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风险管理

释义

质量风险管理是在整个产品生命周期中采用前瞻或回顾的方式，对质量风险进行评估、控制、沟通、审核的系统过程（中国GMP 第二章质量管理）

释义出处：Quality System Approach to Pharmaceutical cGMP Regulations

ICH Q9中关于风险管理（Risk Management, RM）的定义为：风险管理是质量管理方针、程序及规范在评估、控制、沟通和回顾风险时的系统应用。Risk management：The systematic application of quality management policies, procedures, and practices to the tasks of assessing, controlling, communicating and reviewing risk. ICH Q9 Quality Risk Management

PIC/S 于2021年1月也发布了关于质量风险管理的检查备忘PI 038-2 Aide Memoire on Assessment of Quality Risk Management (QRM) Implementation ，在提出风险体系化管理的同时，强调风险管理不是独立于质量系统之外的独立体系，必须是质量系统不可或缺的一部分（QRM should not be an isolated System of QA, it should be fully embedded into the QA or QM System）。风险管理作为一个理念和工具应融入到生产质量管理的各个方面中，应有全面的规划，风险的清晰定义，管理层的参与和沟通。

基本信息

英文名称	Risk Management

法规指南

国内法规

中华人民共和国药品管理法 - 2019/08/26

第三条　药品管理应当以人民健康为中心，坚持风险管理、全程管控、社会共治的原则，建立科学、严格的监督管理制度，全面提升药品质量，保障药品的安全、有效、可及。

第三十七条　药品上市许可持有人应当建立年度报告制度，每年将药品生产销售、上市后研究、风险管理等情况按照规定向省、自治区、直辖市人民政府药品监督管理部门报告。

第七十七条　药品上市许可持有人应当制定药品上市后风险管理计划，主动开展药品上市后研究，对药品的安全性、有效性和质量可控性进行进一步确证，加强对已上市药品的持续管理。

中国GMP 第二章质量管理

第十三条　质量风险管理是在整个产品生命周期中采用前瞻或回顾的方式，对质量风险进行评估、控制、沟通、审核的系统过程。

第十四条　应当根据科学知识及经验对质量风险进行评估，以保证产品质量。

第十五条　质量风险管理过程所采用的方法、措施、形式及形成的文件应当与存在风险的级别相适应。

药品生产监督管理办法 - 2020/01/22

第二十四条从事药品生产活动，应当遵守药品生产质量管理规范，按照国家药品标准、经药品监督管理部门核准的药品注册标准和生产工艺进行生产，按照规定提交并持续更新场地管理文件，对质量体系运行过程进行风险评估和持续改进，保证药品生产全过程持续符合法定要求。生产、检验等记录应当完整准确，不得编造和篡改。

第二十九条药品生产企业的法定代表人、主要负责人应当对本企业的药品生产活动全面负责，履行以下职责：

（四）发生与药品质量有关的重大安全事件，应当及时报告并按企业制定的风险管理计划开展风险处置，确保风险得到及时控制；

第四十二条药品上市许可持有人委托生产药品的，应当符合药品管理的有关规定。

药品上市许可持有人委托符合条件的药品生产企业生产药品的，应当对受托方的质量保证能力和风险管理能力进行评估，根据国家药品监督管理局制定的药品委托生产质量协议指南要求，与其签订质量协议以及委托协议，监督受托方履行有关协议约定的义务。

第五十三条药品生产监督检查的主要内容包括：

（五）风险管理计划实施情况；

CDE 临床风险管理计划撰写指导原则试行 - 2022/01/06

CDE 临床风险管理计划撰写指导原则试行 - 2022/01/06[7]

风险控制措施（risk minimization measures）包括常规措施和特殊措施，目的在于预防/降低重要风险的发生。常规风险控制措施包括修订药品说明书、标签、包装，改变药品包装规格，改变药品管理状态等。通过药品在销售、处方和使用过程中必须配备的材料或环节实现风险控制的措施，应被列为常规措施；国家针对特殊药物（如麻醉药品、血液制品、精神疾病用药等）的处方和销售限制也属于常规措施。药品说明书是最重要的常规风险控制工具；为了预防用药错误，在包装上进行特殊的提醒，或者不同规格产品采用不同颜色或外形的包装设计，也属于常规风险控制措施。

当常规措施不足以将风险降低到可接受水平时，应提出特殊风险控制措施。科学合理的特殊措施可以对药品的“获益风险评估”产生积极的作用。特殊措施通常有医患教育材料、用药指南、处方/流通渠道管理、用药登记、妊娠预防计划等。在撰写特殊措施时应该以具体措施为中心，对各项措施的名称、拟控制风险和目标、实施计划表和有效性评价计划进行摘要。应将风险控制措施所涉及的工具和实施方案作为“临床风险管理计划”的附件（可在产品获批后完善）。

CDE 药物临床试验过程中一般风险管控及责令暂停、终止工作程序（征求意见稿） - 2019/11/13[8]

根据2019年8月26日修订发布的《药品管理法》，“国家建立药物警戒制度，对药品不良反应及其他与用药有关的有害反应进行监测、识别、评估和控制”，“药物临床试验期间，发现存在安全性问题或者其他风险的，临床试验申办者应当及时调整临床试验方案、暂停或者终止临床试验，并向国务院药品监督管理部门报告。必要时，国务院药品监督管理部门可以责令调整临床试验方案、暂停或者终止临床试验”。

2019年新修订的《药品注册管理办法》中也进一步明确，药物临床试验期间，发现存在安全性问题或者其他风险的，国家药品监督管理局药品审评中心可以根据相关情形，责令申请人调整临床试验方案、暂停或者终止药物临床试验。

FDA

Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach: Second Progress Report and Implementation Plan

FDA Guidance Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations

C. Quality Risk Management

Quality risk management is a valuable component of an effective quality systems framework. Quality risk management can, for example, help guide the setting of specifications and process parameters for drug manufacturing, assess and mitigate the risk of changing a process or specification, and determine the extent of discrepancy investigations and corrective actions.

EU

EU GMP Chapter 1 Pharmaceutical Quality System

Quality Risk Management

1.12 Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively.

1.13 The principles of quality risk management are that:

i) The evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient

ii) The level of effort, formality and documentation of the quality risk management process is commensurate with the level of risk

Examples of the processes and applications of quality risk management can be found inter alia in ICH Q9 which is reproduced in Part III of the Guide.

Chapter 5 Production

Prevention of cross-contamination in production

5.20 A Quality Risk Management process, which includes a potency and toxicological evaluation, should be used to assess and control the cross-contamination risks presented by the products manufactured. Factors including; facility/equipment design and use, personnel and material flow, microbiological controls, physico-chemical characteristics of the active substance, process characteristics, cleaning processes and analytical capabilities relative to the relevant limits established from the evaluation of the products should also be taken into account. The outcome of the Quality Risk Management process should be the basis for determining the necessity for and extent to which premises and equipment should be dedicated to a particular product or product family. This may include dedicating specific product contact parts or dedication of the entire manufacturing facility. It may be acceptable to confine manufacturing activities to a segregated, self contained production area within a multiproduct facility, where justified.

5.21 The outcome of the Quality Risk Management process should be the basis for determining the extent of technical and organisational measures required to control risks for cross-contamination. These could include, but are not limited to, the following:

Technical Measures…

Organisational Measures…

Chapter 8 Complaints and Product Recall

Principle

In order to protect public and animal health, a system and appropriate procedures should be in place to record, assess, investigate and review complaints including potential quality defects, and if necessary, to effectively and promptly recall medicinal products for human or veterinary use and investigational medicinal products from the distribution network. Quality Risk Management principles should be applied to the investigation and assessment of quality defects and to the decision-making process in relation to product recalls corrective and preventative actions and other risk-reducing actions. Guidance in relation to these principles is provided in Chapter 1.

ICH

ICH Q9 质量风险管理

Risk management principles are effectively utilized in many areas of business and government including finance, insurance, occupational safety, public health, pharmacovigilance, and by agencies regulating these industries. Although there are some examples of the use of quality risk management in the pharmaceutical industry today, they are limited and do not represent the full contributions that risk management has to offer. In addition, the importance of quality systems has been recognized in the pharmaceutical industry and it is becoming evident that quality risk management is a valuable component of an effective quality system.

Q9(R1) 质量风险管理

ICH E2C 药物警戒中的风险管理

Actions related to investigational drugs:

risk management activities, including:

Protocol modifications due to safety or efficacy concerns (e.g., dosage changes, changes in study inclusion/exclusion criteria, intensification of subject monitoring , limitation in trial duration);

Restrictions in study population or indications;

Changes to the informed consent document relating to safety concerns; o formulation changes;

Addition by regulators of a special safety-related reporting requirement; o Issuance of a communication to investigators or healthcare professionals; and o Plans for new studies to address safety concerns. See ICH E2C(R2)[16]

Actions related to marketed drugs:

risk management activities including:

Significant restrictions on distribution or introduction of other risk minimisation measures;

Significant safety-related changes in labelling documents that could affect the development programme, including restrictions on use or population treated; o Communications to health care professionals; and o New post-marketing study requirement(s) imposed by regulator(s). See ICH E2C(R2)

WHO

WHO GMP

Quality risk management

1.8 QRM is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively.

1.9 QRM should ensure that:

the evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient;

the level of effort, formality and documentation of the QRM process is commensurate with the level of risk.

PICS

PICS 质量风险管理 (QRM) 实施的评估备忘录 -- 2021/01/18

提出了当下对药品生产经营企业对质量风险管理实施方面的要求和监管期待。需要指出的是，质量风险管理是在将质量风险管理基本要求整合到医药企业的运营体系并得到高级管理层的积极支持的系统方法。

PICS 关于如何评估和证明药品质量体系在基于风险的变更管理方面的有效性建议 -- 2021/07/15[19]

3.1. The purpose of this document is to provide guidance on evaluating and demonstrating the effectiveness of a PQS in relation to risk-based change management as are governed by the PIC/S GMP Guide. This is in recognition of the fact that the PIC/S GMP Guide requires companies to demonstrate the effectiveness of their PQS and to apply quality risk management (QRM) principles to change control activities.