ICH-Q9质量风险管理.pdf

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1、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 Tripartite 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Current Step 4 version现行第四步版本dated 9 November 20052005 年十一月 9 日This Guideline has b

2、een developed by the appropriate ICH Expert Working Groupand has been subject to consultation by the regulatory parties,in accordance withthe ICH Process.At Step 4 of the Process the final draft is recommended for adoptionto the regulatory 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

3、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、日本和美国药的政部门采用的最终文本。Document History文件历史Codification最初编码Q9History历史Approval by the Steering CommitteeDateunder Step 2 and release for public日期consultation.22 March 2005指导委员会批准第二步文件并发放用于2005/3/22公开咨询Approval by the Steering Committee

4、 of15 June 2005Post Step 2 correction2005/6/15指导委员会在批准第二步后的订正文件Approval by the Steering Committee9 Novemberunder Step 4 and recommendation for2005adoption to the three ICH regulatory2005/11/9bodies.指导委员会批准第四步文件并推荐 ICH三方药政部门批准CurrentStep 4version现行第四步版本Having reached Step 4 of the ICH Process at the

5、ICH Steering Committee meeting on9 November 2005,this guideline is recommended for adoption to the threeregulatory 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，本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序，本指南已经推荐给人用药注册技术要求国际协调会议三方的药政部门采用。TABLE OF CONTENTS目录1.INTRODUCTION 简介.12.SCOPE 范围.23.PRINCIPLES OF QUALITY R

6、ISK MANAGEMENT 质量风险管理的原则.24.GENERAL QUALITY RISK MANAGEMENT PROCESS 常规质量风险管理程序.2 Responsibilities 职责.4 Initiating a Quality Risk Management Process 启动质量风险管理过程.4 Risk Assessment 风险评估.4 Risk Control 风险控制.5 Risk Communication 风险沟通.6 Risk Review 风险评审.65.RISK MANAGEMENT METHODOLOGY 风险管理方法学.76.INTEGRATION

7、 OF QUALITY RISK MANAGEMENT INTO INDUSTRY ANDREGULATORY OPERATIONS 质量风险管理与业界及药政运行整合.87.DEFINITIONS 定义.98.REFERENCES 参考文献.11Annex 附录 I:Risk Management Methods and Tools 风险管理方法与工具.12 Basic Risk Management Facilitation Methods 基本风险管理简易方法.12 Failure Mode Effects Analysis 故障模式效应分析(FMEA).12 Failure Mode,E

8、ffects and Criticality Analysis 故障模式影响与严重性分析(FMECA).13 Fault Tree Analysis 故障树分析(FTA).13 Hazard Analysis and Critical Control Points 危害分析关键控制点(HACCP).14 Hazard Operability Analysis 危害及可操作性分析(HAZOP).14 Preliminary Hazard Analysis 预先危险分析(PHA).15 Risk Ranking and Filtering 风险排序及过滤.15 Supporting Statist

9、ical Tools 辅助性统计工具.16Annex 附录 II:Potential Applications for Quality Risk Management 实施质量风险管理的潜在机会.16 Quality Risk Management as Part of Integrated Quality Management 整合质量管理部分的质量风险管理.16 Quality Risk Management as Part of Regulatory Operations 药政操作部分的质量风险管理.18 Quality Risk Management as Part of develo

10、pment 开发部分的质量风险管理.19 Quality Risk Management for Facilities,Equipment and Utilities 厂房，设备和公用设施的质量风险管理.19 Quality Risk Management as Part of Materials Management 物料管理部分的质量风险管理.21 Quality Risk Management as Part of Production 生产部分的质量风险管理.21 Quality Risk Management as Part of Laboratory Control and Sta

11、bility Studies 实验室控制和稳定性研究部分的质量Quality Risk Management 质量风险管理风险管理.22 Quality Risk Management as Part of Packaging and Labelling 包装和标签部分的质量风险管理.221.INTRODUCTION 导言Risk management principles are effectively utilized in many areas of business andgovernment including finance,insurance,occupational safet

12、y,public health,pharmacovigilance,and by agencies regulating these industries.Although there aresome examples of the use of quality risk management in the pharmaceutical industrytoday,they are limited and do not represent the full contributions that riskmanagement has to offer.In addition,the import

13、ance of quality systems has beenrecognized in the pharmaceutical industry and it is becoming evident that quality riskmanagement is a valuable component of an effective quality system.风险管理原则被有效地应用于许多商业和政府的领域，包括金融、保险、职业安全、公共健康、药物预警，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

14、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 probabilityof occurrence of harm and the severity of that harm.However,achieving a sharedunderstanding of the application of risk management among diverse stakeholders i

15、sdifficult because each stakeholder might perceive different potential harms,place adifferent probability on each harm occurring and attribute different severities toeach harm.In relation to pharmaceuticals,although there are a variety ofstakeholders,including patients and medical practitioners as w

16、ell as government andindustry,the protection of the patient by managing the risk to quality should beconsidered 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同的潜在伤害，对每个所发生的伤害设置不同的概率以及伤害不同的严重性属性。对于药品来说，尽管有多种的风险涉众，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

17、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 ofthe overall risk.It is important to understand that product quality should bemaintained throughout the product lifecycle such that

18、the attributes that areimportant to the quality of the drug(medicinal)product remain consistent withthose used in the clinical studies.An effective quality risk management approach canfurther ensure the high quality of the drug(medicinal)product to the patient byproviding a proactive means to identi

19、fy and control potential quality issues duringdevelopment and manufacturing.Additionally,use of quality risk management canimprove the decision making if a quality problem arises.Effective quality riskmanagement can facilitate better and more informed decisions,can provideregulators with greater ass

20、urance of a companys ability to deal with potential risksand 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。其质量风险仅是全部风险中的一个。重要的是要了解到，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。通过前瞻意义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管理方法能进一步给患者提供高质量药物(医疗

21、)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，更基于可靠信息的决策，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，并且会对药政监督的水平和范围直接产生有利影响。The purpose of this document is to offer a systematic approach to quality riskmanagement.It serves as a foundation or resource document that is independent of,yet supports,other ICH Qu

22、ality documents and complements existing qualitypractices,requirements,standards,and guidelines within the pharmaceuticalindustry and regulatory environment.It specifically provides guidance on theprinciples and some of the tools of quality risk management that can enable moreeffective and consisten

23、t risk based decisions,both by regulators and industry,regarding the quality of drug substances and drug(medicinal)products across theproduct lifecycle.It is not intended to create any new expectations beyond thecurrent 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，其独立并支撑其它的 ICH 质量文

24、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到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策。其并未试图建立任何超越当前管理要求的新的要求。It is neither always appropriate nor always necessary to use a formal riskmanagement process(using recognized tools and/or internal procedures.,standardoper

25、ating procedures).The use of informal risk management processes(usingempirical tools and/or internal procedures)can also be considered acceptable.Appropriate use of quality risk management can facilitate but does not obviateindustrys obligation to comply with regulatory requirements and does not rep

26、laceappropriate 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。采用非正式的风险管理过程(使用经验的工具，和/或内部程序)也是可以考虑接受。恰当运用质量风险管理可以促进，但并不能免除业界遵守药政要求的责任，也不能取代业界和药政部门之间适当的沟通。2.SCOPE 范围This guideline provides principles and examples of tools for quality risk managem

27、entthat can be applied to different aspects of pharmaceutical quality.These aspectsinclude development,manufacturing,distribution,and the inspection andsubmission/review processes throughout the lifecycle of drug substances,drug(medicinal)products,biological and biotechnological products(including t

28、he use ofraw materials,solvents,excipients,packaging and labeling materials in drug(medicinal)products,biological and biotechnological products).本指南给出了质量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面。这些方面包括开发、制造、分销以及原料药、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、赋形剂、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

29、OF QUALITY RISK MANAGEMENT 质量风险管理的原则Two primary principles of quality risk management are:质量风险管理的两个基本原则为：The evaluation of the risk to quality should be based on scientific knowledge andultimately link to the protection of the patient;and应该基于科学知识和最终与对患者的保护相关联对质量风险进行评价；以及 The level of effort,formalit

30、y and documentation of the quality risk managementprocess should be commensurate with the level of risk.质量风险管理过程的力度、正式程度和文件化程度都应该与风险水平相适应。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 t

31、o the quality of the drug(medicinal)productacross the product lifecycle.A model for quality risk management is outlined in thediagram(Figure 1).Other models could be used.The emphasis on each componentof the framework might differ from case to case but a robust process willincorporate consideration

32、of all the elements at a level of detail that iscommensurate 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。图中概括了质量风险管理模式(图 1)。也可以使用其他模式。所强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。Figure 1:Overview of a typical quality risk management process图 1：典型的质量风险管理过

33、程概述Initiate Quality Risk Management Process启动风险管理过程Risk Assessment 风险评估Risk Identification 风险辩识Decision nodes are not shown in the diagram above because decisions can occur atany point in the process.These decisions might be to return to the previous step andseek further information,to adjust the ri

34、sk models or even to terminate the riskmanagement process based upon information that supports such a decision.Note:“unacceptable”in the flowchart does not only refer to statutory,legislative orregulatory requirements,but also to the need to revisit the risk assessment process.在上图中并未标明判断结点，因为判断可出现在这

35、个过程中的任何一个点。这些判断将会退回到前一步，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“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。）Responsibilities 职责Quality risk management activities are usually,but not always,undertaken byinterdisciplinary teams.When teams are formed,they should include experts fromthe appropriate ar

36、eas.,quality unit,business development,engineering,regulatoryaffairs,production operations,sales and marketing,legal,statistics and clinical)inaddition to individuals who are knowledgeable about the quality risk managementprocess.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，应当要包括适当领域的专家(例如，质量部门、商业开发、工程、药政、生产运

37、行、销售和市场、法律和临床)，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 variousfunctions and departments of their organization;and负责在其组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 defined,deployed and reviewedand that ade

38、quate 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。Initiating a Quality Risk Management Process 启动质量风险管理过程Quality risk management should include systematic processes designed tocoordinate,facilitate and improve science-based decision making with respect to risk.Possible steps used to initiate

39、 and plan a quality risk management process mightinclude the following:质量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。可能用于启动和策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/or risk question,including pertinent assumptionsidentifying the potential for risk;明确问题和/或风险问题，包括辨识潜在风险相关假设；Assemble background informa

40、tion and/or data on the potential hazard,harm orhuman health impact relevant to the risk assessment;收集与风险评估相关的潜在危险、伤害或影响人体健康的背景信息和资料和/或数据；Identify a leader and necessary resources;辩识领导与必要的资源；Specify a timeline,deliverables and appropriate level of decision making for therisk management process.指定风险管

41、理程序的时限、交付日期与决策水平。Risk Assessment 风险评估Risk assessment:consists of the identification of hazards and the analysis andevaluation of risks associated with exposure to those hazards(as defined below).Quality risk assessments begin with a well-defined problem description or riskquestion.When the risk in q

42、uestion is well defined,an appropriate risk managementtool(see examples in section 5)and the types of information needed to address therisk question will be more readily identifiable.As an aid to clearly defining the risk(s)for risk assessment purposes,three fundamental questions are often helpful:风

43、险评估：其包括辨识危险因素与暴露在这些危险因素(定义于后)相关风险的分析和评估。质量风险评估开始于一个明确的问题或风险问题。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)和需要用于风险问题说明的资料类型。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非常有用的：1.What might go wrong什么可能出错2.What is the likelihood(probability)it will go wrong会出错的可能性(概率)是什么3.What are the consequences(severity)结果(严重性)是

44、什么Risk identification:is a systematic use of information to identify hazards referring tothe risk question or problem description.Information can include historical data,theoretical analysis,informed opinions,and the concerns of stakeholders.Riskidentification addresses the“What might go wrong”quest

45、ion,including identifyingthe possible consequences.This provides the basis for further steps in the qualityrisk management process.风险辨识：其是指参照风险问题或问题描述，系统地运用信息来辨识危险因素。这些信息可能包括历史数据、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”这个问题，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

46、with the identified hazards.It isthe qualitative or quantitative process of linking the likelihood of occurrence andseverity of harms.In some risk management 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

47、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 the strength of evidence for all three of the fundamentalquestions.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本问题的证据强度。In doing an effective risk

48、 assessment,the robustness of the data set is importantbecause it determines the quality of the output.Revealing assumptions andreasonable sources of uncertainty will enhance confidence in this output and/or helpidentify its limitations.Uncertainty is due to combination of incomplete knowledgeabout

49、a process and its expected or unexpected variability.Typical sources ofuncertainty include gaps in knowledge gaps in pharmaceutical science and processunderstanding,sources of harm.,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，数据集的完美性很重要，因

50、为它决定了输出的质量。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造成。典型的不确定来源包括制药科学知识差距、对过程理解差距、伤害来源(如一个过程的失效模式，变异行来源)以及发现问题概率。The output of a risk assessment is either a quantitative estimate of risk or aqualitative description of a range of risk.When risk is expressed quantitatively