ICH Q11 Step3 原料药的开发和生产-化学实体和生物技术生物实体

7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416 E-mail ich@ema.europa.eu Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged. May 2011 EMA/CHMP/ICH/425213/2011 ICH/ Committee for medicinal products for human use (CHMP) ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) ICH 指导原则 Q11 原料药的开发和生产 (化学实体和生物技术/生物实体) Step 3 翻译/审核：谢永/Chank Transmission to CHMP May 2011 Adoption by CHMP for release for consultation May 2011 End of consultation n (deadline for comments) September 2011 Comments Should be provided using this template. The Completed comments form should be sent to ICH@ema.europa.eu ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) 2 / 37 TABLE OF CONTENTS 目录 1. INTRODUCTION 介绍 ................................................................................................................................ 4 2. SCOPE 范围 ............................................................................................................................................... 4 3. MANUFACTURING PROCESS DEVELOPMENT 制造工艺开发 .................................................................... 5 3.1. General Principles 总则................................................................................................................................................... 5 3.1.1. Drug Substance Quality Link to Drug Product 将原料药质量与制剂药品联系起来........................ 5 3.1.2. Process Development Tools 工艺开发工具....................................................................................... 5 3.1.3. Approaches to Development 开发的方法 ......................................................................................... 6 3.1.4. Drug Substance Critical Quality Attributes 原料药的关键质量属性（CQA） ................................ 7 3.1.5. Linking Material Attributes and Process Parameters to Drug Substance CQAs 将物料属性和工艺参 数与原料药的关键质量属性相关联.......................................................................................................... 8 3.1.6. Design Space 设计空间 ................................................................................................................... 9 3.2. Submission of Manufacturing Process Development Information 制造工艺开发信息的注册递交 .........10 3.2.1. Overall Process Development Summary 全面的工艺开发总结 ...................................................... 10 3.2.2. Drug Substance CQAs 原料药的 CQAs...........................................................................................11 3.2.3. Manufacturing Process History 制造工艺历史 ...............................................................................11 3.2.4. Manufacturing Developmental Studies 制造开发研究.................................................................... 12 4. DESCRIPTION OF MANUFACTURING PROCESS AND PROCESS CONTROLS 制造工艺描述和工艺控制... 12 5. SELECTION OF STARTING MATERIALS AND SOURCE MATERIALS 起始物料和源物料的选择............... 13 5.1. General Principles 通则.................................................................................................................................................13 5.1.1. Selection of Starting Materials for Synthetic Drug Substances 化学合成原料药的起始物料的选择 ................................................................................................................................................................. 13 5.1.2. Selection of Starting Materials for Semi-synthetic Drug Substances 半合成原料药的起始物料的选 择 ............................................................................................................................................................. 14 5.1.3. Selection of Source Materials for Biotechnological/Biological Products生物产品的起始物料的选择 ................................................................................................................................................................. 15 5.2. Submission of Information for Starting Material or Source Material 起始物料或源物料的信息申报.....15 5.2.1. Justification of Starting Material Selection for Synthetic Drug Substances 合成原料药的起始物料的 选择的合理解释 ...................................................................................................................................... 15 5.2.2. Justification of Starting Material Selection for Semi-Synthetic Drug Substances 半合成原料药的起 ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) 3 / 37 始原料选择的合理解释........................................................................................................................... 16 5.2.3. Qualification of Source Materials for Biotechnological/Biological Products 生物产品源物料的确认 ................................................................................................................................................................. 16 6. CONTROL STRATEGY 控制策略 ............................................................................................................. 16 6.1. General Principles 通则.................................................................................................................................................16 6.1.1. Approaches to Developing a Control Strategy 开发控制策略的方法 ............................................. 17 6.1.2. Considerations in Developing a Control Strategy 开发控制策略中的考虑 .................................... 17 6.2. Submission of Control Strategy Information 控制策略信息的注册申报.........................................................18 7. PROCESS VALIDATION/EVALUATION 工艺验证/评估 ............................................................................. 19 7.1. General Principles 一般原则........................................................................................................................................19 7.2. Principles Specific to Biotechnological/Biological Products 生物制品的特殊原则 .....................................20 8. SUBMISSION OF MANUFACTURING PROCESS DEVELOPMENT AND RELATED INFORMATION IN COMMON TECHNICAL DOCUMENTS (CTD) FORMAT 生产工艺开发及相关信息在 CTD格式的递交 .................... 21 8.1. Quality Risk Management and Process Development 质量风险管理和工艺开发 ........................................21 8.2. Critical Quality Attributes (CQAs) 关键质量属性（CQAs） ............................................................................21 8.3. Design Space 设计空间 ................................................................................................................................................21 8.4. Control Strategy 控制策略 ...........................................................................................................................................22 9. LIFECYCLE MANAGEMENT 生命周期管理 ............................................................................................ 22 10. Illustrative Examples 实例 .................................................................................................................. 23 10.1. Example 1: Linking Material Attributes and Process Parameters to Drug Substance CQAs - Chemical Entity 将物料属性和工艺参数与原料药的关键质量属性（CQA）相关联—化学药部分 ............................23 10.2. Example 2: Use of Quality Risk Management to Support Lifecycle Management of Process Parameters 使用质量风险管理支持工艺参数的生命周期管理 ......................................................................................................27 10.3. Example 3: Presentation of a Design Space for a Biotechnological Product Unit Operation 例 3：生物产 品单元操作设计空间的介绍 ...............................................................................................................................................28 10.4. Example 4: Selecting an Appropriate Starting Material 例 4：选择一个恰当的起始物料.......................30 10.5. Example 5: Summary of Control Elements for select CQAs 选择 CQA 的控制要素的小结...................31 11. GLOSSARY 术语 .................................................................................................................................... 35 ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) 4 / 37 1. INTRODUCTION 介绍 This guideline describes approaches to developing process and drug substance understanding and also provides guidance on what information should be provided in CTD sections 3.2.S.2.2 ¨C 3.2.S.2.6. It provides further clarification on the principles and concepts described in ICH guidelines on Pharmaceutical Development (Q8), Quality Risk Management (Q9) and Pharmaceutical Quality Systems (Q10) as they pertain to the development and manufacture of drug substance. 此指南描述了开发原料药工艺及理解的方法，也提供了那些信息需要在 CTD 章节 3.2.S.2.2 和 3.2.S.2.6 中提 供的指南。并提供对在 ICHQ8（药物开发）、Q9（质量风险管理）和 Q10（药物质量系统）中提到的关于 原料药开发和生产的原则和理念的进一步的说明。 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 more extensive scientific knowledge are used to select process parameters and unit operations that impact critical quality attributes (CQAs) for evaluation in further studies to establish any design space(s) and control strategies applicable over the lifecycle of the drug substance. 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 authorization. 各个公司可以选择按照不同的方法去开发原料药。在本指南中，用术语“传统方法”和“改进方法”来区别两种 可能不同的原料药开发方法。在传统方法中，工艺参数的设定点及操作范围是确认好的，典型的原料药的 控制策略是证明工艺的可重复性以及测试产品是否符合已建立的可接受的规格标准。在改进方法中，风险 管理和更广泛的科学知识被用来选择可能影响关键质量属性的工艺参数和单元操作，并在进一步研究中对 其评估，以建立在整个原料药生命周期中都可应用的设计空间和控制策略。如 ICH Q8 中制剂产品一样，， 对原料药及其生产工艺的更多的理解可以成为搭建一个更加灵活的药政监管方法的基础。药政监管方法的 灵活程度通常取决于提供在为上市递交的申报文件中的相关科学知识的水平。 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. 传统的和改进的方法互相并不排斥。一个公司可以使用传统的或者改进的方法或者同时使用两种方法来开 发原料药。 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 organization of the contents of sections 3.2.S.2.2 ¨C 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. 此指导原则适用于 ICH Q6A 和 Q6B 指南的范围章节中定义的原料药，但是也可与合适的药政当局咨询后用 于其它类型的产品开发。本指南主要规范了 ICH M4Q 中模块 3 中的章节 3.2.S.2.2 到章节 3.2.S.2.6 相关内容 ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) 5 / 37 的准备和组织。此指南不适用于新药物开发阶段的临床研究状态的注册递交的内容。然而此指南中的开发 原则对于在临床研究阶段的新药开发是重要的。 Regional requirements for post-approval changes are not covered by this guideline. 各个药政当局对于产品批准后变更的相关要求并不涵盖于本指南。 3. MANUFACTURING PROCESS DEVELOPMENT 制造工艺开发 3.1. General Principles 总则 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. 原料药制造工艺开发的目的是建立一个能够始终如一地生产预期质量的原料药的商业化制造工艺。 3.1.1. Drug Substance Quality Link to Drug Product 将原料药质量与制剂产品联系起来 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 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) and potential CQAs of the drug product (as defined in ICH Q8) can help identify potential CQAs of the drug substance. Knowledge and understanding of the CQAs can evolve during the course of development. 原料药的预期质量应该通过考虑其在制剂中的用途及其对制剂开发的潜在影响（例如，原料药的溶解性可 能影响剂型的选择），并结合原料药的物理、化学、生物和微生物属性或特性的知识和理解来定义。制剂的 质量目标产品档案（QTPP）和潜在关键质量属性 CQA（QTPP 和 CQA 的定义请参见 ICH Q8）可以有助于 识别原料药的潜在关键质量属性。关键质量属性(CQA)的知识和对 CQA 的理解可以在开发的过程中不断发 展。 3.1.2. Process Development Tools 工艺开发工具 Quality Risk Management (QRM, as described in ICH Q9) can be used in a variety of activities including assessing options for the design of the manufacturing process, assessing quality attributes and manufacturing process parameters, and increasing the assurance of routinely achieving acceptable quality results. Risk assessments can be carried out early in the development process and repeated as greater knowledge and understanding become available. It is neither always appropriate nor always necessary to use a formal risk management process (using recognized tools and/or internal procedures, e.g., standard operating procedures). The use of informal risk management processes (using empirical tools and/or internal procedures) can also be considered acceptable. 质量风险管理（QRM, 定义请参见 ICH Q9）可以用在各种活动中，包括为制造工艺的设计评估可选项、评 估质量属性和生产工艺参数，增加日常获得可接受质量结果的保证。风险评估可以在开发工艺的早期就展 开，当可以得到更多的知识和理解时可以重复进行。并不要求一定或必须使用正式的风险管理程序（指的 是使用公认的工具和/或内部的程序，例如，SOP）。使用非正式风险管理程序（使用经验工具和/或内部程 序）的也是可接受的。 Knowledge management (as described in ICH Q10) can also facilitate manufacturing process development. In this context, potential sources of information can include prior knowledge and development studies. Prior knowledge can include established biological, chemical and engineering principles and applied manufacturing experience. Data derived from relevant prior knowledge, including platform manufacturing (see glossary) can be leveraged to support development of the commercial process and expedite scientific understanding. ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) 6 / 37 知识管理（定义参见 ICH Q10）也可促进制造工艺开发。在此环境下，信息的潜在来源可以包括先前的知 识和开发研究。先前的知识可以包括已经建立的生物学、化学和工程学的原理和已经应用了的制造经验。 来源于有关的先前知识包括平台生产（见术语）可以用于支持商业化工艺的开发和加快科学理解。 3.1.3. Approaches to Development 开发的方法 ICH Q8 recognizes that “Strategies for product developments vary from company to company and from product to product. The approach to, and extent of, development can also vary and should be outlined in the submission”. These concepts apply equally to the development of the drug substance manufacturing process. An applicant can choose either a traditional approach or an enhanced approach to drug substance development, or a combination of both. ICH Q8 提到“产品开发策略因不同公司和不同产品而不同。开发的方法和范围也可以改变，应该在申报递 交中概述”。这些理念同样应用于原料药制造工艺的开发。申请者可以选择传统方法或改进方法，或两者结 合的方法来做原料药的开发。 Manufacturing process development should include, at a minimum, the following elements: 制造工艺开发应该包括以下要素（至少涵盖但不限于）：  Identifying potential CQAs associated with the drug substance so that those characteristics having an impact on product quality can be studied and controlled; 识别与原料药有关的潜在 CQAs 以便这些对于产品质量有影响的特性能够被研究和控制。  Defining an appropriate manufacturing process; 定义一个适当的制造工艺。  Defining a control strategy to ensure process performance and drug substance quality (see Section 6 on Control Strategy). 定义一个控制策略确保工艺性能和原料药质量（见章节 6，控制策略） An enhanced approach to manufacturing process development would additionally include the following elements: 一个生产工艺开发的改进方法将增加以下的要素：  A systematic evaluation, understanding and refining of the manufacturing process, including; 对制造工艺的系统的评估、理解和细化，包括：  Identifying, through e.g. prior knowledge, experimentation and risk assessment, the material attributes and process parameters that can have an effect on drug substance CQAs; 通过先前的知识、试验和风险评估来识别可能对原料药关键质量属性（CQA）有影响的物料属性 和工艺参数。  Determining the functional relationships that link material attributes and process parameters to drug substance CQAs; 定义联系物料属性和工艺参数和原料药关键质量属性 CQA 之间的效应关系。 Using the enhanced approach in combination with QRM to establish an appropriate control strategy which can, for example, include a proposal for a design space(s) and/or real-time release testing (RTRT). 用改进方法结合 QRM（质量风险管理）去建立一个合适的控制策略，例如提出设计空间和/或实时放行测试 ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) 7 / 37 （RTRT）之类的控制方案。 The increased knowledge and understanding obtained from taking an enhanced approach could facilitate continual improvement and innovation throughout the product lifecycle (see ICH Q10). 从实施改进方法获得的增加的知识和理解可以促进持续改进和贯穿整个产品生命周期的创新。 3.1.4. Drug Substance Critical Quality Attributes 原料药的关键质量属性（CQA） A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. Potential drug substance CQAs are used to guide process development. The list of potential CQAs can be modified as drug substance knowledge and process understanding increase. 关键质量属性（CQA）是物理的、化学的、生物学的或微生物学的属性或特性，且必须在一定合适的限度、 范围或分布内以确保产品质量符合要求。潜在原料药 CQA 用来指导工艺开发。当原料药知识和工艺理解增 加时潜在 CQA 可以被修正。 Drug substance CQAs typically includes those properties or characteristics that affect identity, purity, biological activity and stability. When physical properties are important with respect to in vivo performance or drug product manufacture, these can be designated as CQAs. In the case of biotechnological/biological products, most of the CQAs of the drug product are associated with the drug substance and thus are a direct result of the design of the drug substance or its manufacturing process. 原料药的 CQAs 一般包括哪些影响鉴别、纯度、生物活性和稳定性的属性或特性。当物理属性对于产品在 人体内的活性或制剂产品生产过程非常重要时，也可以指定为 CQAs。至于生物技术或生物制剂产品，他们 的 CQAs 大多都是与原料药相关的，既是原料药或其生产工艺的设计的直接结果。 Impurities are an important class of potential drug substance CQAs because of their potential impact on drug product safety. For chemical entities, impurities can include organic impurities (including potential genotoxic impurities), inorganic impurities, for example metal residues, and residual solvents (see ICH Q6A, Q3A, and Q3C). For biotechnological/biological products, impurities may be process-related or product-related (see ICH Q6B). Process-related impurities include: cell substrate-derived impurities (e.g., Host Cell Proteins and DNA); cell culture-derived impurities (e.g.，media components); and downstream-derived impurities (e.g., column leachable). CQAs for biotechnology/biological products should also include consideration of contaminants, as defined in Q6B, including all adventitiously introduced materials not intended to be part of the manufacturing process (e.g., adventitious viral, bacterial, or mycoplasma contamination). 杂质是一类重要的潜在的原料药 CQAs 因为他们对药品安全的潜在影响。对与化学分子实体，杂质可能包 括有机杂质（包括潜在基因毒性杂质）、无机杂质，例如金属残留物和残留溶剂（参见 ICH Q6A,Q3A 和 Q3C）。 对于生物技术/生物制剂产品，杂质可能是工艺相关或产品相关的（参见 ICH Q6B）。工艺杂质相关杂质包 括：细胞基质源杂质（如宿主细胞蛋白质和 DNA）；细胞培养源杂质（如培养基组分）和后续工艺源杂质 （如柱滤出物）。生物技术/生物制剂杂质相关的 CQAs 也包括在 Q6B 中定义的对污染的考虑，包括所有不 是制造工艺一部分的偶然引