ICH中英文对照版本word资料64页.doc

如有侵权，请联系网站删除，仅供学习与交流ICH中英文对照版本【精品文档】第 63 页人用药物注册技术要求国际协调会议( I C H ：International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use)ICH三方协调指南原料药的优良制造规范（GMP）指南ICH指导委员会2000年11月10日按ICH规程第4步建议采用本指南根据ICH规程由合适的ICH专家工作组起草并经向法规部门咨询。在规程的第4步，建议欧洲共同体、日本和美国的药政部门采用其最终的草案。原料药的优良制造规范（GMP）指南ICH三方协调指南ICH指导委员会2000年11月10日的会议按ICH规程第4步建议ICH的三个药政部门采用本指南目 录1 引言INTRODUCTION61.1 目的Objective61.2 法规的适用性 Regulatory Applicability71.3 范围 Range72 质量管理 QUALITY MANAGEMENT82.1 原则 Principles82.2 质量部门的职责 Responsibilities of the Quality Unit(s)92.3 生产作业的职责 Responsibility for Production Activities122.4 内部审计（自检） Internal Audits (Self Inspection)132.5 产品质量审核 Product Quality Review133 人员 PERSONNEL133.1 员工的资质 Personnel qualifications143.2 员工的卫生 Personnel Hygiene143.3 顾问 Consultants154 建筑和设施 BUILDINGS AND FACILITIES154.1 设计和结构 Design and Construction154.2 公用设施 Utilities164.3 水 Water174.4 限制 Containment174.5 照明 Lighting184.6 排污和垃圾 Sewage and Refuse184.7 清洁和保养 Sanitation and Maintenance185 工艺设备 PROCESS EQUIPMENT195.1 设计和结构 Design and Construction195.2 设备保养和清洁 Equipment Maintenance and Cleaning205.3 校验 Calibration215.4 计算机控制系统 Computerized Systems216 文件和记录 DOCUMENTATION AND RECORDS226.1 文件系统和规格 Documentation System and Specifications226.2 设备的清洁和使用记录Equipment Cleaning and Use Record246.3 原料、中间体、原料药的标签和包装材料的记录 Records of Materials , Intermediates, API Labeling and Packaging Materials246.4 生产工艺规程Master Production Instructions256.5 批生产记录Batch Production Records256.6 实验室控制记录 Laboratory Control Records276.7 批生产记录审核 Batch Production Record Review287 物料管理 MATERIALS MANAGEMENT287.1 控制通则General Controls287.2 接收和待验 Receipt and Quarantine297.3 进厂物料的取样和测试 Sampling and Testing of Incoming Production Materials307.4 储存 Storage317.5 重新评估 Re-evaluation318 生产和中间控制 PRODUCTION AND IN-PROCESS CONTROLS318.1 生产操作 Production Operations318.2 时间限制 Time Limits328.3 工序间的取样和控制 In-process Sampling and Controls338.4 中间体或原料药的混合 Blending Batches of Intermediates or APIs348.5 污染的控制 Contamination Control359 原料药和中间体的包装和贴签 PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES359.1 总则 General359.2 包装材料 Packaging Materials369.3 标签的发放和控制 Labeling Issuance and Control369.4 包装和贴签操作 Packaging and Labeling Operations3710 储存和分发 STORAGE AND DISTRIBUTION3810.1 入库程序 Warehousing Procedures3810.2 分发程序 Distribution Procedures3811 实验室控制 LABORATORY CONTROLS3811.1 控制通则 General Controls3911.2 中间体和原料药的测试 Testing of Intermediates and APIs4011.3 分析程序的验证参见12章 Validation of Analytical Procedures - See Section 12. (11.3)4111.4 分析报告单 Certificates of Analysis4111.5 原料药的稳定性监测 Stability Monitorint of APIs4211.6 有效期和复验日期 Expiry and Retest Dating4311.7 留样 Reserve/Retention Samples4312 验证 VALIDATION4412.1 验证方针 Validation Policy4412.2 验证文件 Validation Documentation4412.3 确认 Qualification4512.4 工艺验证的方法 Approaches to Process Validation4512.5 工艺验证的程序 Process Validation Program4712.7 清洗验证Cleaning Validation4712.8 分析方法的验证 Validation of Analytical Methods4913 变更的控制 CHANGE CONTROL5014 物料的拒收和再用 REJECTION AND RE-USE OF MATERIALS5114.1 拒收 Rejection5114.2 返工 Reprocessing5114.3 重新加工 Reworking5214.4 物料和溶剂的回收 Recovery of Materials and Solvents5214.5 退货 Returns5315 投诉和召回 COMPLAINTS AND RECALLS5316 协议制造商(包括实验室) CONTRACT MANUFACTURES (INCLUDING LABORATORIES)5417 代理商、经纪人、贸易商、经销商、重新包装者和重新贴签者55AGENTS,BROKERS, TRADERS,DISTRIBUTORS,REPACKERS ,AND RELABELLERS5517.1 适用性 Applicability5517.2 已分发原料药的可追溯性 Traceability of Distributed APIs and Intermediates5517.3 质量管理 Quality Management5517.4 原料药和中间体的重新包装、重新贴签和待检 Repackaging,Relabeling,and Holding of APIs and Intermediates.5617.5 稳定性 Stability5617.6 信息的传达 Transfer of Information5617.7 投诉和召回的处理 Handing of Complaints and Recalls5717.8 退货的处理 Handing of Returns5718 用细胞繁殖/发酵生产的原料药的特殊指南57SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION5718.1 总则 General5718.2 细胞库的维护和记录的保存Cell Bank Maintenance and Record Keeping6018.3 细胞繁殖/发酵 Cell Culture/Fermentation6018.4 收取、分离和精制 Harvesting, Isolation and Purifation6118.5 病毒的去除/灭活步骤 Viral Removal/Inactivation Steps6219 用于临床研究的原料药 (APIS FOR USE IN CLINICAL TRIALS)6219.1 总则 General6219.2 质量 quality6319.3 设备和设施 Equipment and Facilities6319.4 原料的控制 Control of Raw Materials6419.5 生产 Production6419.6 验证Validation6419.7 变更 Changes6519.8 实验室控制 Laboratory Controls6519.9 文件Documentation6520. 术语表 （GLOOSSARY）66原料药的优良制造规范(GMP) 指南Guidance for IndustryQ7A Good Manufacturing Practice Guidancefor Active Pharmaceutical IngredientsThis guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.1 引言INTRODUCTION 1.1 目的Objective本文件(指南)旨在为在合适的质量管理体系下制造活性药用成分(原料药以下称原料药)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。 (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。在本指南中，“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。 (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 statutes. For the purposes of this guidance, the terms current good manufacturing practices and good manufacturing practices are equivalent.)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。 (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.)本指南没打算规定注册/归挡的要求、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/归挡要求的能力。注册/归挡的所有承诺必须做到。(This guidance is not intended to define registration and/or filing requirements or modify pharmacopoeias requirements. This guidance does not affect the ability of the responsible regulatory agency to establish specific registration/filing requirements regarding APIs within the context of marketing/manufacturing authorizations or drug applications. All commitments in registration/filing documents should be met. )1.2 法规的适用性 Regulatory Applicability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。(Within the world community, materials may vary as to their legal classification as an API. When a material is classified as an API in the region or country in which it is manufactured or used in a drug product, it should be manufactured according to this guidance.)1.3 范围 Range本文件适用于人用药品（医疗用品）所含原料药的制造。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。 (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 guidance 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 XVIII (18).)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。值得注意的是细胞酶解物(哺乳动物、植物、昆虫或微生物的细胞、组织或动物来源物，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、散装药品(医疗用品)，和放射性药物的特殊的制造/控制。 (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.)第19章的指南只适用于用在药品(医疗产品)生产中的原料药制造，特别是临床实验用药(研究用医疗产品)的原料药制造。 “原料药的起始物料”是指一种原料、中间体或原料药，用来生产一种原料药，或者以主要结构单元的形式被结合进原料药结构中。原料药的起始物料可能是在市场上有售、能够通过合同或商业协议从一个或多个供应商处购得，或由生产厂家自制。原料药的起始物料一般来说有特定的化学特性和结构。(Section XIX (19) contains guidance that only applies to the manufacture of APIs used in the production of drug (medicinal) products specifically for clinical trials (investigational medicinal products). An API starting material is a raw material, an intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials normally have defined chemical properties and structure.)生产厂商要定义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。 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.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。 本文件的指南通常适用于表1中的灰色步骤。这并不意味必需完成所有步骤。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。原料药的物料加工，如制粒、包衣或颗粒度的物理处理(例如制粉、微粉化)至少应当按本指南的标准进行。(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 step as critical. The guidance in this document would normally be applied to the steps shown in gray in Table 1. However, all steps shown may not need to 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。 (This GMP guidance does not apply to steps prior to the introduction of the defined API starting material.)2 质量管理 QUALITY MANAGEMENT 2.1 原则 Principles2.1.0 参与原料药制造的每一个人都应当对质量负责。 Quality should be the responsibility of all persons involved in manufacturing.2.1.1 每家制造商都应当建立、证明其有，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。 (Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.)2.1.2 质量管理体系应当包括组织结构、程序、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，并有文件证明。 (The system for managing quality should encompass the organizational structure, procedures, processes 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. )2.1.3 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。依照组织结构的大小，可以是分开的QA 和QC 部门，或者只是一个人或组。 (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.)2.1.4 应当指定授权发放中间体和原料药的人员。 The persons authorized to release intermediates and APIs should be specified.2.1.5 所有有关质量的活动应当在其执行时就记录。 All quality-related activities should be recorded at the time they are performed.2.1.6 任何偏离确定程序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。 Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented. 2.1.7 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)。 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 X (10) or the use of raw materials or intermediates pending completion of evaluation).2.1.8 应当有程序能确保公司的责任管理人员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。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 质量部门的职责 Responsibilities of the Quality Unit(s)2.2.0 质量部门应当参与所有与质量有关的事务。 The quality unit(s) should be involved in all quality-related matters.2.2.1 所有与质量有关的文件应当由质量部门审核批准。 The quality unit(s) should review and approve all appropriate quality-related documents.2.2.2 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： 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. 所有原料药的放行和否决。用于制造商控制范围以外的中间体的放行和否决；Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of