1、FDA 原料药 GMP 指南Table of Contents 目录1. INTRODUCTION 1. 简介1.1 Objective 1.1 目的1.2 Regulatory Applicability 1.2 法规的适用性1.3 Scope 1.3 范围2. QUALITY MANAGEMENT 2.质量管理2.1 Principles 2.1 总则2.2 Responsibilities of the Quality Unit 2.2 质量部门的责任2.3 Responsibility for Production Activities 2.3 生产作业的职责2.4 Internal
2、Audits (Self Inspection) 2.4 内部审计（自检）2.5 Product Quality Review 2.5 产品质量审核3. PERSONNEL 3. 人员3.1 Personnel Qualifications 3.人员的资质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 4.3 水4.4 Contai
3、nment 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 Computerized Systems 5.4 计算机控制系统6. DOCUMENTATION AND RECO
4、RDS 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 Production Instructions (Master Production and Control Record
5、s) 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 6.7 批生产记录审核7. MATERIALS MANAGEMENT 7. 物料管理7.1 General Controls 7.1 控制通则7.2 Receipt and Quarantine 7.2 接收和待验7.3 Sa
6、mpling and Testing of Incoming Production Materials 7.3 进厂物料的取样与测试 7.4 Storage 7.4 储存7.5 Re-evaluation 7.5 复验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-process Sampling and Controls 8.3 工序取样和控制8.4 Blending Batches of Intermediates o
7、r 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 总则9.2 Packaging Materials 9.2 包装材料9.3 Label Issuance 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 DISTR
8、IBUTION 10.储存和分发10.1 Warehousing Procedures 10.1 入库程序10.2 Distribution Procedures 10.2 分发程序11. LABORATORY CONTROLS 11.实验室控制11.1 General Controls 11.1 控制通则11.2 Testing of Intermediates and APIs 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
9、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.验证12.1 Validation Policy 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
10、 Process Validation Program 12.5 工艺验证的程序12.6 Periodic Review of Validated Systems 12.6 验证系统的定期审核12.7 Cleaning Validation 12.7 清洗验证12.8 Validation of Analytical Methods 12.8 分析方法的验证13. CHANGE CONTROL 13.变更的控制14. REJECTION AND RE-USE OF MATERIALS 14.拒收和物料的再利用14.1 Rejection 14.1 拒收14.2 Reprocessing 14.
11、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. COMPLAINTS AND RECALLS 15.投诉与召回16. CONTRACT MANUFACTURERS (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
12、新贴签者17.1 Applicability 17.1 适用性17.2 Traceability of Distributed APIs and Intermediates 17.2 已分发的原料药和中间体的可追溯性17.3 Quality Management 17.3 质量管理17.4 Repackaging, Relabeling, 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 17.5 稳定性17.6 Transfer of Information 17.6 信息的传达17.7
13、 Handling of Complaints 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. 用细胞繁殖/发酵生产的原料药的特殊指南18.1 General 18.1 总则18.2 Cell Bank Maintenance and Record Keeping 18.2 细胞库的维护和记录的保存18.3 Cell Culture/Fermentation 18.3 细
14、胞繁殖/发酵18.4 Harvesting, Isolation and Purification 18.4 收取、分离和精制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19.1 General 19.1 总则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 Productio
15、n 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. 术语1. INTRODUCTION 1. 简介1.1 Objective 1.1 目的This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharm
16、aceutical ingredients (APIs) under an appropriate system for managing quality. It is 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
17、的质量与纯度要求。In this guidance, the term manufacturing is defined to include all operations 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
18、recommendations that, when followed, will ensure compliance with CGMPs. An alternative 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 eq
19、uivalent. 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。The guidance as a whole does not cover safety aspects for the personnel engaged in manufacturing, nor aspects related
20、 to protecting the environment. These controls are inherent responsibilities of the manufacturer and are governed by national laws. 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。This guidance is not intended to define registration and/or filing requirements or modify pharmacopoeial requi
21、rements. This guidance does not affect the ability of the responsible regulatory agency to establish specific registration/filing requirements regarding APIs within the context of marketing/manufacturing authorizations or drug applications. All commitments in registration/filing documents should be
22、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。注册/ 归档的所有承诺必须做到。1.2 Regulatory Applicability 1.2 法规的适用性Within the world community, 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
23、is manufactured or used in a drug product, it should be manufactured according to this guidance. 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。1.3 Scope 1.3 范围This guidance applies to the manufacture of APIs for use in human drug (medicinal) products. It applies to the manufacture of
24、 sterile APIs only up to the point immediately prior to the APIs being rendered 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.
25、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。This guidance covers APIs that are manufactured by chemical synthesis, extraction, cell culture/fermentation, recovery from natural sources, or any combination of these processes. Specific guidance for AP
26、Is manufactured by cell culture/fermentation is described in Section 18. 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。This guidance excludes all vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy
27、APIs. However, it does include APIs that are produced using blood or plasma 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 guida
28、nce. In addition, the guidance does not apply to medical gases, bulk-packaged 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
29、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。 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
30、用药（研究用医疗产品）的原料药制造。An API starting material is a raw material, 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 commerce, a material purchased
31、from one or more suppliers under contract or commercial agreement, 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
32、结构。The company should designate and document the rationale for 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 r
33、ationale should be established on a case-by-case basis. Table 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则。From thi
34、s point on, appropriate GMP as defined in this guidance 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 company chooses to
35、 validate a process step does not necessarily define that steps as critical. 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。The guidance in this document would normally be applied to the steps shown in gray in Table 1. However, all steps shown may
36、 not be completed. The stringency of GMP in API manufacturing 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) sho
37、uld be conducted according to this guidance. 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。This GMP guidance does not apply to steps prior to the introduction of the defined API starting mate
38、rial. 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: Application of this Guidance to API ManufacturingType of Manufacturing Application of this guidance to steps (shown in gray) used in this type of manufacturingChemical manufacturing Production of the API Starting material Introduction of the API start
39、ing material into process Production of Intermediate Isolation and purification Physical processing, and packagingAPI 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 puri
40、fication Physical processing, and packagingAPI extracted from plant sources Collection of plant Cutting and initial extraction Introduction of the API starting material into process Isolation and purification Physical processing, and packagingHerbal extracts used as API Collection of plants Cutting
41、and initial extraction Further extraction Physical processing, and packagingAPI consisting of comminuted or powdered herbs Collection of plants and/or cultivation and harvesting Cutting/comminuting Physical processing, and packagingBiotechnology: fermentation/cell culture Establishment of master cel
42、l bank 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 fermentation I
43、solation and purification Physical processing, and packaging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 分离和纯化 物理加工和包装从植物源提取的原料药 植物的收集 切割和初步提取 原料药起始物料引入工艺过程分离和纯化 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
44、 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 分离和纯化 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 分离和纯化 物理加工和包装2. QUALITY MANAGEMENT 2质量管理2.1 Principles 2.1 总则2.10 Quality should be the responsibilities of all persons involved in manufacturing. 2.10 参与
45、原料药生产的每一个人都应当对质量负责。2.11 Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and 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。2.12 The system for managing
46、 quality should encompass the organizational structure, procedures, process and resources, as well as activities to ensure confidence that the API will meet its intended specifications for quality and purity. All quality-related activities should be defined and documented. 2.12 质量管理体系应当包括组织机构、规程、工艺和
47、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。2.13 There should be a quality unit that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. The quality unit can be in the form of separate QA and QC units or a single individu
48、al or group, depending upon the size and structure of the organization. 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。2.14 The persons authorized to release intermediates and APIs should be specified. 2.14 应当指定授权发放中间体和原料药的人员。2.15 All quality-related activit
49、ies should be recorded at the time they are performed. 2.15 所有有关质量的活动应当在其执行时就记录。2.16 Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented. 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。2.17 No materials should be released or used before th
