日期：2018-02-11 / 人气： / 来源：http://www.rzfanyi.com/ 作者：译声翻译公司美国FDA原料药生产质量管理规范（上部分 中英文）
DIRECTION OF GMP (GOOD MANUFACTURING PRACTICE )OF RAW MATERIALS BY FDA
Table of Contents 目录
1.1 Objective 目的
1.2 Regulatory Applicability法规的适用性
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) 质量部门的责任
2.3 Responsibility for Production Activities 生产作业的职责
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 人员的资质
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 文件和记录
6.1 Documentation System and Specifications 文件系统和质量标准
6.2 Equipment cleaning and Use Record 设备的清洁和使用记录
6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials
6.4 Master Production Instructions (Master Production and Control Records)
6.5 Batch Production Records (Batch Production and Control Records)
6.6 Laboratory Control Records 实验室控制记录
6.7 Batch Production Record Review 批生产记录审核
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 进厂物料的取样与测试
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 中间体或原料药的混批
8.5 Contamination Control 污染控制
9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES
9.1 General 总则
9.2 Packaging Materials 包装材料
9.3 Label Issuance and Control 标签发放与控制
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 实验室控制
11.1 General Controls 控制通则
11.2 Testing of Intermediates and APIs 中间体和原料药的测试
11.3 Validation of Analytical Procedures 分析方法的验证
11.4 Certificates of Analysis分析报告单
11.5 Stability Monitoring of APIs 原料药的稳定性监测
11.6 Expiry and Retest Dating 有效期和复验期
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 确认
12.4 Approaches to Process Validation 工艺验证的方法
12.5 Process Validation Program 工艺验证的程序
12.6 Periodic Review of Validated Systems 验证系统的定期审核
12.7 Cleaning Validation 清洗验证
12.8 Validation of Analytical Methods 分析方法的验证
13. CHANGE CONTROL 变更的控制
14. REJECTION AND RE-USE OF MATERIALS.拒收和物料的再利用
14.1 Rejection 拒收
14.2 Reprocessing 返工
14.3 Reworking 重新加工
14.4 Recovery of Materials and Solvents 物料与溶剂的回收
14.5 Returns 退货
15. COMPLAINTS AND RECALLS 投诉与召回
16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)
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已分发的原料药和中间体的可追溯性
17.3 Quality Management 质量管理
17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates
17.5 Stability 稳定性
17.6 Transfer of Information 信息的传达
17.7 Handling of Complaints and Recalls 投诉和召回的处理
17.8 Handling of Returns 退货的处理
18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation
18.1 General 总则
18.2 Cell Bank Maintenance and Record Keeping 细胞库的维护和记录的保存
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 病毒的去除/灭活步骤
19. APIs for Use in Clinical Trials 用于临床研究的原料药
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 原料的控制
19.5 Production 生产
19.6 Validation 验证
19.7 Changes 变更
19.8 Laboratory Controls 实验室控制
19.9 Documentation 文件
20. Glossary 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 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.
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.
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.
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.
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 is manufactured or used in a drug product, it should be manufactured according to this guidance.
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.
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 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.
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).
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.
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.
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.
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.
This GMP guidance does not apply to steps prior to the introduction of the defined API starting material.
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.
2.11 Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.
2.12 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.
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.
2.15 All quality-related activities should be recorded at the time they are performed.
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.
2.17 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).
2.18 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).
2.2 Responsibilities of the Quality Unit(s) 2.2质量部门的责任
2.20 The quality unit(s) should be involved in all quality-related matters.
2.21 The quality unit(s) should review and approve all appropriate quality-related documents.
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 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 affect intermediate or API quality
10. Reviewing and approving validation protocols and reports
11. Making sure that quality-related complaints are investigated and resolved
12. Making sure that effective systems are used for maintaining and calibrating critical equipment
13. Making sure that materials 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 2.5)
2.3 Responsibility for Production Activities 2.3生产作业的职责
The responsibility for production activities should be described in writing and should include, but not 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 batch records and ensuring that these are completed 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
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 equipment
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：
2.4 Internal Audits (Self Inspection) 2.4内部审计(自检)
2.40 To verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.
2.41 Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner.
2.5 Product Quality Review 2.5产品质量审核
2.50 Regular quality-reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least:
A review of critical in-process control and critical API test results
A review of all batches that failed to meet established specification(s)
A review of all critical deviations or nonconformances and related investigations
A review of any changes carried out to the processes or analytical methods
A review of results of the stability monitoring program
A review of all quality-related returns, complaints and recalls
A review of adequacy of corrective actions
2.51 The results of this review should be evaluated and an assessment made of whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented. Agreed corrective actions should be completed in a timely and effective manner.
3. PERSONNEL 3. 人员
3.1 Personnel Qualifications 3.1员工的资质
3.10 There should be an adequate number of personnel qualified by appropriate education, training, and/or experience to perform and supervise the manufacture of intermediates and APIs.
3.11 The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing.
3.12 Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee’s functions. Records of training should be maintained. Training should be periodically assessed.
3.2 Personnel Hygiene 3.2 员工的卫生
3.20 Personnel should practice good sanitation and health habits.
3.21 Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be changed, when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn, when necessary, to protect intermediates and APIs from contamination.
3.22 Personnel should avoid direct contact with intermediates and APIs.
3.23 Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas separate from the manufacturing areas.
3.24 Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs. Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions should be excluded from activities where the condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the person’s inclusion would not jeopardize the safety or quality of the APIs.
3.3 Consultants 3.3 顾问
3.30 Consultants advising on the manufacture and control of intermediates or APIs should have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.
3.31 Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants.
4. BUILDINGS AND FACILITIES 4. 建筑和设施
4.1 Design and Construction 4.1 设计和结构
4.10 Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture. Facilities should also be designed to minimize potential contamination. Where microbiological specifications have been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable microbiological contaminants, as appropriate.
4.11 Buildings and facilities should have adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination.
4.12 Where the equipment itself (e.g., closed or contained system) provides adequate protection of the material, such equipment can be located outdoors.
4.13 The flow of materials and personnel through the building or facilities should be designed to prevent mix-ups and contamination.
4.14 There should be defined areas or other control systems for the following activities:
4.15 Adequate and clean washing and toilet facilities should be provided for personnel. These facilities should be equipped with hot and cold water, as appropriate, soap or detergent, air dryers, or single service towels. The washing and toilet facilities should be separate from, but easily accessible to, manufacturing areas. Adequate facilities for showering and/or changing clothes should be provided, when appropriate.
4.16 Laboratory areas/operations should normally be separated from production areas. Some laboratory areas, in particular those used for in-process controls, can be located in production areas, provided the operations of the production process do not adversely affect the accuracy of the laboratory measurements, and the laboratory and its operations do not adversely affect the production process, intermediate, or API.
4.2 Utilities 4.2 公用设施
4.20 All utilities that could affect product quality (e.g., steam, gas, compressed air, heating, ventilation, and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. Drawings for these utility systems should be available.4.20 对产品质量会有影响的所有公用设施(如蒸汽，气体，压缩空气和加热，通风及空调)都应当确认合格，并进行适当监控，在超出限度时应当采取相应措施。应当有这些公用设施的系统图。
4.21 Adequate ventilation, air filtration and exhaust systems should be provided, where appropriate. These systems should be designed and constructed to minimize risks of contamination and cross-contamination and should include equipment for control of air pressure, microorganisms (if appropriate), dust, humidity, and temperature, as appropriate to the stage of manufacture. Particular attention should be giving to areas where APIs are exposed to the environment.
4.22 If air is recirculated to production areas, appropriate measures should be taken to control risks of contamination and cross-contamination.
4.23 Permanently installed pipework should be appropriately identified. This can be accomplished by identifying individual lines, documentation, computer control system, or alternative means. Pipework should be located to avoid risks of contamination of the intermediate or ApI.
4.24 Drains should be of adequate size and should be provided with an air break or a suitable device to prevent back-siphonage, when appropriate.
4.3 Water 4.3 水
4.30 Water used in the manufacture of APIs should be demonstrated to be suitable for its intended use.
4.31 Unless otherwise justified, process water should, at a minimum, meet World Health Organization (WHO) guidelines for drinking (portable) water quality.
4.32 If drinking (portable) water is insufficient to ensure API quality and tighter chemical and/or microbiological water quality specifications are called for, appropriate specifications for physical/chemical attributes, total microbial counts, objectionable organisms, and/or endotoxins should be established.
4.33 Where water used in the process is treated by the manufacturer to achieve a defined quality, the treatment process should be validated and monitored with appropriate action limits.
4.34 Where the manufacturer of a nonsterile API either intends or claims that it is suitable for use in further processing to produce a sterile drug (medicinal) product, water used in the final isolation and purification steps should be monitored and controlled for total microbial counts, objectionable organisms, and endotoxins.
- 技术顾问协议（中英文翻译模板） 02-11