Quality Risk Management 质量风险管理

1. Quality Risk Management 质量风险管理 Overview Training 概要培训 Ronald Tang Sep. 2010

2. Agenda 流程 • Introductions介绍 • Learning Objectives 学习目的 • Background 背景 • Overview of Directive • Purpose / Scope 目的/范围 • Requirements / Definitions 要求/定义 • Key Roles and Responsibilities 关键角色和责任 • Summary 总结 • Questions & Answers 问答

3. Learning Objectives 学习目标 • This training course is an overview of the Quality Risk Management. • 此培训课程是针对质量风险管理的概要培训。 • At the conclusion of this module, you will have an understanding of: • 完成此培训课程你将了解到： • What is Quality Risk Management(QRM)? 什么质量风险管理？ • TheBMS Technical Operations systematic approach to Quality Risk Management (QRM) 施贵宝技术操作部针对质量风险管理的系统方法 • Key requirements, purpose and scope 关键要求，目的和范围 • Key roles and responsibilities关键角色和责任 • Therecommended QRM tools for cGMP processes cGMP推荐的质量风险管理工具

4. Overview Training: Intended Audience概要培训：受众 The QRM Overview course is for individuals who… 质量风险管理概要培训课程是针对： • Must become knowledgeable about the Quality Risk Management process 必须对质量风险管理流程熟悉的人 • May have oversight responsibility for the implementation of the process 可能对质量风险管理的实施负监督责任的人

5. Background 背景 • Used in many industries for the past several decades (i.e. Insurance, IT, Medical Devices, Business). 在过去的几十年间已应用于许多行业，例如保险、信息、医疗器械、商务 • Pharmaceutical industry has lagged behind. 制药行业已经落在后面 • EU GMP’s and inspectors have always “expected” risk management to be utilized. 欧盟GMP和检察官一直期望风险管理的应用 • 2005 November - ICH Q8 & Q9 adopted. 2005年11月ICH Q8 & Q9 采用 • 2008 February – ICH Q9 becomes Annex 20 in EU GMP’s and Chapter 1 was revised. 2008年2月欧盟GMP的附件20借鉴了ICH Q9并据此修改了第一章 • 2008 June – ICH Q10 adopted. 2008年6月ICH Q10采用

6. EU GMP’s Chapter 1 欧盟GMP第一章 • Quality Risk Management (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. 质量风险管理(QRM)是一个系统化的流程，是对药品的质量风险进行评估，控制，交流并且回顾的过程。它既是前瞻性的也是可回顾的。 • The quality risk management system should ensure that: 质量风险管理系统应该确保： • the evaluation of the risk to quality isbased on scientific knowledge, experiencewith the process and ultimately links to theprotection of the patient 对质量风险的评估是基于科学知识，生产经验，并最终联系到对患者的保护 • thelevel of effort, formality and documentationof the quality risk management process iscommensurate with the level of risk 质量风险管理流程的程度，格式和文件应与风险的级别相一致 • Examples of the processes and applications of quality risk management can be found in Annex 20. 质量风险管理的流程和应用实例参见欧盟GMP的附件20.

7. FDA cGMPs for the 21st Century – Desired State FDA cGMP的期望状态 • In response to today’s challenges facing pharmaceutical manufacturing and quality, FDA launched its “Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach” in August 2002 to: 为回应今天的药品生产和质量所面临的挑战，美国FDA在2002年8月推出了“21世纪的制药CGMP：一个基于风险的方法”： • Encourage innovation and early adoption of advanced manufacturing technologies – PAT / QbD 鼓励创新和先进制造技术的早期采用-性能加速技术/质量源于设计 • Facilitate continuous improvement through robust Quality Systems 通过强有力的推动持续改进质量体系 • Encourage the use of risk-based and science-basedapproaches to focus on critical areas. 鼓励以风险为本和以科学为基础的方式，重点加强关键领域 • 2004FDA’s “GMPs for the 21st Century” challenges usto use a Risk Based Approach in our operations. 2004年FDA的“21世纪GMP”挑战我们在实际操作中采用基于风险的方法

8. How do we get to Desired State?如何达到期望状态？

9. Quality Risk Management 质量风险管理 (ICH Q9) Quality Systems 质量系统(ICH Q10) Quality by Design QbD 质量源于设计 (ICH Q8) ICH Q8, Q9, Q10 - Desired State! ICH Q8,Q9,Q10的期望状态 The Three Musketeers

10. Key Definitions 关键定义 Detectability探测度 Occurrence发生率 Severity严重性 Risk风险 Residual Risk 残留风险 Risk Management 风险管理 Risk Identification风险识别

11. Key Definitions (continued) 关键定义 Risk Analysis风险分析 Risk Evaluation风险估算 Risk Control风险控制 Risk Acceptance风险接受 Risk Reduction风险降低 Risk Communication风险交流 Risk Review风险回顾

12. Purpose 目的 WWQC-1.4.3 QRM 质量风险管理： To provide a systematic approach to the QRM and examples of the tools for the use, integration and application of QRM to varying aspects of pharmaceutical quality, including development, manufacturing, distribution, inspection and submission/review processes throughout the lifecycle of the drug product, API, medical devices and biological drug substances. 为质量风险管理提供一个系统方法和管理工具应用范例去评估药品质量的各个方面，包括研发，生产，分销，检查和以及药品，API，医疗器械和生物药整个生病周期中的提交/回顾流程。 Provides a structured approach to of QRM across the product lifecycle and within cGMP systems/processes. In-line with the principles outlined in ICH Q9 and ISO 14971. 在cGMP系统/流程内，为贯穿于整个药品生命周期的质量风险管理提供一个结构化的工具。与ICH Q9和ISO14971的原则相一致。

13. Scope 范围 This Directive applies to: 本指南使用于： • The utilization of QRM when applied to all operations at all BMS Technical Operations facilities and employees engaged in the development, management, manufacture, control and/or distribution throughout the lifecycle of drug product, API, medical devices and biological drug substances (including the use of raw materials, solvents, excipients and packaging components). 质量风险管理适用于所有BMS技术操作部，以及所有致力于开发，管理， 生产，控制和/或药品/原料药/医疗器械/生物药整个生病周期中的分销（包括使用原料，溶剂，辅料和包装材料）。 The principles outlined are also applicable in the management of vendors and contractors engaged in the manufacturing and testing on behalf of BMS. 本指南所列条款也适用于代表BMS生产和测试的供应商和合同商的管理

14. General Requirements 总则： Appropriate use of quality risk management must facilitate but not obviateBMS responsibilities to comply with regulatory requirements (e.g. cGMP, regulatory filings). 质量风险管理的合理应用必须促进但不违背BMS职责去附和法规要求（例如cGMP, 法规注册）。 QRM is intended to reduce risk to an acceptable level that is appropriate to the nature of the product involved. Since risk can be minimized but not totally eliminated, criteria to be applied in accepting residual risks must be considered (and where possible pre-defined), endorsed by appropriate management, and applied consistently. 质量风险管理是为了适应药品的性质将风险降低到可接受的程度。由于风险是可以降到最低但不可能完全消除的，所以必须考虑可接受残留风险的标准（可能要预先设定），通过适当的管理部门批准，并且贯彻应用 The extent of QRM documentation, communication, mitigation and escalation must be appropriate to the level of risk. 质量风险管理的记录，沟通，减轻和升级的程度必须和风险的级别相符合。 QRM is a systematic process (QRM flowchart) for the assessment, control, communication and review of risks to the quality of the drug product and risk to patient safety. 质量风险管理是一个系统化的流程（QRM工作流程），对药品的质量风险和患者的安全风险进行评估、控制、交流和回顾的流程。

15. Why risk assessment?为什么要进行风险评估？ Go to QRM Flowchart

16. How bad? Severity 多严重？ Risk Identification 风险识别 Risk Evaluation 风险估算 What can go wrong? 什么可能出错？ How often? Occurrence 多频繁？ Is there a need for action? 需要采取行动？ How detectable? 多难探测？ Risk Analysis风险分析 (qualitative or quantitative process) Risk Assessment 风险评估 The process of risk assessment seeks to answer five simple, related questions: 风险评估为了5个简单而相关的问题寻求答案： Go to QRM Flowchart

17. General Requirements (continued) 总则： The evaluation of the risk to the quality of the drug product, active pharmaceutical ingredients (API), medical device and biological drug substances is based on scientific knowledge and ultimately link to the protection of the patient. 对药品，活性成分，医疗器械和生物药品的质量风险的估算是基于科学知识并最终联系到对病人的保护。 QRM must be either a formal or an informal process (algorithm) and must be applied proactively or retrospectively. 质量风险管理必须是正式或非正式的程序（算法）且被预见性或追溯性的应用。 Formal QRM processes require independent risk assessment reports, documentation and the use of recognized QRM tools. 正式的质量风险管理流程要有一个独立的风险评估报告，记录和公认的风险管理工具的使用。

18. General Requirements (continued) 总则： • Factors used to determine the scope of the QRM effort, the size of the cross-functionalteam, and the level of effort and rigor applied to data collection include the following: 决定质量风险管理的范围、跨职能团队的规模、努力程度和收集数据的精确性的因素包括： • Criticality of the problem / risk question 问题/风险的关键性 • Complexity and/or novelty of the issue/process/system 问题/过程/系统的复杂性和/或新颖性 • Availability of relevant historical data相关历史数据的可用性 • Level of available process knowledge and experience 现有的工艺知识水平和经验 • The requirement to use formal Quality Risk Assessments must be determined on a case-by-case basis in order to identify and evaluate potential hazards and associated risk in an attempt to control these risks. 规定使用正式的质量风险评估的要求必须逐案确定，以识别和估算潜在危害和相关风险，旨在控制这些风险

19. General Requirements (continued)总则： • QRM decisions (e.g. plan) must be clearly documented, traceable to documented supporting rationale, approved by Quality Assurance and properly communicated. 质量风险管理决定必须被清晰记录，可追溯到记录的支持理由，被质量保证部批准且适当沟通。 • QRM methodologies are used to differentiateand establish priorities among products, critical and non-criticalprocesses and systems. 质量管理方法是用于区分和在产品，关键和非关键工艺和系统间建立优先权。 • Whenperformingthe risk assessment, the problem and/or risk question must be defined and include pertinent assumptions identifying the potential for risk. The background information and/or data on the potential hazard, harm or human health impact relevant to the risk must be assembled. 在进行风险评估，问题和/或风险问题必须加以界定并包括确定潜在风险有关的假设。背景信息和/或潜在危险，危害或影响人体健康的有关风险数据必须进行组合。 • QRM must include the review and communication of the results from the risk assessment activities at intervals to ensure continuing effectiveness and suitabilityof the process. 质量风险管理必须包括阶段性地对风险评估活动的结果进行回顾和沟通，以确保过程的持续有效和适用。 • The output from the QRM process must be documented and communicatedthroughout the QRM effort to appropriate internal and external stakeholders. 从QRM流程得出的结论必须被记录，整个QRM努力应与内部及外部的风险承担人适当沟通。

20. Applicability and QRM Tools 适用性和质量风险管理工具 • QRM is applicable for any part of the product lifecycle when a determination of risk to product quality is needed. QRM is also be used to make key decisions within Quality Systems that support cGMP operations. 质量风险管理适用于产品生命周期的任一部分，在需要确定产品质量的风险时。质量风险管理也用于质量系统内的关键决策，支持cGMP操作。 QRM is used to identify possible risk and ensure the provision of adequate engineering and procedural controls with the appropriate resources in place to control this risk. 质量风险管理用于识别潜在的风险，并确保有适当的工程和具有相应资源的程序控制去控制这种风险。 QRM is used throughout various aspects of the process as appropriate. For example, as part of the Integrated Quality Management, Regulatory Operations, Development, Materials Management, Production. Laboratory Control and Stability. Packaging, Labeling Computerized Systems, Calibration and Disposition. 质量风险管理可用于整个过程的各个方面。例如，作为整合质量管理，法规操作，开发，物料管理，生产，实验室控制和稳定性考察，包装，标签，电脑系统，校验和处置的一部分。

21. Applicability and QRM Tools (continued)适用性和质量风险管理工具 The most commonly used tools for QRM are listed in Appendix D which provides a general overview of the tools used in the QRM Process; however other recognized tools are available. 附件D列出了最通用的质量风险管理工具，它提供了用于QRM流程的工具的概述。其他公认的工具也是适用的。 It is important to note that no one tool or set of tools is applicable to every situation in which a QRM process is used. An individual tool or a combination of tools may be used, but the rationale for the tools chosen must be included in the QRM document. 重要的是要注意没有一种工具或一套工具是适用于每一个QRM过程中的每个情况。一个单独的工具或工具组合可以使用，但对所选择的工具的理由必须记录QRM文件中。 The following examples show how QRM can be incorporated into GMP systems and process… 下面的例子展示了如何将质量风险管理嵌入GMP系统和过程之中...

22. QRM within GMP ProcessesGMP过程中的质量风险管理 Annual Product Review 年度产品回顾: QRM can be incorporated into annual product review process by performing documented review on critical processes and critical quality attributes of the product. Any new risks are considered, evaluated, mitigated and documented. 质量风险管理可用于年度产品回顾，通过对关键流程，产品关键质量参数的文件回顾。应考虑，估算，减轻和记录任何新的风险。 Recommended Tools: Control Charts-Trending, Process Capability Analysis 推荐工具：变量控制图，工艺能力分析 Deviations & CAPA 偏差和整改预防措施: QRM can be incorporated into the Deviation and CAPA process by trending and prioritizing. In addition, individual reports can prompt a review of the process knowledge and criticality analysis of the process from which the problem arose. 质量风险管理可嵌入偏差和整改预防措施过程，通过趋势和优先级别分析。此外，个别报告可提示对问题发生的过程的知识和关键分析进行回顾。 Recommended Tools: Pareto Charts, Control Charts, Process FMEA, Design FMEA, Root Cause Analysis 推荐工具：帕累托图，控制表，工艺的失败模型和效应分析，设计的失败模型和效应分析，根本原因分析 Quality Systems 质量系统

23. QRM within GMP ProcessesGMP过程中的质量风险管理 Process Validation工艺验证: QRM can be incorporated into Process Validation by conducting criticality analysis of the process to identify high-risk areas that require focus during validation. These high-risk areas would be associated with critical to quality attributes that relate to safety and efficacy for the product. 质量风险管理可用于工艺验证，通过对验证过程中需要关注的焦点的关键性分析以确定高风险领域，这些高风险的领域将与产品安全性和疗效相关的关键质量属性进行关联。 Recommended Tools: Process FMEA, Process Flowcharts, Criticality Analysis 推荐工具：工艺的失败模型和效应分析，工艺流程图，关键性分析 Manufacture of Product 产品生产: QRM can be incorporated into the manufacture of product process by conducting an analysis of the process to determine which process steps and specific operations contribute to the critical quality attributes of the product. 质量风险管理可用于产品制造过程，通过过程分析去确定哪个工艺步骤和具体操作有助于产品的关键质量属性。 Recommended Tools: Process FMEA, Criticality Analysis, Trend Analysis 推荐工具：工艺的失败模型和效应分析，关键性分析，趋势分析 Production Systems生产系统

24. QRM within GMP ProcessesGMP过程中的质量风险管理 Maintenance 维护: QRM can be incorporated into the maintenance of facilities, equipment and utilities based on the criticality analysis of the process(es) and associated criticality for each facility, utility and piece of equipment. Appropriate maintenance frequencies can be determined based on criticality and performance. 质量风险管理可用于设施，设备和能效系统的维护，基于对每个设施，能效和设备的每一部分的关键性分析。根据重要程度和性能确定适当的维护频率。 Recommended Tools: Criticality Analysis, Decision Trees, Relative Ranking/Risk Indexing, Reliability Analysis 推荐工具：关键性分析，决策图表，相对排名/风险索引，可靠性分析 Qualification of Facilities, Equipment & Utilities 设施，设备及能效的确认: QRM can be incorporated into the qualification of facilities, equipment and utilities to help determine the scope and extent of commissioning and qualification based on criticality of use in processing. 质量风险管理可用于设施，设备及能效的确认，以帮助决定调试和确认的范围和程度。 Recommended Tools: Decision Trees, FMEA, IPSE Impact Assessment 推荐工具：决策图表，失败模型和效应分析，IPSE影响评估 Facilities, Equipment and Utilities Systems 设施，设备和能效系统

25. QRM within GMP ProcessesGMP过程中的质量风险管理 Distribution of Final Product 成品分发: QRM can be incorporated into the distribution of final product by conducting a process risk analysis to identify high-risk areas in the distribution network that require special attention or mitigaion. Particular attention should be given to any requirements for cold chain management. 质量风险管理可嵌入成品分发流程中，通过风险分析去识别在分发流程中需要特别注意或缓解的高风险领域。 Recommended Tools: Process FMEA 推荐工具：工艺的失败模型和效应分析 Supplier Management 供应商管理: QRM can be incorporated into supplier management by establishing a matrix for supplier criticality. The criticality of the services/products a supplier can help establish audit frequency in order that the critical suppliers receive the most focus. 质量风险管理可用于供应商管理，通过对供应商的重要性建立矩阵。根据供应商提供的服务/产品的重要性建立审计频率，以使关键供应商应得到最大关注。 Recommended Tools: Pareto Charts, Decision Matrix, Relative Ranking/Risk Indexing 推荐工具：帕累托图，决策图表，相对排名/风险索引 Materials Management Systems 物料管理系统

26. QRM within GMP ProcessesGMP过程中的质量风险管理 Control of Labels & Packaging Materials 标签和包装材料控制: QRM can be incorporated into the control of labels and packaging materials by conducting a process risk analysis to identify high-risk areas that require mitigation and/or additional controls to prevent failure. 质量风险管理可用于对标签和包装材料的控制，通过风险分析去识别需要缓解和/或额外控制预防失败的高风险领域 Recommended Tools: Process FMEA, Criticality Analysis 推荐工具：工艺的失败模型和效应分析，关键性分析 Graphics Management 图形管理: QRM can be incorporated into graphics management by mapping of processes for the creation, review and approval of the control for printed packaging materials, and for all steps in the supply chain between suppliers and customers. Particular attention should be given to review and approval of masters, incoming delivery controls and change control. 质量风险管理可嵌入图形管理，通过映射创建，审核和批准印刷包装材料控制的过程，以及在供应商和客户之间的供应链的所有步骤。应特别应注意审查和批准人，来料交付控制和变更控制。 Recommended Tools: Process FMEA 推荐工具：工艺的失败模型和效应分析 Packaging and Labeling Systems 包装和标签系统

27. QRM within GMP ProcessesGMP过程中的质量风险管理 Sample Control 取样控制: QRM can be incorporated into the sample control process by conducting a process risk analysis to identify high-risk areas that require mitigation. 质量风险管理可用于取样过程控制，同过风险分析去识别需要缓解的高风险领域。 Recommended Tools: Process FMEA 推荐工具：工艺的失败模型和效应分析 Stability Monitoring Program 稳定性考察程序: QRM can be incorporated into the stability program by systematic use of bracketing and statistical techniques. Stability investigations that occur as a result of the product not meeting its intended specification can prompt a Health Hazard Evaluation (HHE) to identify potential patient risk. Risks of this nature must be raised immediately to ExecutiveManagement. 质量风险管理可用于稳定性考察程序中，通过统计技术和架构的系统使用。由于不符合其预定的标准而产生的稳定性调查可促使健康危害评估（HHE）以找出对患者的潜在风险。这种性质的风险必须立即提交至公司高级管理层。 Recommended Tools: Regression Analysis, Hypothesis Testing, Trending Charts 推荐工具：衰减分析，假设检验，趋势图 Laboratory Control Systems 实验室控制系统

28. Summary总结 You should have an understanding of: 你应该了解到： • TheQuality Risk Management process 质量风险管理流程 • Thesystematic approach to Quality Risk Management 质量风险管理的系统工具 • Key requirements, purpose and scope 关键要求，目的和范围 • Keyroles and responsibilities 关键角色和责任 • Therecommended QRM tools for cGMP processes 针对cGMP流程推荐的QRM工具 • Apply RM to only the most critical and/or complexissues or problems 只针对最关键和/或最复杂的问题或难题应该风险管理 • It is not intended to be used to address more minor issues which can be addressed by other, less formal, means. 不适用于一些小问题，可用其他不太正式的方法去记录 • QRM decisions (e.g. plan) must be clearly documented, traceable to documented supporting rationale, approved by Quality Assurance and properly communicated. 质量风险管理决策（例如，计划）必须被清晰记录，可追溯到记录的支持理由，被质量保证部批准且适当沟通。

29. Questions 问题

30. Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation unacceptable R i n s o k i t a M c Risk Control a i n n a u g m Risk Reduction e m m o e C n t k t s Risk Acceptance o i o R l s Output / Result of the Quality Risk Management Process Risk Review Review Events Quality Risk Management Flowchart 质量风险管理流程图 Go to Risk Assessment Picture Go to Risk Assessment slide

31. Algorithm for Formal Risk Assessments Return to Requirements

32. Quality Risk Management Tools 质量风险管理工具 Failure Mode Effects Analysis (FMEA)失效模式和效应分析 Fault Tree Analysis (FTA) 故障树分析 Hazard Analysis and Critical Control Points (HACCP) 危害分析与关键控制点 Hazard Operability Analysis (HAZOP)危险可操作性分析 Preliminary Hazard Analysis (PHA)预先危险性分析 Risk Ranking and Filtering (RRF)风险排序和过滤 Return to Requirements

33. Risk Management Tools风险管理工具 General 概要

34. Supporting Statistical Tools 支持的统计工具 Quality Statistics Handbook 质量统计手册 Basic/Advanced Statistical Analysis 基础/高级统计分析 Measurement System Analysis 测量系统分析 Design of Experiments 实验设计 Acceptance Sampling by Attributes/Variables 基于属性/变量的取样标准 Failure Mode and Effect Analysis 失败模型和效应分析 Pareto Diagrams 帕累托图 Cause-and-Effect Diagrams (Fishbone) 因果效应图（鱼骨图） Histograms 柱状图 Scatter Diagrams 散布图 Control Charts 控制图 Return to Requirements