美国FDA原料药生产质量管理标准规范中英文.doc

DIRECTION OF GMP (GOOD MANUFACTURING PRACTICE )OF RAW MATERIALS BY FDA

美国FDA原料药生产质量管理规范（ 中英文）

Table of Contents   目录
1. INTRODUCTION    介绍
1.1 Objective  目标
1.2 Regulatory Applicability法规适用性
1.3 Scope       范围

2. QUALITY MANAGEMENT    .质量管理
2.1 Principles  总则
2.2 Responsibilities of the Quality Unit(s)    质量部门责任
2.3 Responsibility for Production Activities  生产作业职责
2.4 Internal Audits (Self Inspection)     内部审计（自检）
2.5 Product Quality Review   产品质量审核

3. PERSONNEL    人员
3.1 Personnel Qualifications  人员资质
3.2 Personnel Hygiene   人员卫生
3.3 Consultants      顾问

4. BUILDINGS AND FACILITIES      建筑和设施
4.1 Design and Construction  设计和结构
4.2 Utilities    公用设施
4.3 Water       水
4.4 Containment     限制
4.5 Lighting    照明
4.6 Sewage and Refuse  排污和垃圾
4.7 Sanitation and Maintenance     卫生和保养

5. PROCESS EQUIPMENT  工艺设备
5.1 Design and Construction  设计和结构
5.2 Equipment Maintenance and Cleaning    设备保养和清洁
5.3 Calibration. 校验
5.4 Computerized Systems    计算机控制系统

6. DOCUMENTATION AND RECORDS 文件和统计
6.1 Documentation System and Specifications     文件系统和质量标准
6.2 Equipment cleaning and Use Record      设备清洁和使用统计
6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials
 原料、中间体、原料药标签和包装材料统计
6.4 Master Production Instructions (Master Production and Control Records)   
生产工艺规程（主生产和控制统计）
6.5 Batch Production Records (Batch Production and Control Records)    
 批生产统计（批生产和控制统计）
6.6 Laboratory Control Records    试验室控制统计
6.7 Batch Production Record Review    批生产统计审核

7. MATERIALS MANAGEMENT       物料管理
7.1 General Controls      控制通则
7.2 Receipt and Quarantine    接收和待验
7.3 Sampling and Testing of Incoming Production Materials 进厂物料取样和测试
7.4 Storage     储存
7.5 Re-evaluation   复验

8. PRODUCTION AND IN-PROCESS CONTROLS   生产和过程控制
8.1 Production Operations     生产操作
8.2 Time Limits     时限
8.3 In-process Sampling and Controls   工序取样和控制
8.4 Blending Batches of Intermediates or APIs    中间体或原料药混批
8.5 Contamination Control    污染控制

9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES   
  原料药和中间体包装和贴签
9.1 General     总则
9.2 Packaging Materials 包装材料
9.3 Label Issuance and Control     标签发放和控制
9.4 Packaging and Labeling Operations 包装和贴签操作

10. STORAGE AND DISTRIBUTION.储存和分发
10.1 Warehousing Procedures 入库程序
10.2 Distribution Procedures 分发程序

11. LABORATORY CONTROLS   试验室控制
11.1 General Controls    控制通则
11.2 Testing of Intermediates and APIs 中间体和原料药测试
11.3 Validation of Analytical Procedures      分析方法验证
11.4 Certificates of Analysis分析汇报单
11.5 Stability Monitoring of APIs 原料药稳定性监测
11.6 Expiry and Retest Dating      使用期和复验期
11.7 Reserve/Retention Samples    留样

12. VALIDATION  .验证
12.1 Validation Policy    验证方针
12.2 Validation Documentation     验证文件
12.3 Qualification  确定
12.4 Approaches to Process Validation  工艺验证方法
12.5 Process Validation Program   工艺验证程序
12.6 Periodic Review of Validated Systems  验证系统定时审核
12.7 Cleaning Validation       清洗验证
12.8 Validation of Analytical Methods 分析方法验证

13. CHANGE CONTROL     变更控制

14. REJECTION AND RE-USE OF MATERIALS.拒收和物料再利用
14.1 Rejection 拒收
14.2 Reprocessing  返工
14.3 Reworking     重新加工
14.4 Recovery of Materials and Solvents      物料和溶剂回收
14.5 Returns   退货

15. COMPLAINTS AND RECALLS    投诉和召回

16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)
协议生产商（包含试验室）

17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS  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   适用性
17.2 Traceability of Distributed APIs and Intermediates已分发原料药和中间体可追溯性
17.3 Quality Management     质量管理
17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates
原料药和中间体重新包装、重新贴签和待检
17.5 Stability  稳定性
17.6 Transfer of Information 信息传达
17.7 Handling of Complaints and Recalls     投诉和召回处理
17.8 Handling of Returns      退货处理

18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation    
用细胞繁殖/发酵生产原料药特殊指南
18.1 General   总则
18.2 Cell Bank Maintenance and Record Keeping       细胞库维护和统计保留
18.3 Cell Culture/Fermentation     细胞繁殖/发酵
18.4 Harvesting, Isolation and Purification   收取、分离和精制
18.5 Viral Removal/Inactivation steps   病毒去除/灭活步骤

19. APIs for Use in Clinical Trials 用于临床研究原料药
19.1 General   总则
19.2 Quality   质量
19.3 Equipment and Facilities设备和设施
19.4 Control of Raw Materials 原料控制
19.5 Production     生产
19.6 Validation       验证
19.7 Changes  变更
19.8 Laboratory Controls      试验室控制
19.9 Documentation      文件
20. Glossary   术语

1. INTRODUCTION     1. 介绍
1.1 Objective  1.1目标
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 also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess.     
本文件意在为在适宜质量管理体系下制造活性药用成份（以下称原料药）提供相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意在达成或表明拥有质量和纯度要求。

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 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 equivalent.
本指南中所指“制造”包含物料接收、生产、包装、重新包装、贴签、重新贴签、质量控制、放行、原料药储存和分发及其相关控制全部操作。本指南中，“应该”一词表示期望采取提议，除非证实其不适用或可用一个已证实有相同或更高质量确保水平供选物来替换。本指南中“现行优良生产管理规范（cGMP）”和“优良生产管理规范（GMP）”是等同。

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 the manufacturer and are governed by national laws. 
本指南在总体上未包含生产人员安全问题，亦不包含环境保护方面内容。这方面管理是生产者固有责任，也是国家法律要求。

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 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 met.      
本指南未要求注册/归档要求、或修改药典要求。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/归档要求能力。注册/归档全部承诺必需做到。

1.2 Regulatory Applicability  1.2法规适用性
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 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法定定义是各不相同。当某种物料在其制造或用于药品地域或国家被称为原料药，就应该根据本指南进行生产。

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 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.      
本文件适适用于人用药品（医疗用具）所含原料药生产。它适适用于无菌原料药在灭菌前步骤。本指南不包含无菌原料药消毒和灭菌工艺，不过，应该符合地方当局所要求药品（医疗用具）生产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 APIs manufactured by cell culture/fermentation is described in Section 18.本文件适适用于经过化学合成、提取、细胞培养/发酵，经过从自然资源回收，或经过这些工艺结合而得到原料药。经过细胞培养/发酵生产原料药特殊指南则在第18章叙述。

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 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 guidance. 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.    
本指南不包含全部疫苗、完整细胞、全血和血浆、全血和血浆衍生物（血浆成份）和基因诊疗原料药。不过却包含以血或血浆为原材料生产原料药。值得注意是细胞培养基（哺乳动物、植物、昆虫或微生物细胞、组织或动物源包含转基因动物）和前期生产可能应遵照GMP规范，但不包含在本指南之内。另外，本指南不适适用于医用气体、散装制剂药（比如，散装片剂和胶囊）和放射性药品生产。

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章指南只适适用于用在药品（医疗用具）生产中原料药制造，尤其是临床试验用药（研究用医疗产品）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 from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials normally have defined chemical properties and structure.  
“原料药起始物料”是指一个原料、中间体或原料药，用来生产一个原料药，或以关键结构单元形式被结合进原料药结构中。原料药起始物料可能是在市场上有售、能够经过协议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。原料药起始物料通常来说有特定化学特征和结构。

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 rationale 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生产从何处开始理论依据。对于合成工艺而言，就是“原料药起始物料”进入工艺那一点。对其它工艺（如：发酵，提取，纯化等）可能需要具体问题具体对待。表1给出了原料药起始物料从哪一点引入工艺过程指导标准。

From this 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 validate a process step does not necessarily define that steps as critical.   
从这步开始，本指南中相关GMP规范应该应用在这些中间体和/或原料药制造中。这包含对原料药质量有影响关键工艺步骤验证。不过，值得注意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 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) should be conducted according to this guidance.     
本文件指南通常适适用于表1中灰色步骤。但在表中表现全部步骤并不是将应用GMP管理全部步骤全部表现出来了。原料药生产中GMP要求应该伴随工艺进行，从原料药前几步到最终几步，精制和包装，越来越严格。原料药物理加工，如制粒、包衣或颗粒度物理处理（比如制粉、微粉化）应该按本指南标准进行。

This GMP guidance does not apply to steps prior to the introduction of the defined API starting material.
本GMP指南不适适用于引入定义了“原料药起始物料”以前步骤。

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.      
 参与原料药生产每一个人全部应该对质量负责。

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.    
 每一个生产商全部应该建立并实施一套有管理人员和相关职员主动参与有效质量管理体系，并使其文件化。

2.12 The system for managing 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.     
质量管理体系应该包含组织机构、规程、工艺和资源，和确保原料药会符合其预期质量和纯度要求所必需活动。全部包含质量管理活动全部应该明确要求，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) and 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.    
2.13 应该设置一个独立于生产部门质量部门，同时推行质量确保(QA)和质量控制 (QC)职责。依据组织机构大小，能够是分开QA和QC部门，或只是一个人或小组。

2.14 The persons authorized to release intermediates and APIs should be specified.  
2.14 应该指定授权发放中间体和原料药人员。

2.15 All quality-related activities should be recorded at the time they are performed.      
2.15 全部相关质量活动应该在其实施时就统计。

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 任何偏离既定规程情况全部应该有文字统计并加以解释。对于关键性偏差应该进行调查，并统计调查经过及其结果。

2.17 No materials should be released or used before the satisfactory completion of evaluation 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 10 or the use of raw materials or intermediates pending completion of evaluation).   
2.17 在质量部门对物料完成满意评价之前，任何物料全部不应该发放或使用，除非有适宜系统许可这类使用（如10.20条款所述待检情况下使用，或是原料或中间体在等候评价结束时使用）。

2.18 Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality-related complaints, recalls, and regulatory actions).
2.18 应该有规程能确保企业责任管理部门能立即得到相关药政检验、严重GMP缺点、产品缺点及其相关活动（如质量投诉，召回，药政活动等）通知。

2.2 Responsibilities of the Quality Unit(s)    2.2质量部门责任
2.20 The quality unit(s) should be involved in all quality-related matters. 
2.20 质量部门应该参与全部和质量相关事物。

2.21 The quality unit(s) should review and approve all appropriate quality-related documents.
2.21 全部和质量相关文件应该由质量部门审核同意。

2.22 The main responsibilities of the independent quality unit(s) 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 company
2.    Establishing a system to release or reject raw materials, intermediates, packaging, and labeling materials
3.    Reviewing completed 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 all specificatio