ICH-Q7A

什么叫Q7a，它和我国GMP有何不同?

为了严格管理药品,必须对药品的研制、开发、生产、销售、进品等进行审批，形成了药品的注册制度，不同国家对药品注册要求各不相同，这不利于国际技术和贸易交流，造成人类社会资源浪费，不利于人类医药事业的发展，因此，客观上有必要就药品注册问题进行国际性的共同协商，在主要问题上取得一致，由美国、日本和欧盟三方的政府药品管理部门和制药行业在1990年发起的ICH（人用药物注册技术要求国际协调会议,International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use）就是这样应运而生的。ICH是由指导委员会、专家工作组和秘书处组成。 秘书处设在日内瓦。Q7A是ICH 制定的技术文件内容之一。ICH文件分为质量(quality)、安全性(safety)、有效性(efficacy)和综合学科(multidisciplinary)4类。其中，质量技术要求文件以Q开头，分别以1、2、3、4、5、6、7、8和9代表药品的1稳定性、2方法学、3杂质、4药典、5生物技术产品质量、6标准规格和7GMP、8制药研发、9质量风险管理，再以a,b,c,d代表小项，Q7a（原料药的优良制造规范指南）就代表GMP方面唯一的一项----药物活性成分（通常指原料药）的GMP. Q7a是由ICH的EWG(专家工作组)于2000年9月份最终完成。目前Q7a是欧美官方对原料药生产厂进行现场检查的依据。

ICH中以美国、日本和欧盟为首的17个国家的制药工业产值占了全世界的80%，研发费占了全世界的90%，并集中了国际上最先进的药品研发和审评技术和经验。

总的来说，Q7a和中国GMP 的精神、原则、主要内容和要求方面是一致的。但有许多方面确实有其特点性的不同：

一．Q7a把GMP 提高到了必须建立质量管理体系的高度，要求“每家制造商都应该建立、实施由管理人员和有关员工积极参加的、有效的质量管理体系，并形成文件。（”Q7a2.11），但中国GMP没提高到这个高度。Q7a的这个要求和国际上ISO9000的发展是相适应的。质量管理发展到本世纪，已经形成了以ISO9000为代表的一整套成熟的体系。ISO9000适合于各行各业，医药行业也不例外。GMP是制药行业的管理/技术规范，它本来应该早些和ISO9000同步进行，但是，历史还是安排了一段进程距离。目前在ICH 中GMP和ISO9000已经同步了，但在国内制药界二者还有距离。

二．虽然Q7a没有像中国GMP那样规定质量管理部门直属企业负责人领导，但Q7a对质量管理部门所赋予的权力更权威更具体，明确规定企业所有的与质量有关的文件都要由质量管理部门审核和批准（Q7a-2.12），其中包括生产中所有的规格标准和主要的生产指导文件的批准、供应厂商的批准、生产中所有验证方案和报告的批准、与GMP有关的任何变更方案和报告的批准、与GMP 有关的任何变更方案的批准（Q7a-13.12）等等。

三．中国GMP虽然涉及原料药的一些内容，但对于原料药的专门规范还未出台。因此，一些基本概念未作规定。而Q7a首先对原料药作了定义和分类。

1．“在世界范围内对原料药的法定定义是各不相同的。但是，只要某种原料在某一国家或地区中被分类为原料药，并被用于医药品或医药品的制造中，则这种原料的制造过程应该符合本掼的规定。”（Q7a-1.2）

2．Q7a把原料药按“生产类型”分为：（1）化学品（合成品）；（2）从动物源得到的原料药；（3）从植物源得到的原料药；（4）从草药提取的原料药；（5）从粉碎或粉末状草药得到的原料药；（6）从生物技术发酵/细胞培养得到的原料药（Q7a-1。3）

四．Q7a要求产品质量评审。中国GMP只在第83条提出自检要求（“药品生产企业应组织自检，自检应按预定的程序对人员、厂房、设备、文件、生产、质量控制、药品销售、用户投诉和产品的收回的处理等项定期进行检查，以证实与本规范的一致性”），尚未出现产品质量评审的概念和规定。Q7a除了有“同部审查（自检）”（Q7a-2.4）外，还提出了“产品

Q7a

质量评审”（Q7a-2.5）。在中国GMP对质量管理部门的主要职责要求中，也没有规定进行质量评审的工作，而Q7a在“质量部门的职责”中明确规定“开展质量评审活动”（Q7a-2.22）。

自检的目的是检查实操与规范的一致性，而评审的目的是探讨规范与客观的适合性；自检是评审的基础之一，评审是自检基础上的更高级活动。

五．Q7a增加了“计算机控制系统”（Q7a-5.4）的10点要求，这是中国GMP没有要求的内容，因为这一要求对我国许多药厂尚不现实。

六．Q7a对文件化的要求更普遍、更严格，贯穿在整个规定中。

例如：1。连原料药的生产从何阶段开始也要求定义和文件化说明（Q7a-1.3）；2。“应该指定授权发放中间体和原料药的人员。”（Q7a-2.14）；3，“所有有关质量的活动都应该在执行时加以记录。”（Q7a-2.15）；4。“任何偏离确定程序的情况都应该有文字记录并加以解释。对于关键性偏差应该进行调查，并记录调查经过及其结果。”（Q7a-2.16）。5。“对于顾问的姓名、地址、资格和提供服务的类型都应该保留文字记录。“（Q7a-3.31）等等。

七．Q7a非常强调以数据说话，一切都要有充分理由，十分强调验证和审评。

除了在各大项中有这种要求外（甚至连培训效果也要求评估，这在中国GMP中不作要求），还有专门章节（Q7a-12）对验证加以详细规定：12。1难规定（3项）；12。2验证文件（4项）；12。3确认（1项）；12。4工艺验证文件文件（6项）；12。5工艺验证程序（3项）；12。6已验证系统的定期审核（1项）；12。7清洗验证（7项）；12。8分析方法验证（3项）。

有关验证工作一共有28项。而中国GMP“验证”一章只有4项。

八．Q7a具有一定灵活性，目的是使质量管理更切合实际，有利于/方便于生产。

例如：1。中国GMP规定“生产工艺规程、岗位操作法和标准操作堆积不得任意更改，如需更改，应按制定时的程序办理修订、审批手续”（第66条）。完全没有余地，无论大小更改都必须如此执行。但Q7a则认为“工序控制可以由有资格的生产部门的人员来实施。对于工艺的调节可以事先不经质量管理部门批准，只要相关调节在由质量管理部门批准的限度内。所有测试及结果都应该作为批记录的一部分加以记录。”（Q7a-8。33）；2。中国GMP规定只有质量管理部门才有权决定物料和中间产品的使用（第75条）。但Q7a认为“质量部门可将发放中间体的职责和权力委派给生产部门，但不包括运往制造商控制范围以外区域的中间体。”（Q7a-6。73）

九．其他不同之处：1。Q7a对顾问人员作为单独一项提出，表示对其影响十分重视“（Q7a-3。3）；2。提醒在公用设施生产能力”在超出限度时应该采取相应措施。“（Q7a-4。20）；3。照明条件不但要在生产工位上得以保证，”应该向所有区域提供充足的照明，便于清洗、维护及其他操作。“（Q7a-4。50）；4。”在保存期限内，记录的原件或副本都应保留在记录所描述的活动发生的场所。“（Q7a-6。15）；5。。”为确保各批产品的一致性，对于每一种中间体和原料的主要生产工艺应该由同一人来制定，标注时间及签名，并由质量部门的另一个人独立进行检查、标注日期及签名。“（Q7a-6。40）；6。”在一批原较药放行或分发之前，关键工序的批生产记录和实验室控制记录应该由质量部门进行审核和批准。非关键工序的生产和实验室记录可按照经质量部门批准的程序，由有资格的生产人员或其它部门进行审核。“（Q7a-6。71）等等。

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Q7a

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

5.4 Computerized Systems

6. DOCUMENTATION AND RECORDS 6.1 Documentation System and

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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

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

Q7a

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

11. LABORATORY CONTROLS 11.1 General Controls

11.2 Testing of Intermediates and APIs

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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

11.实验室控制 11.1 控制通则

11.2 中间体和原料药的测试

Q7a

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 17.5 Stability

17.6 Transfer of Information

17.7 Handling of Complaints and Recalls 17.8 Handling of Returns

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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

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

Q7a

18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18.1 General

18.2 Cell Bank Maintenance and Record Keeping

18.3 Cell Culture/Fermentation

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

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 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. 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

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

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Q7a

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.

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

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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。

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。

Q7a

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 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

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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。

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。

Q7a

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.

9

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。

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。

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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.

Table 1: Application of this Guidance to API Manufacturing Type of Manufacturing Chemical manufacturing Production of the API Starting material Introduction of the API starting material into process API derived from animal sources Collection of organ, fluid, or tissue Cutting, mixing, and/or initial processing Introduction of the API starting material into process API extracted from plant sources Collection of plant Cutting and initial extraction(s) Introduction of the API starting material into process Herbal extracts used as API API consisting of comminuted or powdered herbs Biotechnology: fermentation/cell culture “Classical” fermentation to produce an API Collection of plants and/or cultivation and harvesting Establishment of master cell bank and working cell bank Establishment of cell bank Maintenance of the cell bank Introduction of the cells into fermentation Isolation and purification Physical processing, and packaging Maintenance of working cell bank Cell culture and/or fermentation Isolation and purification Physical processing, and packaging Collection of plants Cutting and initial extraction Cutting/comminuting Further extraction Physical processing, and packaging Physical processing, and packaging Isolation and purification Physical processing, and packaging Isolation and purification Physical processing, and packaging Production of Intermediate(s) Isolation and purification Physical processing, and packaging Application of this guidance to steps (shown in gray) used in this type of manufacturing

Increasing GMP requirements 10

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表 1: 本指南在原料药生产中的应用

生产类型 化学品的生产 本指南在用于各类生产的工艺步骤（灰色背景）中的应用 原料药起始物料的生产 动物源原料药 器官、分泌物或组织的收集 从植物源提取的原料药 草药提取物用作原料药 由粉碎的或粉末状草药组成的原料药 生物技术：发酵/细胞培养 “经典” 发酵生产原料药 植物的收集和/或培养和收获 主细胞库和工作细胞库的建立 细胞库的建立 细胞库的维护 细胞引入发酵 分离和纯化 物理加工和包装 工作细胞库的维护 细胞培养和/或发酵 分离和纯化 物理加工和包装 切割/粉碎 物理加工和包装 植物的收集 切割和初步提取 植物的收集 原料药起始物料引入工艺过程 切割、混合和/或初步加工 切割和初步提取 原料药起始物料引入工艺过程 原料药起始物料引入工艺过程 进一步提取 物理加工和包装 分离和纯化 物理加工和包装 分离和纯化 物理加工和包装 中间体的生产 分离和纯化 物理加工和包装

GMP的要求增加

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.

2.12 The system for managing quality should 2.12 质量管理体系应当包括组织机构、规程、encompass the organizational structure, 工艺和资源，以及确保原料药会符合其预期procedures, process and resources, as well as 的质量与纯度要求所必需的活动。所有涉及activities to ensure confidence that the API will 质量管理的活动都应当明确规定，并使其文meet its intended specifications for quality and 件化。 purity. All quality-related activities should be defined and documented.

2.13 There should be a quality unit(s) that is 2.13 应当设立一个独立于生产部门的质量部independent of production and that fulfills both 门，同时履行质量保证(QA)和质量控制 (QC)quality assurance (QA) and quality control 的职责。依照组织机构的大小，可以是分开(QC) responsibilities. The quality unit can be in 的QA和QC部门，或者只是一个人或小组。

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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).

2.2 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

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。

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：

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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 The responsibility for production activities should be described in writing and should include, but not necessarily be limited to:

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：

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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

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 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

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。

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：

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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 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

● 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。

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。

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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 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

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。

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。

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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.

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:

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。

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：

● Receipt, identification, sampling, and ● 来料的接收、鉴别、取样和待验，等待放

quarantine of incoming materials, pending 行或拒收； release or rejection ● 中间体和原料药放行或拒收前的待验； ● Quarantine before release or rejection of ● 中间体和原料药的取样

intermediates and APIs ● 不合格物料处理（如退货、返工或销毁）

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前的贮存； ● Sampling of intermediates and APIs

● Holding rejected materials before further ● 已放行物料的贮存；

disposition (e.g., return, reprocessing or ● 生产操作； destruction) ● 包装及贴标签操作；

● 实验室操作。 ● Storage of released materials

● Production operations

● Packaging and labeling operations ● Laboratory operations

4.15 Adequate and clean washing and toilet 4.15 应当为员工提供足够和清洁的盥洗设facilities should be provided for personnel. 施。这些盥洗设施应当装有冷热水（视情况These facilities should be equipped with hot 而定）、肥皂或洗涤剂，干手机和一次性毛巾。and cold water, as appropriate, soap or 盥洗室应当与生产区隔离，但要便于达到。detergent, air dryers, or single service towels. 应当根据情况提供足够的淋浴和/或更衣设The washing and toilet facilities should be 施。 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 4.16 实验室区域/操作通常应当与生产区隔normally be separated from production areas. 离。有些实验室区域，特别是用于中间控制Some laboratory areas, in particular those used 的，可以位于生产区内，只要生产工艺操作for in-process controls, can be located in 对实验室测量的准确性没有负面影响，而且，production areas, provided the operations of the 实验室及其操作对生产过程，或中间体，或production process do not adversely affect the 原料药也没有负面影响。 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 4.20 对产品质量会有影响的所有公用设施quality (e.g., steam, gas, compressed air, （如蒸汽，气体，压缩空气和加热，通风及heating, ventilation, and air conditioning) 空调）都应当确认合格，并进行适当监控，should be qualified and appropriately 在超出限度时应当采取相应措施。应当有这monitored and action should be taken when 些公用设施的系统图。 limits are exceeded. Drawings for these utility systems should be available.

4.21 Adequate ventilation, air filtration and 4.21 应当根据情况，提供足够的通风、空气exhaust systems should be provided, where 过滤和排气系统。这些系统应当根据相应的appropriate. These systems should be designed 生产阶段，设计和建造成将污染和交叉污染and constructed to minimize risks of 降至最低限度，并包括控制气压、微生物（如

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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 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

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

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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 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.

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。

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。

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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 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.

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。

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。

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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.

5.16 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.

5.11 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。

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）。

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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 carry-over of a material that would alter the quality of the intermediate or API beyond the official or other established specifications.

5.23 Where equipment is assigned to continuous production or campaign production of successive batches of the same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants (e.g., degradants or objectionable levels of microorganisms).

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定的或其它已规定的质量标准。

5.23 若设备指定用于同一中间体或原料药的连续生产，或连续批号的集中生产，应当在适宜是时间间隔对设备进行清洗，以防污染物（如降解物或达到有害程度的微生物）的累积和夹带。

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5.24 Nondedicated equipment should be cleaned between production of different materials to prevent cross-contamination.

5.25 Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified.

5.26 Equipment should be identified as to its contents and its cleanliness status by appropriate means.

5.3 Calibration

5.30 Control, weighing, measuring, monitoring, and testing equipment critical for ensuring the quality of intermediates or APIs should be calibrated according to written procedures and an established schedule.

5.31 Equipment calibrations should be performed using standards traceable to certified standards, if they exist.

5.32 Records of these calibrations should be maintained.

5.33 The current calibration status of critical equipment should be known and verifiable.

5.34 Instruments that do not meet calibration criteria should not be used.

5.35 Deviations from approved standards of calibration on critical instruments should be investigated to determine if these could have had an effect on the quality of the intermediates(s) or API(s) manufactured using this equipment since the last successful calibration.

5.4 Computerized Systems

5.40 GMP-related computerized systems should be validated. The depth and scope of validation depends on the diversity, complexity, and

5.24 非专用设备应当在生产不同物料之间作清洁，以防止交叉污染。

5.25 对残留物的可接受限量、清洗程序和清洁剂的选择应当规定并说明理由。

5.26 设备内容物及其清洁状况应当用合适的方法标明。

5.3 校验

5.30 用于保证中间体或原料药质量的控制、称量、测量、监测和测试设备应当按照书面程序和规定的计划周期进行校验。

5.31 如果有的话，应当用可追溯到已检定的标准的标准来进行设备校验。

5.32 校验记录应当加以保存。

5.33 应当知道并可证实关键设备的当前校验状态。

5.34 不应当使用不符合校验标准的仪器。

5.35 应当调查关键仪器相对于合格校验标准的偏差，以便确定这些偏差对自上次成功校验以来，用该设备生产的中间体或原料药的质量是否有影响。

5.4 计算机控制系统

5.40 与GMP相关的计算机化系统应当验证。验证的深度和广度取决于计算机应用的差异性、复杂性和关键性。

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criticality of the computerized application.

5.41 Appropriate installation and operational qualifications should demonstrate the suitability of computer hardware and software to perform assigned tasks.

5.42 Commercially available software that has been qualified does not require the same level of testing. If an existing system was not validated at time of installation, a retrospective validation could be conducted if appropriate documentation is available.

5.43 Computerized system should have sufficient controls to prevent unauthorized access or changes to data. There should be controls to prevent omissions in data (e.g., system turned off and data not captured). There should be a record of any data change made, the previous entry, who made the change, and when the change was made.

5.44 Written procedures should be available for the operation and maintenance of computerized system.

5.45 Where critical data are being entered manually, there should be an additional check on the accuracy of the entry. This can be done by a second operator or by the system itself.

5.46 Incidents related to computerized system that could affect the quality of intermediates or APIs or the reliability of records or test results should be recorded and investigated.

5.47 Changes to computerized system should be made according to a change procedure and should be formally authorized, documented, and tested. Records should be kept of all changes, including modifications and enhancements made to the hardware, software, and any other critical component of the system.

5.41 适当的安装确认和操作确认应当能证明计算机硬件和软件适合于执行指定的任务。

5.42 经证明合格的商用软件不需要进行系统水平的检验。如果现行系统在安装时没有进行验证，有合适的文件证明时可进行回顾性验证。

5.43 计算机化系统应当有足够的控制，以防止未经许可存取或改动数据。应当有防止数据丢失（如系统关闭而数据未捕获）的控制。任何数据的变更、上一次输入、谁作的变更和什么时候变更都应当有记录。

5.44 应当有计算机化系统操作和维护的书面程序。

5.45 手工输入关键性数据时，应当另外检查输入的准确性。这可由第二位操作人员或系统本身来进行。

5.46 应当加以记录可能影响中间体或原料药质量、或者记录或测试结果可靠性的与计算机化系统有关的偶发事件，并作调查。

5.47 对计算机化系统所作的变更应当按照变更程序进行，并应当经过正式批准、记录成文并作测试。所有变更记录都应当保存，包括对系统的硬件、软件和任何其它关键组件的修改和升级。这些记录应当证明该系统维持在验证过的状态。

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These records should demonstrate that the system is maintained in a validated state.

5.48 If system breakdowns or failures would result in the permanent loss of records, a back-up system should be provided. A means of ensuring data protection should be established for all computerized system.

5.49 Data can be recorded by a second means in addition to the computer system.

6. DOCUMENTATION AND RECORDS 6.1 Documentation System and Specifications

6.10 All documents related to the manufacture of intermediates or APIs should be prepared, reviewed, approved, and distributed according to written procedures. Such documents can be in paper or electronic form.

6.11 The issuance, revision, superseding, and withdrawal of all documents should be controlled by maintaining revision histories.

6.12 A procedure should be established for retaining all appropriate documents (e.g., development history reports, scale-up reports, technical transfer reports, process validation reports, training records, production records, control records, and distribution records). The retention periods for these documents should be specified.

6.13 All production, control, and distribution records should be retained for at least 1 year after the expiry date of the batch. For APIs with retest dates, records should be retained for at least 3 years after the batch is completely distributed.

6.14 When entries are made in records, these should be made indelibly in spaces provided for

5.48 如果计算机的故障或失效会导致记录的永久丢失，则应当提供备份系统。所有计算机化的系统都应当有数据保护措施。

5.49 除计算机系统之外，数据可以用第二种方式记录。

6. 文件和记录

6.1 文件系统和质量标准

6.10 与中间体或原料药生产有关的所有文件都应当按照书面程序进行拟定、审核、批准和分发。这些文件可以是纸张或电子形式。

6.11 所有文件的发放、修订、替换和收回应当通过保存修订历史来控制。

6.12 应当制订一个保存所有适用文件（如开发历程报告、扩产报告、技术转移报告、工艺验证报告、培训记录、生产记录、控制记录和分发记录）的程序。应当规定这些文件的保存期。

6.13 所有生产、控制、销售记录都应保留至该批的有效期后至少一年。对于有复验期的原料药，记录应当保留至该批全部发出后三年。

6.14 做记录时，应当在刚做操作活动后就在所提供的空白处以不易擦掉的方式填写，并

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such entries, directly after performing the activities, and should identify the person making the entry. Corrections to entries should be dated and signed and leave the original entry still legible.

6.15 During the retention period, originals or copies of records should be readily available at the establishment where the activities described in such records occurred. Records that can be promptly retrieved from another location by electronic or other means are acceptable.

6.16 Specifications, instructions, procedures, and records can be retained either as originals or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques such as microfilming or electronic records are used, suitable retrieval equipment and a means to produce a hard copy should be readily available.

6.17 Specifications should be established and documented for raw materials, intermediates where necessary, APIs, and labeling and packaging materials. In addition, specifications may be appropriate for certain other materials, such as process aids, gaskets, or other materials used during the production of intermediates or APIs that could critically affect quality. Acceptance criteria should be established and documented for in-process controls.

6.18 If electronic signatures are used on documents, they should be authenticated and secure.

6.2 Equipment cleaning and Use Record

6.20 Records of major equipment use, cleaning, sanitation, and/or sterilization and maintenance should show the date, time (if appropriate), product, and batch number of each batch processed in the equipment and the person who

标明填写者。修改记录时应当注明日期、签名并保持原来的记录仍可识读。

6.15 在保存期间，记录的原件或副本都应保留在记录中描述的活动发生的地方。能以电子或其它方式从另一地点即时恢复的记录也可以接受。

6.16 质量标准、指令、规程和记录保存方式可以是原件，或者真实的副本如影印本、缩微胶卷、缩微平片，或其它原始记录的准确复制件。在使用压缩技术如缩微胶卷或电子记录时，应当有适当的制备纸张副本的恢复设备和方法。

6.17 应当制订原料、中间体（必要时）、原料药和标签及包装材料的质量标准。此外，应当为工艺助剂、垫圈，或中间体或原料药生产中使用的能决定性地影响质量的物料制订质量标准。中间控制应当制定可接受的标准，并成文备查。

6.18 如果文件采用电子签名，它们应当经过证实，并且确保其安全可靠。

6.2 设备的清洁和使用记录

6.20 主要设备的使用、清洁、消毒和/或灭菌和保养记录应当记有日期、时间（如有必要的话）、产品、设备中加工的每批批号以及进行清洁和保养的人。

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performed the cleaning and maintenance.

6.21 If equipment is dedicated to manufacturing one intermediate or API, individual equipment records are not necessary if batches of intermediate or API follow in traceable sequence. In case where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately. 6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials

6.30 Records should be maintained including: ● The name of the manufacturer, identity, and

quantity of each shipment of each batch of raw materials, intermediates, or labeling and packaging materials for API’s; the name of the supplier; the supplier’s control number(s), if known, or other identification number; the number allocated on receipt; and the date of receipt ● The results of any test or examination

preformed and the conclusions derived from this ● Records tracing the use of materials

● Documentation of the examination and

review of API labeling and packaging materials for conformity with established specifications ● The final decision regarding rejected raw

materials, intermediates, or API labeling and packaging materials

6.31 Master (approved) labels should be maintained for comparison to issued labels.

6.4 Master Production Instructions (Master Production and Control Records)

6.40 To ensure uniformity from batch to batch, master production instructions for each intermediate and API should be prepared, dated, and signed by one person and independently checked, dated, and signed by a

6.21 如果设备专门用于一种中间体或原料药的生产，而且该中间体或原料药的批号有可追溯性的顺序，那就不需要有单独的设备记录。专门设备的清洁、保养及使用记录可以作为批记录的一部分或单独保存。

6.3 原料、中间体、原料药的标签和包装材料的记录

6.30 需保存的记录应当包括： ● 每次到货的每批原料、中间体、原料药标

签和包装材料的生产商的名称，标识和数量；供应商的名称、供应商的管理编号，或其它识别号码；物料接收编号和接收日期；

● 所进行的任何测试或检查结果，以及由此

得出的结论；

● 跟踪物料使用的记录；

● 检查和审核原料药的标签和包装材料与

规定标准符合度的证明文件；

● 拒收原料、中间体或原料药的标签和包装

材料的最终决定。 6.31 标准标签（已批准的）应当保留，用来与发放的标签作比较。

6.4 生产工艺规程（主生产和控制记录） 6.40 为确保批与批的一致性，每种中间体和原料药的生产工艺规程应当由一人拟定、注明日期并签名，并由质量部门的另一人独立进行检查、填写日期和签名。

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person in the quality unit(s).

6.41 Master production instructions should 6.41 生产工艺规程应当包括： include:

如有可● The name of the intermediate or API being ● 要生产的中间体或原料药的名称，

manufactured and an identifying document 能，写明文件编号； reference code, if applicable

● A complete list of raw materials and ● 完整地列出原料和中间体的足以区分任

intermediates designated by names or 何质量特性的名称或代码； codes sufficiently specific to identify any special quality characteristics

● An accurate statement of the quantity or ● 准确说明所用的每种原料或中间体的投

ratio of each raw material or intermediate 料量或投料比，包括计量单位。如果投料to be used, including the unit of measure. 量不是固定的，应当写明每批的批量或产Where the quantity is not fixed, the 率的计算方法。还应当包括经证明是合理calculation for each batch size or rate of 的量的偏差； production should be included. Variations to quantities should be included where they are justified

● The production location and major ● 生产地点及使用的主要设备；

production equipment to be used

● Detailed production instructions, including ● 详细的生产规程，包括：

the: - sequences to be followed - 操作顺序， - ranges of process parameters to be - 工艺参数的范围，

used - sampling instructions and in-process - 取样方法，过程控制及其认可标准，

controls with their acceptance criteria, where appropriate - time limits for completion of - 某些情况下，要说明完成某一工序和

individual processing steps and/or the /或整个工艺过程的时间， total process, where appropriate - expected yield ranges at appropriate - 在某一工艺阶段或时间的预期产率。

phases of processing or time

写明注意事项、要遵循的预防● Where appropriate, special notations and ● 根据情况，

precautions to be followed, or 措施，或它们的相互参照； cross-references to these

包括标● The instructions for storage of the ● 中间体或原料药的适宜贮存规定，

intermediate or API to ensure its suitability 签、包装材料，某些情况下写明特殊的贮for use, including the labeling and 存条件、时间限制，以确保其使用。 packaging materials and special storage conditions with time limits, where appropriate.

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6.5 Batch Production Records (Batch Production and Control Records)

6.50 Batch production records should be prepared for each intermediate and API and should include complete information relating to the production and control of each batch. The batch production record should be checked before issuance to ensure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction. If the batch production record is produced from a separate part of the master document, that document should include a reference to the current master production instruction being used.

6.51 These records should be numbered with a unique batch or identification number, dated and signed when issued. In continuous production, the production code together with the date and time can serve as the unique identifier until the final number is allocated.

6.52 Documentation of completion of each significant step in the batch production records (batch production and control records) should include:

● Dates, and when appropriate, times

● Identify of major equipment (e.g., reactors,

driers, mills, etc.) used ● Specific identification of each batch,

including weights, measures, and batch numbers of raw materials, intermediates, or any reprocessed materials used during manufacturing ● Actual results recorded for critical process

parameters ● Any sampling performed

● Signatures of the persons performing and

directly supervising or checking each critical step in the operation ● In-process and laboratory test results

● Actual yield at appropriate phases or times ● Description of packaging and label for

6.5 批生产记录（批生产和控制记录） 6.50 应当为每种中间体和原料药准备批生产记录，内容应当包括与各批生产和控制有关的完整资料。批记录发放之前，应当检查版本是否正确，是否是相应生产规程的准确明了的再现。如果批生产记录是按主文件的另一独立部分制定的，该文件应当包括对现行的生产工艺规程的参考。

6.51 批记录在发放时应当有一个唯一的批号或标识号，有日期和签名。连续生产时，在最终批号确定前，可以将产品代码、日期和时间结合起来作为唯一的识别符。

6.52 在批生产记录（批生产记录和控制记录）中提供每一重要步骤完成的证明，应当包括：

● 日期，某些情况下还有时间； ● 主要设备（如反应釜，干燥器，磨粉机等）

的标识；

● 每一批的识别特征，包括原料、中间体或

任何用于生产的返工物料的重量、计量单位、批号；

● 记录关键工艺参数的实际值；

● 取样；

● 每个关键步骤的操作者和直接指导者或

检查者的签名；

● 过程控制和实验室的测试结果； ● 适当阶段或时间的实际产率；

● 中间体或原料药的包装材料和标签的描

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intermediate or API

● Representative label of API or intermediate

if made commercially available ● Any deviation noted, its evaluation,

investigation conducted (if appropriate) or reference to that investigation if stored separately ● Results of release testing

6.53 Written procedures should be established and followed for investigating critical deviations or the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation.

6.6 Laboratory Control Records

6.60 Laboratory control records should include complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays, as follows:

● A description of samples received for

testing, including the material name or source, batch number or other distinctive code, date sample was taken, and, where appropriate, the quantity and date the sample was received for testing ● A statement of or reference to each test

method used ● A statement of the weight or measure of

sample used for each test as described by the method; data on or cross-reference to the preparation and testing of reference standards, reagents and standard solutions ● A complete record of all raw data generated

during each test, in addition to graphs, charts and spectra from laboratory instrumentation, properly identified to show the specific material and batch tested ● A record of all calculations performed in

connection with the test, including, for example, units of measure, conversion

述；

● 原料药或中间体的商业标签的样张；

● 发现的任何偏差，进行的评估、调查（视

情况而定），和索引到单独存放的调查报告；

● 放行测试的结果。

6.53 应当建立并执行一种书面程序，对在符合规格上有重大偏差或不合格的一批中间体或原料药进行调查。调查还应当延伸到与这批失误或偏差有关的其它批号。

6.6 实验室控制记录

6.60 实验室控制记录应当包括从为了确保符合规定的规格和标准所做的所有测试中得到的下列完整的数据，包括下列检验和测定：

● 所收到检测样品的描述，包括物料名称和

来源、批号或其它编号、取样日期，某些情况下记录收到样品的量和时间；

● 每个所用检测方法的陈述或参引；

● 按方法描述的所用样品重量或计量；标准

品、试剂和标准溶液的配制和测试的数据或相互参考；

● 除了正确地标明所测试的特定物料和批

号的实验室仪器的图谱、图表和光谱外，还有一套从每次测试得到的所有原始数据的完整记录；

● 与测试有关的所有计算记录，包括测量单

位、转换因子以及等量因子等；

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factors, and equivalency factors

● A statement of the test results and how they

compare with established acceptance criteria ● The signature of the person who performed

each test and the date(s) the tests were performed

● The date and signature of a second person

showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards

6.61 Complete records should also be 6.61 应当保存完整的下列记录： maintained for:

● Any modifications to an established ● 既定的分析方法的任何修改；

analytical method

设备、仪表和记录装置的定● Periodic calibration of laboratory ● 实验室仪器、

instruments, apparatus, gauges, and 期校验； recording devices

● 原料药的所有稳定性测试； ● All stability testing performed on APIs

● Out-of-specification (OOS) investigations ● 不合格的调查。 6.7 Batch Production Record Review 6.7批生产记录审核

6.70 Written procedures should be established 6.70 应当制定并执行审核和批准批生产记录and followed for the review and approval of 和实验室控制记录，包括包装和贴签的书面batch production and laboratory control 程序，以便放行或分发前确定中间体或原料records, including packaging and labeling, to 药是否符合规定标准。 determine compliance of the intermediate or API with established specifications before a batch is released or distributed.

6.71 Batch production and laboratory control 6.71 在一批原料药放行或分发之前，关键工records of critical process steps should be 序的批生产记录和实验室控制记录应当由质reviewed and approved by the quality unit(s) 量部门审核和批准。非关键性工序的生产和before an API batch is released or distributed. 实验室控制记录可按照经质量部门批准的程Production and laboratory control records of 序，由有资格的生产人员或其它部门审核。 noncritical process steps can be reviewed by qualified production personnel or other units following procedures approved by the quality unit(s).

6.72 All deviation, investigation, and OOS 6.72 在批放行前，所有偏差，调查和不合格reports should be reviewed as part of the batch 报告都应当作为批记录的一部分进行审核。 record review before the batch is released.

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● 检测结果的陈述以及与规定的认可标准

的比较；

● 每项测试的操作者的签名以及测试的日

期；

● 日期和第二个人的签名，表明对原记录的

准确性、完整性和规定的标准的符合性已复核过。

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6.73 The quality unit(s) can delegate to the production unit the responsibility and authority for release of intermediates, except for those shipped outside the control of the manufacturing company.

7. MATERIALS MANAGEMENT 7.1 General Controls

7.10 There should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of materials.

7.11 Manufacturers of intermediates and/or APIs should have a system for evaluating the suppliers of critical materials.

7.12 Materials should be purchased against an agreed specification, from a supplier, or suppliers, approved by the quality unit(s).

7.13 If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer.

7.14 Changing the source of supply of critical raw materials should be treated according to Section 13, Change Control.

7.2 Receipt and Quarantine

7.20 Upon receipt and before acceptance, each container or grouping of containers of materials should be examined visually for correct labeling (including correlation between the name used by the supplier and the in-house name, if these are different), container damage, broken seals and evidence of tampering or contamination. Materials should be held under quarantine until they have been sampled, examined, or tested, as appropriate, and released for use.

6.73 质量部门可将发放中间体的职责和权力委派给生产部门，运往生产商控制范围以外的中间体除外。

7. 物料管理 7.1 控制通则

7.10 应当有书面程序阐明物料的接收、鉴别、待验、贮存、搬运、取样、测试和批准或拒收。

7.11 原料药和/或中间体生产商应当有对关键原料供应商的评估系统。

7.12 应当根据已确定的规格从经过质量部门核准的一个或多个供应商处购买物料。

7.13 如果关键物料的供应商不是该物料的生产商，原料药或中间体的生产商应当获知该物料生产商的名称和地址。

7.14 关键原料的供应商的变更应当参照第13章“变更控制”进行。

7.2接收和待验

7.20 一旦收到物料而尚未验收，应当目测检查物料每个或每组包装容器的标签是否正确（包括如果供应商所用名称与内部使用的名称不一致，应当检查其相互关系）、容器是否损坏、密封处和开启证据有无破裂或污染。物料应当存放的待验区，直至它们被取样、检查或酌情测试，并放行使用。

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7.21 Before incoming materials are mixed with existing stocks (e.g., solvents or stocks in silos), they should be identified as correct, tested, if appropriate, and released. Procedures should be available to prevent discharging incoming materials wrongly into the existing stock.

7.22 If bulk deliveries are made in nondedicated tankers, there should be assurance of no cross-contamination from the tanker. Means of providing this assurance could include one or more of the following:

7.21 在进厂的物料与现有的库存（如储仓中的溶剂或货物）混合之前，应当确认货是否对、必要时进行测试并放行。应当有程序来防止把来料错放到现有的库存中。

7.22 对于非专用槽车运送的大宗物料，应当确保没有来自槽车的交叉污染。可用以下的一种或几种方法来提供这种保证：

● 清洁证书 ● certificate of cleaning

● 残留物的测试 ● testing for trace impurities

● 供应商审计 ● audit of the supplier

7.23 Large storage containers and their 7.23 大的储存容器及其随附的管路、填充和attendant manifolds, filling, and discharge lines 排放管都应当适当标明。 should be appropriately identified.

7.24 Each container or grouping of containers 7.24 每个或每组物料容器（几批）的物料都(batches) of materials should be assigned and 应当指定并标上编号、批号或接收号。此号identified with a distinctive code, batch, or 码应当用于记录每批的处置情况。应当有一receipt number. This number should be used in 个识别每批状态的系统。 recording the disposition of each batch. A system should be in place to identify the status of each batch.

7.3 Sampling and Testing of Incoming 7.3 进厂物料的取样与测试 Production Materials

7.30 At least one test to verify the identity of 7.30 除了7.32中指出的物料，对于每批物料each batch of material should be conducted, 至少要做一个鉴别试验。在生产商对供应商with the exception of the materials described 有一套审计体系的前提下，供应商的分析报below. A supplier’s certificate of analysis can 告可以用来替代其他项目的测试。 be used in place of performing other tests, provided that the manufacturer has a system in place to evaluate suppliers.

7.31 Supplier approval should include an 7.31 对供应商的核准应当包括一次评估，提evaluation that provides adequate evidence 供足够的证据（如过去的质量记录）证明该(e.g., past quality history) that the manufacturer 生产商始终都能提供符合质量标准的物料。can consistently provide material meeting 在减少内部测试之前至少应当对三批物料作specifications. Complete analyses should be 全检。然而，最低限度每隔一定时间应当进

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conducted on at least three batches before reducing in-house testing. However, as a minimum, a complete analysis should be performed at appropriate intervals and compared with the certificates of analysis. Reliability of certificates of analysis should be checked at regular intervals.

7.32 Processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit within the company’s control do not need to be tested if the manufacturer’s certificate of analysis is obtained, showing that these raw materials conform to established specifications. Visual examination of containers, labels, and recording of batch numbers should help in establishing the identity of these materials. The lack of on-site testing for these materials should be justified and documented.

7.33 Samples should be representative of the batch of material from which they are taken. Sampling methods should specify the number of containers to be sampled, which part of the container to sample, and the amount of material to be taken from each container. The number of containers to sample and the sample size should be based on a sampling plan that takes into consideration the criticality of the material, material variability, past quality history of the supplier, and the quality needed for analysis.

7.34 Sampling should be conducted at defined locations and by procedures designed to prevent contamination of the material sampled and contamination of other materials.

7.35 Containers from which samples are withdrawn should be opened carefully and subsequently reclosed. They should be marked to indicate that a sample has been taken.

7.4 Storage

行一次全检，并与分析报告进行比较。分析报告的可靠性应当定期进行检查。

7.32 工艺助剂、有害或剧毒的原料、其它特殊物料、或转移到公司控制范围内的另一个部门的物料不用测试，前提是能取得生产商的分析报告，证明这些原料符合规定的质量标准。对容器、标签和批号记录进行目测检查应当有助于鉴别这些原料。对这些物料不作现场测试应当说明理由，并用文件证明。

7.33 取样应当能代表被取的那批物料。取样方法应当规定：取样的容器数，取样部位，每个容器的取样量。取样容器数和取样量应当根据取样方案来决定。取样方案的制定要综合考虑物料的重要程度、变异性、供应商过去的质量情况，以及分析需用量。

7.34 应当在规定的地点，用规定的方法取样，以避免取样的物料被污染，或污染其它物料。

7.35 被取样的容器应当小心开启，随后重新密封。这些容器应当做标记表明样品已抽取。

7.4储存

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7.40 Materials should be handled and stored in a manner to prevent degradation, contamination, and cross-contamination.

7.41 Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning and inspection.

7.42 Materials should be stored under conditions and for a period that have no adverse effect on their quality, and should normally be controlled so that the oldest stock is used first.

7.43 Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and containers are appropriately cleaned before opening and use.

7.44 Rejected materials should be identified and controlled under a quarantine system designed to prevent their unauthorized use in manufacturing.

7.5 Re-evaluation

7.50 Materials should be re-evaluated, as appropriate, to determine their suitability for use (e.g., after prolonged storage or exposure to heat or humidity).

8. PRODUCTION AND IN-PROCESS CONTROLS

8.1 Production Operations

8.10 Raw materials for intermediate and API manufacturing should be weighed or measured under appropriate conditions that do not affect their suitability for use. Weighing and measuring devices should be of suitable accuracy for the intended use.

8.11 If a material is subdivided for later use in production operations, the container receiving the material should be suitable and should be so

7.40 物料的搬运和贮存应当防止降解、污染和交叉污染。

7.41 纤维板桶、袋子或盒装物料应当离地贮存，并根据情况留出适当空间便于清洁和检查。

7.42 物料应当在对其质量没有不良影响的条件下和时限内贮存，而且通常应当加以控制，做到先进先出。

7.43 某些装在适当容器中的物料可以存放在室外，只要识别标签保持清晰，而且容器在开启和使用前进行适当清洁。

7.44 不合格物料应当做标识，并用隔离系统控制，已防止未经许可而用于生产。

7.5重新评估

7.50 应当根据情况对物料进行重新评估以便确定其使用的适合性（例如长期存放或暴露于热或潮湿的环境中）。

8. 生产和过程控制

8.1 生产操作

8.10 用于生产中间体和原料药的原料应当在适宜的条件下称重或测量，以便不影响其使用的适合性。称重和测量装置应当有适合于其用途的精度。

8.11 如果某物料分出一部分留待以后的生产操作中使用，应当用适合的容器来盛装该物料，并应当标明下列信息：

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identified that the following information is available:

● 物料的名称和/或货号； ● Material name and/or item code

● 接收号或控制号； ● Receiving or control number

● Weight or measure of material in the new ● 新容器中物料的重量或计量；

container

● 如有必要，标明复验期。 ● Re-evaluation or retest date if appropriate

8.12 Critical weighing, measuring, or 8.12 关键的称重、测量或分装操作应当有人subdividing operations should be witnessed or 作证或接受相应的控制。使用前，生产人员subjected to an equivalent control. Prior to use, 应当确认该物料是要生产的中间体或原料药production personnel should verify that the 的批记录中指定的。 materials are those specified in the batch record for the intended intermediate or API.

8.13 Other critical activities should be 8.13 其它关键活动应当有人作证或接受相应witnessed or subjected to an equivalent control. 的控制。

8.14 Actual yields should be compared with 8.14 在生产过程中的指定步骤，实际收率应expected yields at designated steps in the 当与预计的收率作比较。具有合适范围的预production process. Expected yields with 计收率应当根据以前的实验室、中试规模或appropriate ranges should be established based 生产的数据来确定。应当调查与关键工艺步on previous laboratory, pilot scale, or 骤有关的收率偏差，以确定其对相关批号最manufacturing data. Deviations in yield 终质量的影响或潜在影响。 associated with critical process steps should be investigated to determine their impact or potential impact on the resulting quality of affected batches.

8.15 Any deviation should be documented and 8.15 任何偏差都应当记录，并作解释。任何explained. Any critical deviation should be 关键的偏差应当作调查。 investigated.

8.16 The processing status of major units of 8.16 应当标明主要设备的生产状态，可以标equipment should be indicated either on the 在每个设备上，或者用文件、计算机控制系individual units of equipment or by appropriate 统或其它替代的方法。 documentation, computer control systems, or alternative means.

8.17 Materials to be reprocessed or reworked 8.17 对需要进行返工或重新加工的物料应当should be appropriately controlled to prevent 适当地加以控制，防止未经许可就使用。 unauthorized use. 8.2 Time Limits 8.2 时限

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8.20 If time limits are specified in the master production instruction (see 6.40), these time limits should be met to ensure the quality of intermediates or APIs. Deviations should be documented and evaluated. Time limits may be inappropriate when processing to a target value (e.g., pH adjustment, hydrogenation, drying to predetermined specification) because completion of reactions or processing steps are determined by in-process sampling and testing.

8.21 Intermediates held for further processing should be stored under appropriate conditions to ensure their suitability for use.

8.3 In-process Sampling and Controls

8.30 Written procedures should be established to monitor the progress and control the performance of processing steps that cause variability in the quality characteristics of intermediates and APIs. In-process controls and their acceptance criteria should be defined based on the information gained during the developmental stage or from historical data.

8.31 The acceptance criteria and type and extent of testing can depend on the nature of the intermediate or API being manufactured, the reaction or process step being conducted, and the degree to which the process introduces variability in the product’s quality. Less stringent in-process controls may be appropriate in early processing steps, whereas tighter controls may be appropriate for later processing steps (e.g., isolation and purification steps).

8.32 Critical in-process controls (and critical process monitoring), including control points and methods, should be stated in writing and approved by the quality unit(s).

8.33 In-process controls can be performed by qualified production department personnel and

8.20 如果生产工艺规程（见6.40）中规定了时限，应当遵守这些时限，以保证中间体和原料药的质量。所有偏差都要有记录并解释原因。在加工到一个目标值时（例如，调节pH、氢化、干燥到预定标准），时限可能就不合适了，因为反应或加工步骤的完成是取决于过程中的取样和测试的。

8.21 留作进一步加工的中间体应当在适宜的条件下储存，以保证其适宜于使用。

8.3 工序间的取样和控制

8.30 应当制定书面程序来监测会造成中间体和原料药质量特性变异的工艺步骤的进程，并控制其生产情况。工序间控制及其接受标准应当根据项目开发阶段或者以往的生产数据来确定。

8.31 综合考虑所生产中间体和原料药的特性，反应类型，该工序对产品质量影响的程度大小等因素来确定可接受的标准，检测类型和范围。前期生产的中间体控制标准可以松一些，越接近成品，中间控制的标准越严（如分离，纯化）。

8.32 关键的中间控制（和工艺监测），包括控制点和方法，应当书面规定，并经质量部门批准。

8.33 中间控制可以由合格的生产部门的人员来进行，而调节的工艺可以事先未经质量部

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the process adjusted without prior quality unit(s) approval if the adjustments are made within pre-established limits approved by the quality unit(s). All test and results should be fully documented as part of the batch record.

8.34 Written procedures should describe the sampling methods for in-process materials, intermediates, and APIs. Sampling plans and procedures should be based on scientifically sound sampling practices.

8.35 In-process sampling should be conducted using procedures designed to prevent contamination of the sampled material and other intermediates or APIs. Procedures should be established to ensure the integrity of samples after collection.

8.36 Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process.

8.4 Blending Batches of Intermediates or APIs

8.40 For the purpose of this document, blending is defined as the process of combining materials within the same specification to produce a homogeneous intermediate or API. In-process mixing of fractions from single batches (e.g., collecting several centrifuge loads from a single crystallization batch) or combining fractions from several batches for further processing is considered to be part of the production process and is not considered to be blending.

8.41 Out-of-specification batches should not be blended with other batches for the purpose of meeting specifications. Each batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending.

门批准，只要该调节在由质量部门批准的预先规定的限度以内。所有测试及结果都应当作为批记录的一部分全部归档。

8.34 应当制定书面程序，说明中间物料、中间体和原料药的取样方法。取样方案和程序应当基于科学合理的取样实践。

8.35 工序间取样应当按能防止污染所取的样品、其它中间体或原料药的程序进行。应当制定保证样品收集后的完整性的程序。

8.36 生产操作中的正常监控过程和工艺调节过程中出现的超出标准的偏差（OOS），通常情况不需要调查。

8.4 中间体或原料药的混批

8.40 根据本文件的目的，混合的定义是为了生产出均匀的中间体或原料药而将同一质量标准的物料混在一起的过程。同一批号几部分（例如，收集一个结晶批号出来的几次离心机装的料）的工艺间的混合，或者混合从几个批号来的部分作进一步加工，看作是生产工艺的一部分，而不是混合。

8.41 不合格的批号不能与其他批号混合在一起来达到符合质量标准的目的。混合的每一个批号都应该是用规定的生产工艺生产的，混合前应当单独检测，并符合相应的质量标准。

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8.42 Acceptable blending operations include, 8.42 可接受的混合操作包括但不限于： but are not limited to:

● Blending of small batches to increase batch ● 将小批混合，增大批量；

size

● Blending of tailings (i.e., relatively small ● 将多批同一中间体或原料药的尾料（例

quantities of isolated material) from 如，分离出的相对较少的量）混合成为一batches of the same intermediate or API to 个批号。 form a single batch

8.43 Blending processes should be adequately 8.43 混合过程应当充分控制并记录，混合后controlled and documented, and the blended 的批号应当根据情况进行测试，以确认是否batch should be tested for conformance to 达到质量标准。 established specifications, where appropriate.

8.44 The batch record of the blending process 8.44 混合过程的批记录应当允许追溯到参与should allow traceability back to the individual 混合的每个单独批号。 batches that make up the blend.

8.45 Where physical attributes of the API are 8.45 如果原料药的物理性质至关重要（例如，critical (e.g., APIs intended for use in solid oral 用于固体口服制剂或混悬剂的原料药），混合dosage forms or suspensions), blending 工艺应当验证，以显示混合后批号的均匀性。operations should be validated to show 验证应当包括测试可能受混合过程影响的关homogeneity of the combined batch. Validation 键属性（例如，粒度分布，堆密度和振实密should include testing of critical attributes (e.g., 度）。 particle size distribution, bulk density, and tap density) that may be affected by the blending process.

8.46 If the blending could adversely affect 8.46 如果混合会对稳定性有不良影响，应当stability, stability testing of the final blended 对最终混合批号进行稳定性测试。 batches should be performed.

8.47 The expiry or retest date of the blended 8.47 混合批号的有效期或复验期应当以混合batch should be based on the manufacturing 中生产日期最早的尾料或批次的批号为基date of the oldest tailings or batch in the blend. 准。 8.5 Contamination Control 8.5 污染控制

8.50 Residual materials can be carried over into 8.50 在得到充分控制的前提下，上一批号的successive batches of the same intermediate or 同一中间体或原料药的剩余物可以带入下几API if there is adequate control. Examples 个连续批号。例如，黏附在微粉机壁上的残include residue adhering to the wall of a 留，离心出料后残留在离心机筒体内的潮湿micronizer, residual layer of damp crystals 的结晶，将物料转至下一步工序时无法从反remaining in a centrifuge bowl after discharge, 应器中彻底放尽的物料。此类带入不应当导

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