【转载】ICH Q12 药品生命周期管理中技术与注册考量(2019年11月20日采纳)中英文

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TECHNICAL AND REGULATORY CONSIDERATIONS FOR PHARMACEUTICAL PRODUCT LIFECYCLEMANAGEMENT

药品生命周期管理中技术与注册考量

Q12

Finalversion

Adopted on 20 November 2019

2019年11月20日采纳

1. INTRODUCTION	前言
1.1. Objectives	目的
1.2. Scope	范围
1.3.  ICH Q12 Regulatory Tools and Enablers	ICH Q12注册工具和实现方法
2. CATEGORISATION OF POST-APPROVAL CMC CHANGES	批准后CMC变更的类别
3. ESTABLISHED CONDITIONS(ECS)	既定条件（EC）
3.1. Introduction	概述
3.2. ECs in the Regulatory Submission	注册资料中的EC
3.2.1.      ECsDefinition	EC定义
3.2.2.      ECsinaRegulatoryDossier	注册文档中的EC
3.2.3.      IdentificationofECs	EC定义
3.2.3.1. Identification of ECs for the Manufacturing Processes	识别生产工艺的EC
3.2.3.2. Identification of ECs for Analytical Procedures	识别分析方法的EC
3.2.4. Revision of ECs	EC修改
3.3.Roles and Responsibilities	角色与职责
4. POST-APPROVAL CHANGE MANAGEMENT PROTOCOL(PACMP)	批准后变更管理方案（PACMP）
4.1. Definition of a PACMP	PACMP的定义
4.2. Application of a PACMP	PACMP的应用
4.3. Elements of a PACMP	PACMP的要素
4.4. Modification to an Approved PACMP	已批准PACMP的修改
4.5. Types of PACMPs	PACMP的类别
5. PRODUCT LIFECYCLE MANAGEMENT(PLCM) DOCUMENT	产品生命周期管理（PLCM）文件
5.1.  PLCM Document: Scope	PLCM文件：范围
5.2.  Submitting the PLCM Document	提交PLCM文件
5.3. Maintenance of the PLCM Document	PLCM文件的维护
5.4. Format and Location of PLCM Document	PLCM文件的格式与位置
6.  PHARMACEUTICAL QUALITY SYSTEM(PQS) AND CHANGE MANAGEMENT	药物质量体系（PQS）和变更管理
6.1. PQS General Considerations	PQS一般考量
6.2. Change Management Across the Supply Chain and Product Lifecycle	供应链和产品生命周期中的变更管理
7. RELATIONSHIP  BETWEEN REGULATORY ASSESSMENT AND INSPECTION	注册审评与现场检查之间的关系
8. STRUCTURED  APPROACHES FOR FREQUENT CMC POST-APPROVAL CHANGES	频繁批准后CMC变更的结构化方法
9. STABILITY  DATA APPROACHES TO  SUPPORT THE EVALUATION OF CMC CHANGES	支持CMC变更评估的稳定性数据方法
10. GLOSSARY	术语
11. REFERENCES	参考文献
APPENDIX 1: CTD SECTIONS THAT CONTAIN ECS	附录1：包括EC的CTD章节
APPENDIX 2: PRINCIPLES OF CHANGE MANAGEMENT	附录2：变更管理原则

1     INTRODUCTION 前言

1.1  Objectives 目的

This guideline provides a framework to facilitate the management of post-approval CMC changes in a more predictable and efficient manner. A harmonised approach regarding technical and regulatory considerations for lifecycle management will benefit patients, industry, and regulatory authorities by promoting innovation and continual improvement in the pharmaceutical sector, strengthening quality assurance and improving supply of medicinal products.

本指南提供了一个框架，以帮助采用可预期且高效的方式管理批准后CMC变更。技术和注册的生命周期管理考量的协调一致将有助于患者、行业和药监机构，促进生物药品部分的创新的持续改进，加强药品供应的保障和改善。

The concepts outlined in prior ICH Quality Guidelines (ICH Q8(R2), Q9, Q10 and Q11) provide opportunities for science- and risk-based approaches for use in drug development and regulatory decisions. These guidelines are valuable in the assessment of Chemistry, Manufacturing and Controls (CMC) changes across the product lifecycle. ICH Q8(R2) and Q11 guidelines focus mostly on early stage aspects of the product lifecycle (i.e., product development, registration and launch). This guideline addresses the commercial phase of the product lifecycle (as described in ICH Q10); and it both complements and adds to the flexible regulatory approaches to post-approval CMC changes described in ICH Q8(R2) and Q10 Annex 1.

之前的ICH质量指南（ICH Q8(R2)、Q9、 Q10 和 Q11）中所列概念提供了将基于风险的科学方法应用于药品开发和法规决策的机会。这些指南对于药品生命周期中研发、生产和检测（CMC）变更评估有着重要价值。ICH Q8(R2) 和 Q11指南主要关注于药品生命周期的早期开发（即药品研发、注册和上市）。本指南关注的则是药品生命周期的商业化阶段（ICH Q10所述），同时补充和丰富了ICH Q8(R2) 和 Q10附录1中所述批准后CMC变更的灵活注册方法。

This guideline is also intended to demonstrate how increased product and process knowledge can contribute to a more precise and accurate understanding of which post- approval changes require a regulatory submission as well as the definition of the level of reporting categories for such changes (i.e., a better understanding of risk to product quality). Increased knowledge and effective implementation of the tools and enablers described in this guideline should enhance industry’s ability to manage many CMC changes effectively under the company’s Pharmaceutical Quality System (PQS) with less need for extensive regulatory oversight prior to implementation. This approach can incentivize continual improvement by providing an opportunity for greater flexibility in making post-approval changes. It could also result in fewer associated post-approval submissions to the Marketing Authorisation Application (MAA), and less associated regulatory burden. The extent of this operational and regulatory flexibility and its adequate implementation is subject to the regulatory framework in place, as well as product and process understanding (ICH Q8(R2) and Q11), application of quality risk management principles (ICH Q9), and an effective pharmaceutical quality system (ICH Q10).

本指南亦旨在展示药品和工艺知识的增长如何有助于更为精准了解需要注册申报的批准后变更，以及此类变更的报告类别层次定义（即，更好理解对产品质量的风险）。知识的增长和对本指南中所述工具和推动因素的有效使用，可增强企业在公司的药品质量体系（PQS）下有效管理许多CMC变更的能力，从而减少变更实施前的监管机构批准。本方法可通过为批准后变更提供更大灵活性机会而激励持续改进。它亦可能减少上市许可申报（MAA）的相关批准后申报，减少相关注册工作。此种操作和注册灵活性及其充分实施的程度取决于现有注册框架、对产品和工艺的理解（ICH Q8(R2) 和 Q11）、质量风险管理原则的应用（ICH Q9），和药品质量体系（ICH Q10）的可靠程度。

Regulatory Members of ICH are encouraged to provide publicly available information, preferably on their website, about the implementation of ICH Q12 in their region, especially with regard to regulatory considerations.

我们鼓励ICH的药监成员向提供在其地区执行ICH Q12的公开信息（最好在其官网上），尤其是关于注册考量的信息。

1.2  Scope 范围

This guideline applies to pharmaceutical drug substances  and products (both chemical and biological) that require a marketing authorization; and to drug-device combination products that meet the definition of a pharmaceutical or biological product. Changes needed to comply with new or revised pharmacopoeial monographs are not within the scope of this guideline.

本指南适用于需要上市许可的原料药和制剂（化学和生物药），以及符合药品和生物药品定义的药械组合产品。需要符合新的或修订后药典各论的变更不在本指南范围内。

1.3  ICH Q12 Regulatory Tools and Enablers ICH Q12注册工具和实现方法

Use of the following harmonised regulatory tools and enablers with associated guiding principles, as described in this guideline, will enhance the management of post-approval changes, and transparency between industry and regulatory authorities, supporting innovation and continual improvement.

使用以下统一的注册工具和与相关指导原则有关的工具，正如本指南所述，将加强批准后变更的管理，促进企业与药监当局之间的透明度，支持创新的持续改进。

•      Categorisation of Post-Approval CMC Changes (Chapter 2) 批准后CMC变更分类（第2章）

Categorisation of Post-Approval CMC Changes describes a framework that encompasses arisk-based categorisation for the type of communication expected of the Marketing Authorisation Holder (MAH) with the regulatory authority regarding CMC changes.

批准后CMC变更分类阐述的是指导基于风险对MAH与药监当局关于CMC变更预期沟通类型的分类框架。

•      Established Conditions (ECs) (Chapter 3) 既定条件（EC）（第3章）

The concept of ECs provides a clear understanding between the MAH and regulatory authorities regarding the elements to assure product quality and that involve a regulatory communication, if changed. This guideline describes how ECs are identified as well as what information can be designated as supportive information that would not involve a regulatory communication, if changed. Inaddition, guidance is included for managing revisions of the ECs.

EC概念使得MAH与药监当局可以清晰理解确保药品质量和所涉及注册申报（如有变更）所需的要素。本指南描述了如何识别EC，以及哪些信息可指定作为支持性信息，而不需要注册申报（如有变更）。另外，还包括了管理EC修订的指南。

•      Post-Approval Change Management Protocol(PACMP) (Chapter 4) 批准后变更管理方案（PACMP）（第4章）

The PACMP is a regulatory tool that provides predictability regarding the information required to support a CMC change and the type of regulatory submission based on prior agreement between the MAH and regulatory authority.Such a mechanism enables planning and implementation of future changes to ECs in an efficient and predictable manner.

PACMP是一种注册工具，可根据MAH与药监当局之前的协定预测支持CMC变更所需信息和注册申报类型。此机制使得能以可预测的有效方式规划和实施未来的EC变更。

•      Product Lifecycle Management (PLCM)Document (Chapter 5) 药品生命周期管理（PLCM）文件（第5章）

The PLCM document serves as a central repository for the ECs and the associated reporting category for changes made to ECs. The document also captures how a product will be managed during the commercial phase of the lifecycle including relevant post-approval CMC commitments and PACMPs.

PLCM文件是EC PLCM文件用途是作为EC和对EC所做变更的相关报告类型的集中存贮工具。该文件也包括一个产品在生命周期中的商业化阶段如何管理，包括相关批准后CMC承诺和PACMP的信息。

•      Pharmaceutical Quality System (PQS) and Change Management (Chapter 6) 药物质量体系（PQS）和变更管理（第6章）

An effective PQS as described in ICH Q10 and compliance with regional GMPs are necessary to gain full benefit from this guideline. In particular, management of manufacturing changes across the supply chain is an essential part of an effective change management system. This guideline provides recommendations for robust change management across single or multiple entities involved in the manufacture of a pharmaceutical product.

ICH Q10中所述的有效PQS和地区GMP合规性在全面实施本指南时是必须的。尤其是，供应链中生产变更管理是有效变更管理体系的基础部分。本指南提供对药品生产涉及单个或多个实体的稳健变更管理的建议。

•      Relationship Between Regulatory Assessment and Inspection (Chapter 7) 注册审评与现场检查之间的关系（第7章）

This guideline outlines the complementary roles of regulatory assessment and inspection in the oversight of post-approval changes; and how communication between assessors and inspectors facilitates the use of the tools included herein.

本指南列出了注册评审和检查在批准后变更监管中的互补作用，以及评审员与检查员之间的沟通如何促进使用此处所包括的工具。

•      Structured Approaches for Frequent CMC Post-Approval Changes (Chapter 8) 频繁CMC批准后变更的结构化方法（第8章）

In addition to the other tools described above, this guideline describes a strategy for a structured approach applicable to frequent CMC changes, and a discussion of data expectations, to enable the use of immediate or other post-implementation notification.

除了上述工具外，本指南还描述了一种适用于频繁CMC变更的结构化方法，并讨论了对数据的要求，以促进立即通知或其它实施后通知的使用。

•      Stability Data Approaches to Support the Evaluation of CMC Changes (Chapter  9) 支持CMC变更评估的稳定性数据方法（第9章）

This guideline provides additional science- and risk-based approaches that are relevant to strategies for confirmatory stability studies to enable more timely implementation of CMC changes.

本指南提供了与有利稳定性研究策略有关的其它的基于风险的科学方法，以促进更为及时地实施CMC变更。

Tools and enablers described above are complementary and are intended to link different phases of the product lifecycle. Pharmaceutical development activities result in an appropriate control strategy, elements of which are considered to be Established Conditions. All CMC changes to an approved productare managed through a company’s Pharmaceutical Quality System; changes to ECs must also be reported to the regulatory authority. Where the regulatory system provides for Categorisation of Post-approval CMC Changes for reporting according to risk, the MAH may propose reporting categories for changes to ECs based on risk and knowledge gained through enhanced pharmaceutical development. A system with risk-based reporting categories also facilitates the use of Post-Approval Change Management Protocols, which provide predictability regarding planning for future changes to ECs. The Product Lifecycle Management Document is a summary that transparently conveys to the regulatory authority how the MAH plans to manage post-approval CMC changes. The tools and enablers in this guideline do not change the Relationship Between Regulatory Assessment and Inspection; however, collaboration and communication between assessors and inspectors are necessary for the implementation of this guideline by regulators. This guideline provides Structured Approaches for Frequent CMC Post-Approval Changes to enable the implementation of certain CMC changes for authorised products without the need for prior regulatory review and approval. Finally, this guideline provides Stability Data Approaches to Support the Evaluation of CMC Changes; i.e., where the stability study is undertaken to confirm previously approved storage conditions and shelf-life.

上述工具和驱动力是互补的，意在关联产品生命周期的不同阶段。药物开发活动产生一个适当的控制策略，其要素被认为是既定条件。所有对已批准产品的CMC变更应通过公司的药物质量体系进行管理，对EC的变更也必须报告给药监当局。如果监管系统根据风险提供了批准后CMC变更的报告分类时，MAH可以根据通过增强药物开发获得的风险和知识拟定EC变更的报告类别。具有基于风险的报告类别的系统亦有利于使用批准后变更管理协议，其提供关于今后EC变更规划的可预测性。产品生命周期管理文件是一份总结，明确清晰地传达给监管机构MAH如何计划管理批准后CMC变更。本指南中的工具和推动因素不改变注册审评和现场检查之间的关系；但是审评员和检查员之间的协作和沟通对于药监当局实施本指南是必要的。本指南提供了促进上市产品实施特定CMC变更而不需要提前进行注册审评和批准的频繁CMC批准后变更结构化方法。最后，本指南提供了支持CMC变更评估的稳定性数据方法，即执行稳定性研究用以确认之前已批准的存贮条件和货架期。

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