1、ICH Q11 原料药开发和制造 中英对照 Page 1 of 45 DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES(CHEMICAL ENTITIES AND BIOTECHNOLOGICAL/BIOLOGICAL ENTITIES)Q11 Current Step 4 version dated 1 May 2012 TABLE OF CONTENTS 1.Introduction 介绍.3 2.Scope 范围.4 3.Manufacturing Process Development 制造工艺开发.4 3.1 General Princip
2、les 总则.4 3.1.1 Drug Substance Quality Link to Drug Product 原料药质量与制剂产品的联系.4 3.1.2 Process Development Tools 工艺开发工具.5 3.1.3 Approaches to Development 开发方法.5 3.1.4 Drug Substance Critical Quality Attributes 原料药关键质量属性（CQA）.7 3.1.5 Linking Material Attributes and Process Parameters to Drug Substance CQAs
3、 物料属性及工艺参数与原料药关键质量属性的联系.8 3.1.6 Design Space 设计空间.10 3.2 Submission of Manufacturing Process Development Information 制造工艺开发信息的申报.12 3.2.1 Overall Process Development Summary 全面工艺开发总结.12 3.2.2 Drug Substance CQAs 原料药的关键质量属性.13 3.2.3 Manufacturing Process History 制造工艺历史.13 3.2.4 Manufacturing Developm
4、ent Studies 制造开发研究.14 4.Description of Manufacturing Process and Process Controls 制造工艺描述与工艺控制.15 5.Selection of Starting Materials and Source Materials 起始物料筛选及物料来源.16 5.1 General Principles 总则.16 5.1.1 Selection of Starting Materials for Synthetic Drug Substances 化学合成原料药起始物料的筛选.16 5.1.2 Selection of
5、 Starting Materials for Semi-Synthetic Drug Substances 半合成原料药起始物料的筛选.18 5.1.3 Selection of Source and Starting Materials for Biotechnological/Biological Drug Substances 生物技术/生物制品起始物料的选择.18 5.2 Submission of Information for Starting Material or Source Material 起始物料或物料来源的信息申报 19 5.2.1 Justification of
6、 Starting Material Selection for Synthetic Drug Substances 合成原料药起始物料的选择依据.19 5.2.2 Justification of Starting Material Selection for Semi-Synthetic Drug Substances 半合成原料药起始物料的选择依据.20 5.2.3 Qualification of Source or Starting Materials for Biotechnological/Biological Drug Substances 生物技术/生物制品原料药源物料或起始
7、物料源物料的确认.20 6.Control Strategy 控制策略.21 6.1 General Principles 总则.21 ICH Q11 原料药开发和制造 中英对照 Page 2 of 45 6.1.1 Approaches to Developing a Control Strategy 开发控制策略的方法.21 6.1.2 Considerations in Developing a Control Strategy 开发控制策略的考虑事项.22 6.2 Submission of Control Strategy Information 控制策略信息的申报.23 7.Pro
8、cess Validation/Evaluation 工艺验证/评价.24 7.1 General Principles 总则.24 7.2 Principles Specific to Biotechnological/Biological Drug Substance 生物技术/生物制品原料药的特殊原则.25 8.Submission of Manufacturing Process Development and Related Information in Common Technical Documents(CTD)Format 通用技术文件（CTD）格式的制造工艺开发及相关信息的申
9、报.26 8.1 Quality Risk Management and Process Development 质量风险管理与工艺开发.27 8.2 Critical Quality Attributes(CQAs)关键质量属性（CQAs）.27 8.3 Design Space 设计空间.28 8.4 Control Strategy 控制策略.28 10.Illustrative Examples 例证.31 10.1 Example 1:Linking Material Attributes and Process Parameters to Drug Substance CQAs-C
10、hemical Entity 例 1：化学实体原料药关键质量属性与物料属性和工艺参数的联系.31 10.2 Example 2:Use of Quality Risk Management to Support Lifecycle Management of Process Parameters例 2：使用质量风险管理来支持工艺参数的生命周期管理.34 10.3 Example 3:Presentation of a Design Space for a Biotechnological Drug Substance Unit Operation 例 3：生物技术原料药单元操作设计空间介绍.3
11、6 10.4 Example 4:Selecting an Appropriate Starting Material 例 4：选择合适的起始物料.38 10.5 Example 5:Summary of Control Elements for select CQAs 例 5：选择关键质量属性的控制要素总结.39 11.Glossary 术语.43 ICH Q11 原料药开发和制造 徐禾丰&郭鸽翻译 中英对照 Page 3 of 45 1.Introduction This guideline describes approaches to developing and understand
12、ing 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 th
13、e 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 ma
14、nufacture of drug substance.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
15、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 proc
16、ess 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 scienti