（中英文对照）GMP Guidance for APIs （FDA原料药GMP指南）

 
1. INTRODUCTION
 
1. 简介
 
1.1 Objective
 
1.1目的
 
This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess.
 
本文件旨在为在合适的质量管理体系下制造活性药用成分（以下称原料药）提供有关优良药品生产管理规范（GMP）提供指南。它也着眼于帮助确保原料药符合其旨在达到或表明拥有的质量与纯度要求。
 
 
 
In this guidance, the term manufacturing is defined to include all operations of receipt of materials, production, packaging, repackaging, labeling, relabeling, quality control, release, storage and distribution of APIs and the related controls. In this guidance, the term should identifies recommendations that, when followed, will ensure compliance with CGMPs. An alternative approach may be used if such approach satisfies the requirements of the applicable statues. For the purposes of this guidance, the terms current good manufacturing practices and good manufacturing practices are equivalent.
 
本指南中所指的“制造”包括物料接收、生产、包装、重新包装、贴签、重新贴签、质量控制、放行、原料药的储存和分发及其相关控制的所有操作。本指南中，“应当”一词表示希望采用的建议，除非证明其不适用或者可用一种已证明有同等或更高质量保证水平的供选物来替代。本指南中的“现行优良生产管理规范（cGMP）”和“优良生产管理规范（GMP）”是等同的。
 
 
 
The guidance as a whole does not cover safety aspects for the personnel engaged in manufacturing, nor aspects related to protecting the environment. These controls are inherent responsibilities of the manufacturer and are governed by national laws.
 
本指南在总体上未涉及生产人员的安全问题，亦不包括环保方面的内容。这方面的管理是生产者固有的责任，也是国家法律规定的。
 
 
 
This guidance is not intended to define registration and/or filing requirements or modify pharmacopoeial requirements. This guidance does not affect the ability of the responsible regulatory agency to establish specific registration/filing requirements regarding APIs within the context of marketing/manufacturing authorizations or drug applications. All commitments in registration/filing documents should be met.
 
本指南未规定注册/归档的要求、或修改药典的要求。本指南不影响负责药政审理部门在原料药上市/制造授权或药品申请方面建立特定注册/归档要求的能力。注册/归档的所有承诺必须做到。
 
 
 
1.2 Regulatory Applicability
 
1.2法规的适用性
 
Within the world community, materials may vary as to their legal classification as an API. When a material is classified as an API in the region or country in which it is manufactured or used in a drug product, it should be manufactured according to this guidance.
 
在世界范围内对原料药的法定定义是各不相同的。当某种物料在其制造或用于药品的地区或国家被称为原料药，就应该按照本指南进行生产。
 
 
 
1.3 Scope
 
1.3范围
 
This guidance applies to the manufacture of APIs for use in human drug (medicinal) products. It applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs being rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by this guidance, but should be performed in accordance with GMP guidances for drug (medicinal) products as defined by local authorities.
 
本文件适用于人用药品（医疗用品）所含原料药的生产。它适用于无菌原料药在灭菌前的步骤。本指南不包括无菌原料药的消毒和灭菌工艺，但是，应当符合地方当局所规定的药品（医疗用品）生产的GMP指南。
 
 
 
This guidance covers APIs that are manufactured by chemical synthesis, extraction, cell culture/fermentation, recovery from natural sources, or any combination of these processes. Specific guidance for APIs manufactured by cell culture/fermentation is described in Section 18.
 
本文件适用于通过化学合成、提取、细胞培养/发酵，通过从自然资源回收，或通过这些工艺的结合而得到的原料药。通过细胞培养/发酵生产的原料药的特殊指南则在第18章论述。
 
 
 
This guidance excludes all vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy APIs. However, it does include APIs that are produced using blood or plasma as raw materials. Note that cell substrates (mammalian, plant, insect or microbial cells, tissue or animal sources including transgenic animals) and early process steps may be subject to GMP but are not covered by this guidance. In addition, the guidance does not apply to medical gases, bulk-packaged drug (medicinal) products (e.g., tablets or capsules in bulk containers), or radiopharmaceuticals.
 
本指南不包括所有疫苗、完整细胞、全血和血浆、全血和血浆的衍生物（血浆成分）和基因治疗的原料药。但是却包括以血或血浆为原材料生产的原料药。值得注意的是细胞培养基（哺乳动物、植物、昆虫或微生物的细胞、组织或动物源包括转基因动物）和前期生产可能应遵循GMP规范，但不包括在本指南之内。另外，本指南不适用于医用气体、散装的制剂药（例如，散装的片剂和胶囊）和放射性药物的生产。
 
 
 
Section 19 contains guidance that only applies to the manufacture of APIs used in the production of drug (medicinal) products specifically for clinical trials (investigational medicinal products).
 
第19章的指南只适用于用在药品（医疗用品）生产中的原料药制造，特别是临床实验用药（研究用医疗产品）的原料药制造。
 
 
 
An API starting material is a raw material, an intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials normally have defined chemical properties and structure.
 
“原料药的起始物料”是指一种原料、中间体或原料药，用来生产一种原料药，或者以主要结构单元的形式被结合进原料药结构中。原料药的起始物料可能是在市场上有售、能够通过合同或商业协议从一个或多个供应商处购得，或由生产厂家自制。原料药的起始物料一般来说有特定的化学特性和结构。
 
 
 
The company should designate and document the rationale for the 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.
 
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。
 
 
 
From this point on, appropriate GMP as defined in this guidance should be applied to these intermediate and/or API manufacturing steps. This would include the validation of critical process steps determined to impact the quality of the API. However, it should be noted that the fact that a company chooses to validate a process step does not necessarily define that steps as critical.
 
从这步开始，本指南中的有关GMP规范应当应用在这些中间体和/或原料药的制造中。这包括对原料药质量有影响的关键工艺步骤的验证。但是，值得注意的是厂商选择某一步骤进行验证，并不一定将该步骤定为关键步骤。
 
 
 
The guidance in this document would normally be applied to the steps shown in gray in Table 1. However, all steps shown may not be completed. The stringency of GMP in API manufacturing should increase as the process proceeds from early API steps to final steps, purification, and packaging. Physical processing of APIs, such as granulation, coating or physical manipulation of particle size (e.g., milling, micronizing) should be conducted according to this guidance.
 
本文件的指南通常适用于表1中的灰色步骤。但在表中体现的所有步骤并不是将应用GMP管理的所有步骤全部体现出来了。原料药生产中的GMP要求应当随着工艺的进行，从原料药的前几步到最后几步，精制和包装，越来越严格。原料药的物理加工，如制粒、包衣或颗粒度的物理处理（例如制粉、微粉化）应当按本指南的标准进行。
 
 
 
This GMP guidance does not apply to steps prior to the introduction of the defined API starting material.
 
本GMP指南不适用于引入定义了的“原料药的起始物料”以前的步骤。
Table 1: Application of this Guidance to API Manufacturing
 
Type of Manufacturing
 
Application of this guidance to steps (shown in gray) used in this type of manufacturing
 
Chemical manufacturing
 
Production of the API Starting material
 
Introduction of the API starting material into process
 
Production of Intermediate(s)
 
Isolation and purification
 
Physical processing, and packaging
 
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
 
Isolation and purification
 
Physical processing, and packaging
 
API extracted from plant sources
 
Collection of plant
 
Cutting and initial extraction(s)
 
Introduction of the API starting material into process
 
Isolation and purification
 
Physical processing, and packaging
 
Herbal extracts used as API
 
Collection of plants
 
Cutting and initial extraction
 
 
Further extraction
 
Physical processing, and packaging
 
API consisting of comminuted or powdered herbs
 
Collection of plants and/or cultivation and harvesting
 
Cutting/comminuting
 
 
 
Physical processing, and packaging
 
Biotechnology: fermentation/cell culture
 
Establishment of master cell bank and working cell bank
 
Maintenance of working cell bank
 
Cell culture and/or fermentation
 
Isolation and purification
 
Physical processing, and packaging
 
“Classical” fermentation to produce an API
 
Establishment of cell bank
 
Maintenance of the cell bank
 
Introduction of the cells into fermentation
 
Isolation and purification
 
Physical processing, and packaging
 
Increasing GMP requirements
表 1: 本指南在原料药生产中的应用
 
生产类型
 
本指南在用于各类生产的工艺步骤（灰色背景）中的应用
 
化学品的生产
 
原料药起始物料的生产
 
原料药起始物料引入工艺过程
 
中间体的生产
 
分离和纯化
 
物理加工和包装
 
动物源原料药
 
器官、分泌物或组织的收集
 
切割、混合和/或初步加工
 
原料药起始物料引入工艺过程
 
分离和纯化
 
物理加工和包装
 
从植物源提取的原料药
 
植物的收集
 
切割和初步提取
 
原料药起始物料引入工艺过程
 
分离和纯化
 
物理加工和包装
 
草药提取物用作原料药
 
植物的收集
 
切割和初步提取
 
 
进一步提取
 
物理加工和包装
 
由粉碎的或粉末状草药组成的原料药
 
植物的收集和/或培养和收获
 
切割/粉碎
 
 
 
物理加工和包装
 
生物技术：发酵/细胞培养
 
主细胞库和工作细胞库的建立
 
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
 
“经典” 发酵生产原料药
 
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
 
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 persons involved in manufacturing.
 
2.10 参与原料药生产的每一个人都应当对质量负责。
 
 
 
2.11 Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.
 
2.11 每一个生产商都应当建立并执行一套有管理人员和有关员工积极参与的有效的质量管理体系，并使其文件化。
 
 
 
2.12 The system for managing quality should encompass the organizational structure, procedures, process and resources, as well as activities to ensure confidence that the API will meet its intended specifications for quality and purity. All quality-related activities should be defined and documented.
 
2.12 质量管理体系应当包括组织机构、规程、工艺和资源，以及确保原料药会符合其预期的质量与纯度要求所必需的活动。所有涉及质量管理的活动都应当明确规定，并使其文件化。
 
 
 
2.13 There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. The quality unit can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.
 
2.13 应当设立一个独立于生产部门的质量部门，同时履行质量保证(QA)和质量控制 (QC)的职责。依照组织机构的大小，可以是分开的QA和QC部门，或者只是一个人或小组。
 
 
 
2.14 The persons authorized to release intermediates and APIs should be specified.
 
2.14 应当指定授权发放中间体和原料药的人员。
 
 
 
2.15 All quality-related activities should be recorded at the time they are performed.
 
2.15 所有有关质量的活动应当在其执行时就记录。
 
 
 
2.16 Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented.
 
2.16 任何偏离既定规程的情况都应当有文字记录并加以解释。对于关键性偏差应当进行调查，并记录调查经过及其结果。
 
 
 
2.17 No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g., release under quarantine as described in Section 10 or the use of raw materials or intermediates pending completion of evaluation).
 
2.17 在质量部门对物料完成满意的评价之前，任何物料都不应当发放或使用，除非有合适的系统允许此类使用（如10.20条款所述的待检情况下的使用，或是原料或中间体在等待评价结束时的使用）。
 
 
 
2.18 Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality-related complaints, recalls, and regulatory actions).
 
2.18 应当有规程能确保公司的责任管理部门能及时得到有关药政检查、严重的GMP缺陷、产品缺陷及其相关活动（如质量投诉，召回，药政活动等）的通知。
 
 
 
2.2 Responsibilities of the Quality Unit(s)
 
2.2质量部门的责任
 
2.20 The quality unit(s) should be involved in all quality-related matters.
 
2.20 质量部门应当参与所有与质量有关的事物。
 
 
 
2.21 The quality unit(s) should review and approve all appropriate quality-related documents.
 
2.21 所有与质量有关的文件应当由质量部门审核批准。
 
 
 
2.22 The main responsibilities of the independent quality unit(s) should not be delegated. These responsibilities should be described in writing and should include, but not necessarily be limited to:
1.       Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing company
2.       Establishing a system to release or reject raw materials, intermediates, packaging, and labeling materials
3.       Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution
4.       Making sure that critical deviations are investigated and resolved
5.       Approving all specifications and master production instructions
6.       Approving all procedures affecting the quality of intermediates or APIs
7.       Making sure that internal audits (self-inspections) are performed
8.       Approving intermediate and API contract manufacturers
9.       Approving changes that potentially affect intermediate or API quality
10.   Reviewing and approving validation protocols and reports
11.   Making sure that quality-related complaints are investigated and resolved
12.   Making sure that effective systems are used for maintaining and calibrating critical equipment
13.   Making sure that materials are appropriately tested and the results are reported
14.   Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates, where appropriate
15.   Performing product quality reviews (as defined in Section 2.5)
 
2.22 独立的质量部门的主要职责不应当委派给他人。这些责任应当以文字形式加以说明，而且应当包括，但不限于：
1.       所有原料药的放行与否。用于生产商控制范围以外的中间体的放行与否；
2.       建立一个放行与拒收原材料、中间体、包装材料和标签的系统；
3.       在供销售的原料药放行前，审核已完成的关键步骤的批生产记录和实验室检验记录；
4.       确保已对重大偏差进行了调查并已解决；
5.       批准所有的规格标准和主生产指令；
6.       批准所有可能影响原料药和中间体质量的规程；
7.       确保进行内部审计（自检）；
8.       批准中间体或原料药的委托生产商；
9.       批准可能影响到中间体或原料药质量的变更；
10.   审核并批准验证方案和报告；
11.   确保调查并解决质量问题的投诉；
12.   确保用有效的体系来维护和校验关键设备；
13.   确保物料都经过了适当的检验并报告结果；
14.   确保有稳定性数据支持中间体或原料药的复验期或有效期和储存条件；
15.   开展产品质量审核（详见2.5节）。
 
 
 
2.3 Responsibility for Production Activities
 
2.3生产作业的职责
 
The responsibility for production activities should be described in writing and should include, but not necessarily be limited to:
1.       Preparing, reviewing, approving, and distributing the instructions for the production of intermediates or APIs according to written procedures
2.       Producing APIs and, when appropriate, intermediates according to pre-approved instructions
3.       Reviewing all production batch records and ensuring that these are completed and signed
4.       Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded
5.       Making sure that production facilities are clean and, when appropriate, disinfected
6.       Making sure that the necessary calibrations are performed and records kept
7.       Making sure that the premises and equipment are maintained and records kept
8.       Making sure that validation protocols and reports are reviewed and approved
9.       Evaluating proposed changes in product, process or equipment
10.   Making sure that new and, when appropriate, modified facilities and equipment are qualified
 
生产作业的职责应当以文字形式加以说明，并应当包括，但不限于以下内容：
1.       按书面程序起草、审核、批准和分发中间体或原料药的生产指令；
2.       按照已批准的指令生产原料药或者中间体；
3.       审核所有的批生产记录确保其完整并有签名；
4.       确保所有的生产偏差都已报告、评价，对关键的偏差已做了调查，并记录结论；
5.       确保生产设施的清洁，必要时要消毒；
6.       确保进行必要的校验，并有记录；
7.       确保对厂房和设备进行保养，并有记录；
8.       确保验证方案和报告的审核与批准；
9.       对产品、工艺或设备拟作的变更进行评估；
10.   确保新的或已改进的生产设施和设备经过了确认。
 
 
 
2.4 Internal Audits (Self Inspection)
 
2.4内部审计（自检）
 
2.40 To verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.
 
2.40 为确实符合原料药GMP原则，应当按照批准的计划进行定期的内部审计。
 
 
 
2.41 Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner.
 
2.41 审计结果及整改措施应当形成文件，并引起公司责任管理人员的重视。获准的整改措施应当及时、有效地完成。
 
 
 
2.5 Product Quality Review
 
2.5产品质量审核
 
2.50 Regular quality-reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least:
●     A review of critical in-process control and critical API test results
●     A review of all batches that failed to meet established specification(s)
●     A review of all critical deviations or nonconformances and related investigations
●     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
 
2.50 原料药的定期质量审核应当以证实工艺的一致性为目的来进行。此种审核通常应当每年进行一次，并记录，内容至少应当包括：
●     关键工艺控制以及原料药关键测试结果的审核；
●     所有不符合既定质量标准的产品批号的审核；
●     所有关键的偏差或违规行为及有关调查的审核；
●     任何工艺或分析方法变动的审核；
●     稳定性监测的审核；
●     所有与质量有关的退货、投诉和召回的审核；
●     整改措施的适当性的审核。
 
 
 
2.51 The results of this review should be evaluated and an assessment made of whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented. Agreed corrective actions should be completed in a timely and effective manner.
 
2.51 应当对质量审核结果进行评估，并做出是否需要整改或做任何再验证的评价。此类整改措施的理由应当文件化。获准的整改措施应当及时、有效地完成。