1、Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507 公众微信号： QRMxiedaxia 1 / 15 European Journal of Parenteral 13(3): 31-35 2008 Pharmaceutical and Healthcare SciencesSociety Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 Canadell Heredia, E G
2、arcia Vidal, S Herrero Sas, J Llaja Villena, L Noguera Salvans, A Pias Llagostera, D Pual Peces, E Tardo Prez, A Tbar Prez ICH Q9 Quality Risk Management working party of the Quality Assurance Committee of the Catalan Section of the Spanish Association of Industrial Pharmacists (AEFI) The Spanish As
3、sociation of Industrial Pharmacists (AEFI) monograph ICH Q9 Quality Risk Management not only describes the general principles of risk management set out in that guideline, but also takes an approach that is highly practical for the pharmaceutical industry. It therefore contains examples of how to us
4、e various risk analysis tools, including definitions, usage, objectives, operation, and advantages and disadvantages in each case. This article forms part of one of the examples of the use of failure mode and effects analysis (FMEA) risk analysis tools. Key words: ICH Q9/Q10, risk management, critic
5、al and non-critical deviations, flowchart, failure mode and effects analysis Introduction: deviation management issues 介绍：偏差管理问题 In general terms, a deviation is non-compliance with an established standard. The EU Guide to Good Manufacturing Practice (GMP) states that any deviation from the approved
6、 requirements and procedures must be documented and explained. 一般而言，偏差就是不符合已建立的标准。欧盟 GMP 指导原则写明任何偏离已批准需求和程序的偏差都必须记录并解释。 The concept of deviation is so broad that deviation management as applied to the pharmaceutical industry presents a few problems, such as: 偏差的概念是如此之宽以致于 偏差管理在用于制药行业时出现一些问题，比如 A ten
7、dency towards deviation overload, because “everything is reported”. This can result in poor investigation of the root cause, and poor analysis of the effectiveness of the corrective and preventive action (CAPA) implemented. 偏差 有处理过度的趋势 ，因为“任何事都要报告”。这个可能导致根 本 原因缺乏调查和实Deviation management in the conte
8、xt of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507 公众微信号： QRMxiedaxia 2 / 15 施的纠正预防措施缺乏有效性的分析。 Thorough handling of all deviations can exhaust the available resources and mean that a really important problem is not dealt with properly. From a business point of view, it is best to assign resourc
9、es according to the importance of each incident/deviation. 所有偏差彻底处理可能耗尽可利用的资源意味着真正重要的问题没有正确处理。从商业的角度讲最好遵照每个事件 /偏差的重要性分派资源。 Evaluating the criticality of each individual deviation also uses up valuable resources. If critical points in the process and critical product quality attributes have not been
10、defined in advance, each new deviation that arises means a new investigation. 要评估每个偏差的关键性也会用尽有价值的资源。如果 工艺中的关键和关键产品质量属性没有提前确定，每个出现的新的偏差都意味着新的调查。 Difficulties in quantifying the effectiveness of corrective/preventive actions taken, and in communicating them to the rest of the organization. 要 量化开展的纠正预防
11、措施和与公司其他部门交流存在困难。 Using risk management to handle deviations 使用风险管理处理偏差 ICH Q9 (now incorporated in the EU GMP Guide as Annex 20) suggests applying the risk management process to both productive processes and procedures involved in the quality management system. Deviation management is one of the la
12、tter, and can be optimized by using risk management tools in two main ways: prioritization and decision-making. ICHQ9（现在已经整合如 EU GMP 指导原则附录 20 中）建议在涉及到质量管理体系的生产工艺和过程中应用风险管理程序。偏差管理是后者的一部分可以在两个方面通过使用风险管理来优化：优先排序和决策。 Prioritization: The tool is used to classify undesirable events according to pre-estab
13、lished criteria. The aim is to tailor the handling of the deviation, depending on the risk it presents to product quality. This is a preliminary “screening” phase that allows the subsequent treatment of irrelevant events to be simplified. 优 先排序：风险管理工具用于遵照已确定的标准给不良事件分类。目的是根据存在对产品质量的风险调整偏差的处理。这个是初步“筛选
14、”阶段允许简化对不相干事件的后续处理。 Decision-making: The tool is used to examine the impact of the deviation on product quality, and to justify ensuing preventive and corrective actions. This is really a risk analysis of the process in which the deviation arose. In this way, events are not assessed in isolation, bu
15、t their severity and probability are already defined in the history. New entries update the process risk Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507 公众微信号： QRMxiedaxia 3 / 15 matrix, facilitating risk review. 决策：风险管理工具用于 检查产品质量偏差的影响并证明纠正预防措施能保证。这个实际上对出现偏差
16、的工艺的风险分析 。用这种方法，事件不是孤立地评估，但其严重性和可能性已经事先确定。新的内容可以输入工艺风险评估表中并更新工艺风险评估并推进 风险回顾。 Using risk management to deal with deviations provides a consistent framework for decision-making based on documentary and scientific records, while also enabling decisions to be confidently upheld before the regulatory bod
17、ies. 使用风险管理处理偏差为基于文件化 和科学记录的决策提供了一致的框架，同时也 能够 在药监机构 面前决策时有自信的支持 。 Two examples are given below for using risk event has been management tools to classify and handle deviations: 以下 为风险事件 给出两个实例用于 使用风险管理工具对风险事件 分类和处理偏差： Flowchart for deciding the criticality of deviations; 决定偏差关键性的流程图 Failure mode and
18、 effects analysis (FMEA), introducing the probability of a problem not being detected. 失效模式和影响分析（ FMEA），介绍没有检测出问题的可能性。 Of the many tools described in ICH Q9, FMEA is one that is adapted and used in a related sector, i.e. the medical devices industry. 在 ICHQ9 描述的众多工具中， FMEA 是 一个适用 并 普遍 用于相关行业的工具，例如医疗
19、器械行业。 In the examples, it is assumed that the process in which the deviation arose has undergone appropriate risk analysis, so the following are known: 在此例中，假定工艺中出现的偏差已经经过适当的风险分析，所以以下信息是已知的： Failure (deviation) history with associated severity assessment criteria; 失效（偏差）的历史及相关严重性评估标准 Probability dat
20、a for the most commonly occurring failures (deviations); 最经常发生失效（偏差）的可能性数据 Critical points and/or stages in the process; 工艺中的关键点和 /或关键步骤 A definition of the products critical quality attributes. 产品关键质量属性的定义 Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507 公众微信
21、号： QRMxiedaxia 4 / 15 The same methodology is employed in both examples: 相同的方法在也在以下两个例子中使用： Analysis phase (differs according to the tool used in each case); 分析阶段（依据不同情况使用的工具而不同） Classification phase; 分类阶段 Treatment phase. 处理阶段 Using a flowchart to manage deviations 使用流程图管理偏差 In order to classify an
22、d define the handling of events (potential deviations), a system such as the following can be set up. 为了分类和定义事件（潜在偏差），可以建立如以下的系统。 Analysis phase 分析阶段 The aim of this phase is to place the event that has occurred into one of the pre-established categories. 此阶段的目的是将发生的事 件归类到已建立的分类中去。 This is done usin
23、g a decision tree based on a set of questions with yes/no answers, directly defining the category of the event: 这个可以基于设置带有是或否答案的一系列问题使用决策树来直接确定事件的分类。 Q1: Are the corrective actions to be taken described in a procedure? Q1：纠 正措施是否已在程序中被描述？ Q2: Does the deviation affect critical quality attributes? Q2
24、：偏差是否影响关键质量属性？ Q3: Does the deviation affect critical process parameters or stages? Q3：偏差是否影响关键工艺参数或步骤？ Q4: Does the deviation affect the calibration of instruments that measure critical process parameters or quality attributes? Q4：偏差是否影响测量关键工艺参数或关键质量属性的仪表的校准？ Classification phase 分类阶段 Having follow
25、ed the strategy, the event is classified into one of the following categories: 按照这个策略，事件被归为以下类别的一种： Incident; 事件（ 事件 ） Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507 公众微信号： QRMxiedaxia 5 / 15 Non-critical deviation; 非关键偏差 Critical deviation. 关键偏差 Treatment p
26、hase 处理阶段 Based on the category into which the placed, actions are taken as follows: 基于这里的分类，应按照以下方式制定措施： Incident: If the event is classed as an “Incident” it is closed, as the actions required to resolve it are described. 事件 ：如果事件被分类为一个 事件 ，当需要解决 事件 的措施被描述时，偏差就关闭。 Non-critical deviation: The proce
27、ss deviation database is consulted to see how many times it has happened. If the specified maximum number of repeats allowed has not been exceeded, the event stays in the “Non-critical deviation” category. The appropriate corrective measures are then applied and the deviation is closed as an isolate
28、d occurrence. This event is then entered in the process deviation database, to feed into and update the general FMEA for the process. 非关键偏差：查询工艺偏差数据库看它已经发生了多少次。如果没有超过允许的特定的最大重复数量，事件就停留在“非关键偏差”分类。然后实施恰当的纠正措施并作为单独的时间关闭偏差。事件然后进入工艺偏差数据库、填入并更新为工艺生成的 FMEA。 Critical deviation: The event is placed in this c
29、ategory: 关键偏差：事件放置入这个分类中： when the answers given in the decision tree point to a “Critical deviation”; -当答案在决策树点中给出是一个“关键偏差”； if it was first classified as “Non-critical”, but has exceeded the maximum number of repeats allowed. 如果首先归类为“非关键”，但超过了允许重复的最大数量。 When a critical deviation occurs, a full ass
30、essment of its impact on product quality must be carried out, using the established tool for general process risk analysis. 当关键偏差发生时，必须使用 整体工艺风险分析 的已建立的工具实施对产品质量影响的完整的评估。 It is worth noting that other tools, eg fault tree analysis, can be used to determine the root cause of any type of deviation. On
31、ce the cause is known, the appropriate corrective and preventive measures are put in place and the risk levels are recalculated. Lastly, the final report is written, and the event is closed. Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507 公众微信号： QRMxiedaxia 6
32、 / 15 值得注意的是其他工具，比如故障树，可以用来确定所有类型偏差的根 原因。一旦原因已知，适当的纠正预防措施应落实到位，并重新计算风险等级。最后，编写最终报告关闭偏差。 This information will be used to update and feed back into general process risk analysis at the time of risk review. 此信息将在风险回顾时用来更新和反馈 整体工艺风险分析 。 Figure 1 illustrates the event-management scheme described above.
33、图 1 举例说明了上面描述的事件管理方案。 Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507 公众微信号： QRMxiedaxia 7 / 15 偏 差 描 述Q 1 ： 纠 正 措 施 是 否 在 程 序 中 有 规 定 ？Q 2 ： 偏 差 是 否 影 响 关 键 质 量 属 性 ？Q 3 ： 偏 差 是 否 影 响 关 键 工 艺 参 数 或 步 骤 ？Q 4 ： 偏 差 是 否 影 响 测 量 关 键 质 量 属 性 或 关 键 工 艺 参 数 的 仪 表 的
34、 校 准 ？分析事 件 非 关 键 偏 差 关 键 偏 差在 偏 差 数 据 库 中 检查 发 生 次 数 （ n ）整 体 工 艺 F M E A 风 险降 低确 定 根 本 原 因整 体 工 艺 F M E A 风 险评 估实 施 纠 正 措 施 作 为单 个 事 件 关 闭 偏 差录 入 偏 差 数 据 库最 终 报 告偏 差 关 闭故 障 树分类处理否否否否是是是是n x在 整 体 工 艺 F M E A 中输 入 新 的 内 容Example of using a flowchart to manage deviations 使用流程图管理偏差的实例 Description of e
35、vent 事件描述 Contamination of a work surface in the dispensing room for medicinal products for injection. Action limits are exceeded. 注射剂配剂室工作台被污染。已超过行动限。 Key features 主要特征 Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507 公众微信号： QRMxiedaxia 8 / 15 Class B dispens
36、ing room (ISO 7); B 级配剂室 The product being dispensed undergoes terminal sterilization employing an overkill cycle (with no incidents); 配制的产品经过使用过度杀灭的最终灭菌（没有 事件 ） The bioburden of the product is controlled on a batch-by-batch basis; 产品微生物负荷批批都控制。 The room is monitored weekly; 房间每周监测。 Other work surfa
37、ces in the same room are within control limits; 房间其他工作台都在控制限度内。 The microorganism has been identified as Staphylococcus aureus; 微生物已经经鉴定为金黄色葡萄球菌。 This is the first time it has been detected. 这是第一次监测到。 Once a full description of the event is available, it is analyzed. 一旦有了事件的完整的描述，就要对其分析。 Analysis an
38、d classification phase 分析和分类阶段 Q1:Are the corrective actions to be taken described in a procedure? Q1：纠正多事是否已经描述在程序中？ No, the actions are not described in a procedure. 没有，措施没有在程序中描述。 Q2: Does the deviation affect critical quality attributes? Q2：偏差是否影响关键质量属性？ Contamination of a surface is not regarde
39、d as a critical product attribute. 台面 的污染不被认为是一个关键质量属性。 Q3: Does the deviation affect critical process parameters or stages? Q3：偏差是否影响关键工艺参数或步骤？ It is not considered to affect a critical stage, because terminal sterilization is performed at the end of the process. 这个事件不被考虑影响关键步骤，因为工艺最终实施最终灭菌。 Q4: Do
40、es the deviation affect the calibration of instruments that measure critical process parameters or quality attributes? Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507 公众微信号： QRMxiedaxia 9 / 15 Q4：偏差是否影响测量关键工艺参数或质量属性的仪表的校准？ It does not affect calibration. 不影响校
41、准。 The answers given in the above decision tree, together with the fact that this is the first time such contamination has been detected, mean that the event is classified as a non-critical deviation. 在上述决策树中给出的答案与是第一次检测到污染的事实一起意味着这次事件被分类为非关键偏差。 表 1 评估事件严重性和检测不到的可能性的标准 严重性 5=偏差影响关键质量属性或参数 3=偏差影响对质量不
42、关键的属性或参数 1=偏差不影响质量但必须记录 检测不到的可能性 5=无控制措施实施 3=仅仅生产产品的最终控制 1=中间控制 Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507 公众微信号： QRMxiedaxia 10 / 15 检测不到的可能性 5 3 1 严 重 性 5 25 15 5 3 15 9 3 1 5 3 1 措施 关键偏差（单独调查） 非关键偏差（风险相应的调查） 事件（记录并关闭） Treatment phase 处理阶段 As this is a
43、 non-critical deviation and the maximum number of repeats allowed (n) has not been exceeded, it would merely require a corrective measure, such as subjecting the area to special cleaning. The deviation must also be entered in the deviation database to be counted. 因为这是一个非关键偏差且也没有超出允许重复的最大数量，仅仅需要一个纠正措
44、施，比如要求这个区域进行特殊清洁。这个也必须 算做偏差收进偏差数据库中。 Using FMEA to manage deviations 使用 FMEA 管理偏差 This example suggests using an FMEA-based risk analysis tool to classify and handle deviations. 这个例子建议使用基于 FMEA 的风险分析工具去分类和处理偏差。 Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507
45、公众微信号： QRMxiedaxia 11 / 15 Analysis and classification phase 分析和分类阶段 The severity of the events consequences and the probability of non-detection are assessed to determine the risk level. Depending on the risk level, events are classified as critical deviations, non-critical deviations or incidents,
46、 and the corresponding actions are taken. 评估事件的后果的严重性和检测不到的可能性来确定风险等级。根据风险等级，事件被分为关键偏差、非关键偏差或事件并采取相应的措施。 The analysis is performed by reference to the assessment scales shown in Table 1. Using these criteria, the risk matrix shown in Figure 2 is constructed. Events assessed using the matrix are give
47、n a risk level score, which falls into one of three categories: 参考表 1 中的评估分值实施分析。使用这些标准，建立图 2 中显示的风险矩阵。使用矩阵评估的事件都被给出一个风险等级分，分成三个类别： Risk level 9 (red zone): Critical deviation. Requires in-depth investigation, root cause and impact assessment; 风险等级分 9（红 色区域）：关键偏差。需要深入调查、根本原因和影响评估； Risk level 3 (oran
48、ge zone): Non-critical deviation. To be investigated in proportion to the risk; 风险等级分 3（橙色区域）：非关键偏差。实施与风险相适应的调查。 Risk level 3 (green zone): Incident. Record and close. 风险等级分 3（绿色区域）：事件。记录并关闭。 Treatment phase 处理阶段 Depending on the risk level score obtained, actions are taken as described above. This
49、phase is exactly the same as in the previous example (Figure 3). 依据获得的风险等级分，采取上面描述的措施。这个阶段与前面的例子（图 3）完全一样。 Example of using FMEA to manage deviations 使用 FMEA 管理偏 差的例子 Description of event 偏差描述 Tablet capping detected during in-process control. 在中间控制时发现片子起盖。 Key features 主要特征 Deviation management in the context of ICH Q9/Q10 ICHQ9/Q10 背景下的偏差管理 翻译 /校对：谢永 /20140507 公众微信号：
