ICH中英文对照注释(Q7a-原料药部分)

cGMP文件,新版

Q7a（中英文对照）

FDA原料药GMP指南

Table of Contents

1. INTRODUCTION 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 Audits (Self Inspection) 2.5 Product Quality Review

3. PERSONNEL

3.1 Personnel Qualifications 3.2 Personnel Hygiene 3.3 Consultants

4. BUILDINGS AND FACILITIES 4.1 Design and Construction 4.2 Utilities 4.3 Water

4.4 Containment 4.5 Lighting

4.6 Sewage and Refuse

4.7 Sanitation and Maintenance

5. PROCESS EQUIPMENT 5.1 Design and Construction

5.2 Equipment Maintenance and Cleaning 5.3 Calibration

目录

1. 简介 1.1目的

1.2法规的适用性 1.3范围

2.质量管理 2.1总则

2.2质量部门的责任 2.3生产作业的职责 2.4内部审计（自检） 2.5产品质量审核

3. 人员

3.人员的资质 3.2 人员卫生 3.3 顾问

4. 建筑和设施 4.1 设计和结构 4.2 公用设施 4.3 水 4.4 限制 4.5 照明

4.6 排污和垃圾 4.7 卫生和保养

5. 工艺设备 5.1 设计和结构

5.2 设备保养和清洁 5.3 校验

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5.4 Computerized Systems

6. DOCUMENTATION AND RECORDS 6.1 Documentation System and Specifications

6.2 Equipment cleaning and Use Record 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 6.7 Batch Production Record Review

7. MATERIALS MANAGEMENT 7.1 General Controls

7.2 Receipt and Quarantine

7.3 Sampling and Testing of Incoming Production Materials 7.4 Storage

7.5 Re-evaluation

8. PRODUCTION AND IN-PROCESS CONTROLS

8.1 Production Operations 8.2 Time Limits

8.3 In-process Sampling and Controls

8.4 Blending Batches of Intermediates or APIs

8.5 Contamination Control

9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES 9.1 General

9.2 Packaging Materials

9.3 Label Issuance and Control

9.4 Packaging and Labeling Operations

10. STORAGE AND DISTRIBUTION 10.1 Warehousing Procedures 10.2 Distribution Procedures

5.4 计算机控制系统

6. 文件和记录

6.1 文件系统和质量标准

6.2 设备的清洁和使用记录

6.3 原料、中间体、原料药的标签和包装材料的记录

6.4 生产工艺规程（主生产和控制记录） 6.5 批生产记录（批生产和控制记录） 6.6 实验室控制记录 6.7批生产记录审核

7. 物料管理 7.1 控制通则 7.2接收和待验

7.3 进厂物料的取样与测试 7.4储存 7.5复验

8. 生产和过程控制 8.1 生产操作 8.2 时限

8.3 工序取样和控制

8.4 中间体或原料药的混批 8.5 污染控制

9. 原料药和中间体的包装和贴签

9.1 总则 9.2 包装材料

9.3 标签发放与控制 9.4 包装和贴签操作

10.储存和分发 10.1 入库程序 10.2 分发程序

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11. LABORATORY CONTROLS 11.1 General Controls

11.2 Testing of Intermediates and APIs 11.3 Validation of Analytical Procedures 11.4 Certificates of Analysis

11.5 Stability Monitoring of APIs 11.6 Expiry and Retest Dating 11.7 Reserve/Retention Samples

12. VALIDATION 12.1 Validation Policy

12.2 Validation Documentation 12.3 Qualification

12.4 Approaches to Process Validation 12.5 Process Validation Program

12.6 Periodic Review of Validated Systems 12.7 Cleaning Validation

12.8 Validation of Analytical Methods

13. CHANGE CONTROL

14. REJECTION AND RE-USE OF MATERIALS 14.1 Rejection 14.2 Reprocessing 14.3 Reworking

14.4 Recovery of Materials and Solvents 14.5 Returns

15. COMPLAINTS AND RECALLS

16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)

17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS 17.1 Applicability

17.2 Traceability of Distributed APIs and Intermediates

17.3 Quality Management

17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates

11.实验室控制 11.1 控制通则

11.2 中间体和原料药的测试 11.3 分析方法的验证 11.4 分析报告单

11.5 原料药的稳定性监测 11.6 有效期和复验期 11.7 留样

12.验证

12.1 验证方针 12.2 验证文件 12.3 确认

12.4 工艺验证的方法 12.5 工艺验证的程序 12.6验证系统的定期审核 12.7 清洗验证

12.8 分析方法的验证

13.变更的控制

14.拒收和物料的再利用 14.1 拒收 14.2 返工 14.3 重新加工

14.4 物料与溶剂的回收 14.5 退货

15.投诉与召回

16.协议生产商（包括实验室）

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适用性

17.2已分发的原料药和中间体的可追溯性 17.3质量管理

17.4原料药和中间体的重新包装、重新贴签和待检

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17.5 Stability

17.6 Transfer of Information

17.7 Handling of Complaints and Recalls 17.8 Handling of Returns 18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18.1 General

18.2 Cell Bank Maintenance and Record 17.5稳定性

17.6 信息的传达

17.7 投诉和召回的处理 17.8 退货的处理

18. 用细胞繁殖/发酵生产的原料药的特殊指南

18.1 总则

18.2细胞库的维护和记录的保存 Keeping

18.3 Cell Culture/Fermentation

18.4 Harvesting, Isolation and Purification 18.5 Viral Removal/Inactivation steps

19. APIs for Use in Clinical Trials 19.1 General 19.2 Quality

19.3 Equipment and Facilities 19.4 Control of Raw Materials 19.5 Production 19.6 Validation 19.7 Changes

19.8 Laboratory Controls 19.9 Documentation

20. Glossary

18.3细胞繁殖/发酵 18.4收取、分离和精制 18.5 病毒的去除/灭活步骤

19. 用于临床研究的原料药 19.1 总则 19.2 质量

19.3 设备和设施 19.4 原料的控制 19.5 生产 19.6 验证 19.7 变更

19.8 实验室控制 19.9 文件

20. 术语

cGMP文件,新版

Q7a GMP Guidance for APIs

Q7a原料药的GMP指南

1. INTRODUCTION 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 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.

1. 简介 1.1目的

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。

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。

cGMP文件,新版

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

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

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

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。

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法规的适用性

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范围

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。

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。

cGMP文件,新版

described in Section 18.

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

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。

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。

“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。

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。

cGMP文件,新版

process.

From this point on, appropriate GMP as defined 从这步开始，本指南中的有关GMP规范应当in this guidance should be applied to these 应用在这些中间体和/或原料药的制造中。这intermediate and/or API manufacturing steps. 包括对原料药质量有影响的关键工艺步骤的This would include the validation of critical 验证。但是，值得注意的是厂商选择某一步process steps determined to impact the quality 骤进行验证，并不一定将该步骤定为关键步of the API. However, it should be noted that the 骤。 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 本文件的指南通常适用于表1中的灰色步骤。be applied to the steps shown in gray in Table 但在表中体现的所有步骤并不是将应用1. However, all steps shown may not be GMP管理的所有步骤全部体现出来了。原料completed. The stringency of GMP in API 药生产中的GMP要求应当随着工艺的进行，manufacturing should increase as the process 从原料药的前几步到最后几步，精制和包装，proceeds from early API steps to final steps, 越来越严格。原料药的物理加工，如制粒、purification, and packaging. Physical 包衣或颗粒度的物理处理（例如制粉、微粉processing of APIs, such as granulation, coating 化）应当按本指南的标准进行。 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 本GMP指南不适用于引入定义了的“原料药prior to the introduction of the defined API 的起始物料”以前的步骤。 starting material.

cGMP文件,新版

表 1: 本指南在原料药生产中的应用

2. QUALITY MANAGEMENT 2．质量管理 2.1 Principles 2.1总则

2.10 Quality should be the responsibilities of all 2.10 参与原料药生产的每一个人都应当对质persons involved in manufacturing. 量负责。

2.11 Each manufacturer should establish, 2.11 每一个生产商都应当建立并执行一套有document, and implement an effective system 管理人员和有关员工积极参与的有效的质量for managing quality that involves the active 管理体系，并使其文件化。 participation of management and appropriate manufacturing personnel.

cGMP文件,新版

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.

2.14 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).

2.12 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 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 应当指定授权发放中间体和原料药的人员。

2.15 所有有关质量的活动应当在其执行时就记录。

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 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 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。

cGMP文件,新版

2.2 Responsibilities of the Quality Unit(s) 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

2.2质量部门的责任

2.20 质量部门应当参与所有与质量有关的事物。

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 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；

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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 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

2.4 Internal Audits (Self Inspection)

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

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生产作业的职责

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. 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内部审计（自检）

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。

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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

2.50 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

3.1 Personnel Qualifications

3.10 There should be an adequate number of personnel qualified by appropriate education, training, and/or experience to perform and

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产品质量审核

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；

● 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 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. 人员

3.1员工的资质

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。

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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

3.20 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

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 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 员工的卫生

3.20 员工应当养成良好的卫生和健康习惯。

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 员工应当避免与中间体或原料药的直接接触。

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 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。

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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

3.30 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 4.1 Design and Construction

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.

3.3 顾问

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 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. 建筑和设施 4.1 设计和结构

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 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 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.

4.14 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

4.15 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

4.13 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 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 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 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 公用设施

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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.

4.21 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

4.30 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

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 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 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 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 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 水

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 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

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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.

4.4 Containment

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.

4.41 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.

4.42 Appropriate measures should be established and implemented to prevent cross-contamination from personnel and

指南。

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 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 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。

4.4 限制

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 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 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。

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materials moving from one dedicated area to another.

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.

4.5 Lighting

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

4.6 Sewage and Refuse

4.60 Sewage, refuse, and other waste (e.g., solids, liquids, or gaseous 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.

4.7 Sanitation and Maintenance

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

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 buildings and facilities.

4.72 When necessary, written procedures should be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of

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 照明

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 排污和垃圾

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 卫生和保养

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 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。

4.72 必要时，还应当对合适的灭鼠药、杀虫剂、杀真菌剂、烟熏剂和清洁消毒剂的使用制定书面程序，以避免对设备、原料、包装/标签、中间体和原料药的污染。

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equipment, raw materials, packaging/labeling materials, intermediates, and APIs.

5. PROCESS EQUIPMENT 5.1 Design and Construction

5.10 Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size, and suitably located for its intended use, cleaning, sanitation (where appropriate), and maintenance.

5.11 Equipment should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or other established specifications.

5.12 Production equipment should only be used within its qualified operating range.

5.13 Major equipment (e.g., reactors, storage containers) and permanently installed processing lines used during the production of an intermediate or API should be appropriately identified.

5.14 Any substances associated with the operation of equipment, such as lubricants, heating fluids or coolants, should not contact intermediates or APIs so as to alter the quality of APIs or intermediates beyond the official or other established specifications. Any deviations from this practice should be evaluated to ensure that there are no detrimental effects on the material’s fitness for use. Wherever possible, food grade lubricants and oils should be used.

5.15 Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination.

5. 工艺设备 5.1 设计和结构

5.10 中间体和原料药生产中使用的设备应当有合理的设计和足够的尺寸，并且放置在适宜于其使用、清洁、消毒（根据情况而定）和保养的地方。

5.11 设备的构造中与原料、中间体或原料药接触的表面不会改变中间体和原料药的质量而使其不符合法定的或其他已规定的质量标准。

5.12 生产设备应该只在其确认的操作范围内运行。

5.13 中间体或原料药生产过程中使用的主要设备（如反应釜、贮存容器）和永久性安装的工艺管道，应当作适当的识别标志。

5.14 设备运转所需的任何物质，如润滑剂、加热液或冷却剂，不应当与中间体或原料药接触，以免影响其质量，导致无法达到法定的或其它已规定的质量标准。任何违背该规定的情况都应当进行评估，以确保对该物质效果的适用性没有有害的影响。可能的话，应当使用食用级的润滑剂和油类。

5.15 应当尽量使用关闭的或封闭的设备。若使用开放设备或设备被打开时，应当采取适当的预防措施，将污染的风险降至最小。

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5.16 A set of current drawings should be maintained for equipment and critical installations (e.g., instrumentation and utility systems).

5.2 Equipment Maintenance and Cleaning 5.20 Schedules and procedures (including assignment of responsibility) should be established for the preventative maintenance of equipment.

5.21 Written procedures should be established for cleaning equipment release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include: ● Assignment of responsibility for cleaning

of equipment ● Cleaning schedules, including, where

appropriate, sanitizing schedules ● A complete description of the methods and

materials, including dilution of cleaning agents used to clean equipment ● When appropriate, instructions for

disassembling and reassembling each article of equipment to ensure proper cleaning ● Instructions for the removal or obliteration

of previous batch identification ● Instructions for the protection of clean

equipment from contamination prior to use ● Inspection of equipment for cleanliness

immediately before use, if practical ● Establishing the maximum time that may

elapse between the completion of processing and equipment cleaning, when appropriate

5.22 Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent contamination or

5.16 应当保存一套现在的设备和关键装置的图纸（如测试设备和公用系统）。

5.2 设备保养和清洁

5.20 应当制订设备预防性保养的计划和程序（包括职责的分配）。

5.21 应当制订设备清洗及允许用于中间体和原料药生产的书面程序。清洁程序应当尽量详细，使操作者能对各类设备进行可重复的、有效 的清洗。这些程序应当包括：

● 设备清洗职责分配；

● 清洗计划，必要时包括消毒计划；

● 方法和材料的详尽描述，包括用于清洗设

备的清洗剂的稀释方法；

● 为确保正确的清洗，根据具体情况还应当

包括包装设备拆卸和安装的方法；

● 拿走或抹掉上一批的标识；

● 使用前防止已清洁的设备被污染；

● 如果可行，使用前对设备进行检查；

● 根据情况，规定生产结束和清洗之间允许

的最大时间间隔。

5.22 设备和用具应当清洁、存放，必要时还应进行消毒或灭菌，以防止污染或夹带物质影响中间体或原料药的质量导致其不符合法

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