于临床研究的原料药

15、 19.1 General 19.1 总如此 19.2 Quality 19.2 质量 19.3 Equipment and Facilities 19.3 设备和设施 19.4 Control of Raw Materials 19.4 原料的控制 19.5 Production 19.5 生产 19.6 Validation 19.6 验证 19.7 Changes 19.7 变更 19.8 Laboratory Controls 19.8 实验室控制 19.9 Documentation 19.9 文件 20. Glossary 20. 术

16、语 Q7a GMP Guidance for APIs Q7a原料药的GMP指南 1. INTRODUCTION 1. 简介 1.1 Objective This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is

17、 also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess. 本文件旨在为在适宜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X〔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明确拥有的质量与纯度要求。 In this guidance, the term manufacturing is defined to include all o

18、perations of receipt of materials, production, packaging, repackaging, labeling, relabeling, quality control, release, storage and distribution of APIs and the related controls. In this guidance, the term should identifies remendations that, when followed, will ensure pliance with CGMPs. An alternat

19、ive approach may be used if such approach satisfies the requirements of the applicable statues. For the purposes of this guidance, the terms current good manufacturing practices and good manufacturing practices are equivalent. 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与其相关控制的所有操作。本指南中，“

20、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X〔cGMP〕〞和“优良生产管理规X〔GMP〕〞是等同的。 The guidance as a whole does not cover safety aspects for the personnel engaged in manufacturing, nor aspects related to protecting the environment. These controls are inherent responsibilities of t

21、he manufacturer and are governed by national laws. 本指南在总体上未涉与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。 This guidance is not intended to define registration and/or filing requirements or modify pharmacopoeial requirements. This guidance does not affect the ability of the responsible regu

22、latory agency to establish specific registration/filing requirements regarding APIs within the context of marketing/manufacturing authorizations or drug applications. All mitments in registration/filing documents should be met. 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。

23、注册/归档的所有承诺必须做到。 1.2 Regulatory Applicability Within the world munity, materials may vary as to their legal classification as an API. When a material is classified as an API in the region or country in which it is manufactured or used in a drug product, it should be manufactured according to

24、this guidance. 在世界X围内对原料药的法定定义是各不一样的。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展生产。 1.3 Scope This guidance applies to the manufacture of APIs for use in human drug (medicinal) products. It applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs being rendere

25、d sterile. The sterilization and aseptic processing of sterile APIs are not covered by this guidance, but should be performed in accordance with GMP guidances for drug (medicinal) products as defined by local authorities. 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

26、药品〔医疗用品〕生产的GMP指南。 This guidance covers APIs that are manufactured by chemical synthesis, extraction, cell culture/fermentation, recovery from natural sources, or any bination of these processes. Specific guidance for APIs manufactured by cell culture/fermentation is described in Section 18. 本文

27、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如此在第18章论述。 This guidance excludes all vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy APIs. However, it does include APIs that are produced using blood or p

28、lasma as raw materials. Note that cell substrates (mammalian, plant, insect or microbial cells, tissue or animal sources including transgenic animals) and early process steps may be subject to GMP but are not covered by this guidance. In addition, the guidance does not apply to medical gases, bulk-p

29、ackaged drug (medicinal) products (e.g., tablets or capsules in bulk containers), or radiopharmaceuticals. 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X，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。

30、 Section 19 contains guidance that only applies to the manufacture of APIs used in the production of drug (medicinal) products specifically for clinical trials (investigational medicinal products). 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。 An API starting material is a raw mater

31、ial, an intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of merce, a material purchased from one or more suppliers under contract or mercial agreeme

32、nt, or produced in-house. API starting materials normally have defined chemical properties and structure. “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给商处购得，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。 The pany should designate and document the rationale f

33、or the point at which production of the API begins. For synthetic processes, this is known as the point at which API starting materials are entered into the process. For other processes (e.g., fermentation, extraction, purification), this rationale should be established on a case-by-case basis. Tabl

34、e 1 gives guidance on the point at which the API starting material is normally introduced into the process. 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如此。 From this point on, appropriate GMP as defined in this guidanc

35、e should be applied to these intermediate and/or API manufacturing steps. This would include the validation of critical process steps determined to impact the quality of the API. However, it should be noted that the fact that a pany chooses to validate a process step does not necessarily define that

36、 steps as critical. 从这步开始，本指南中的有关GMP规X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展验证，并不一定将该步骤定为关键步骤。 The guidance in this document would normally be applied to the steps shown in gray in Table 1. However, all steps shown may not be pleted. The stringency of GMP in API manufa

37、cturing should increase as the process proceeds from early API steps to final steps, purification, and packaging. Physical processing of APIs, such as granulation, coating or physical manipulation of particle size (e.g., milling, micronizing) should be conducted according to this guidance. 本文件的指某某常

38、适用于表1中的灰色步骤。但在表中表现的所有步骤并不是将应用GMP管理的所有步骤全部表现出来了。原料药生产中的GMP要求应当随着工艺的进展，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展。 This GMP guidance does not apply to steps prior to the introduction of the defined API starting material. 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。 Table 1: A

39、pplication of this Guidance to API Manufacturing Type of Manufacturing Application of this guidance to steps (shown in gray) used in this type of manufacturing Chemical manufacturing Production of the API Starting material Introduction of the API starting material into process Production of In

40、termediate(s) Isolation and purification Physical processing, and packaging API derived from animal sources Collection of organ, fluid, or tissue Cutting, mixing, and/or initial processing Introduction of the API starting material into process Isolation and purification Physical processing,

41、and packaging API extracted from plant sources Collection of plant Cutting and initial extraction(s) Introduction of the API starting material into process Isolation and purification Physical processing, and packaging Herbal extracts used as API Collection of plants Cutting and initial extr

42、action Further extraction Physical processing, and packaging API consisting of minuted or powdered herbs Collection of plants and/or cultivation and harvesting Cutting/minuting Physical processing, and packaging Biotechnology: fermentation/cell culture Establishment of master cell bank

43、 and working cell bank Maintenance of working cell bank Cell culture and/or fermentation Isolation and purification Physical processing, and packaging “Classical〞 fermentation to produce an API Establishment of cell bank Maintenance of the cell bank Introduction of the cells into fermentatio

44、n Isolation and purification Physical processing, and packaging Increasing GMP requirements 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 别离和纯化 物理加工和包装 动物源原料药 器官、分泌物或组织的收集 切割、混合和/或初步加工 原料药起始物料引入工艺过程 别离和纯化 物理加工和包装 从植物源提取的原料药 植物的

45、收集 切割和初步提取 原料药起始物料引入工艺过程 别离和纯化 物理加工和包装 草药提取物用作原料药 植物的收集 切割和初步提取 进一步提取 物理加工和包装 由粉碎的或粉末状草药组成的原料药 植物的收集和/或培养和收获 切割/粉碎 物理加工和包装 生物技术：发酵/细胞培养 主细胞库和工作细胞库的建立 工作细胞库的维护 细胞培养和/或发酵 别离和纯化 物理加工和包装 “经典〞 发酵生产原料药 细胞库的建立 细胞库的维护 细胞引入发酵 别离和纯化 物理加工和包装 GMP的要求增加 2. QUALITY MANAGE

46、MENT 2．质量管理 2.1 Principles Quality should be the responsibilities of all persons involved in manufacturing. 参与原料药生产的每一个人都应当对质量负责。 Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management an

47、d appropriate manufacturing personnel. 2.11 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。 The system for managing quality should enpass the organizational structure, procedures, process and resources, as well as activities to ensure confidence that the API will meet its intended specificat

48、ions for quality and purity. All quality-related activities should be defined and documented. 质量管理体系应当包括组织机构、规程、工艺和资源，以与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。所有涉与质量管理的活动都应当明确规定，并使其文件化。 2.13 There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) a

49、nd quality control (QC) responsibilities. The quality unit can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization. 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。 The persons a

50、uthorized to release intermediates and APIs should be specified. 应当指定授权发放中间体和原料药的人员。 All quality-related activities should be recorded at the time they are performed. 所有有关质量的活动应当在其执行时就记录。 Any deviation from established procedures should be documented and explained. Critical deviations

51、 should be investigated, and the investigation and its conclusions should be documented. 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展调查，并记录调查经过与其结果。 No materials should be released or used before the satisfactory pletion of evaluation by the quality unit(s) unless there are appropriate systems in pl

52、ace to allow for such use (e.g., release under quarantine as described in Section 10 or the use of raw materials or intermediates pending pletion of evaluation). 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，QA签字 放行 除非有适宜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完毕时的使用〕。 Procedures should exist for notifying

53、 responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality-related plaints, recalls, and regulatory actions). 应当有规程能确保公司的责任管理部门能与时得到有关药政检查、严重的GMP缺陷、产品缺陷与其相关活动〔如质量投诉，召回，药政活动等〕的通知。 2.2 Responsibilities of th

54、e Quality Unit(s) The quality unit(s) should be involved in all quality-related matters. 质量部门应当参与所有与质量有关的事物。 The quality unit(s) should review and approve all appropriate quality-related documents. 所有与质量有关的文件应当由质量部门审核批准。 The main responsibilities of the independent quality unit(s

55、) should not be delegated. These responsibilities should be described in writing and should include, but not necessarily be limited to: 1. Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing pany 2. Establishing a system to release

56、 or reject raw materials, intermediates, packaging, and labeling materials 3. Reviewing pleted batch production and laboratory control records of critical process steps before release of the API for distribution 4. Making sure that critical deviations are investigated and resolved 5. Approving al

57、l specifications and master production instructions 6. Approving all procedures affecting the quality of intermediates or APIs 7. Making sure that internal audits (self-inspections) are performed 8. Approving intermediate and API contract manufacturers 9. Approving changes that potentially affec

58、t intermediate or API quality 10. Reviewing and approving validation protocols and reports 11. Making sure that quality-related plaints are investigated and resolved 12. Making sure that effective systems are used for maintaining and calibrating critical equipment 13. Making sure that materials

59、are appropriately tested and the results are reported 14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates, where appropriate 15. Performing product quality reviews (as defined in Section ) 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

60、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X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展了调查并已解决； 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. 确保进展内部审计〔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

61、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〔详见节〕。 2.3 Responsibility for Production Activities The responsibility for production activities should be described in writing and should include, but not

62、necessarily be limited to: 1. Preparing, reviewing, approving, and distributing the instructions for the production of intermediates or APIs according to written procedures 2. Producing APIs and, when appropriate, intermediates according to pre-approved instructions 3. Reviewing all production ba

63、tch records and ensuring that these are pleted and signed 4. Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded 5. Making sure that production facilities are clean and, when appropriate, disinfected

64、6. Making sure that the necessary calibrations are performed and records kept 7. Making sure that the premises and equipment are maintained and records kept 8. Making sure that validation protocols and reports are reviewed and approved 9. Evaluating proposed changes in product, process or equipme

65、nt 10. Making sure that new and, when appropriate, modified facilities and equipment are qualified 生产作业的职责应当以文字形式加以说明，并应当包括，但不限于以下内容： 1. 按书面程序起草、审核、批准和分发中间体或原料药的生产指令； 2. 按照已批准的指令生产原料药或者中间体； 3. 审核所有的批生产记录确保其完整并有签名； 4. 确保所有的生产偏差都已报告、评价，对关键的偏差已做了调查，并记录结论； 5. 确保生产设施的清洁，必要时要消毒； 6.

66、 确保进展必要的校验，并有记录； 7. 确保对厂房和设备进展保养，并有记录； 8. 确保验证方案和报告的审核与批准； 9. 对产品、工艺或设备拟作的变更进展评估； 10. 确保新的或已改良的生产设施和设备经过了确认。 2.4 Internal Audits (Self Inspection) 2.4内部审计〔自检〕 To verify pliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule. 为确实符合原料药GMP原如此，应当按照批准的计划进展定期的内部审计。 Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed correc