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
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 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
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
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. 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
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
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 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
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。
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.
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
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。
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
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。
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.
“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。
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
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。
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：
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
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:
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：
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 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； 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
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：
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。
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
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
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。
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）
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 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
4.20 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
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
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
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, 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
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
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 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.
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。
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。
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）。
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。
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。
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
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.
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。
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
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。
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
5.49 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
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 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
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。
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。
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 ratio of each raw material or intermediate to be used, including the unit of measure. Where the quantity is not fixed, the calculation for each batch size or rate of production should be included. Variations to quantities should be included where they are justified ● The production location and major production equipment to be used ● Detailed production instructions, including the: - sequences to be followed - ranges of process parameters to be used - sampling instructions and in-process controls with their acceptance criteria, where appropriate - time limits for completion of individual processing steps and/or the total process, where appropriate - expected yield ranges at appropriate phases of processing or time ● Where appropriate, special notations and precautions to be followed, or cross-references to these ● The instructions for storage of the intermediate or API to ensure its suitability for use, including the labeling and packaging materials and special storage conditions with time limits, where appropriate. 准确说明所用的每种原料或中间体的投
料量或投料比，包括计量单位。如果投料量不是固定的，应当写明每批的批量或产率的计算方法。还应当包括经证明是合理的量的偏差； 生产地点及使用的主要设备；
详细的生产规程，包括：
- 操作顺序， - 工艺参数的范围，
- 取样方法，过程控制及其认可标准，
- 某些情况下，要说明完成某一工序和
/或整个工艺过程的时间， - 在某一工艺阶段或时间的预期产率。
根据情况，
写明注意事项、要遵循的预防措施，或它们的相互参照； 中间体或原料药的适宜贮存规定，
包括标签、包装材料，某些情况下写明特殊的贮存条件、时间限制，以确保其使用。
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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
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；
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.
● 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。
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
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。
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.
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。
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
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
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 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。
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
7.42 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：
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
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
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。
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 controlled and documented, and the blended batch should be tested for conformance to established specifications, where appropriate. 8.44 The batch record of the blending process should allow traceability back to the individual batches that make up the blend. 8.45 Where physical attributes of the API are critical (e.g., APIs intended for use in solid oral dosage forms or suspensions), blending operations should be validated to show homogeneity of the combined batch. Validation should include testing of critical attributes (e.g., particle size distribution, bulk density, and tap density) that may be affected by the blending process. 8.46 If the blending could adversely affect stability, stability testing of the final blended batches should be performed. 8.47 The expiry or retest date of the blended batch should be based on the manufacturing date of the oldest tailings or batch in the blend. 8.5 Contamination Control 8.50 Residual materials can be carried over into successive batches of the same intermediate or API if there is adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals remaining in a centrifuge bowl after discharge,
8.43 混合过程应当充分控制并记录，混合后的批号应当根据情况进行测试，以确认是否达到质量标准。
8.44 混合过程的批记录应当允许追溯到参与混合的每个单独批号。
8.45 如果原料药的物理性质至关重要（例如，用于固体口服制剂或混悬剂的原料药），混合工艺应当验证，以显示混合后批号的均匀性。验证应当包括测试可能受混合过程影响的关键属性（例如，粒度分布，堆密度和振实密度）。
8.46 如果混合会对稳定性有不良影响，应当对最终混合批号进行稳定性测试。
8.47 混合批号的有效期或复验期应当以混合中生产日期最早的尾料或批次的批号为基准。 8.5 污染控制
8.50 在得到充分控制的前提下，上一批号的同一中间体或原料药的剩余物可以带入下几个连续批号。例如，黏附在微粉机壁上的残留，离心出料后残留在离心机筒体内的潮湿的结晶，将物料转至下一步工序时无法从反应器中彻底放尽的物料。此类带入不应当导
and incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. Such carryover should not result in the carryover of degradants or microbial contamination that may adversely alter the established API impurity profile.
8.51 Production operations should be 致因带入降解物或微生物的污染而对已经建立的原料药杂质概况有不良影响。
8.51 生产操作应当防止中间体或原料药被其conducted in a manner that prevents contamination of intermediates or APIs by other materials.
8.52 Precautions to avoid contamination should be taken when APIs are handled after purification.
9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES 9.1 General
9.10 There should be written procedures describing the receipt, identification, quarantine, sampling, examination, and/or testing, release, and handling of packaging and labeling materials.
9.11 Packaging and labeling materials should conform to established specifications. Those that do not comply with such specifications should be rejected to prevent their use in operations for which they are unsuitable.
9.12 Records should be maintained for each shipment of labels and packaging materials showing receipt, examination, or testing, and whether accepted or rejected.
9.2 Packaging Materials
9.20 Containers should provide adequate protection against deterioration or contamination of the intermediate or API that may occur during transportation and
它物料污染。
8.52 处理精制后的原料药应当采取预防污染的措施。
9. 原料药和中间体的包装和贴签
9.1 总则
9.10 应当有书面程序描述包装和贴签用物料的接收、鉴别、待验、取样、检查和/或测试、放行和搬运。
9.11 包装和贴签用物料应当符合规定的质量标准。不合格者要拒收，不得用于不适合于其的操作中。
9.12 每次运来的标签和包装材料应当有接收、检查或测试、以及合格还是拒收的记录。
9.2 包装材料
9.20 容器应当能够对中间体和原料药提供足够的保护，使其在运输和建议的贮存条件下不会变质或受到污染。
recommended storage.
9.21 Containers should be clean and, where indicated by the nature of the intermediate or API, sanitized to ensure that they are suitable for their intended use. These containers should not be reactive, additive, or absorptive so as to alter the quality of the intermediate or API
9.21 容器应当清洁，如果中间体或原料药有要求时，应当进行消毒，以确保适合于其预期的用途。这些容器应无反应活性、加和性或吸附性，一面改变中间体或原料药的质量使其超出质量标准的限度。
beyond the specified limits.
9.22 If containers are reused, they should be cleaned in accordance with documented procedures, and all previous labels should be removed or defaced.
9.3 Label Issuance and Control
9.30 Access to the label storage areas should be limited to authorized personnel.
9.31 Procedures should be established to reconcile the quantities of labels issued, used, and returned and to evaluate discrepancies found between the number of containers labeled and the number of labels issued. Such discrepancies should be investigated, and the investigation should be approved by the quality unit(s).
9.32 All excess labels bearing batch numbers or other batch-related printing should be destroyed. Returned labels should be maintained and stored in a manner that prevents mix-ups and provides proper identification.
9.33 Obsolete and out-dated labels should be destroyed.
9.34 Printing devices used to print labels for packaging operations should be controlled to ensure that all imprinting conforms to the print specified in the batch production record.
9.35 Printed labels issued for a batch should be carefully examined for proper identity and
9.22 容器被重新使用时，应当按照规定程序进行清洁，并出去或涂毁以前的所有标签。
9.3 标签发放与控制
9.30 只有获准人员才能进入标签贮存区。
9.31 应当建立规程来平衡发出的、使用的和退回的标签的数量，并评估已贴签的容器数和发出的标签数之间的偏差值。此种差异应当加以调查，调查应当由质量保证部门批准。
9.32 所有剩余的印有批号或与批有关内容的标签都应当销毁。收回的标签应当以防止混淆并提供适当标识的方式加以保留和贮存。
9.33 废弃的和过期的标签应当销毁。
9.34 包装操作中用于印刷标签的印刷设备应当加以监控，以确保所有印刷内容符合批生产记录中的内容。
9.35 应当仔细检查发放给某批的打印好的标签，其标识是否正确，并符合主生产记录的
conformity to specifications in the master production record. The results of this examination should be documented.
9.36 A printed label representative of those used should be included in the batch production record.
9.4 Packaging and Labeling Operations
9.40 There should be documented procedures designed to ensure that correct packaging materials and labels are used.
9.41 Labeling operations should be designed to prevent mix-ups. There should be physical or spatial separation from operations involving other intermediates or APIs.
9.42 Labels used on containers of intermediates or APIs should indicate the name or identifying code, batch number, and storage conditions when such information is critical to ensure the quality of intermediate or API.
9.43 If the intermediate or API is intended to be transferred outside the control of the manufacturer’s material management system, the name and address of the manufacturer, quantity of contents, special transport conditions, and any special legal requirements should also be included on the label. For intermediates or APIs with an expiry date, the expiry date should be indicated on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.
9.44 Packaging and labeling facilities should be inspected immediately before use to ensure that all materials not needed for the next packaging operation have been removed. This examination should be documented in the batch production records, the facility log, or other documentation
内容。检查结果应当记录在批生产记录中。
9.36 批生产记录中应当附一张代表那些所用标签的印制好的标签。
9.4 包装和贴签操作
9.40 应当有文件化的规程确保使用正确的包装材料和标签。
9.41 帖签操作应当防止混淆。应当与涉及其它中间体或原料药的操作有物理的或空间的隔离。
9.42 用于中间体或原料药容器的标签应当注明：确保中间体或原料药质量的关键信息，如名称、识别代码、产品批号和储存条件。
9.43 如果中间体或原料药要向生产商的物料管理系统控制范围以外运输，标签上还应当包括生产商的名称、地址，装量，特殊的运输要求，和其它特殊的法定要求。对于有失效期的中间体或原料药，标签和分析报告单上应当注明失效期。对于有复验期的中间体或原料药，标签和/或分析报告单上应当注明复验期。
9.44 包装和帖签设施应当在使用前进行检查，以确定下一次包装操作不需要的所有物料都已清除。该检查应当记录在批生产记录、设备使用记录或其它文件系统中。
system.
9.45 Packaged and labeled intermediates or APIs should be examined to ensure that containers and packages in the batch have the correct label. This examination should be part of the packaging operation. Results of these examinations should be recorded in the batch production or control records.
9.46 Intermediate or API containers that are transported outside of the manufacturer’s control should be sealed in a manner such that, if the seal is breached or missing, the recipient will be alerted to the possibility that the contents may have been altered.
10. STORAGE AND DISTRIBUTION 10.1 Warehousing Procedures
10.10 Facilities should be available for the storage of all materials under appropriate conditions (e.g., controlled temperature and humidity when necessary). Records should be maintained of these conditions if they are critical for the maintenance of material characteristics.
10.11 Unless there is an alternative system to prevent the unintentional or unauthorized use of quarantined, rejected, returned, or recalled materials, separate storage areas should be assigned for their temporary storage until the decision as to their future use has been made.
10.2 Distribution Procedures
10.20 APIs and intermediates should only be released for distribution to third parties after they have been released by the quality unit(s). APIs and intermediates can be transferred under quarantine to another unit under the company’s control when authorized by the quality unit(s) and if appropriate controls and documentation are in place.
9.45 应当检查已包装和帖签的中间体或原料药，以确保该批的容器和包装的标签正确。该检查应当作为包装操作的一部分。检查结果应当记录在批生产或控制记录中。
9.46需向生产商的物料管理系统控制范围以外运输的中间体或原料药的容器应当用一种密封形式，以至于一旦密封破损或遗失，收货者会留意到其内容物有可能被动过。
10.储存和分发 10.1 入库程序
10.10 应当提供在适当条件下（需要时控制温度和湿度）贮存所有物料的设施。应当记录对保持物料特性至关重要的贮存条件。
10.11 除非另有其它系统可以防止待验的、不合格的退回或召回的物料的误用或未经许可擅自使用，应当为其临时存放指定单独的存放区域，直至其今后用途确定为止。
10.2 分发程序
10.20 原料药和中间体经质量部门放行后才能分发给第三方。经质量部门授权，而且如果有合适的控制并有文件证明，可允许待验的原料药和中间体在公司的控制范围下，转移到另一部门。
10.21 APIs and intermediates should be transported in a manner that does not adversely affect their quality.
10.22 Special transport or storage conditions for an API or intermediate should be stated on the label.
10.21 原料药和中间体应当以对其质量不产生负面影响的方式运输。
10.22 原料药或中间体的特殊运输或贮存条件应当在标签上注明。
10.23 The manufacturer should ensure that the contract acceptor (contractor) for transportation of the API or intermediate knows and follows the appropriate transport and storage conditions.
10.24 A system should be in place by which the distribution of each batch of intermediate and/or API can be readily determined to permit its recall.
11. LABORATORY CONTROLS 11.1 General Controls
11.10 The independent quality unit(s) should have at its disposal adequate laboratory facilities.
11.11 There should be documented procedures describing sampling, testing, approval, or rejection of materials and recording and storage of laboratory data. Laboratory records should be maintained in accordance with Section 6.6.
11.12 All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to ensure that raw materials, intermediates, APIs, and labels and packaging materials conform to established standards of quality and/or purity. Specifications and test procedures should be consistent with those included in the registration/filing. There can be specifications in addition to those in the registration/filing. Specifications, sampling plans, and test procedures, including changes to
10.23 生产商应当确保运输原料药或中间体的合同接受方（订约人）了解并遵从相关的运输和贮存条件。
10.24 应当建立一个系统，可用它来对每批中间体和/或原料药的分发随时决定召回。
11.实验室控制 11.1 控制通则
11.10 独立的质量部门应当有受其支配的、足够的实验室设施。
11.11 应当备有阐述物料取样、测试、物料批准或拒收，和实验室的记录及保存的书面程序。实验室记录应当按照6.6节中所述要求保存。
11.12 所有的质量标准，取样方案和测试程序都应当科学合理并适当，以确保原料、中间体、原料药，标签和包装材料能达到规定的质量和/或纯度标准。质量标准和测试方法应当与注册/申报中的一致。可以有注册/申报以外的附加的质量标准。质量标准、取样方案和测试程序，包括相应的变更，应当由相关的组织机构起草，并由质量部门审核、批准。
them, should be drafted by the appropriate organizational unit and reviewed and approved by the quality unit(s).
11.13 Appropriate specifications should be established for APIs in accordance with accepted standards and consistent with the manufacturing process. The specifications should include control of impurities (e.g.,
11.13 应当根据已接受的标准和与生产工艺的一致性来制订合适的原料药质量标准。质量标准应当包括对杂质的控制（如有机杂质、无机杂质，和残留溶剂）。如果原料药有微生物纯度的质量规格，应当制订并达到合适的organic impurities, inorganic impurities, and residual solvents). If the API has a specification for microbiological purity, appropriate action limits for total microbial counts and objectionable organisms should be established and met. If the API has a specification for endotoxins, appropriate action limits should be established and met.
11.14 Laboratory controls should be followed and documented at the time of performance. Any departures from the above-described procedures should be documented and explained.
11.15 Any out-of-specification result obtained should be investigated and documented according to a procedure. This procedure should include analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any resampling and/or retesting after OOS results should be performed according to a documented procedure.
11.16 Reagents and standard solutions should be prepared and labeled following written procedures. Use by dates should be applied, as appropriate, for analytical reagents or standard solutions.
11.17 Primary reference standards should be obtained, as appropriate, for the manufacture of APIs. The source of each primary reference standard should be documented. Records
总菌落数和致病菌的处置限度。如果原料药有内毒素的质量规格，应当制订并达到合适的内毒素的处置限度。
11.14 应当遵守实验室控制，并边操作边记录。对上述程序的任何偏离都应当有记录并作解释。
11.15 得到的任何不符合质量标准的结果都应当按照程序进行调查，并备案。该程序应当要求对数据进行分析，评价是否有值得注意的问题存在，分配整改措施的任务和结论。发现不符合质量标准的结果后，任何重新取样和/或重新测试都应当按照成文的程序进行。
11.16 应当按照书面程序来配制试剂和标准溶液以及贴标签。分析试剂或标准溶液应当酌情采用“用至”日期。
11.17 原料药生产时应当酌情获得合适的基本参考标准品。每一个基本参考标准品的来源要备案。应根据标准品供应商的要求进行标准品的储存和使用，并进行相应记录同时
should be maintained of each primary reference standard’s storage and use in accordance with the supplier’s recommendations. Primary reference standards obtained from an officially recognized source are normally used without testing if stored under conditions consistent with the supplier’s recommendations.
11.18 Where a primary reference standard is not 保存记录。对于从官方认可的渠道获得的基本参考标准品，在按照供应商的建议的保存条件进行保存的情况下，通常无需检验就可以使用。
11.18 从官方认可的货源处无法得到基本参available from an officially recognized source, an in-house primary standard should be established. Appropriate testing should be performed to establish fully the identity and purity of the primary reference standard. Appropriate documentation of this testing should be maintained.
11.19 Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard should be periodically requalified in accordance with a written protocol.
11.2 Testing of Intermediates and APIs
11.20 For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications.
11.21 An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API. The impurity profile should include the identity or some qualitative analytical designation (e.g., retention time), the range of each impurity observed, and classification of each identified impurity (e.g., inorganic, organic, solvent). The impurity profile is normally dependent upon the
考标准品时，应该制备一个“内部基本标准品”。应当做合适的测试来全面制订该基本参考标准品的鉴别和纯度。该测试的相关证明文件应当保留。
11.19 二级参考标准品应当用合适的方法来制备，鉴别，测试，批准和储存。每一批二级参考标准品在第一次使用前，应当与基本参考标准品进行比较，来确定其适用性。每一批二级参考标准品应当根据书面方案，定期进行重新确认。
11.2 中间体和原料药的测试
11.20 每一批中间体和原料药都应当进行适当的实验室测试，以确定是否符合质量标准。
11.21 每一种原料药都应当有杂质概况，描述用一特别控制的生产工艺生产出的典型批号中存在的已确定和未确定的杂质。杂质概况应当包括观测到的每一个杂质的鉴别或某个定量分析的标志（如保留时间）、范围，以及已确定杂质的类别（如有机的、无机的、溶剂）。杂质概况一般与原料药的生产工艺和起源有关。从植物或动物组织中得到的原料药通常不一定要有杂质概况。ICH指南Q6B讲述了对生物技术的考虑。
production process and origin of the API. Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin. Biotechnology considerations are covered in ICH guidance Q6B.
11.22 The impurity profile should be compared at appropriate intervals against the impurity profile in the regulatory submission or
11.22 每隔一端时间应当将杂质概况与药政申报中的杂质概况，或与以往的数据比较，以查明原材料、设备操作参数和生产工艺的compared against historical data to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.
11.23 Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified.
11.3 Validation of Analytical Procedures See Section 12.
11.4 Certificates of Analysis
11.40 Authentic certificates of analysis should be issued for each batch of intermediate or API on request.
11.41 Information on the name of the intermediate or API including, where appropriate, its grade, the batch number, and the date of release should be provided on the certificate of analysis. For intermediates or APIs with an expiry date, the expiry date should be provided on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.
11.42 The certificate should list each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained (if test results are numerical).
11.43 Certificates should be dated and signed
修改所造成的原料药的变化。
11.23 在规定微生物质量时，应当对每一批中间体和原料药作适当的微生物测试。
11.3 分析方法的验证 见第12章
11.4 分析报告单
11.40 有要求时应当为每一批中间体或原料药出具可信的分析报告单。
11.41 分析报告单应当提供中间体或原料药的名称，必要时包括其等级、批号和放行日期。有有效期的中间体或原料药，应当在标签和分析报告单上提供失效期。有复验期的中间体或原料药，应当在标签和/或分析报告单上提供复验期。
11.42 报告单应当列明按药典或客户要求所做的各项测试，包括可接受的限度，和得到的数值结果（如果测试结果是数值）。
11.43 报告单应当由指定的质量部门人员写
by authorized personnel of the quality unit(s) and should show the name, address, and telephone number of the original manufacturer. Where the analysis has been carried out by a repacker or reprocessor, the certificate of analysis should show the name, address, and telephone number of the repacker/reprocessor and reference the name of the original 明日期并签名，而且应当注明原生产商的名称、地址和电话。如果测试是由重新包装者或重新加工者做的，则分析报告单应当注明重新包装者/重新加工者的名称、地址和电话，并附注原生产商的名称。
manufacturer.
11.44 If new certificates are issued by or on behalf of repackers/reprocessors, agents or brokers, these certificates should show the name, address, and telephone number of the laboratory that performed the analysis. They should also contain a reference to the name and address of the original manufacturer and to the original batch certificate, a copy of which should be attached.
11.5 Stability Monitoring of APIs
11.50 A documented, on-going testing program should be established to monitor the stability characteristics of APIs, and the results should be used to confirm appropriate storage conditions and retest or expiry dates.
11.51 The test procedures used in stability testing should be validated and be stability indicating.
11.52 Stability samples should be stored in containers that simulate the market container. For example, if the API is marketed in bags within fiber drums, stability samples can be packaged in bags of the same material and in small-scale drums of similar or identical material composition to the market drums.
11.53 Normally, the first three commercial production batches should be placed on the stability monitoring program to confirm the retest or expiry date. However, where data from previous studies show that the API is expected
11.44 如果由重新包装者/重新加工者、代理人，中间人或由其代表出具新的报告单，这些报告单上应当注明做分析的实验室的名称、地址和电话。还应当附注原生产商的名称和地址，并附上原始检验报告单复印件。
11.5 原料药的稳定性监测 11.50 应当建立一个文件化的、持续监测的规程，以监测原料药的稳定性特征，而其结果应当用于确定适当的贮存条件和复验日期或有效期。
11.51 用于稳定性测试的测试规程应当经过验证，并能显示稳定性。
11.52 稳定性样品应当存放在与销售容器相仿的容器中。例如，如果原料药是装在纤维桶内的袋子里销售的，稳定性样品可以包装在同样材料的袋中，放入相似或相同与销售容器的材料的材料较小的桶中。
11.53 通常头三个销售批号应当放入稳定性监测计划，以证实复验期或有效期。然而，如果以前的研究数据表明原料药至少在两年内可望保持稳定，则所用的批号可少于三批。
to remain stable for at least 2 years, fewer than three batches can be used.
11.54 Thereafter, at least one batch per year of API manufactured (unless none is produced that year) should be added to the stability monitoring program and tested at least annually
11.54 以后每年至少应当加一批生产的原料药到稳定性监测计划（除非当年不生产），并且至少每年测试，以证实其稳定性。
to confirm the stability.
11.55 For APIs with short shelf-lives, testing should be done more frequently. For example, for those biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly for the first three months, and at 3-month intervals after that. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals (e.g., 9-month testing) can be considered.
11.56 Where appropriate, the stability storage conditions should be consistent with the ICH guidances on stability.
11.6 Expiry and Retest Dating
11.60 When an intermediate is intended to be transferred outside the control of the manufacturer’s material management system and an expiry or retest date is assigned, supporting stability information should be available (e.g., published data, test results).
11.61 An API expiry or retest date should be based on an evaluation of data derived from stability studies. Common practice is to use a retest date, not an expiration date.
11.62 Preliminary API expiry or retest dates can be based on pilot scale batches if (1) the pilot batches employ a method of manufacture and procedure that simulates the final process to be used on a commercial manufacturing scale and (2) the quality of the API represents the
11.55 对于储存期较短的原料药，应当更频繁的测试。例如，储存期不超过一年的生物工程/生物制品或其它原料药，应当有稳定性样品，头三个月内应当每月测试，随后每三个月测试一次。如果有数据表明原料药的稳定性不会受影响，可以考取消特定的测试间隔（如9个月的测试）。
11.56 根据情况，稳定性储存条件应当与ICH的稳定性指南一致。
11.6 有效期和复验期
11.60 当一个中间体要运送到生产商物料管理系统控制范围以外，并已制定了有效期或复验期时，那就应当有支持的稳定性信息（如发表的数据、测试结果）。
11.61 一种原料药的有效期或复验期应当基于稳定性研究所得数据的评估。通常会用复验期，而不用有效期。
11.62 如果（1）中试批号采用的生产方法和规程是模拟用于商业生产规模的最终工艺，而且（2）原料药的质量代表了商业生产规模的物料，则原料药的初步有效期或复验期可基于中试规模的批号。
material to be made on a commercial scale.
11.63 A representative sample should be taken for the purpose of performing a retest.
11.7 Reserve/Retention Samples
11.70 The packaging and holding of reserve samples is for the purpose of potential future evaluation of the quality of batches of API and
11.63 应当取一个具有代表性的样品进行复验。
11.7 留样
11.70 留样的包装和储存是为了今后可能会对原料药批号的质量进行评价，而不是以将来的稳定性测试为目的的。
not for future stability testing purposes.
11.71 Appropriately identified reserve samples of each API batch should be retained for 1 year after the expiry date of the batch assigned by the manufacturer, or for 3 years after distribution of the batch, whichever is longer. For APIs with retest dates, similar reserve samples should be retained for 3 years after the batch is completely distributed by the manufacturer.
11.72 The reserve sample should be stored in the same packaging system in which the API is stored or in one that is equivalent to or more protective than the marketed packaging system. Sufficient quantities should be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial monograph, two full specification analyses.
12. VALIDATION 12.1 Validation Policy
12.10 The company’s overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval, and documentation of each validation phase, should be documented.
12.11 The critical parameters/attributes should normally be identified during the development
11.71 适当标识的每一批原料药的留样应当保留到由生产商规定的该批号的有效期满后一年，或该批产品销售后三年，以较长时间为准。对于有复验期的原料药，相似的留样应当保留到生产商全部销售完该批号后三年。
11.72 留样应当储存在原料药储存的同样的包装系统中，或者与销售包装相同，或更具保护性。应当留足够的量来至少做两次法定的全检，或者没有药典专论时，两次质量标准的全检。
12.验证
12.1 验证方针
12.10 公司的总体验证原则、目的和方法，包括生产工艺、清洁规程、分析方法、过程控制测试规程以及计算机系统的验证和负责设计、审核、批准和为各个验证阶段提供证明文件的人员都应当明文规定。
12.11 关键的工艺参数/属性通常应当在开发阶段或从以往的数据中加以确定，并应当规
stage or from historical data, and the necessary 定工艺可重复性操作所必需的范围。包括： ranges for the reproducible operation should be defined. This should include:
● Defining the API in terms of its critical ● 定义原料药生产的关键产品属性；
product attributes
● Identifying process parameters that could ● 确认可能对原料药关键质量属性有影响
affect the critical quality attributes of the 的工艺参数； API
● Determining the range for each critical ● 确定在日常生产和工艺控制中会用到的
process parameter expected to be used during routine manufacturing and process control 12.12 Validation should extend to those operations determined to be critical to the quality and purity of the API. 12.2 Validation Documentation 12.20 A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units. 12.21 The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g., retrospective, prospective, concurrent) and the number of process runs. 12.22 A validation report that cross-references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies. 12.23 Any variations from the validation protocol should be documented with appropriate justification. 12.3 Qualification 12.30 Before initiating process validation activities, appropriate qualification of critical 每个关键工艺参数的范围。
12.12 验证还应当涉及到那些对原料药质量和纯度至关重要的操作。 12.2 验证文件
12.20 应当有书面的验证方案，阐明如何进行某个工艺的验证。验证方案应当由质量部门和其他指定的部门审核并批准。
12.21 验证方案应当明确规定验证的关键工序和认可标准，所要进行的验证类型（回顾性验证、预验证、同步验证）和工序运转的次数。
12.22 应当拟定一份能交叉引用验证方案的验证报告，概括得到的结果，说明发现的任何偏差，并作出必要的结论，包括为整改而必须做的变更。
12.23 任何对验证方案的偏离都应当归档备案，并作适当说明。 12.3 确认
12.30 在开始工艺验证活动前，应当完成适当的关键设备和辅助系统的确认。确认一般是
equipment and ancillary systems should be completed. Qualification is usually carried out by conducting the following activities, individually or combined:
● Design Qualification (DQ): documented
verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose ● Installation Qualification (IQ): documented
通过单独或联合进行以下活动来实行的：
● 设计确认（DQ）：是对提议的设施、设备
或系统适用于预期的目的的一种成文的确认；
● 安装确认（IQ）：对安装好的和调整过的
verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations and/or user requirements ● Operational Qualification (OQ):
documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges ● Performance Qualification (PQ):
documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications
12.4 Approaches to Process Validation
12.40 Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.
12.41 There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the other approaches can be used. These approaches and their applicability are discussed here.
12.42 Prospective validation should normally be performed for all API processes as defined in 12.1. Prospective validation for an API process should be completed before the
设备或系统符合已批准的设计、制造商建议的和/或用户的要求的成文的确认；
● 运行确认（OQ）：对安装好的和调整过的
设备或系统能在整个预期的操作范围内按要求运行的成文的确认；
● 性能确认（PQ）：是对设备或其辅助系统
在相互连接后，能根据已获准工艺方法和质量标准有效的、重现的进行运转的成文的确认。
12.4 工艺验证的方法
12.40 工艺验证（PV）是证明在预定的工艺参数范围内运行的工艺能持续有效地生产出符合预定的质量标准和质量属性的中间体或原料药的证明文件。
12.41 验证方法有三种，预验证是首选的方法，但在其它方法可采用的情况下也有例外。这些方法及其适用性见下文。
12.42 12.1中所述的所有原料药生产工艺一般来说都应当进行预验证。对原料药工艺所作的预验证的结果，必须在用该原料药制成的制剂产品销售前完成。
commercial distribution of the final drug product manufactured from that API.
12.43 Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been
12.43 有时由于原料药生产批号有限，原料药批号不是经常生产，或原料药是用验证过的，但已变更的工艺生产的，无法从连续生产中得到数据，可进行同步验证。同步验证完成之前，只要对原料药批号进行了充分的监控和测试，这些批号可以放行并用于最终制剂modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches.
12.44 An exception can be made for retrospective validation well-established processes that have been used without significant changes to API quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approach may be used where:
1. Critical quality attributes and critical
process parameters have been identified 2. Appropriate in-process acceptance criteria
and controls have been established
3. There have not been significant
process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability
4. Impurity profiles have been established for
the existing API
12.45 Batches selected for retrospective validation should be representative of all batches produced during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.
12.5 Process Validation Program
药的商业销售。
12.44 某些工艺已确立了很久，而且原料、设备、系统、设施或生产工艺的变化对原料药的质量没有明显的影响，此时就可以例外地进行回顾性验证。这一验证方法适合于下列情况：
1. 关键质量属性和关键工艺参数均已确定；
2. 已确立了合适的过程控制和认可标准；
3. 从来没有因为除了操作人员失误或设备
故障这些与设备适应性无关的因素之外的原因而造成值得注意的工艺/产品的不合格；
4. 现有原料药的杂质概况已确定。
12.45 回顾性验证选用的批号应当能够代表审核时段中的所有批号，包括任何不合格的批号，而且应当有足够的批数来证明工艺的稳定。可用测试留样来获取回顾性工艺验证数据。
12.5 工艺验证的程序
12.50 The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process (e.g., complex API 12.50 验证时生产工艺的运行次数，应当由工艺的复杂性或要考虑的工艺变更的大小来决定。作为一个指南，预验证和同步验证应当采用三个连续的、成功的批号，但可能在某些情况下需要更多的批号来保证工艺的一致性（例如，复杂的原料药生产工艺，或原料药工艺耗时很长）。回顾性验证一般应当审查从10到30个连续批号得到的数据来评估工艺的一致性，但是，如果有理由，审查的批processes or API processes with prolonged completion times). For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.
12.51 Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.
12.52 Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies.
12.6 Periodic Review of Validated Systems 12.60 Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.
12.7 Cleaning Validation
数可以少些。
12.51 在工艺验证研究时应当控制并监测关键的工艺参数。与质量无关的参数，例如为了将能量消耗或所用设备减到最低而控制的变量，无需包括在工艺验证中。
12.52 工艺验证应当确认每一个原料药的杂质概况都在规定的限度内。杂质概况应当与以往的数据相似或更好，如果可能，应当与工艺开发阶段确定的杂质概况，或用于关键的临床和毒理研究的批号的数据相似或更好。
12.6验证系统的定期审核
12.60 应当对系统和工艺进行周期性的评价，以确认它们仍然能有效地运作。如果系统或工艺并没有大的变动，而质量回顾证实系统和工艺在稳定地生产着符合其质量标准的物料，通常就不必验证了。
12.7 清洗验证
12.70 Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent 12.70 通常应当验证清洗程序。一般来说，清洗验证应当针对那些如果受到污染或偶然带入异物就会对原料药的质量带来极大危险的情况或工序。例如，在生产的前期阶段，可能就无需验证设备的清洗程序，那里的残留物会被后面的纯化步骤除去。
purification steps.
12.71 Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.
12.72 The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labeled.
12.73 Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and
12.71 清洗程序的验证应当反映实际的设备使用情况。如果多个原料药或中间体都在同一设备内生产，而该设备用同一个程序清洗，那么就要选择代表性的中间体或原料药来作清洗验证。应当根据溶解性，清洗难度，以及依据效价、毒性和稳定性计算出来的残留物的限量来作选择。
12.72 清洗验证方案应当描述要清洗的设备、程序、物料、可接受的清洗程度、要监测和控制的参数、以及分析方法。方案还应当指出要得到的样品的种类，和如何取样及标记。
12.73 取样应当包括擦拭法、冲洗法或可供选择的方法（如直接萃取），如果合适的话，同时检测不溶性和可溶性的残留物。所用的取样方法应当能定量地检测出清洗之后留在设备表面的残留物质。当与产品接触的表面，由于设备的设计和/或工艺限制（如，软管的内表面，运输管道，反应釜的开口很小或装卸有毒物质，以及一些小的复杂的设备，如微粉粉碎机，流化床式微粉机），很难触及时，擦拭取样就无法实施。
microfluidizers).
12.74 Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be
12.74 应当采用验证过的、具有检测残留物或污染物的灵敏度的分析方法。每一个分析方法的检测限度必须足够灵敏，来检测到残留物或污染物的规定的可接受水平。应当规定方法的可达到的回收率。残留物的限度切实可行的，可检测的，并由最有害的残留物来确定。可以根据原料药或其最有害的组分的established. Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.
12.75 Equipment cleaning/sanitation studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).
12.76 Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.
12.8 Validation of Analytical Methods
12.80 Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognized standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented.
已知最小药理、毒理或生理活性浓度来制定限度。
12.75 对于需要降低原料药中的总微生物数或内毒素的工艺，或担心此类污染的其它工艺（如，用于生产无菌产品的非无菌原料药），设备清洗/消毒的研究应当对付微生物和内毒素污染。
12.76 验证后，清洗程序应当在适当的时间间隔进行监测，以确保这些程序用在日常生产中是有效的。设备的清洁程度可以根据可行性通过测试或目测来监测。目测能检测到用取样和/或分析方法测不到的集中在小面积上的严重的污染。
12.8 分析方法的验证
12.80 分析方法应当进行验证，除非采用的方法列在相关的药典或其它公认的参照标准中。然而，所有测试方法的适应性应当在实际使用条件下加以证实，并归档备查。
12.81 Methods should be validated to include consideration of characteristics included within the ICH guidances on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production
12.81 方法验证应当包括ICH分析方法验证指南中的特征的考虑。方法验证进行的程度应当反映分析的目的和原料药生产工艺的步骤。
process.
12.82 Appropriate qualification of analytical equipment should be considered before initiating validation of analytical methods.
12.83 Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method.
13. CHANGE CONTROL
13.10 A formal change control system should be established to evaluate all changes that could affect the production and control of the intermediate or API.
13.11 Written procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labeling and packaging materials, and computer software.
13.12 Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality unit(s).
13.13 The potential impact of the proposed change on the quality of the intermediate or
12.82 在开始分析方法验证前，应当考虑对分析设备的适当的确认。
12.83 已验证过的分析方法的任何修改都应当保存完整的记录。这类记录应当包括修改的理由和合适的数据，以证实该修改所产生的结果和规定的方法同样准确、可靠。
13.变更的控制
13.10 应当建立正式的变更控制系统，以评估可能影响中间体或原料药生产和控制的所有变更。
13.11 对原料、质量标准、分析方法、设施、支持系统、设备（包括计算机硬件）、工艺步骤、标签和包装材料、计算机软件的变更进行认证、提供文件、适当的审核和批准，应当提供书面程序。
13.12 与GMP有关的任何变更提案都应当由相应的部门进行拟定、审核和批准，并由质量部门审核和批准。
13.13 应当评估所提议的变更对中间体或原料药质量的潜在影响。一种分类方法可能有
API should be evaluated. A classification procedure may help in determining the level of testing, validation, and documentation needed to justify changes to a validated process. Changes can be classified (e.g., as minor or major) depending on the nature and extent of the changes, and the effects these changes may impart on the process. Scientific judgment should determine what additional testing and 助于确定为了说明对一个已验证的工艺作变更所需的测试、验证和文件工作的程度。变更可以根据变更的性质和程度及其可能对工艺产生的影响来分类（如，次要的或主要的）。应当用科学的判断来决定，为证明对一个已验证工艺的变更可行，什么样的附加测试和验证研究是适当的。
validation studies are appropriate to justify a change in a validated process.
13.14 When implementing approved changes, measures should be taken to ensure that all documents affected by the changes are revised.
13.15 After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change.
13.16 The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the intermediate or API produced by the modified process can be placed on an accelerated stability program and/or can be added to the stability monitoring program.
13.17 Current dosage form manufacturers should be notified of changes from established production and process control procedures that can affect the quality of the API.
14. REJECTION AND RE-USE OF MATERIALS 14.1 Rejection
14.10 Intermediates and APIs failing to meet established specifications should be identified as such and quarantined. These intermediates or APIs can be reprocessed or reworked as described below. The final disposition of rejected materials should be recorded.
13.14 实施已核准的变更时，应当采取措施确保所有变更影响的文件都已修订。
13.15 变更实施后，应当对变更之后生产或测试的的头几个批次进行评估。
13.16 关键的变更对规定的复验期和有效期的影响可能性应当进行评估。如有必要，可以将用修改了的工艺生产的中间体或原料药的样品放入一个加速稳定性计划，并/或稳定性监测计划。
13.17 应当将可能影响原料药质量的对已确定的生产及工艺控制步骤所作的变更通知目前制剂药制造商。
14.拒收和物料的再利用
14.1 拒收
14.10 不合格中间体和原料药应当做有标志，并隔离。这些中间体和原料药可以按下述方法进行返工或重新加工。应当记录不合格物料的最终处置情况。
14.2 Reprocessing
14.20 Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and reprocessing by repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing 14.2 返工
14.20 将不符合标准或规格的一个中间体或原料药返回工艺过程，重复规定的生产工艺中的某一结晶步骤或其它合适的化学或物理处理步骤（如，蒸馏、过滤、层析、磨粉），这种做法通常是可以接受的。然而，如果这种返工用于大多数的批号，那么该返工就应当作为标准生产工艺的一部分。
process is generally considered acceptable. However, if such reprocessing is used for a majority of batches, such reprocessing should be included as part of the standard manufacturing process.
14.21 Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process. This is not considered to be reprocessing.
14.22 Introducing unreacted material back into a process and repeating a chemical reaction is considered to be reprocessing unless it is part of the established process. Such reprocessing should be preceded by careful evaluation to ensure that the quality of the intermediate or API is not adversely affected due to the potential formation of by-products and over-reacted materials.
14.3 Reworking
14.30 Before a decision is taken to rework batches that do not conform to established standards or specifications, an investigation into the reason for nonconformance should be performed.
14.31 Batches that have been reworked should be subjected to appropriate evaluation, testing, stability testing if warranted, and documentation to show that the reworked product is of equivalent quality to that produced by the original process. Concurrent validation is
14.21 在中间控制的测试表明一工艺步骤没有完成，从而继续该步骤，是正常工艺的一部分，不属于返工。
14.22 将未反应的物料返回某一工序，并重复化学反应，这是进行返工，除非它已被列入规定的工艺中。在进行这种返工前，要仔细评估，以确保不会由于可能形成的副产物和过度反应物而对中间体或原料药的质量产生不良影响。
14.3 重新加工
14.30 在决定对不符合规定的标准或规格的批号进行重新加工前，应当对不符合的原因进行调查。
14.31 重新加工的批号应当接受适当的评估、测试，如有理由还要做稳定性测试，并成文备查，以表明重新加工后的产品与原工艺生产的产品质量相等。同步验证常常是重新加工程序的合适的验证方法。允许用一方案来规定重新加工程序、如何进行和预期结果。
often the appropriate validation approach for reworked procedures. This allows a protocol to define the rework procedure, how it will be carried out, and the expected results. If there is only one batch to be reworked, a report can be written and the batch released once it is found to be acceptable.
14.32 Procedures should provide for comparing 如果只有一批产品重新加工，利用写一份报告，一旦认为该批可接受，即可放行。
14.32 应当有程序对每一重新加工过的批号the impurity profile of each reworked batch against batches manufactured by the established process. Where routine analytical methods are inadequate to characterize the reworked batch, additional methods should be used.
14.4 Recovery of Materials and Solvents
14.40 Recovery (e.g., from mother liquor or filtrates) of reactants, intermediates, or the API is considered acceptable, provided that approved procedures exist for the recovery and the recovered materials meet specifications suitable for their intended use.
14.41 Solvents can be recovered and reused in the same processes or in different processes, provided that the recovery procedures are controlled and monitored to ensure that solvents meet appropriate standards before reuse or commingling with other approved materials.
14.42 Fresh and recovered solvents and reagents can be combined if adequate testing has shown their suitability for all manufacturing processes in which they may be used.
14.43 The use of recovered solvents, mother liquors, and other recovered materials should be adequately documented.
14.5 Returns
14.50 Returned intermediates or APIs should be identified as such and quarantined.
与用规定的工艺生产的批号进行杂质概况的比较。如果常规分析方法不足以描绘重新加工批号的特征，应当采用另外的方法。
14.4 物料与溶剂的回收
14.40 只要有核准的回收方法，并且回收的物料符合其使用标准，反应物、中间体或原料药的回收（例如，从母液或滤液中）是可以接受的。
14.41 溶剂可以回收，并在同一工序或不同工序重新使用，只要回收过程得到了控制和监测，确保在重新使用或与其它核准的物料混合前，这种溶剂符合一定的标准。
14.42 新鲜的和回收溶剂和试剂可以混合，如果有足够的测试表明它们适用于所参与的生产工序。
14.43 回收溶剂、母液和其它回收的物料的使用应当有足够的文件作证。
14.5 退货
14.50 退回的原料药和中间体应当作有标志，并隔离。
14.51 If the conditions under which returned intermediates or APIs have been stored or shipped before or during their return or the condition of their containers casts doubt on their quality, the returned intermediates or APIs should be reprocessed, reworked, or destroyed, as appropriate.
14.51 如果在中间体或原料药退货之前或退货期间的储存或运输条件，或者其包装容器的状况可能对其质量产生影响，退回的中间体或原料药应当根据情况进行返工、重新加工或销毁。
14.52 Records of returned intermediates or APIs should be maintained. For each return, documentation should be include:
● Name and address of the consignee
● Intermediate or API, batch number, and quantity returned ● Reason for return
● Use or disposal of the returned intermediate or API 15. COMPLAINTS AND RECALLS 15.10 All quality-related complaints, whether received orally or in writing, should be recorded and investigated according to a written procedure. 15.11 Complaint records should include: ● Name and address of complainant
● Name (and, where appropriate, title) and phone number of person submitting the complaint ● Complaint nature (including name and batch number of the API) ● Date complaint is received
● Action initially taken (including dates and identity of person taking the action) ● Any follow-up action taken
● Response provided to the originator of complaint (including date response sent) ● Final decision on intermediate or API batch or lot 15.12 Records of complaints should be retained to evaluate trends, product-related frequencies, 14.52 退回的中间体或原料药应当存有记录。每次退货的记录内容应当包括：
● 收货人姓名和地址； ● 退回的中间体或原料药、批号和数量；
● 退货原因； ● 退回中间体或原料药的用途或处置。
15.投诉与召回
15.10 所有与质量有关的投诉，无论以口头或书面方式收到，都应当根据书面程序进行记录和调查。 15.11 投诉记录应当包括：
● 投诉人姓名地址 ● 递交投诉者的姓名
（必要时包括头衔）和电话
● 投诉性质（包括原料药名称和批号）
● 收到投诉的日期 ● 最初采取的措施
（包括日期和执行者的身份）
● 随后采取的任何措施 ● 对投诉人的回复（包括发出回复的日期）
● 对该批中间体或原料药的最终处置
15.12 投诉记录应当保存，旨在评估其变化趋势、涉及产品的发生频率及其严重性，以便
and severity with a view to taking additional, and if appropriate, immediate corrective action.
15.13 There should be a written procedure that defines the circumstances under which a recall of an intermediate or API should be considered.
15.14 The recall procedure should designate who should be involved in evaluating the 采取额外的，有时是即时的纠正措施。
15.13 应当有书面程序规定在何种情况下应当考虑召回中间体或原料药。
15.14 召回程序应当规定参与评估情况的人员、启动召回的方法、召回应当通知到的对information, how a recall should be initiated, who should be informed about the recall, and how the recalled material should be treated.
15.15 In the event of a serious or potentially life-threatening situation, local, national, and/or international authorities should be informed and their advice sought.
16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)
16.10 All contract manufacturers (including laboratories) should comply with the GMP defined in this guidance. Special consideration should be given to the prevention of cross-contamination and to maintaining traceability.
16.11 Companies should evaluate any contractors (including laboratories) to ensure GMP compliance of the specific operations occurring at the contractor sites.
16.12 There should be a written and approved contract or formal agreement between a company and its contractors that defines in detail the GMP responsibilities, including the quality measures, of each party.
16.13 A contract should permit a company to audit its contractor’s facilities for compliance with GMP.
16.14 When subcontracting is allowed, a
象、以及召回后物料的处理方法。
15.15 如果情况严重或可能威胁生命，则应当通知地方、国家或国际当局，并征求其建议。
16.协议生产商（包括实验室）
16.10 所有协议生产商（包括实验室）应当遵循本指南所规定的GMP。特别应当注意防止交叉污染，并保持可追溯性。
16.11 合同委托方应当对协议生产商（包括实验室）进行评估，以确保在合同地点发生的特定操作符合GMP。
16.12 合同委托方与合同接受方之间应当有经过认定的书面合同或正式协议书，详细规定各方的GMP责任，包括质量措施。
16.13 合同应当允许合同委托方对合同接受方的设施进行GMP审计。
16.14 在允许分包的情况下，未经合同委托方
contractor should not pass to a third party any of the work entrusted to it under the contract without the company’s prior evaluation and approval of the arrangements.
16.15 Manufacturing and laboratory records should be kept at the site where the activity 事先的评估和核准，合同接受方不应当将合同中委托给他的工作转交给第三方。
16.15 生产和分析记录应当保存在操作现场，并随时可得。
occurs and be readily available.
16.16 Changes in the process, equipment, test methods, specifications, or other contractual requirements should not be made unless the contract giver is informed and approves the changes.
17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS 17.1 Applicability
17.10 This section applied to any party other than the original manufacturer who may trade and/or take possession, repack, relabel, manipulate, distribute, or store an API or intermediate.
17.11 All agents, brokers, traders, distributors, repackers, and relabelers should comply with GMP as defined in this guidance.
17.2 Traceability of Distributed APIs and Intermediates
17.20 Agents, brokers, traders, distributors, repackers, and relabelers should maintain complete traceability of APIs and intermediates that they distribute. Documents that should be retained and available include:
● Identity of original manufacturer
● Address of original manufacturer
● Purchase orders
● Bills of lading (transportation documentation) ● Receipt documents
● Name or designation of API or
16.16 应当在通知合同委托方，并得到批准后，才可以对工艺、设备、测试方法、规格标准或其它合同要求进行变更。
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
17.10 本章内容适用于除原生产商以外，参与贸易和/或持有、处理、重新包装、重新贴签、运作和储存原料药或中间体的任何一方。
17.11 所有的代理、经纪人、贸易商、经销商、重新包装者和重新贴签者都必须遵循本指南的GMP。
17.2已分发的原料药和中间体的可追溯性
17.20 代理、经纪人、贸易商、经销商、重新包装者和重新贴签者应当保留完整的已分发原料药和中间体的可追溯性。应当保留和可得到的文件包括：
● 原生产商的身份 ● 原生产商的地址 ● 订单 ● 装运帐单（运输文件）
● 接收文件 ● 原料药或中间体的名称或命名
intermediate
● Manufacturer’s batch number
● Transportation and distribution records ● All authentic Certificates of Analysis,
including those of the original manufacturer ● Retest or expiry date
17.3 Quality Management
17.30 Agents, brokers, traders, distributors, repackers, or relabelers should establish, document and implement an effective system of managing quality, as specified in Section 2.
17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates
17.40 Repackaging, Relabeling, and holding APIs and intermediates should be performed under appropriate GMP controls, as stipulated in this guidance, to avoid mix-ups and loss of API or intermediate identity or purity.
17.41 Repackaging should be conducted under appropriate environmental conditions to avoid contamination and cross-contamination.
17.5 Stability
17.50 Stability studies to justify assigned expiration or retest dates should be conducted if the API or intermediate is repackaged in a different type of container than that used by the API or intermediate manufacturer.
17.6 Transfer of Information
17.60 Agents, brokers, distributors, repackers, or relabelers should transfer all quality or regulatory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or intermediate manufacturer.
17.61 The agent, broker, trader, distributor, repacker, or relabeler who supplies the API or intermediate to the customer should provide the
● 生产商的批号 ● 运输和分发记录
● 所有确认的分析报告单，包括原生产商的
● 复验期或失效期
17.3质量管理
17.30 代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当按第2节的规定建立并执行一个有效的质量管理系统。
17.4原料药和中间体的重新包装、重新贴签和待检
17.40 原料药和中间体的重新包装、重新贴签和待检应当在本指南中所制定的适当的GMP控制下进行，以防原料药或中间体的特性或纯度的混淆和损失。
17.41 重新包装应当在合适的，能防止污染和交叉污染的环境条件下进行。
17.5稳定性
17.50 如果原料药或中间体的重新包装所使用的容器与原料药或中间体的生产商所使用的不同，就应当进行稳定性研究，以确认规定的失效期或复验期。
17.6 信息的传达
17.60 代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当将从原料药或中间体生产商和客户之间传递所有质量或药政的信息。
17.61 将原料药或中间体提供给客户的代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当提供所供原料药或中间体的原
name of the original API or intermediate manufacturer and the batch number(s) supplied.
17.62 The agent should also provide the identity of the original API or intermediate manufacturer to regulatory authorities upon request. The original manufacturer can respond to the regulatory authority directly or through its authorized agents, depending on the legal 生产商的名称和原批号。
17.62 需要时，代理还应当向药政当局提供原生产商的身份。按照原料药或中间体的原生产商和授权代理人之间的法律关系，原生产商可直接地或通过其授权代理向药政当局作回复。（此处“授权”是指由原生产商所给的授权）
relationship between the authorized agents and the original API or intermediate manufacturer. (In this context authorized refers to authorized by the manufacturer.)
17.63 The specific guidance for certificate of analysis included in Section 11.4 should be met.
17.7 Handling of Complaints and Recalls 17.70 Agents, brokers, traders, distributors, repackers, or relabelers should maintain records of complaints and recalls, as specified in Section 15, for all complaints and recalls that come to their attention.
17.71 If the situation warrants, the agents, brokers, traders, distributors, repackers, or relabelers should review the complaint with the original API or intermediate manufacturer to determine whether any further action, either with other customers who may have received this API or intermediate or with the regulatory authority, or both, should be initiated. The investigation into the cause for the complaint or recall should be conducted and documented by the appropriate party.
17.72 Where a complaint is referred to the original API or intermediate manufacturer, the record maintained by the agents, brokers, traders, distributors, repackers, or relabelers should include any response received from the original API or intermediate manufacturer (including date and information provided).
17.63 应当遵循第11.4章所述有关报告单的指南。
17.7 投诉和召回的处理
17.70 参照第15章的要求，代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当保留他们收到的所有投诉和召回的记录。
17.71 如果情况允许，代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当与原料药或中间体的生产商一起审阅投诉，以确定是否应当与其它收到该原料药或中间体的客户，或者药政当局一起采取进一步的措施。对投诉和召回的原因应当由合适的一方进行调查，并记录备查。
17.72 如果投诉是针对原料药或中间体的原生产商，由代理、经纪人、贸易商、经销商、重新包装者或重新贴签者保存的记录应当包括从原料药或中间体原生产商处得到的任何反馈信息（包括提供的日期和内容）。
17.8 Handling of Returns
17.80 Returns should be handled as specified in Section 14.5. The agents, brokers, traders, distributors, repackers, or relabelers should maintain documentation of returned APIs and intermediates. 18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18.1 General
18.10 Section 18 is intended to address specific controls for APIs or intermediates manufactured by cell culture or fermentation using natural or recombinant organisms and that have not been covered adequately in the previous sections. It is not intended to be a stand-alone Section. In general, the GMP principles in the other sections of this document apply. Note that the principles of fermentation for “classical” processes for production of small molecules and for processes using recombinant and nonrecombinant organisms for production of proteins and/or polypeptides are the same, although the degree of control will differ. Where practical, this section will address these differences. In general, the degree of control for biotechnological processes used to produce proteins and polypeptides is greater than that for classical fermentation processes.
18.11 The term “biotechnological process” (biotech) refers to the use of cells or organisms that have been generated or modified by recombinant DNA, hybridoma or other technology to produce APIs. The APIs produced by biotechnological processes normally consist of high molecular weight substances, such as proteins and polypeptides, for which specific guidance is given in this Section. Certain APIs of low molecular weight, such as antibiotics, amino acids, vitamins, and carbohydrates, can also be produced by recombinant DNA technology. The level of
17.8 退货的处理
17.80 退货应当按照14.5章进行处理。代理、经纪人、贸易商、经销商、重新包装者或重新贴签者应当保留原料药或中间体退货的文档。
18. 用细胞繁殖/发酵生产的原料药的特殊指南
18.1 总则
18.10第18节旨在描述对通过细胞繁殖或用天然或重组组织发酵生产的原料药或中间体的一些在前面的章节中没有充分阐明的特殊控制。它不是一个独立的章节。通常，本文件中其他章节的GMP 原则也适用。值得注意的是尽管生产小分子的“经典”工艺的发酵原理和用重组或非重组组织生产蛋白质和/或多肽类的发酵原理是一样的，但是，它们的控制程度不同。本章节将在适当的地方阐述这些不同点。总的来说，用于生产蛋白质和多肽的生物技术工艺的控制要严于经典的发酵工艺。
18.11 “生物技术”是指用重组DNA、杂交瘤或其它技术产生或修饰的细胞或组织来生产原料药。用生物技术生产的原料药通常由蛋白质和多肽这类高分子量的物质组成，本节介绍其特殊指南。有些低分子量的原料药，如抗生素、氨基酸、维生素和糖类也可以用重组DNA来生产。这几类原料药的控制程度与经典发酵的相似。
control for these types of APIs is similar to that employed for classical fermentation.
18.12 The term “classical fermentation” refers to processes that use microorganisms existing in nature and/or modified by conventional methods (e.g. irradiation or chemical mutagenesis) to produce APIs. APIs produced by “classical fermentation” are normally low
18.12 “经典发酵”是指用天然的和/或以传统方法(如，辐照或化学诱变)修改的微生物来生产原料药的工艺。用“经典发酵”生产的原料药通常是低分子量的产品，如，抗生素、氨基酸、维生素和糖类。
molecular weight products such as antibiotics, amino acids, vitamins, and carbohydrates.
18.13 Production of APIs or intermediates from cell culture or fermentation involves biological processes such as cultivation of cells or extraction and purification of material from living organisms. Note that there may be additional process steps, such as physicochemical modification, that are part of the manufacturing process. The raw materials used (media, buffer components) may provide the potential for growth of microbiological contaminants. Depending on the source, method of preparation, and the intended use of the API or intermediate, control of bioburden, viral contamination, and/or endotoxins during manufacturing and monitoring of the process at appropriate stages may be necessary.
18.14 Appropriate controls should be established at all stages of manufacturing to assure intermediate and/or API quality. While this Guide starts at the cell culture/fermentation step, prior steps (e.g. cell banking) should be performed under appropriate process controls. This Guide covers cell culture/fermentation from the point at which a vial of the cell bank is retrieved for use in manufacturing.
18.15 Appropriate equipment and environmental controls should be used to minimize the risk of contamination. The acceptance criteria for quality of the environment and the frequency of monitoring
18.13用细胞培养或发酵来生产原料药或中间体涉及到诸如细胞培养，或从活体组织提取和纯化物料等生物过程。值得注意的是，还有一些附加的隶属于生产工艺一部分的物理化学修饰。使用的原材料(培养基、缓冲成分)可能为微生物污染提供了可能性。根据物料来源、制备方法和原料药或中间体的预期用途，可能有必要在制造和工艺监测的适当阶段控制微生物、病毒污染和/或内毒素。
18.14制造过程的所有阶段都应当建立必要的控制，以保证中间体和/或原料药的质量。尽管本指南从细胞培养/发酵步骤开始，但是前期步骤(如细胞库) 应当在必要的控制下进行。本指南含盖了从细胞库取得用于生产的细胞开始的细胞培养/发酵过程。
18.15应当采取适当的设备和环境控制来将污染的风险降低到最低程度。环境质量的认可标准和监控的频率应当根据生产步骤和生产条件(开口，闭口，或封闭系统)而定。
should depend on the step in production and the production conditions (open, closed, or contained systems).
18.16 In general, process controls should take 18.16通常，应当考虑的工艺控制有： into account:
● Maintenance of the Working Cell Bank ● 工作细胞库的维护(视情况而定)；
(where appropriate);
● Proper inoculation and expansion of the ● 恰当的接种和培养；
culture;
● Control of the critical operating parameters ● 发酵/细胞培养过程中关键操作参数的控
during fermentation/cell culture; 制；
● Monitoring of the process for cell growth, ● 细胞生长、活性(大多数生物技术工艺)和
viability (for most cell culture processes) 生产能力的监控； and productivity where appropriate;
● Harvest and purification procedures that ● 为保护中间体和原料药不受污染(特别是
remove cells, cellular debris and media 微生物学特征)和不损害质量而作的去除components while protecting the 细胞、细胞碎片和培养基组分的收集和纯intermediate or API from contamination 化过程； (particularly of a microbiological nature) and from loss of quality;
必● Monitoring of bioburden and, where ● 在适当的生产阶段进行生物负载控制，
needed, endotoxin levels at appropriate 要时做内毒素的控制； stages of production; and
● Viral safety concerns as described in ICH ● ICH 指南Q5A “生物制品的质量：从人
Guideline Q5A Quality of Biotechnological 体或动物组织细胞族得到的生物制品的Products: Viral Safety Evaluation of 病毒安全性评估”中描述的生物制品的病Biotechnology Products Derived from Cell 毒安全性。 Lines of Human or Animal Origin.
18.17 Where appropriate, the removal of media 18.17应当根据情况证明培养基、宿主细胞蛋components, host cell proteins, other 白、其它与工艺有关的杂质、与产品相关的process-related impurities, product-related 杂质和污染物的去除效果。 impurities and contaminants should be demonstrated.
18.2 Cell Bank Maintenance and Record 18.2细胞库的维护和记录的保存 Keeping
18.20 Access to cell banks should be limited to 18.20应当只有授权的人员才能进入细胞库。 authorized personnel.
18.21 Cell banks should be maintained under 18.21细胞库应当维持在保持细胞活力、防止storage conditions designed to maintain 污染的储存条件下。 viability and prevent contamination.
18.22 Records of the use of the vials from the cell banks and storage conditions should be maintained.
18.23 Where appropriate, cell banks should be periodically monitored to determine suitability for use.
18.24 See ICH Guideline Q5D Quality of Biotechnological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products for a more complete discussion of cell banking.
18.3 Cell Culture/Fermentation
18.30 Where aseptic addition of cell substrates, media, buffers, and gases is needed, closed or contained systems should be used where possible. If the inoculation of the initial vessel or subsequent transfers or additions (media, buffers) are performed in open vessels, there should be controls and procedures in place to minimize the risk of contamination.
18.31 Where the quality of the API can be affected by microbial contamination, manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment.
18.32 Personnel should be appropriately gowned and take special precautions handling the cultures.
18.33 Critical operating parameters (for example temperature, pH, agitation rates, addition of gases, pressure) should be monitored to ensure consistency with the established process. Cell growth, viability (for most cell culture processes), and, where appropriate, productivity should also be monitored. Critical parameters will vary from
18.22细胞库中小瓶细胞的使用和储存条件应当有记录。
18.23细胞库应当根据情况进行周期性的监测，以确定其适用性。
18.24有关细胞库的详细论述请参见ICH 指南Q5D“生物制品的质量：用于生物技术/生物制品生产的细胞质的诱导和特性描述”。
18.3细胞繁殖/发酵
18.30在需要进行来进行细胞质、培养基、缓冲液和气体的无菌添加的场合，如果可能的话，应当采用闭口或密闭系统。如果接种或转种或加料(培养基，缓冲液)是在敞口容器中操作的，就应当有控制措施和程序将污染的风险减少到最低限度。
18.31在原料药的质量会受微生物污染的影响的情况下，使用敞口容器的操作应当在生物安全橱中，或相似的控制环境下进行。
18.32操作人员应当着装适宜，并采取特殊的处理培养物的措施。
18.33应当监测关键的操作参数(如温度，pH，搅拌速度，通气，压力)，确保与工艺规定一致。对细胞生长，活性(大多数生物技术工艺)， 必要时对生产能力也应当进行监测。不同工艺的关键操作参数是不同的，对经典发酵的某些参数可以不必监测。
one process to another, and for classical fermentation, certain parameters (cell viability, for example) may not need to be monitored.
18.34 Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation equipment should be cleaned, and sanitized or sterilized.
18.34细胞培养物的设备，使用后应当清洗和灭菌。发酵设备必要时应当清洗和消毒或灭菌。
18.35 Culture media should be sterilized before use when appropriate to protect the quality of the API.
18.36 There should be appropriate procedures in place to detect contamination and determine the course of action to be taken. This should include procedures to determine the impact of the contamination on the product and those to decontaminate the equipment and return it to a condition to be used in subsequent batches. Foreign organisms observed during fermentation processes should be identified as appropriate and the effect of their presence on product quality should be assessed, if necessary. The results of such assessments should be taken into consideration in the disposition of the material produced.
18.37 Records of contamination events should be maintained.
18.38 Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as appropriate, to minimize the risk of cross-contamination.
18.4 Harvesting, Isolation and Purification 18.40 Harvesting steps, either to remove cells or cellular components or to collect cellular components after disruption, should be performed in equipment and areas designed to minimize the risk of contamination.
18.41 Harvest and purification procedures that
18.35为了保证原料药的质量，细胞培养基必要时在使用前应当灭菌。
18.36应当有合适的程序来检测是否染菌，并决定所采取的措施。该程序应当包括确定染菌对产品质量的影响，设备去污染，和恢复到用于以后批号的程序。适当情况下，发酵工艺中发现的外来有机物应当根据需要进行鉴别，必要时应当就其存在对产品质量的影响进行评估。在处理生产出来的物料时应当考虑该评估的结果。
18.37应当保存染菌记录。
18.38共用(多产品)设备在换产品的清洁后，根据情况可以进行额外测试，以便将交叉污染的风险减少到最低限度。
18.4收取、分离和精制
18.40收取步骤，不管去除细胞或细胞组分，还是收集破坏后的细胞组分，都应当在按尽可能减少污染的要求而设计的设备和区域内进行。
18.41将生产有机物、细胞碎片或培养基组分
remove or inactivate the producing organism, cellular debris and media components (while minimizing degradation, contamination, and loss of quality) should be adequate to ensure that the intermediate or API is recovered with consistent quality.
18.42 All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive batching without cleaning can be used if intermediate or API quality is not compromised.
18.43 If open systems are used, purification should be performed under environmental conditions appropriate for the preservation of product quality.
18.44 Additional controls, such as the use of dedicated chromatography resins or additional testing, may be appropriate if equipment is to be used for multiple products.
18.5 Viral Removal/Inactivation steps
18.50 See the ICH Guideline Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin for more specific information.
18.51 Viral removal and viral inactivation steps are critical processing steps for some processes and should be performed within their validated parameters.
18.52 Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps. Therefore, open processing should be performed in areas that are separate from other processing activities and have separate air handling units.
18.53 The same equipment is not normally used
去除或灭活(同时减少降解、污染、质量损失)的收取和精制工艺，应当充分保证回收到的中间体或原料药是均质的。
18.42所有的设备使用后应当适当地清洗，根据情况还应当消毒。如果对中间体和原料药的质量没有危害，可以连续生产几批后清洗。
18.43如果使用开口系统，应当在适合于保持产品质量的环境下进行精制。
18.44如果设备用于多个产品，可能有必要作诸如使用专用的层析树脂的额外精制控制，或额外的测试。
18.5 病毒的去除/灭活步骤
18.50更具体的资料参见ICH 指南Q5A“生物制品的质量：从人体或动物组织细胞族得到的生物制品的病毒安全性评估”。
18.51对于某些工艺来说，病毒的去除和灭活是关键的工艺步骤，并按其验证过的参数进行。
18.52应当采取合适的预防措施来防止病毒去除/灭活前的步骤对病毒去除/灭活后的步骤的潜在病毒污染。因此，开口工艺应当在与其它操作活动分开的，有独立的空气处理装置的区域内进行。
18.53不同的精制步骤通常不使用同一台设
for different purification steps. However, if the same equipment is to be used, the equipment should be appropriately cleaned and sanitized before reuse. Appropriate precautions should be taken to prevent potential virus carry-over (e.g. through equipment or environment) from previous steps.
备。如果使用同一台设备，在再使用之前应当进行适当的清洁和消毒。应当采取合适的预防措施来防止病毒从前面的步骤带入(例如，通过设备或环境)。
19. APIs for Use in Clinical Trials 19.1 General
19.10 Not all the controls in the previous sections of this Guide are appropriate for the manufacture of a new API for investigational use during its development. Section 19 provides specific guidance unique to these circumstances.
19.11 The controls used in the manufacture of APIs for use in clinical trials should be consistent with the stage of development of the drug product incorporating the API. Process and test procedures should be flexible to provide for changes as knowledge of the process increases and clinical testing of a drug product progresses from pre-clinical stages through clinical stages. Once drug development reaches the stage where the API is produced for use in drug products intended for clinical trials, manufacturers should ensure that APIs are manufactured in suitable facilities using appropriate production and control procedures to ensure the quality of the API.
19.2 Quality
19.20 Appropriate GMP concepts should be applied in the production of APIs for use in clinical trials with a suitable mechanism of approval of each batch.
19.21 A quality unit(s) independent from production should be established for the approval or rejection of each batch of API for use in clinical trials.
19. 用于临床研究的原料药
19.1 总则
19.10不是本指南前面章节中所有的控制都适合于开发阶段用于研究的新原料药的制造。第19章提供了针对此种情况的特殊指南。
19.11用于生产临床试验用原料药的生产控制应当与含有该原料药的药品的开发阶段一致。工艺和检验程序应当随着工艺知识的积累，从前期临床阶段到临床阶段的药品临床测试的发展，提供变更的可能性。一旦药物的开发到了为用于临床试验的药品生产原料药的阶段，生产者应当确原料药是在适当的设施中，采用保证原料药质量的适当生产和控制程序生产的。
19.2 质量
19.20在对每批有合适的批准机制的临床试验用原料药的生产中应当采用适当的GMP观念。
19.21应当建立独立于生产部的质量部门，来确定每批用于临床试验的原料药合格或不合格。
19.22 Some of the testing functions commonly performed by the quality unit(s) can be performed within other organizational units.
19.23 Quality measures should include a system for testing of raw materials, packaging materials, intermediates, and APIs.
19.22某些通常由质量部门执行的测试功能可以在其它部门进行。
19.23质量措施应当包括一个测试原料、包装材料、中间体和原料药的系统。
19.24 Process and quality problems should be evaluated.
19.25 Labelling for APIs intended for use in clinical trials should be appropriately controlled and should identify the material as being for investigational use.
19.3 Equipment and Facilities
19.30 During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean and suitable for its intended use.
19.31 Procedures for the use of facilities should ensure that materials are handled in a manner that minimizes the risk of contamination and cross-contamination.
19.4 Control of Raw Materials
19.40 Raw materials used in production of APIs for use in clinical trials should be evaluated by testing, or received with a supplier’s analysis and subjected to identity testing. When a material is considered hazardous, a supplier's analysis should suffice.
19.41 In some instances, the suitability of a raw material can be determined before use based on acceptability in small-scale reactions (i.e., use testing) rather than on analytical testing alone.
19.24对工艺和质量问题应当进行评估。
19.25临床实验用原料药的贴签应当有适当的控制，并将物料标明用于研究。
19.3 设备和设施
19.30在临床开发的所有阶段，包括使用小型设备或实验室进行临床试验用原料药的生产，应当提供确保设备经过校验、清洁并适于其预定用途的程序。
19.31设施的使用程序应当确保原料以将污染和交叉污染减少到最低限度的方式操作。
19.4 原料的控制
19.40用于临床试验用原料药生产的原料应当通过测试来评估，或者凭供应商的分析报告单接收，并进行鉴别测试。如果原材料有毒性，一份供应商的分析报告单应当够了。
19.41有时，原料的适用性可以在使用前根据其在小规模反应（如使用测试）中的可接受程度而定，而不单凭分析测试。
19.5 Production
19.50 The production of APIs for use in clinical trials should be documented in laboratory notebooks, batch records, or by other appropriate means. These documents should include information on the use of production materials, equipment, processing, and scientific observations.
19.5 生产
19.50临床试验用原料药的生产应当在实验室记录本、批记录中，或以其它适合的方式成文备查。这些文件应当包括所用的生产原料、设备、工艺，和科学观察。
19.51 Expected yields can be more variable and less defined than the expected yields used in commercial processes. Investigations into yield variations are not expected.
19.6 Validation
19.60 Process validation for the production of APIs for use in clinical trials is normally inappropriate, where a single API batch is produced or where process changes during API development make batch replication difficult or inexact. The combination of controls, calibration, and, where appropriate, equipment qualification assures API quality during this development phase.
19.61 Process validation should be conducted in accordance with Section 12 when batches are produced for commercial use, even when such batches are produced on a pilot or small scale.
19.7 Changes
19.70 Changes are expected during development, as knowledge is gained and the production is scaled up. Every change in the production, specifications, or test procedures should be adequately recorded.
19.8 Laboratory Controls
19.80 While analytical methods performed to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound.
19.81 A system for retaining reserve samples of
19.51预期产量同正式生产的预期产量相比可能更具变异性、更不确定。无需对产量变化进行调查。
19.6 验证
19.60在临床试验用原料药只生产一批，或者有由于原料药开发中工艺的变更使批次的重现困难或不精确的场合，不适合作原料药的工艺验证。控制、校验和必要的设备确认的结合会保证开发阶段的原料药质量。
19.61在生产商业用批号，甚至是中试或小规模生产批号时，应当按照第12章进行工艺验证。
19.7 变更
19.70随着知识的积累和生产规模的扩大，在开发阶段会有变更。生产、规格或检验方法的每一个变更都应当适当地记录。
19.8 实验室控制
19.80虽然评估一批临床试验用原料药的分析方法可能还没有验证，但是，它们应当是科学，合理的。
19.81应当有一套保存所有批号留样的系统。
all batches should be in place. This system should ensure that a sufficient quantity of each reserve sample is retained for an appropriate length of time after approval, termination, or discontinuation of an application.
19.82 Expiry and retest dating as defined in Section 11.6 applies to existing APIs used in clinical trials. For new APIs, Section 11.6 does not normally apply in early stages of clinical trials.
19.9 Documentation
19.90 A system should be in place to ensure that information gained during the development and the manufacture of APIs for use in clinical trials is documented and available.
19.91 The development and implementation of the analytical methods used to support the release of a batch of API for use in clinical trials should be appropriately documented.
19.92 A system for retaining production and control records and documents should be used. This system should ensure that records and documents are retained for an appropriate length of time after the approval, termination, or discontinuation of an application.
20. Glossary
Acceptance Criteria
Numerical limits, ranges, or other suitable measures for acceptance of test results.
Active Pharmaceutical Ingredient (API) (or Drug Substance)
Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity
该系统应当确保在申请批准、终止或中断后能将足够量的每一个留样保存一段适当的时间。
19.82按第11.6节规定的设定有效期或复验期适用于现有的临床试验用原料药。对新的原料药，第11.6节通常不适于临床试验的前期阶段。
19.9 文件
19.90应当有一个系统确保在临床试验用原料药的开发和生产过程中得到的信息均成文备查，并可获得。
19.91支持放行一批临床试验用原料药的分析方法的开发和实施应当适当地成文备查。
19.92应当采用一套保存生产和控制的记录和文件的系统。该系统应当保证记录和文件在申请批准、终止或中断后能记录和文件保存一段适当的时间。
20. 术语 认可标准
接收测试结果的数字限度、范围或其它合适的量度标准。
活性药用成分(原料药)
旨在用于药品制造中的任何一种物质或物质的混合物，而且在用于制药时，成为药品的一种活性成分。此种物质在疾病的诊断，治疗，症状缓解，处理或疾病的预防中有药理活性或其它直接作用，或者能影响机体的功能和结构。
or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body. API Starting Material 原料药的起始物料
A raw material, intermediate, or an API 用在原料药生产中的，以主要结构单元被并that is used in the production of an API 入该原料药的原料、中间体或原料药。原料and that is incorporated as a significant 药的起始物料可能是在市场上有售，能够根structural fragment into the structure of 据合同或商业协议从一个或多个供应商处购the API. An API Starting Material can be 得，或者自己生产。原料药的起始物料通常an article of commerce, a material 有特定的化学特性和结构。
purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials are normally of defined chemical properties and structure.
Batch (or Lot)
A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval.
Batch Number (or Lot Number)
A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined.
Bioburden
The level and type (e.g. objectionable or not) of micro-organisms that can be present in raw materials, API starting materials, intermediates or APIs. Bioburden should not be considered contamination unless the levels have been exceeded or defined objectionable organisms have been detected.
批
由一个或一系列工艺过程生产的一定数量的物料，因此在规定的限度内是均一的。在连续生产中，一批可能对应于与生产的某一特定部分。其批量可规定为一个固定数量，或在固定时间间隔内生产的数量。
批号
用于标识一批的一个数字、字母和/或符号的唯一组合，从中可确定生产和销售的历史。
生物负载
可能存在于原料、原料药的起始物料、中间体或原料药中的微生物的水平和种类(例如，致病的或不致病的)。生物负载不应当当作污染，除非含量超标，或者测得致病生物。
Calibration
The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements.
Computer System
A group of hardware components and associated software, designed and assembled to perform a specific function or group of functions.
Computerized System
A process or operation integrated with a computer system.
Contamination
The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, or API during production, sampling, packaging or repackaging, storage or transport.
Contract Manufacturer
A manufacturer performing some aspect of manufacturing on behalf of the original manufacturer.
Critical
Describes a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.
Cross-Contamination
Contamination of a material or product with another material or product.
校验
证明某个仪器或装置在一适当的量程范围内所测得的结果与一参照物，或可追溯的标准相比在规定限度内。
计算机系统
设计安装用于执行某一项或一组功能的一组硬件元件和关联的软件。
计算机化系统
与计算机系统整合的一个工艺或操作。
污染
在生产、取样、包装或重新包装、贮存或运输过程中，具化学或微生物性质的杂质或外来物质进入或沾染原料、中间体或原料药。
协议制造商
代表原制造商进行部分制造的制造商。
关键的
用来描述为了确保原料药符合规格标准，必须控制在预定范围内的工艺步骤、工艺条件、测试要求或其它有关参数或项目。
交叉污染
一种物料或产品对另一种物料或产品的污染。
Deviation
Departure from an approved instruction or established standard.
Drug (Medicinal) Product
The dosage form in the final immediate packaging intended for marketing. (Reference Q1A)
Drug Substance
See Active Pharmaceutical Ingredient
Expiry Date (or Expiration Date)
The date placed on the container/labels of an API designating the time during which the API is expected to remain within established shelf life specifications if stored under defined conditions, and after which it should not be used.
Impurity
Any component present in the intermediate or API that is not the desired entity.
Impurity Profile
A description of the identified and unidentified impurities present in an API.
In-Process Control (or Process Control)
Checks performed during production in order to monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or API conforms to its specifications.
Intermediate
A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API. Intermediates may or may not be isolated. (Note: this Guide only addresses those intermediates produced after the point that the company has defined as the point at which the production of the API begins.)
偏差
对批准的指令或规定的标准的偏离。
药品
经最后包装准备销售的制剂(参见Q1A)。
原料药
见活性药物成分
有效期
原料药容器/标签上注明的日期，在此规定时间内，该原料药在规定条件下贮存时，仍符合规格标准，超过这一期限则不应当使用。
杂质
存在于中间体或原料药中，任何不希望得到的成分。
杂质概况
对存在于一种原料药中的已知和未知杂质的描述。
过程控制
生产过程中为监测，在必要时调节工艺和/或保证中间体或原料药符合其规格而进行的检查。
中间体
原料药工艺步骤中产生的、必须经过进一步分子变化或精制才能成为原料药的一种物料。中间体可以分离或不分离。(注：本指南只涉及该公司定义为原料药生产起始点以后生产的中间体。)
Manufacture
All operations of receipt of materials, production, packaging, repackaging, labelling, relabelling, quality control, release, storage, and distribution of APIs and related controls.
Material
A general term used to denote raw materials (starting materials, reagents, solvents), process 制造
物料的接收、原料药的生产、包装、重新包装、贴签、重新贴签、质量控制、放行、贮存和分发以及相关控制的所有操作。
物料
原料(起始物料，试剂，溶剂)，工艺辅助用品，中间体，原料药， 和包装及贴签材料的统称。
aids, intermediates, APIs and packaging and labelling materials.
Mother Liquor
The residual liquid which remains after the crystallization or isolation processes. A mother liquor may contain unreacted materials, intermediates, levels of the API and/or impurities. It may be used for further processing.
Packaging Material
Any material intended to protect an intermediate or API during storage and transport.
Procedure
A documented description of the operations to be performed, the precautions to be taken and measures to be applied directly or indirectly related to the manufacture of an intermediate or API.
Process Aids
Materials, excluding solvents, used as an aid in the manufacture of an intermediate or API that do not themselves participate in a chemical or biological reaction (e.g. filter aid, activated carbon, etc).
Process Control
See In-Process Control
母液
结晶或分离后剩下的残留液。母液可能含有未反应的物料、中间体、不同级别的原料药和/或杂质。它可用于进一步加工。
包装材料
在储运过程中保护中间体或原料药的任何物料。
程序
对要进行的操作、要采取的预防措施以及与原料药或中间体生产直接或间接相关的方法的描述文件。
工艺辅料
除溶剂外，在原料药或中间体生产中起辅助作用、本身不参与化学或生物学反应的物料(例如，助滤剂、活性炭)。
工艺控制 见过程控制
Production
All operations involved in the preparation of an API from receipt of materials through processingand packaging of the API.
Qualification
Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.
Quality Assurance (QA)
The sum total of the organised arrangements made with the object of ensuring that all APIs are of the quality required for their intended use and that quality systems are maintained.
Quality Control (QC)
Checking or testing that specifications are met.
Quality Unit(s)
An organizational unit independent of production which fulfills both Quality Assurance and Quality Control responsibilities. This 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.
Quarantine
The status of materials isolated physically or by other effective means pending a decision on their subsequent approval or rejection.
Raw Material
A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or APIs.
生产
在原料药制备过程中，从接收原料，到工艺加工和原料药包装所涉及的所有操作。
确认
证明设备或辅助系统，安装正确、工作正常、确实产生预期的结果，并以文件佐证的行为。确认是验证的一部分，但单独的确认步骤不构成工艺验证。
质量保证
以确保所有原料药达到其应用所要求的质量，并维持质量体系为目的的全部组织安排的总和。
质量控制
是否符合质量规格的检查或测试。
质量部门
独立于生产部门的履行质量保证和质量控制职责的组织机构。按照组织机构的大小和结构，可以是单独的QA 和QC部门，或个人，或小组。
待验
在实物上或以其它有效方式将物料隔离，等待对其随后的批准或拒收做出决定的状态。
原料
用来表示中间体或原料药的生产中要用的起始物料、试剂和溶剂的通用专业名词。
Reference Standard, Primary
A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity. This standard can be: (1) obtained from an officially recognised source, or (2) prepared by independent synthesis, or (3) obtained from existing production material of high purity, or (4) prepared by further purification of existing 基准参考标准品
经广泛分析测试表明具有可信的高纯度的物质。这类标准品可以：1)来源于法定的机构，2)独立合成，3)来自于高纯度的现有生产物料，或4)用进一步精制现有生产物料的方法来制备。
production material.
Reference Standard, Secondary
A substance of established quality and purity, as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory analysis.
Reprocessing
Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process. Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process, and not reprocessing.
Retest Date
The date when a material should be re-examined to ensure that it is still suitable for use.
Reworking
Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or API (e.g., recrystallizing with a different solvent).
二级参考标准品
与基准参考标准品比较显示具有规定的质量和纯度，并用作日常实验室分析的参考标准品。
返工
将不符合标准或规格的一个中间体或原料药返回工艺过程，重复规定的生产工艺中的某一结晶步骤或其它合适的化学或物理处理步骤(如蒸馏，过滤，层析，磨粉)，这种做法通常是可以接受的。在中间控制的测试表明一工艺步骤没有完成，从而继续该步骤，是正常工艺的一部分，而不是返工。
复验日期
物料应当重新检验以确保其仍可使用的日期。
重新加工
将不符合规格标准的中间体或原料药用不同于规定生产工艺的一个或几个步骤进行处理，以得到质量可接受的中间体或原料药(如：用不同溶剂的再结晶)。
Signature (signed)
The record of the individual who performed a particular action or review. This record can be initials, full handwritten signature, personal seal, or authenticated and secure electronic signature.
Solvent
An inorganic or organic liquid used as a vehicle 签名
做过某一特定行动或审核的个人的一种记录。此类记录可以是首字母缩写、手写全名、个人印章或经证实的可靠的电子签名。
溶剂
中间体或原料药中用作制备溶液或悬浮液的for the preparation of solutions or suspensions in the manufacture of an intermediate or API.
Specification
A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. “Conformance to specification” means that the material, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.
Validation
A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria.
Validation Protocol
A written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters/operating ranges, product characteristics, sampling, test data to be collected, number of validation runs, and acceptable test results.
载体的无机或有机液体。
质量标准
一系列的测试项目、有关的分析程序和适当的认可标准，此标准可以是数值限度、范围或所述测试项目的其它标准。它规定一套标准，物料应当符合该标准，才被认为可以用作其预期的用途。“符合规格”表示物料按所列的分析程序测试时，会符合所列的接受标准。
验证
为某一特定的工艺、方法或系统能够持续地产生符合既定接受标准的结果提供充分保证的文件程序。
验证方案
说明如何进行验证和规定接受标准的书面计划。例如，生产工艺验证方案确定工艺设备、关键性工艺参数/操作范围、产品特性、取样、收集的测试数据、验证的次数，以及可接受的测试结果。
Yield, Expected
The quantity of material or the percentage of theoretical yield anticipated at any appropriate phase of production based on previous laboratory, pilot scale, or manufacturing data.
Yield, Theoretical
The quantity that would be produced at any appropriate phase of production, based upon the quantity of material to be used, in the absence of any loss or error in actual production.
预期产量
在以前实验室、中试规模或生产数据的基础上，预计任何适当的生产阶段的物料的量或理论产量的百分比。
理论产量
根据投料量，不计任何实际生产中的损失或过失，计算任何适当的生产阶段生产的量。
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