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1、Q7a（中英文对照）FDA原料药GMP指南Table of Contents目录1. INTRODUCTION1. 简介1.1 Objective1.1目的1.2 Regulatory Applicability1.2法规的适用性1.3 Scope1.3范围2. QUALITY MANAGEMENT2.质量管理2.1 Principles2.1总则2.2 Responsibilities of the Quality Unit(s)2.2质量部门的责任2.3 Responsibility for Production Activities2.3生产作业的职责2.4 Internal Audit
2、s (Self Inspection)2.4内部审计（自检）2.5 Product Quality Review2.5产品质量审核3. PERSONNEL3. 人员3.1 Personnel Qualifications3.人员的资质3.2 Personnel Hygiene3.2 人员卫生3.3 Consultants3.3 顾问4. BUILDINGS AND FACILITIES4. 建筑和设施4.1 Design and Construction4.1 设计和结构4.2 Utilities4.2 公用设施4.3 Water4.3 水4.4 Containment4.4 限制4.5 Li
3、ghting4.5 照明4.6 Sewage and Refuse4.6 排污和垃圾4.7 Sanitation and Maintenance4.7 卫生和保养5. PROCESS EQUIPMENT5. 工艺设备5.1 Design and Construction5.1 设计和结构5.2 Equipment Maintenance and Cleaning5.2 设备保养和清洁5.3 Calibration5.3 校验5.4 Computerized Systems5.4 计算机控制系统6. DOCUMENTATION AND RECORDS6. 文件和记录6.1 Documentati
4、on System and Specifications6.1 文件系统和质量标准6.2 Equipment cleaning and Use Record6.2 设备的清洁和使用记录6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials6.3 原料、中间体、原料药的标签和包装材料的记录6.4 Master Production Instructions (Master Production and Control Records)6.4 生产工艺规程（主生产和控制记录）6.5 Batc
5、h Production Records (Batch Production and Control Records)6.5 批生产记录（批生产和控制记录）6.6 Laboratory Control Records6.6 实验室控制记录6.7 Batch Production Record Review6.7批生产记录审核7. MATERIALS MANAGEMENT7. 物料管理7.1 General Controls7.1 控制通则7.2 Receipt and Quarantine7.2接收和待验7.3 Sampling and Testing of Incoming Producti
6、on Materials7.3 进厂物料的取样与测试 7.4 Storage7.4储存7.5 Re-evaluation7.5复验8. PRODUCTION AND IN-PROCESS CONTROLS8. 生产和过程控制8.1 Production Operations8.1 生产操作8.2 Time Limits8.2 时限8.3 In-process Sampling and Controls8.3 工序取样和控制8.4 Blending Batches of Intermediates or APIs8.4 中间体或原料药的混批8.5 Contamination Control8.5
7、 污染控制9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES9. 原料药和中间体的包装和贴签9.1 General9.1 总则9.2 Packaging Materials9.2 包装材料9.3 Label Issuance and Control9.3 标签发放与控制9.4 Packaging and Labeling Operations9.4 包装和贴签操作10. STORAGE AND DISTRIBUTION10.储存和分发10.1 Warehousing Procedures10.1 入库程序10.2
8、 Distribution Procedures10.2 分发程序11. LABORATORY CONTROLS11.实验室控制11.1 General Controls11.1 控制通则11.2 Testing of Intermediates and APIs11.2 中间体和原料药的测试11.3 Validation of Analytical Procedures11.3 分析方法的验证11.4 Certificates of Analysis11.4 分析报告单11.5 Stability Monitoring of APIs11.5 原料药的稳定性监测11.6 Expiry and
9、 Retest Dating11.6 有效期和复验期11.7 Reserve/Retention Samples11.7 留样12. VALIDATION12.验证12.1 Validation Policy12.1 验证方针12.2 Validation Documentation12.2 验证文件12.3 Qualification12.3 确认12.4 Approaches to Process Validation12.4 工艺验证的方法12.5 Process Validation Program12.5 工艺验证的程序12.6 Periodic Review of Validate
10、d Systems12.6验证系统的定期审核12.7 Cleaning Validation12.7 清洗验证12.8 Validation of Analytical Methods12.8 分析方法的验证13. CHANGE CONTROL13.变更的控制14. REJECTION AND RE-USE OF MATERIALS14.拒收和物料的再利用14.1 Rejection14.1 拒收14.2 Reprocessing14.2 返工14.3 Reworking14.3 重新加工14.4 Recovery of Materials and Solvents14.4 物料与溶剂的回收1
11、4.5 Returns14.5 退货15. COMPLAINTS AND RECALLS15.投诉与召回16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)16.协议生产商（包括实验室）17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS17.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 Applicability17.1适用性17.2 Traceability of Distributed APIs and Intermediates17
12、.2已分发的原料药和中间体的可追溯性17.3 Quality Management17.3质量管理17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates17.4原料药和中间体的重新包装、重新贴签和待检17.5 Stability17.5稳定性17.6 Transfer of Information17.6 信息的传达17.7 Handling of Complaints and Recalls17.7 投诉和召回的处理17.8 Handling of Returns17.8 退货的处理18. Specific Gu
13、idance for APIs Manufactured by Cell Culture/Fermentation18. 用细胞繁殖/发酵生产的原料药的特殊指南18.1 General18.1 总则18.2 Cell Bank Maintenance and Record Keeping18.2细胞库的维护和记录的保存18.3 Cell Culture/Fermentation18.3细胞繁殖/发酵18.4 Harvesting, Isolation and Purification18.4收取、分离和精制18.5 Viral Removal/Inactivation steps18.5 病毒
14、的去除/灭活步骤19. APIs for Use in Clinical Trials19. 用于临床研究的原料药19.1 General19.1 总则19.2 Quality19.2 质量19.3 Equipment and Facilities19.3 设备和设施19.4 Control of Raw Materials19.4 原料的控制19.5 Production19.5 生产19.6 Validation19.6 验证19.7 Changes19.7 变更19.8 Laboratory Controls19.8 实验室控制19.9 Documentation19.9 文件20. G
15、lossary20. 术语Q7a GMP Guidance for APIsQ7a原料药的GMP指南1. INTRODUCTION1. 简介1.1 Objective1.1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
16、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
17、 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
18、 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与其相关控制的所有操作。本指南中，“应当”一词
19、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 manufact
20、urer and are governed by national laws.本指南在总体上未涉与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 es
21、tablish 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
22、 Regulatory Applicability1.2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
23、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 Scope1.3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 steriliz
24、ation 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 gui
25、dance 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
26、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 cel
27、l 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.
28、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
29、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 prod
30、uction 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 n
31、ormally 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
32、 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 starti
33、ng 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 manufacturi
34、ng 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
35、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 ste
36、ps 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
37、，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 ManufacturingType of ManufacturingApplication
38、 of this guidance to steps (shown in gray) used in this type of manufacturingChemical manufacturingProduction of the API Starting materialIntroduction of the API starting material into processProduction of Intermediate(s)Isolation and purificationPhysical processing, and packagingAPI derived from an
39、imal sourcesCollection of organ, fluid, or tissueCutting, mixing, and/or initial processingIntroduction of the API starting material into processIsolation and purificationPhysical processing, and packagingAPI extracted from plant sourcesCollection of plantCutting and initial extraction(s)Introductio
40、n of the API starting material into processIsolation and purificationPhysical processing, and packagingHerbal extracts used as APICollection of plantsCutting and initial extractionFurther extractionPhysical processing, and packagingAPI consisting of comminuted or powdered herbsCollection of plants a
41、nd/or cultivation and harvestingCutting/comminutingPhysical processing, and packagingBiotechnology: fermentation/cell cultureEstablishment of master cell bank and working cell bankMaintenance of working cell bankCell culture and/or fermentationIsolation and purificationPhysical processing, and packa
42、ging“Classical” fermentation to produce an APIEstablishment of cell bankMaintenance of the cell bankIntroduction of the cells into fermentationIsolation and purificationPhysical processing, and packagingIncreasing 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
43、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
44、的要求增加2. QUALITY MANAGEMENT2质量管理2.1 Principles2.1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 particip
45、ation 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 it
46、s 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，以与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。所有涉与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
47、 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