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(s) 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 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 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

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5.4 Computerized Systems 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 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 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 Sampling 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 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 DISTRIBUTION 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

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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.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 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 14.2 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 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

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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 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. 术语

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Q7a GMP Guidance for APIs

Q7a 原料药的GMP 指南

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.

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 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 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 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 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。

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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 chemicalsynthesis, 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.

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

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

化学特性和结构。

The company should designate and document the rationale for the 生产厂商要指定并用书面文件说明原料

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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.

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 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 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 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: Application of this Guidance to API Manufacturing

表 1: 本指南在原料药生产中的应用

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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 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(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.

2.14 应当指定授权发放中间体和原料药的人员。

2.15 All quality-related activities 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 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的评价之前，任何物料都不应当发放或使用，除非有合适的系统允许此类使用（如10.20 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结束时的使用）。

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 应当有规程能确保公司的责任管理部门能及时得到有关药政检查、严重的GMP缺陷、产品缺陷及其相关活动（如质量投诉，召回，药政活动等）的通知。

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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.

2.20 质量部门应当参与所有与质量有关的事物。

2.21 The quality unit(s) should review and approve all appropriatequality-related documents.

2.21 所有与质量有关的文件应当由质量部门审核批准。

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 t

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)

2.22 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。用于生产商控制范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行了调查并已解决；

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. 确保进行内部审计（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 2.5 节）。

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 t

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：

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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

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. 确保进行必要的校验，并有记录；

7. 确保对厂房和设备进行保养，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行评估；

10. 确保新的或已改进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）

2.40 To verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.

2.40 为确实符合原料药GMP 原则，应当按照批准的计划进行定期的内部审计。

2.41 Audit findings and corrective actions should be documentedand brought to the attention of responsible management of the firm.Agreed corrective actions should be completed in a timely and effective manner.

2.41 审计结果及整改措施应当形成文件，并引起公司责任管理人员的重视。获准的整改措施应当及时、有效地完成。

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

2.50 原料药的定期质量审核应当以证实工艺的一致性为目的来进行。此种审核通常应当每年进行一次，并记录，内容至少应当包括：

● 关键工艺控制以及原料药关键测试结果的审核；

● 所有不符合既定质量标准的产品批号的审核；

● 所有关键的偏差或违规行为及有关调查的审核；

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● A review of any changes carried out to the processes oranalytical methods

● A review of results of the stability monitoring program

● A review of all quality-related returns, complaints andrecalls

● A review of adequacy of corrective actions

● 任何工艺或分析方法变动的审核；

● 稳定性监测的审核；

● 所有与质量有关的退货、投诉和召回的

审核；

● 整改措施的适当性的审核。

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.

2.51 应当对质量审核结果进行评估，并做出是否需要整改或做任何再验证的评价。此类整改措施的理由应当文件化。获准的整改措施应当及时、有效地完成。

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.

3.10 应当有足够数量的员工具备从事和监管原料药和中间体生产的教育、培训和/或经历等资格。

3.11 The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing.

3.11 参与原料药和中间体生产的所有人员的职责应当书面规定。

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.

3.12 应当由有资格的人员定期进行培训，内容至少应当包括员工所从事的特定操作和与其职能有关的GMP。培训记录应当保存，并应当定期对培训进行评估。

3.2 Personnel Hygiene 3.2 员工的卫生

3.20 Personnel should practice good sanitation and health habits. 3.20 员工应当养成良好的卫生和健康习惯。

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.

3.21 员工应当穿着适合其所从事生产操作的干净服装，必要时应当更换。其它保护性用品如头、脸、手和臂等遮护用品必要时也应当佩带，以免原料药和中间体受到污染。

3.22 Personnel should avoid direct contact with intermediates and

APIs.

3.22 员工应当避免与中间体或原料药的直

接接触。

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3.23 Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas separate from the manufacturing areas.

3.23 吸烟、吃、喝、咀嚼及存放食品仅限于与生产区隔开的指定区域。

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.

3.24 患传染性疾病或身体表面有开放性创伤的员工不应当从事危及原料药质量的生产活动。在任何时候（经医学检验或监控检查）任何患有危及到原料药质量的疾病或创伤的人员都不应当参与作业，直到健康状况已恢复，或者有资格的医学人员确认该员工不会危及到原料药的安全性和质量。

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.

3.30 中间体或原料药生产和控制的顾问应当有足够的学历，受训和经验，能胜任所承担的工作。

3.31 Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants.

3.31 顾问的姓名、地址、资格和提供服务的

类型都应当有文字记录。

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.

4.10 用于中间体和原料药生产的厂房和设施的选址、设计和建造应当便于清洁，维护和适应一定类型和阶段的生产操作。设施的设计应尽量减少潜在的污染。如果中间体或原料药的生产有微生物限度要求，那么设施设计应相应的限制有害微生物的污染。

4.11 Buildings and facilities should have adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination.

4.11 厂房和设施应有足够空间，以便有秩序

地放置设备和物料，防止混淆和污染。

4.12 Where the equipment itself (e.g., closed or contained system) provides adequate protection of the material, such equipment can be located outdoors.

4.12 自身能对物料提供足够保护的设备（如关闭的或封闭的系统），可以在户外放置。

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4.13 The flow of materials and personnel through the building or facilities should be designed to prevent mix-ups and contamination.

4.13 通过厂房和设施的物流和人流的设计应当能防止混杂和污染。

4.14 There should be defined areas or other control systems for the following activities:

● Receipt, identification, sampling, and quarantine of incoming

materials, pending release or rejection

● Quarantine before release or rejection of intermediates and

APIs

● Sampling of intermediates and APIs

● Holding rejected materials before further disposition (e.g.,

return, reprocessing or destruction)

● Storage of released materials

● Production operations

● Packaging and labeling operations

● Laboratory operations

4.14 以下活动应当有指定区域或其它控制

系统：

● 来料的接收、鉴别、取样和待验，等待放

行或拒收；

● 中间体和原料药放行或拒收前的待验；

● 中间体和原料药的取样

● 不合格物料处理（如退货、返工或销毁）

前的贮存；

● 已放行物料的贮存；

● 生产操作；

● 包装及贴标签操作；

● 实验室操作。

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.

4.15 应当为员工提供足够和清洁的盥洗设施。这些盥洗设施应当装有冷热水（视情况而定）、肥皂或洗涤剂，干手机和一次性毛巾。盥洗室应当与生产区隔离，但要便于达到。应当根据情况提供足够的淋浴和/或更衣设施。

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.

4.16 实验室区域/操作通常应当与生产区隔离。有些实验室区域，特别是用于中间控制的，可以位于生产区内，只要生产工艺操作对实验室测量的准确性没有负面影响，而且，实验室及其操作对生产过程，或中间体，或原料药也没有负面影响。

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

4.21 应当根据情况，提供足够的通风、空气过滤和排气系统。这些系统应当根据相应的生产阶段，设计和建造成将污染和交叉污染

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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.

降至最低限度，并包括控制气压、微生物（如果适用）、灰尘、湿度和温度的设备。特别值
得注意的是原料药暴露的区域。

4.22 If air is recirculated to production areas, appropriate measures should be taken to control risks of contamination and cross-contamination.

4.22 如果空气再循环到生产区域，应当采取适当的控制污染和交叉污染的风险。

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.

4.23 永久性安装的管道应当有适宜的标识。这可以通过标识每根管道、提供证明文件、计算机控制系统，或其它替代方法来达到。管道的安装处应当防止污染中间体或原料药。

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.

4.24 排水沟应当有足够的尺寸，而且应当根据情况装有空断器或适当的装置，防止倒虹吸。

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.

4.30 原料药生产中使用的水应当证明适合于其预定的用途。

4.31 Unless otherwise justified, process water should, at a minimum, meet World Health Organization (WHO) guidelines for drinking (portable) water quality.

4.31 除非有其它理由，工艺用水最低限度应当符合世界卫生组织（WHO）的饮用水质量指南。

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.

4.32 如果饮用水不足以确保原料的质量，并要求更为严格的化学和/或微生物水质规格标准，应当指定合适的物理/化学特性、微生物总数、控制菌和/或内毒素的规格标准。

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.

4.33 在工艺用水为达到规定质量由制造商进行处理时，处理工艺应当经过验证，并用合适的处置限度来监测。

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.

4.34 当非无菌原料药的制造商打算或者声称该原料药适用于进一步加工生产无菌药品（医疗用品）时，最终分离和精制阶段的用水应当进行微生物总数、致病菌和内毒素方面的监测和控制。

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4.4 Containment 4.4 限制

4.40 Dedicated production areas, which can include facilities, air handling equipment and/or process equipment, should be employed in the production of highly sensitizing materials, such as penicillins or cephalosprins.

4.40 在高致敏性物质，如青霉素或头孢菌素类的生产中，应当使用专用的生产区，包括设施、空气处理设备和/或工艺设备。

4.41 The use of dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.

4.41 当涉及具有感染性、高药理活性或毒性的物料时（如，激素类或抗肿瘤类），也应当考虑专用的生产区，除非已建立并维持一套经验证的灭活和/或清洗程序。

4.42 Appropriate measures should be established and implemented to prevent cross-contamination from personnel and materials moving from one dedicated area to another.

4.42 应当建立并实施相应的措施，防止由于 在各专用区域间流动的人员和物料而造成的交叉污染。

4.43 Any production activities (including weighing, milling, or packaging) of highly toxic nonpharmaceutical materials, such as herbicides and pesticides, should not be conducted using the buildings and/or equipment being used for the production of APIs.Handling and storage of these highly toxic nonpharmaceutical materials should be separate from APIs.

4.43 剧毒的非药用物质，如除草剂、杀虫剂的任何生产活动（包括称重、研磨或包装）都不应当使用生产原料药所使用的厂房和/或设备。这类剧毒非药用物质的处理和储存都应当与原料药分开。

4.5 Lighting 4.5 照明

4.50 Adequate lighting should be provided in all areas to facilitate cleaning,maintenance, and proper operations.

4.50 所有区域都应当提供充足的照明，以便于清洗、保养或其它操作。

4.6 Sewage and Refuse 4.6 排污和垃圾

4.60 Sewage, refuse, and other waste (e.g., solids, liquids, orgaseous by-products from manufacturing) in and from buildings and the immediate surrounding area should be disposed of in a safe,timely, and sanitary manner. Containers and/or pipes for waste material should be clearly identified.

4.60 进入和流出厂房及邻近区域的污水、垃圾和其它废物（如生产中的固态、液态或气态的副产物），应当安全、及时、卫生的处理。废物的容器和/或管道应当显著地标明。

4.7 Sanitation and Maintenance 4.7 卫生和保养

4.70 Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition.

4.70 生产中间体和原料药的厂房应当适当地保养、维修并保持清洁。

4.71 Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules,methods, equipment, and materials to be used in cleaning buildingsand facilities.

4.71 应当制定书面程序来分配卫生工作的职责，并描述用于清洁厂房和设施的清洁的计划、方法、设备和材料。