ich q11中文版.pdf

1 / 50 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES (CHEMICAL ENTITIES AND BIOTECHNOLOGICAL/BIOLOGICAL ENTITIES) Q11 Current Step 4 version dated 1 May 2012 2 / 50 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA. 1. Introduction 简介简介 This guideline describes approaches to developing and understanding the manufacturing process of the drug substance, and also provides guidance on what information should be provided in Module 3 of the Common Technical Document (CTD) Sections 3.2.S.2.2 – 3.2.S.2.6 (ICH M4Q). It addresses aspects of development and manufacture that pertain to drug substance, including the presence of steps designed to reduce impurities. In addition, ICH Q11 provides further clarification on the principles and concepts described in ICH Guidelines on Pharmaceutical Development (Q8), Quality Risk Management (Q9) and Pharmaceutical Quality System (Q10) as they pertain to the development and manufacture of drug substance. 本指南描述了原料药工艺研发及对工艺理解的方法，也提供了哪些信息 3 / 50 需要在CTD文件的章节3.2.S.2.2 – 3.2.S.2.6的指南。

描述了原料药相关的研发和生产方面， 包括降低杂质的步骤设计另外，ICH Q11进一步阐明了ICH的Q8药物研发，Q9质量风 险分析及Q10制药质量体系中关于原料药研发和生产的原则及概念 A company can choose to follow different approaches in developing a drug substance. For the purpose of this guideline, the terms “traditional” and “enhanced” are used to differentiate two possible approaches. In a traditional approach, set points and operating ranges for process parameters are defined and the drug substance control strategy is typically based on demonstration of process reproducibility and testing to meet established acceptance criteria. In an enhanced approach, risk management and scientific knowledge are used more extensively to identify and understand process parameters and unit operations that impact critical quality attributes (CQAs) and develop appropriate control strategies applicable over the lifecycle of the drug substance which may include the establishment of design space(s). As discussed in ICH Q8 for drug product, a greater understanding of the drug substance and its manufacturing process can create the basis for more flexible regulatory approaches. The degree of regulatory flexibility is generally predicated on the level of relevant scientific knowledge provided in the application for marketing authorisation. 企业在研发原料药时可 以采用其他方法。

本指南的目的是，用“传统”和“加强”这两个术语来区分两种不同 的研发方式在传统方式中，工艺参数的设定点和操作范围是确定的，原料药的控制策 略通常基于证明工艺的可重复性， 以及测试结果符合建立的接受标准 而在加强方式中， 更加广泛的使用了风险管理和科学知识来识别和理解影响关键质量属性（CQA）的工艺 参数和单元操作，设计适当的控制策略适用于原料药的整个生命周期，其中可能包括建 立设计空间，正如在Q8中讨论的药物制剂，更好的理解原料药及其生产工艺，可以为建 立更灵活的监管方式奠定基础 监管的灵活程度通常取决于上市许可申请中体现出的科 学知识水平 Traditional and enhanced approaches are not mutually exclusive. A company can use either a traditional approach or an enhanced approach to drug substance development, or a combination of both. 传统和加强方式并不互相排斥企业在研发原料药中即可使用传统 方式也可使用加强方式，或者两者结合使用。

4 / 50 2. Scope 范围 This guideline is applicable to drug substances as defined in the Scope sections of ICH Guidelines Q6A and Q6B, but might also be appropriate for other types of products following consultation with the appropriate regulatory authorities. It is particularly relevant to the preparation and organisation of the contents of Sections 3.2.S.2.2 – 3.2.S.2.6 of Module 3 of the Common Technical Document (ICH M4Q). The guideline does not apply to contents of submissions during the clinical research stages of drug development. Nevertheless, the development principles presented in this guideline are important to consider during the investigational stages. 本指南适用于ICH Q6A 和 Q6B中定义的原料药， 也可咨询相关监 管机构后用于其他类型产品。

主要适用于CTD文件模版3的章节3.2.S.2.2 – 3.2.S.2.6内容 的准备和组织本指南不适用于药物研发的临床研究阶段的资料申报但是本指南的研 发原则对是在药物研究阶段应考虑的重要内容 Regional requirements for post-approval changes are not covered by this guideline. 本指南 不覆盖地区性的批准后变更要求 3. Manufacturing Process Development 生产工艺研发生产工艺研发 3.1 General Principles 基本原则基本原则 The goal of manufacturing process development for the drug substance is to establish a commercial manufacturing process capable of consistently producing drug substance of the intended quality. 原料药生产工艺研发的目的是设计出能持续生产出于其质量原料药的 商业生产工艺。

3.1.1 Drug Substance Quality Link to Drug Product 原料药质量与制剂的联系原料药质量与制剂的联系 The intended quality of the drug substance should be determined through consideration of its use in the drug product as well as from knowledge and understanding of its physical, chemical, biological, and microbiological properties or characteristics, which can influence 5 / 50 the development of the drug product (e.g., the solubility of the drug substance can affect the choice of dosage form). The Quality Target Product Profile (QTPP), potential CQA。