ICH_Q9质量风险管理-中文版

1、人用药注册技术要求国际协调会议质量风险管理原文：2005年十一月9日版翻译：徐禾丰英汉对照版2009年五月，第五版INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICALREQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FORHUMAN USE人用药注册技术要求国际协调会议ICH Harmonised Tripaitite Guideline人用药注册技术要求国际协调会议三方协调后的指南Quality Risk Management质量风险管理Q9Current Step 4 version现行

2、第四步版本dated 9 November 20052005年十一月9日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

3、 bodies of the European Union, Japan and USA本指南由人用药注册技术要求国际协调会议专家工作组根据人用药注册技术要求国际协调会议程序开发并提交各 方的药政部门咨询。根据人用药注册技术要求国际协调会议程序第四步，推荐给欧盟.日木和莫国药的政祁门采用的 最终文本.Q9Document History文件历丸First Codification 最初编码History*历丸Date日期New Codification 新编码 November 2005 2005年十一月Q9Approval by the Steering Committee under St

4、ep 2 and release for public consultation.指导委员会批准第二步文件并发放用于公开咨询22 March 20052005年3月22日Q9Q9Approval by the Steering Committee of Post Step 2 correction 指导委员会在批准第二步后的订正文件15 June 20052005年6月15日Q9Current Step 4 version 现行第四步版本Q9Approval by the Steering Comnuttee under Step 4 and recommendation for adopti

5、on to the three ICH regulatory bodies 指导委员会批准第四步文件并推荐ICH三方药政部门 批准9 November 20052005年11月9日Q9Quality Riuk Mansgement 质童风险管理Quality Risk Management质量风险管理ICH Harmonised Tripartite Guideline经过人用药注册技术要求国际协调会议三方协讽的指南Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 9 Novemb

6、er 2005, this guideline is recommended for adoption to the three regulatory parties to ICH在2005年11月9日的人用药注册技术要求国际协调会议上，木指南已经通过人用药注册技术要求国际协调会议 第四步程斤，本指南已经推荐给人用药注册技术要求国际协训会议三方的药政部门釆用.TABLE OF CONTENTS目录1 INTRODUCTION 简介12. SCOPE 范围23. PRINCIPLES OF QUALITY RISK MANAGEMENT 质量风险管理的原則24. GENERAL QUALITr

7、RISK MANAGEMENT PROCESS 常规质量风险管理程序24 1Responsibilities 职责44.2 Initiating a Quality Risk Management Process 启动质 量风险管理过程44.3 Risk Assessment 风险评估44.4 Risk Contiol 风险控 制54.5 Risk Communication 风险沟 通64.6 Risk Review 风险评审65. RISK MANAGEMENT METHODOLOGY 风险管理方法学76. INTEGRATION OF QUALITY RISK MANAGEMENT IN

8、TO INDUSTRY AND REGULATORY OPERATIONS质量风险管理与业界及药政运行整合87. DEFINITIONS定渋9&REFERENCES 参考文献11Annex 附录 I: Risk Management Methods and Tools 风脸管理方法与工具121.1 Basic Risk Management Facilitation Methods 基本风险管理简 易方法121.2 Failure Mode Effects Analysis 故障模式效应分析(FMEA)121.3 Failure Mode, Effects and Criticality An

9、alysis 故障模式影响与严重性分析(FMECA)131.4 Fault Tree Analysis 故障树分析(FTA)131.5 Hazard Analysis and Critical Control Points 危害分析关健控制点(HACCP)141.6 Hazard Operability Analysis 危害及可操作，性分析(HAZOP)141.7 Preliminary Hazard Analysis 预先危险分析(PHA)151.8 Risk Ranking and Filtering 风险扌非序 及过滤151.9 Supporting Statistical Tools

10、 扌甫助寸生统分十 工具16Annex 附录 II: Potential Applications for Quality Risk Management 实施质量风险管理的潜在机会16II. 1Quality Risk Management as Part of Integrated Quality Management 整合质董管理部分的质量风险管理1611.2 Quality Risk Management as Part of Regulatory Operations 药政操作部分的质量风险管理1811.3 Quality Risk Management as Part of dev

11、elopment 开发部分的质量风险管理1911.4 Quality Risk Management for Facilities, Equipment and Utilities 厂房，设备和公用没施的质莹风险管理1911.5 Quality Risk Management as Part of Materials Management 物料管理部分的质量风险管理2111.6 Quality Risk Management as Part of Production 生产部分的质量风险管理2111.7 Quality Risk Management as Part of Laboratory

12、 Control and Stability Studies 实验室控制和稳定性研究部分的质量风险管理22Quality Risk Management as Part of Packaging and Labelling 包装和标签部分的质量风险管理22稠译：徐禾丰2009年五月，第五阪第II页Qinhty Risk Mansgyment 质 童 风险管理Quality Risk Management质量风险管理1. INTRODUCTION 导言Risk management principles are effectively utilized in many areas of busi

13、ness and government including finance, insurance, occupational safety, public health pharinacovigilaiice. and by agencies regulating these industries. Although there are some examples of the use of quality risk management m the pharmaceutical industry today, they are limited and do not represent the

14、 full contributions that risk management has to offer. In addition, the importance of quality systems has been recognized m the pharmaceutical industry and it is becoming evident that quality risk management is a valuable component of an effective quality system 风险管理廉则被有效地应用于许多商业和政府的领域，包括金馳、保险、职业安全、

15、公共健康、药物预譽，以及 这些行业的主管部门.如今，尽管在制药行业也有一些运用质量风险管理的例子.但其非常有限，且没有体现出风险 管理能提供的全部贡献.另外，制药行业已经认识到质量体系的重要性，而且，质量风险管理对一个有效的质量体系 来说，是一个有价值的组成部分这一点越来越明显.It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. However, achieving a s

16、hared understanding of the application of risk management among diverse stakeholders is difficult because each stakeholder might perceive different potential harms place a different probability on each harm occurring and attribute different seventies to each harm In relation to pharmaceuticals, alth

17、ough there are a variety of stakeholders, including patients and medical practitioners as well as government and industry, the protection of the patient by managing the risk to quality should be considered of prime importance.通常将风险理解为，风险是由伤害发生的概率及伤害严重性结合而成然而，在不同的风险涉众中达成对风险管 理应用共识仍是困难的，因为每个风险涉众可能感觉到不

18、同的潜在伤害，对每个所发生的伤害设耳不同的概率以及伤 害不同的严重性属性.对于药品来说，尽管冇多种的风险涉仗，包括患者.医疗从业人员，以及政府和业界，运用质 量风险管理都应该以保护病人为基本出发点。The manufacturing and use of a drug (medicinal) product, including its components, necessarily entail some degree of risk. The risk to its quality is just one component of the overall risk It is import

19、ant to understand that product quality should be maintained throughout the product lifecycle such that the attributes that are miportant to the quality of the drug (medicinal) product remain consistent with those used in the clinical studies. An effective quality risk management approach can furtlie

20、r ensure the high quality of the dmg (medicinal) product to the patient by providing a proactive means to identify and control potential quality issues during development and manufacturing. Additionally, use of quality risk management can improve the decision making if a quality problem arises. Effe

21、ctive quality risk management can facilitate better and more informed decisions, can provide regulators with greater assurance of a companys ability to deal with potential risks and can beneficially affect the extent and level of direct regulatory oversight.药物(医疗)产品制造和使用，包括它的组份，必然要承担一定程度的风险.其质量风险仅是全

22、部风险中的一个. 莹要的是要了解到，产品质量应当贯穿产品的生命周期，这个属性对于药物(医疗)产品保持与临床研究时一致是非常 重要的通过仙唸意渋上辨识与控制在研发与制造中的潜在质量问题，一个有效的质量风险骨理方法能进一步给患者 提供高质量药炀(医疗)产品质量的保证，另外，如果出现质量问题.则采用质量风险管理可以改善决策.有效的质量 风险管理可以促使做出更好，更基于可至信息的决炙，可以为业界药政部门提供更强大应对潜在风险的能力的保证， 并且会对药政监背的水平和范围直接产生有利影响.The purpose of this document is to offer a systematic appro

23、ach to quality risk management. It serves as a foundation or resource document that is independent of, yet supports, other ICH Quality documents and complements existing quality practices, requirements, standards, and guidelines within the pharmaceutical industry and regulatory environment It specif

24、ically provides guidance on the principles and some of the tools of quality risk management that can enable more effective and consistent risk based decisions, both by regulators and industry, regarding the quality of drug substances and drug (medicinal) products across the product lifecycle It is n

25、ot intended to create any new expectations beyond the current regulatory requirements.本文件的目的是提供一个质量风险管理的综合方法.其作为一个基础的或资源性的文件，其肚立并支撑其它的 ICH质量文件，并对现有的质量实践.要求、标准以及制药行业指南与药政环境进行补充.其将明确提供质量风险管 理的原理，以及一些工具，其可以确保在药政部门和业界在考虑列贯穿在整个产品生命周期的原料药和药物(医疗)产 品质量时，做出更有效与更一致的基于风险的决篆.其并未试图建立任何趨越当前管理要求的新的要求。It is neither

26、 always appropriate nor always necessary to use a formal risk management process (using recognized tools and/ or internal procedures e.g, standaid operating procedures). The use of informal risk management processes (using empirical tools and/* or internal procedures) can also be considered acceptab

27、le Appropriate use of quality risk management con facilitate but does not obviate industrys obligation to comply with regulatory requirements and does not replace appropriate communications between industry and regulators使用一个正式的风险管理过程(使用公认的工具，和/或内部程序，例如标准操作程序)既不总是恰当的，也不总是 必须的釆用非正式的风险管理过程(使用经验的工具，和/或

28、内祁仪序)也是可以考虑接受。恰当运用质量风险管理可 新译：徐禾丰2009年五月，第五阪第1页Qinhty Ritk fansgyment 质 童 风险管理以促进，但并不能免除业界連守药政要求的责任，也不能取代业界和药政部门之间适当的沟通.2. SCOPE 范国This guideline provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality These aspects incl

29、ude development, manufacturing, distribution, and the inspection and subnussiowieview processes througliout the lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products (including the use of raw materials, solvents, excipients, packaging and hbelrng materials

30、 in drug (medicinal) products, biological and biotechnological products)机指南给出了质董风险管理的原理以及一些工具的例子，其可以应用于药品质量的不同方而“这些方面包括开 发、制适.分餡以及原料药.药物(医疗)产品.生物和生物技术产品(包括在药物(医疗)产品、生物和生物技术产品中 使用到的原料、溶剂、赋形刑、包装和标签材料)整个生命周期的检查和注册/评审过程.3. PRINCIPLES OF QUALITY RISK MANAGEMENT 质量风险管理的原则Two primary principles of quality

31、risk management are:质量风险管理的两个基本原则为： The evaluation of die risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and应该基于科学知识和聂终与对患者的保护相关联对质董风险进行评价；以及 The level of effort, formality and documentation of the quality risk management process should

32、be commensurate with the level of Tisk质董风险管理过程的力度、正式程度和文件化程度都应该与凤险水平相适应.4. GENERAL QUALITY RISK MANAGEMENT PROCESS 常规质量风险管理程序Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the dnig (medicinal) product across the produc

33、t lifecycle A model for quality risk management is outlined in the diagram (Figure 1 ) Other models could be used The emphasis on each component of the framework might differ from case to case but a robust process will mcorporate consideration of all the elements at a level of detail that is commens

34、urate with the specific risk.质量风险管理指的是对贯穿于药物(医疗)产品生产周期中的风险进行评估、控制、沟通及评审的系统过程。图中 概括了质董风险管理模式(图1)。也可以使用其他模式.所強调的构架中每个组成.可依不同情况而有所不同的，但一 个完善的过程会更加详细地整合考虑到所有因素，其与具体的风险有相同的水平.觀译：徐禾丰2009年五月，第五阪第2页Qinhty Ritk Management 质 童风险管理unaccep-abQRisk Management tootr雨科潯H扫Figure 1: Overview of a typical quality ris

35、k management process 图1:典型的质董风险管理过程概述凹鲁 UOQCOnmunuoo-H&觀译：徐禾丰2009年五月，第五阪第3页Qxnhty Risk Manngyment 质 童 风险管 理Decision nodes are not shown in the diagram above because decisions can occur at any point in the process These decisions might be to return to the previous step and seek further information, t

36、o adjust the risk models or even to terminate the risk management process based upon information that supports such a decision Note: unacceptable11 in the flowchart does not only refer to statutory, legislative or regulatory requirements, but also to the need to revisit the risk assessment process在上

37、图中并未标明判断结点，因为判断可出现在这个过程中的任何一个点.这些刿断将会退回到谊一步，并寻求 进一步的信息以调整风险模型，甚至根据支持这个判断的信息来终止风险管理过程注：在流程图中的鼐不接受”不 仅仅是依据法定.立法或药政要求，同样也需要返回风险评估过程.4.1 Responsibilities 职责Quality risk management actmties are usually, but not always, undertaken by mterdisciplmary teams When teams are formed, they should include experts

38、 from the appropriate areas (e.g, quality unit, business development, engineering, regulatory affairs, production operations, sales and marketing、legal, statistics and clinical) m addition to mdividuals who are knowledgeable about the quality risk management process风险管理活动通常，但并不总是，需要多学科的团队参与.当形成一个团队时

39、，应当要包括适当领域的专家(例 如，质董部门、商业开发.工程.药政.生产运行.销售和市场.：去律和临床)，及精通质量风险管理过程的个人。Decision makers should决策者应当： take responsibility for coordinating quality risk management across various fxmctions and departments of theu organization; and负责在其纽织内各职能部门间协调质量风险管理；以及， assure that a quality risk management process is d

40、efined, deployed and reviewed and that adequate resources are available 确保明确，开展与评审了质量风险管理过程，并有适当的资源.4.2 Initiating a Quality Risk Management Process 启动质量风险管理过程Quality risk management should include systematic processes designed to coordinate, facilitate and improve science-based decision making with

41、 respect to risk Possible steps used to initiate and plan a quality risk management process might include the following:质莹风险管理包括那些用于协调、促进和改善做出与风险相关的基于科学的决策系统过程“可能用于启动和霓划 一个质量风险管理过程的步骤可能包括以下几点： Define the problem and/oT risk question, including pertinent assumptions identifying the potential for risk

42、;明确问題和/或风险问题，包括辨识潜在风险相关假设； Assemble background information and/ or data on the potential hazard, harm or human health impact relevant to the risk assessment;收集与风险评估相关的潜在危险、伤害或彩响人体健康的背景信息和资料和/或数擔； Identify a leader and necessary resources;辩识领导与必要的资源； Specify a timeline, deliverables and appropriate l

43、evel of decision making for the risk management process扌&定风险管理程序的时限、交付日期与决策水平.4.3 Risk Assessment 风险评估Risk assessment: consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards (as defined below). Quality risk assessments begin with

44、a well-defined problem description or risk question. When the risk in question is well defined, an appropriate risk management tool (see examples m section 5) and the types of information needed to address the risk question will be more readily identifiable As an aid to clearly defining the nsk(s) f

45、or risk assessment purposes, three fundamental questions are often helpful:风险评估：其包括辨识危险因素与暴零在这些危险因素(定渋于后)相关风脸的分析和评估.质董风险评估开始于 一个明M的问題或风险问题.当被讨论的风险被明确定义后，则将会很容易确定适当的风险管理工具(见第5节中的例 子)和需要用于风险问題说明的资料类型.在风险评估时，作为明确定义风险的辅助工具，通常如下这三个基本问题是稠译：徐禾丰2009年五月，第五阪第4页Qinhty Riuk fansgyment 质童风险管理非常有用的:What might go

46、wrong? 什么可能出错？What is the likelihood (probability) it will go wrong。 会出错的可能性(概率)址什么？What are the consequences (severity)? 结果(严圭性)是什么？Risk identification: is a systematic use of information to identify hazards referring to the risk question or problem description. Information can include historical d

47、ata, theoretical analysis, informed opinions, and the concerns of stakeholders. Risk identification addresses the What might go wrong? question, includwg identifying the possible consequences Tins provides the basis for further steps in the quality risk management process风险辨识：其是指券照风险问题或问題描述，系统地运用信息来

48、辨识危险因素.这些信息可能包括历臾数据理 论分析意见以及风险涉众的考虑.风险辨识关注什么可能出错厂 这个问題.包括辨识可能的结果.这为进一步的 质量风险管理过程奠定了基础Risk analysis: is the estimation of the risk associated with the identified hazards It is the qualitative or quantitative process of linking the likelihood of occurrence and seventy of harms. In some risk management

49、 tools, the ability to detect the harm (detectability) also factors in the estimation of risk.风险分析：其是对风险所关联已经辨识了的危险因素进行估计.它是对发生事件可能性与及灾害严重性进行定量 或定性过程.在一些风险管理工具中，探测伤害的能力（可检测性）同样是在估计风险中的因素。Risk evaluation: compares the identified and analyzed risk against given risk criteria. Risk evaluations consider

50、 the strength of evidence for all three of the fimdamental questions.风险评价：其是比较已经辨识和分析的风险与给定的风险标准进行比较。风险评价考虑到了所有这三个基木问题 的证据强度.In doing an effective risk assessment, the robustness of the data set is important because it determines the quality of the output. Revealing assumptions and reasonable source

51、s of uncertainty will enhance confidence in this output and/or help identify its limitations. Uncertainty is due to combination of incomplete knowledge about a process and its expected or unexpected variability Typical sources of uncertainty include gaps in knowledge gaps in pharmaceutical science a

52、nd process understanding, sources of harm (e.g., failure modes of a process, sources of variability), and probability of detection of problems在进行一个有效的风险评估时，数据集的完莫性很車要，因为它决定了输出的质莹.显示假设及合理资源不确定 性将会加强输出的可靠性，并且/或有助于辨识其限度不确定性是由于关于过程不完整的知识以及其期望的或非期望 的变异性综合适成。典型的不确定来源包括制药科学知识差距、对过程理解星距.伤害来源（如一个过程的失效模式， 变异行

53、来源）以及发现问题概率.The output of a risk assessment is either a quantitative estimate of risk or a qualitative description of a range of risk. When risk is expressed quantitatively, a muiiencal probability is used Alternatively, risk can be expressed using qualitative descriptors, such as high： medium、： or

54、low； which should be defined in as much detail as possible Sometimes a Mnsk scoreH is used to further define descriptors m risk ranking In quantitative risk assessments, a risk estimate provides the likelihood of a specific consequence, given a set of riskgeneniting circumstances Thus, quantitative

55、risk estimation is useful for one particular consequence at a time. Alternatively, some risk management tools use a relative risk measure to combine multiple levels of seventy and probability into an overall estimate of relative risk The intermediate steps within a scoring process can sometimes empl

56、oy quantitative risk estimation.风险评估的输出既是一个对风险定量估计也是一个对风险范围的定性描述“当风险被定量地表达则运用数值表 达它的概率.另外，风险还可以运用如“高從中撷或低欄等定性描述词来表达，对其应该尽可能详细地确定 一些时候，使用“风险记分户来进一步确定描述风险的排列.在定量风险评估中，对一个风险估计能提供一个特定结 果的可能性，给出一系列产生风险状况。因此，定量风险评估对于在某个时间的特定后果非常有用.另外，一些风险 管理工具釆用了相对的风险度量将多种级别的严車性和概率合并到一个完抢的相对风险估计中。在一个记分过程的中 间步骤有时候可以使用定童风险评

57、估.4.4 Risk Control 风险控制Risk contro上 includes decision making to reduce and- or accept risks. The purpose of risk control is to reduce the risk to an acceptable level. The amount of effort used for risk control should be proportional to the significance of the risk. Decision makers might use differen

58、t processes, including benefit-cost analysis, for understandmg the optimal level of risk control.风险控制：其包括做出的障低和/或接受风险的决定.风险控制的目的是降低风险到一个可接受的水平用于风险2009年五月，第五阪第5页Qunhty Riuk Management 质 童风险管理控制所作工作量应该与风险的显著性相称决寰者可能会采用不同的过程，包括收益成木分析，来了解最佳的风险控 制水平.Risk control might focus on the following questions:风险控制可能会集中在下列问题： Is the risk above an acceptable level?是否风险超过了一个可接受的水平？ What can be done to