ICH-Q8(中英文).doc

ICH Q8（中英文）blueski推荐2009-12-20出处：Julia的blog作者：不详INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE人用药物注册技术要求国际协调会议ICH Harmonised Tripartite Guideline ICH三方协调指南Pharmaceutical Development药物开发Q8Recommended for Adoption at Step 4 of the ICH Process on 10 November 2005 by the ICH Steering Committee ICH指导委员会2005年11月10日ICH第四阶段推荐采用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. 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。TABLE OF CONTENTS目录1. INTRODUCTION简介. 11.1 Objective of the Guideline指南目的. 11.2 Scope范围. 12. PHARMACEUTICAL DEVELOPMENT药物开发. 12.1 Components of the Drug Product制剂产品的组分. 42.1.1 Drug Substance活性成分. 42.1.2 Excipients辅料. 42.2 Drug Product制剂. 52.2.1 Formulation Development配方开发. 52.2.2 Overages超量. 62.2.3 Physicochemical and Biological Properties物化和生化性质. 72.3 Manufacturing Process Development制造工艺开发. 72.4 Container Closure System容器系统. 92.5 Microbiological Attributes微生物属性. 92.6 Compatibility兼容性. 103. GLOSSARY术语. 11 1. INTRODUCTION 简介1.1 Objective of Guideline 指南目的This guideline describes the suggested contents for the 3.2.P.2 (Pharmaceutical Development) section of a regulatory submission in the ICH M4 Common Technical Document (CTD) format. 本指南就 CTD 格式申请文件中第3.2.P.2 章：药物开发需要叙述的内容给出了建议。 The Pharmaceutical Development section provides an opportunity to present the knowledge gained through the application of scientific approaches and quality risk management (for definition, see ICH Q9) to the development of a product and its manufacturing process. It is first produced for the original marketing application and can be updated to support new knowledge gained over the lifecycle of a product. The Pharmaceutical Development section is intended to provide a comprehensive understanding of the product and manufacturing process for reviewers and inspectors. The guideline also indicates areas where the demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches. The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided. 药物开发一章给申请企业提供了一个机会，来阐述其应用科学的方法和风险管理手段，在产品及其生产工艺的开发过程中所获得的知识。它既可以被用于原始的制剂上市申请，又可以经过更新后被用于支持产品生命周期内所获得的新知识。本指导文件也说明了在什么情况下，药物和生产方面的最大程度的理解可以形成灵活的药政管理办法的基础。药物开发一章旨在为审核官和检查官就产品和生产工艺提供更详尽的理解。 1.2 Scope 范围 This guideline is intended to provide guidance on the contents of Section 3.2.P.2 (Pharmaceutical Development) for drug products as defined in the scope of Module 3 of the Common Technical Document (ICH guideline M4). The guideline does not apply to contents of submissions for drug products during the clinical research stages of drug development. However, the principles in this guideline are important to consider during those stages as well. This guideline might also be appropriate for other types of products. To determine the applicability of this guideline to a particular type of product, applicants can consult with the appropriate regulatory authorities. 本指导文件就 CTD 模块3（ICH 标题 M4）中所定义的制剂的第3.2.P.2（药物开发）一章中的内容提供了指南。本指导文件不适用于临床研究阶段制剂递交文件的内容。然而，在这些阶段对本指导文件中的原则进行考虑也是重要的。本指南可能也适用于其他一些类型的产品。申请者向合适的药政管理当局进行咨询来确定本指导文件是否适用于某一特定类型的产品。 2. PHARMACEUTICAL DEVELOPMENT 药物开发 The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls. 药物开发的目的在于设计符合质量要求的产品及符合重复生产模式的制造工艺。在药物开发和研究过程中所获得的信息和知识将为建立质量标准和生产控制提供科学的依据。 Information from pharmaceutical development studies can be a basis for quality risk management. It is important to recognize that quality cannot be tested into products; i.e., quality should be built in by design. Changes in formulation and manufacturing processes during development and lifecycle management should be looked upon as opportunities to gain additional knowledge and further support establishment of the design space. Similarly, inclusion of relevant knowledge gained from experiments giving unexpected results can also be useful. Design space is proposed by the applicant and is subject to regulatory assessment and approval. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. 药物开发研究过程中所获得的信息是风险评估的基础。质量是通过设计建立起来的，而不是通过对产品的检测得来的，认识这一点是很重要的。开发过程中的配方和生产工艺的变更应当被看成是获得更多额外知识的机会，以进一步支持设计空间的建立。包括从失败实验中获得的知识也是有用的，也可以用于支持所选择的产品及其生产工艺。The Pharmaceutical Development section should describe the knowledge that establishes that the type of dosage form selected and the formulation proposed are suitable for the intended use. This section should include sufficient information in each part to provide an understanding of the development of the drug product and its manufacturing process. Summary tables and graphs are encouraged where they add clarity and facilitate review. 药物开发一章应当阐述为满足申请中所规定的目的，建立所选择的剂型和拟定的配方的知识基础。在本章节中的每一个部分都应当要包括足够的资料用以理解制剂及其生产工艺的开发。鼓励使用表格和图表进行概述。At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product. 至少，应当要对关键的且能很大程度上影响产品质量的方面进行确定和讨论，它们包括原料药，赋形剂和生产工艺，这些方面也是需要检测和控制的。通过评估它们的变化程度对制剂质量的影响可确定这些关键的配方属性和工艺参数。 In addition, the applicant can choose to conduct pharmaceutical development studies that can lead to an enhanced knowledge of product performance over a wider range of material attributes, processing options and process parameters. Inclusion of this additional information in this section provides an opportunity to demonstrate a higher degree of understanding of material attributes, manufacturing processes and their controls. This scientific understanding facilitates establishment of an expanded design space. In these situations, opportunities exist to develop more flexible regulatory approaches, for example, to facilitate: 此外，申请者也可以选择进行一些其它的药物开发研究以在更广的物料属性范围，操作选项范围和工艺参数范围内对产品的性能有更深的了解。将这些更多的信息包括在本章节使得可以对生产工艺和过程控制有更高的理解。这样的科学理解确立了设计空间。这些情况为建立更灵活的药政管理办法提供了可能，比如，便于： risk-based regulatory decisions (reviews and inspections); 基于风险管理的药政决议（审核和现场检查）； manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review; 生产工艺改进，在文件所述的已批准的设计空间范围内，不需要进一步的药政审核； reduction of post-approval submissions; 减少预审批呈递 real-time quality control, leading to a reduction of end-product release testing. “实时”质量控制，导致最终产品的放行检测的减少To realise this flexibility, the applicant should demonstrate an enhanced knowledge of product performance over a range of material attributes, manufacturing process options and process parameters. This understanding can be gained by application of, for example, formal experimental designs, process analytical technology (PAT), and/or prior knowledge. Appropriate use of quality risk management principles can be helpful in prioritising the additional pharmaceutical development studies to collect such knowledge. 为了实现这种灵活性，申请者应当要在物性（如：粒径分布、水分、流动性），操作选项和工艺参数等的某一范围内对产品性能进行更高层次的论述。可以通过实行规范的实验设计或工艺分析技术（PAT）来获得这些知识。适当地应用风险管理原则，有助于按其优先性进行排序额外的药物开发研究，以获得这些知识。The design and conduct of pharmaceutical development studies should be consistent with their intended scientific purpose. It should be recognized that the level of knowledge gained, and not the volume of data, provides the basis for science-based submissions and their regulatory evaluation. 药物开发研究的设计和实施应当要和其拟定的科学目的和产品开发阶段相一致。需要认识到的是所获知识的层次，而不是数据量，为科学的申请文件及其药政评审提供了基础。 2.1Components of the Drug Product制剂产品的组分 2.1.1Drug Substance活性成分 The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability, or were specifically designed into the drug substance (e.g., solid state properties), should be identified and discussed. Examples of physicochemical and biological properties that might need to be examined include solubility, water content, particle size, crystal properties, biological activity, and permeability. These properties could be inter-related and might need to be considered in combination. 应当要对原料药的能对制剂的性质及其生产能力产生影响的，或是已被专门设计在原料药方面的（如：晶体工程学）物化性质和生物学特性进行说明和讨论。可能需要检查的物化属性和生物特性有：溶解性、水分、粒径、晶体特性、生物活性、和渗透性等。这些性质可能相互之间是有联系的，因此可能需要综合起来考虑。有些性质会随着时间而改变的，或是和供应商相关。 To evaluate the potential effect of drug substance physicochemical properties on the performance of the drug product, studies on drug product might be warranted. For example, the ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances describes some of the circumstances in which drug product studies are recommended (e.g., Decision Tree #3 and #4 (Part 2). This approach applies equally for the ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products. The knowledge gained from the studies investigating the potential effect of drug substance properties on drug product performance can be used, as appropriate, to justify elements of the drug substance specification (3.2.S.4.5). 为了评估原料药的物理化学性质对制剂产品性能的潜在影响，应当要提供制剂的研究资料。比如说，ICH Q6A 质量标准：新化学原料药及新制剂的检验方法及合格标准中建议的一些情况下需要进行制剂研究（如决策树#3 和#4（第2 部分）。对原料药性质可能会对制剂性能产生的影响进行研究所获得的知识，如果合适，可被用于论证原料药的质量标准建立的原因（3.2.S.4.5）。 The compatibility of the drug substance with excipients listed in 3.2.P.1 should be evaluated. For products that contain more than one drug substance, the compatibility of the drug substances with each other should also be evaluated. 需讨论原料药与第 3.2.P.1 章中所列辅料的兼容性。对于含有多个原料药的制剂，还应讨论各原料药间的兼容性。 2.1.2Excipients辅料The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability should be discussed relative to the respective function of each excipient. This should include all substances used in the manufacture of the drug product, whether they appear in the finished product or not (e.g., processing aids). Compatibility of excipients with other excipients, where relevant (for example, combination of preservatives in a dual preservative system), should be established. The ability of excipients (e.g., antioxidants, penetration enhancers, disintegrants, release controlling agents) to provide their intended functionality, and to perform throughout the intended drug product shelf life, should also be demonstrated. The information on excipient performance can be used, as appropriate, to justify the choice and quality attributes of the excipient, and to support the justification of the drug product specification (3.2.P.5.6). 可以影响制剂产品的性能（例如，稳定性和生物利用度）或是制剂产品的工艺性的辅料选择，辅料的浓度和特性必须按各自的功效逐一讨论。在相关的情况下（比如双防腐剂系统中的防腐剂），还需确定各赋形剂间的兼容性。还应阐述各种辅料（如防氧化剂、穿透增强剂、分解质、释放控制剂）在整个制剂保质期内实现其预期作用的能力。可适当应用辅料性能方面的资料来论证辅料选择及其质量特性的合理性，以支持制剂质量标准的合理性说明（3.2.P.5.6）。 Information to support the safety of excipients, when appropriate, should be cross-referenced (3.2.P.4.6).适当时，还应交叉引用相关资料以支持辅料的安全性论证（3.2.P.4.6）。2.2Drug Product制剂2.2.1Formulation Development处方开发 A summary should be provided describing the development of the formulation, including identification of those attributes that are critical to the quality of the drug product, taking into consideration intended usage and route of administration. Information from formal experimental designs can be useful in identifying critical or interacting variables that might be important to ensure the quality of the drug product. 应综述配方的开发过程，包括那些对制剂产品质量很重要的属性，并考虑拟定用途和给药途径。 The summary should highlight the evolution of the formulation design from initial concept up to the final design. This summary should also take into consideration the choice of drug product components (e.g., the properties of the drug substance, excipients, container closure system, any relevant dosing device), the manufacturing process, and, if appropriate, knowledge gained from the development of similar drug product(s). 该综述应着重说明配方设计从最初概念到最终设计的发展过程。该综述还应当要考虑各制剂组分的选择（如：原料药，赋形剂，包装系统和相关剂型装置），生产工艺和类似制剂产品开发过程中所获得的经验（如果合适的话）。 Any excipient ranges included in the batch formula (3.2.P.3.2) should be justified in this section of the application; this justification can often be based on the experience gained during development or manufacture. 正式的实验设计所获得的资料可用于确定关键的或有相互作用的变量，这些变量对于确保制剂产品的质量可能是重要的。在申请文件的此章节中应对批配方（3.2.P.3.2）中的辅料范围进行合理性说明。通常，该合理性说明会建立在配方和生产工艺的开发所获得的经验这个基础上。 A summary of formulations used in clinical safety and efficacy and in any relevant bioavailability or bioequivalence studies should be provided. Any changes between the proposed commercial formulation and those formulations used in pivotal clinical batches and primary stability batches should be clearly described and the rationale for the changes provided. 应综述在临床安全性和有效性，生物利用度研究或生物等效性研究中所用到的所有配方。对于拟定的市售配方和临床研究与稳定性实验所用批次的配方间的变更都应当进行明确地说明，并提供这些变更的合理性说明。 Information from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) that links clinical formulations to the proposed commercial formulation described in 3.2.P.1 should be summarized and a cross-reference to the studies (with study numbers) should be provided. Where attempts have been made to establish an in vitro/in vivo correlation, the results of those studies, and a cross-reference to the studies (with study numbers), should be provided in this section. A successful correlation can assist in the selection of appropriate dissolution acceptance criteria, and can potentially reduce the need for further bioequivalence studies following changes to the product or its manufacturing process. 应综述和市售配方（如3.2.P.1 中所描述）相关联的对比性体外研究（如：溶出度）或对比性体内研究（如：生物等效性）所获得的信息，并参引这些研究（研究序号）。如果已试图确立体外实验和体内实验之间的相关性，则在此章节中应提供这些研究的结果并参引这些研究（研究序号）。成功的相关性有助于合适的溶出度可接受标准的选择，并可能减少在产品和生产工艺出现变更的情况下，进一步进行生物等效性研究的需要。 Any special design features of the drug product (e.g., tablet score line, overfill, anti-counterfeiting measure as it affects the drug product) should be identified and a rationale provided for their use. 需应标明制剂的所有设计特性（如：药片标记线、过度充填、反伪造措施），并提供使用他们的理由。应提供这些特性的适宜性的支持信息。2.2.2Overages超量In general, use of an overage of a drug substance to compensate for degradation during manufacture or a products shelf life, or to extend shelf life, is discouraged. 总体来说，不鼓励加入过量原料药以补偿生产过程或产品存贮期中原料药的降解，或用以延长保存期。Any overages in the manufacture of the drug product, whether they appear in the final formulated product or not, should be justified considering the safety and efficacy of the product. Information should be provided on the 1) amount of overage, 2) reason for the overage (e.g., to compensate for expected and documented manufacturing losses), and 3) justification for the amount of overage. The overage should be included in the amount of drug substance listed in the batch formula (3.2.P.3.2).对于制剂生产过程中出现的过量现象，无论其是否是出现在最终制剂中，都应当要从产品的安全性和有效性方面对其进行合理性说明。应提供如下信息：1）过量的量；2）过量的原因（如，补偿生产过程中出现的损失）；3）超出量的合理性说明。在典型批配方（3.2.P.3.2）所列的原料药量中应包括超出量。2.2.3Physicochemical and Biological Properties物化和生化性质The physicochemical and biological properties relevant to the safety, performance or manufacturability of the drug product should be identified and discussed. This includes the physiological implications of drug substance and formulation attributes. Studies could include, for example, the development of a test for respirable fraction of an inhaled product. Similarly, information supporting the selection of dissolution vs. disintegration testing, or other means to assure drug release, and the development and suitability of the chosen test, could be provided in this section. See also ICH Q6A Specifications: Test Procedures And Acceptance Criteria For New Drug Substances And New Drug Products: Chemical Substances; Decision Tree #4 (Part 3) and Decision Tree #7 (Part 1) or ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products. The discussion should cross-reference any relevant stability data in 3.2.P.8.3. 应确定和制剂产品的性能或工艺性能相关的物理化学特性和生物学特性，并对它们进行讨论。可以包括如下配方属性：pH 值、摩尔渗透压浓度、离子浓度、亲油性、溶出度、再分散作用、重构、粒径分布、颗粒形状、聚集作用、多晶形、流变性质、乳剂的颗粒尺寸、生物活性/功效、和/或免疫活性。配方属性的生理性质如pH 值也应当要说明。需参引3.2.P.8.3 中的相关稳定性资料。在申请文件中的此章节（3.2.P.2.2.3）中，应综述为了研究物理化学特性和生物学性质对制剂的潜在影响及制剂可接受限度的合适性开展的开发研究。这些研究包括：比如，溶出度实验或释放度实验的开发，吸入制剂的可吸入组分的实验开发。应说明原料药的生理适应性和配方属性。比如说可以包括研究是否需要在制剂质量标准中加入多晶型的合格标准所获得的信息。类似的，关于溶出度VS 崩解实验或其他确保制剂释放的方法的选择，以支持配方和生产工艺的耐用性的信息也可以包括在该章节。也可参见ICH Q6A 质量标准：新原料药和新制剂的测试方法和认可标准：化学物质。决策树#4（Part 3）和决策树#7（Part 1）。2.3Manufacturing Process Development制造工艺开发The selection, the control, and any improvement of the manufacturing process described in 3.2.P.3.3 (i.e., intended for commercial production batches) should be explained. It is important to consider the critical formulation attributes, together with the available manufacturing process options, in order to address the selection of the manufacturing process and confirm the appropriateness of the components. Appropriateness of the equipment used for the intended products should be discussed. Process development studies should provide the basis for process im