环境监测风险评估（中英文版）20130308

Environmental Monitoring Risk Assessment 环境监测风险评估环境监测风险评估环境监测风险评估环境监测风险评估 2006 - Journal of GXP Compliance，2006 年 1 月，10 卷，2 号 翻译/编辑：谢永/http:/blog.sina.com.cn/xiedaxialaile 1111 / 20202020 内部交流，请勿转载/2013 年 3 月 6 日 Environmental Monitoring Risk Assessment 环境监测风险评估环境监测风险评估环境监测风险评估环境监测风险评估 Wednesday, August 30, 2006 - Journal of GXP Compliance, January 2006, Volume 10, Number 2 星期三，8 月 30 日，2006 - Journal of GXP Compliance，2006 年 1 月，10 卷，2 号 目录 INTRODUCTION 引言 ................................................................... 2 DETERMINING THE FREQUENCY OF MONITORING: 确定监测频率 .......................... 2 Criticality Factors：关键因子 .............................................................. 4 RISK ASSESSMENT TOOLS 风险评估工具 ................................................. 7 Tabular Approach 图表法.................................................................. 8 HACCP 危害分析和关键控制点 ........................................................... 9 FMEA 失效模式和影响分析 .............................................................. 10 NUMERICAL APPROACHES 数值法 ...................................................... 11 Individual Assessments 个体评估 .......................................................... 11 Finger Plate Assessment 五指法取样评估 ................................................... 12 Finger Plate Assessment Worked Example 指板评估实例 ....................................... 14 Surface Sample Assessment 表面取样评估 ................................................... 14 Surface Sample Worked Example: 表面取样案例： ........................................... 15 Air Sample Assessment 空气取样评估 ...................................................... 16 An Overall Assessment 整体评估 .......................................................... 17 CRITICALITY SCORING 关键性得分 ..................................................... 17 CONCLUSION 结论 .................................................................... 19 Environmental Monitoring Risk Assessment 环境监测风险评估环境监测风险评估环境监测风险评估环境监测风险评估 2006 - Journal of GXP Compliance，2006 年 1 月，10 卷，2 号 翻译/编辑：谢永/http:/blog.sina.com.cn/xiedaxialaile 2222 / 20202020 内部交流，请勿转载/2013 年 3 月 6 日 INTRODUCTION 引言引言引言引言 Environmental Monitoring describes the microbiological testing undertaken in order to detect changing trends of microbial counts and micro-flora growth within cleanroom or controlled environments. The results obtained provide information about the physical construction of the room, the performance of the Heating, Ventilation, and Air-Conditioning (HVAC) system, personnel cleanliness, gowning practices, the equipment, and cleaning operations. 环境监测描述了在洁净区或控制区内，为了监测微生物数量和菌落生长的变化趋势而进行的微生物检测。所测结果提供房 间物理结构、空调净化系统性能、人员卫生、更衣活动、设备和清洁操作相关信息。 Over the past decade, environmental monitoring has become more sophisticated in moving from random sampling, using an imaginary grid over the room and testing in each grid, to the current focus on risk assessment and the use of risk assessment tools to determine the most appropriate methods for environmental monitoring. 在过去十年里，环境监测已经变得更加复杂，正在从最初的任意取样，到房间内假设一个网格然后监测每个网格，一直到 现阶段注重风险评估并使用风险评估工具来确定最佳合适的环境监测方法。 This paper explores current trends in the application of risk assessment to the practice of environmental monitoring by examining the following key areas: 本文从以下几个重要方面探讨了将风险分析应用于环境监测的现有趋势： • Determining the Frequency of Monitoring: Using the concept of risk assessment to decide how often to monitor different types of cleanrooms • 确定监测频率：按照风险分析理念，确定不同类型洁净区的监测周期。 • Risk Assessment Tools: Applying risk assessment tools to establish methods for environmental monitoring 。 • 风险评估工具：运用风险分析工具建立环境监测的方法。 • Numerical Approaches: Considering a numerical approach to assess risk data using a case study of an aseptic filling operation • 量化的方法：使用无菌灌装操作案例分析来说明如何使用量化的方法去评估风险数据。 The examples used are from a sterile drug manufacturing facility and focus mostly on aseptic filling; however, the concepts and tools are applicable to the environmental monitoring of other types of manufacturing and packaging operations. 使用案例来自无菌药品生产工厂，其中大多数集中于无菌灌装；然而，理念和工具也同样适用于其他类型生产和包装操作 的环境监测。 DETERMINING THE FREQUENCY OF MONITORING: 确定确定确定确定监测频率监测频率监测频率监测频率 In developing an adequate environmental monitoring programme, there should be a balance between using resources efficiently and monitoring at sufficiently frequent intervals so that a meaningful picture can be obtained. Sources of guidance with respect to monitoring frequencies are very limited within Europe, and the monitoring frequencies specified within the United States Pharmacopoeia (USP) <1116> may not be suitable for all facilities. Some guidance can be obtained from the International Organization for Standardization’s (ISO) standards: principally ISO 14644 and ISO 14698. However, these do not always fit Environmental Monitoring Risk Assessment 环境监测风险评估环境监测风险评估环境监测风险评估环境监测风险评估 2006 - Journal of GXP Compliance，2006 年 1 月，10 卷，2 号 翻译/编辑：谢永/http:/blog.sina.com.cn/xiedaxialaile 3333 / 20202020 内部交流，请勿转载/2013 年 3 月 6 日 with regulatory guidance documents because they apply to controlled environments across a range of industries other than pharmaceuticals, where standards can be higher (Jahnke, 2001). 合理的环境监测项目应当平衡高效利用资源和监测频率这二者的关系，只有这样才有意义。在欧洲，关于监测频率方面的 指导资源非常有限，USP规定的监测频率不一定适用于所有的设备。可以从 ISO标准获取一定的指导：主要是 ISO 14644 and ISO 14698. 然而，这些标准不一定符合法律指导性文件，因为它们适用于多个行业的受控环境，不仅仅是标准更 高的药品行业(Jahnke, 2001). When establishing an environmental control programme, the frequency of monitoring different controlled areas can be determined based on ‘criticality factors’ relevant to each specific area. 在确定环境控制程序时，不同控制区域的监测频率可以基于每个功能区的“关键因子”来确定。 Environmental Monitoring Risk Assessment 环境监测风险评估环境监测风险评估环境监测风险评估环境监测风险评估 2006 - Journal of GXP Compliance，2006 年 1 月，10 卷，2 号 翻译/编辑：谢永/http:/blog.sina.com.cn/xiedaxialaile 4444 / 20202020 内部交流，请勿转载/2013 年 3 月 6 日 Criticality Factors：：：：关键因子关键因子关键因子关键因子 The establishment of a criticality scheme on which to base monitoring frequencies is designed to target monitoring of critical process steps. Therefore, the final formulation process would receive more monitoring than an early manufacturing stage with a relatively closed process. 监测频率所基于的临界 机制 综治信访维稳工作机制反恐怖工作机制企业员工晋升机制公司员工晋升机制员工晋升机制图 目的在于监控关键工序步骤。因此，同相对封闭的初阶段生产工序而言，最终制剂工序所接受 的监控更多。 Using a criticality factor is a means of assigning a monitoring frequency based on the risk assessment of each critical area. The risk assessment relates to the potential product impact from any risk. For example, an area of open processing at an ambient temperature, a long exposure time, and the presence of water, would constitute a high risk and would attract a higher risk rating. In contrast, an area of closed processing, in a cold area, would carry a substantially lower risk and associated risk rating. 使用关键因子是一种基于各个关键区域风险分析以确定监测频率的方法。风险评估涉及到任何风险对产品的潜在影响。如， 室温下开放式操作区域，长期暴露时间，存在水，这些将构成高风险并影响更高的风险级别。相反地，密闭工艺的区域， 温度较低的区域形成更低的风险及相关风险级别。 Using a range of 1 to 6, with ‘1’ being the most critical and ‘6’ the least critical, a score of 1 would be assigned to an aseptic filling operation; a score of 2 to final formulation, a score of 3 to open processing, and so on. Each user must adapt such a scheme to his or her particular area and defend it by way of supportable rationale. An example of monitoring frequencies under such a scheme can be seen in Figure 1, and an example of its application is seen in Figure 2. 从 1 到 6，“1”为最关键的，而“6”为最不关键的，无菌灌装操作为 1 分；最终制剂工序为 2 分，开放式操作工艺为 3 分等等。每位使用者都必须在特定区域使用该打分表并使用支持性理由来定义。基于评分表的监测频率的举例见图表 1， 其应用举例见图表 2. 图表 1 监测频率关键因子 关键因子关键因子关键因子关键因子 监测频率监测频率监测频率监测频率 1 每日或每批 2 每周 3 每两周 4 每月 5 每三个月或每个季度 6 每六个月 Each controlled area would be evaluated against set criteria and, with the use of a series of guiding questions, the monitoring frequency would be determined. Decision criteria include considerations in two category areas: areas of higher weighting and areas of higher monitoring frequency. Examples of these categories follow: 每个控制区域都将针对设定参数进行评估并使用使用一系列指导性问题来确定监测频率。确定标准要考虑两个主要区域： 更多监测点的区域和更高监测频率的区域。这些要素的例子如下： Giving Higher Weighting to –给予给予给予给予更多监测点更多监测点更多监测点更多监测点的区域的区域的区域的区域包括包括包括包括 • ‘Dirtier’ activity performed in a room adjacent to a clean activity, even if the clean activity represents later processing “较脏”活动在洁净活动邻近的室内进行，即使是后期工序是洁净活动。 Environmental Monitoring Risk Assessment 环境监测风险评估环境监测风险评估环境监测风险评估环境监测风险评估 2006 - Journal of GXP Compliance，2006 年 1 月，10 卷，2 号 翻译/编辑：谢永/http:/blog.sina.com.cn/xiedaxialaile 5555 / 20202020 内部交流，请勿转载/2013 年 3 月 6 日 • Areas that have a higher level of personnel transit (given that people are the main microbiological contamination source). This may include corridors and changing rooms. 人员流动较多的区域（假设人是最主要的微生物污染 源）。可能包括走廊和更衣室。 • Routes of transfer 转移通道 • Areas that receive in-coming goods 接受物料进入的区域 • Component preparation activities and sites Duration of activity (such as a lower criticality for a 30-minute process compared to a six-hour operation)物料准备活动和放置活动持续时间（如：一个 30 分钟的工序相比一个 6 小时的 操作，关键因子更低） Having Higher Monitoring Frequencies for – 需要需要需要需要更高的监测频率更高的监测频率更高的监测频率更高的监测频率 • Warm or ambient areas as opposed to cold rooms 相比寒冷区域的温暖或室温区域。 • Areas with water or sinks as opposed to dry, ambient areas 相比干燥、室温区域的有水或水池的区域。 • Open processing or open plant assembly compared to processing that is open momentarily or to closed processing (where product risk exposure time is examined) 相比短时间敞开或封闭工序（取决于产品风险暴露时 间）的开放性操作工序或开放式工厂生产线。 • Final formulation, purification, secondary packaging, product filling, etc. 最终制剂步骤，纯化，分装，产品灌装， 等。 Once the monitoring frequency for each controlled area is determined, it should be reviewed at regular intervals. This review may invoke changes to a room’s status, and hence, its monitoring frequency, or to changes for different sample types within the room. For example, it may be that after reviewing data for one year, surface samples produce higher results than air samples for a series of rooms. In this event, the microbiologist may opt to vary the frequency of monitoring and take surface samples more often than air samples. There would also be an increased focus on cleaning and disinfection practices, and their frequencies, based on such data (Sandle, 2004b). 一旦确定了每个控制区的监测频率，就应当定期回顾。回顾可 能发现房间状态的变化从而需要改变监测频率或改成这个房间内使用不同的取样方式。比如回顾一年暑假后，部分房间的 表面取样结果高于空气取样结果。在这种情况下，微生物学家可能选择改变监测频率并更多地做表面取样。基于这些数据， 将更多地关注清洁消毒行为和频率(Sandle, 2004b)。 图表 2 关键因子的应用 环境 关键 因子 环境对最终 产品的影响 可能性 定义 监测频 率 1 非常可能 无后续处理的无菌灌装。污染风险 会带来可预见的产品影响，因为污 染物无法通过后续处理减少或去除 每日或 每批 2 可能 最终配制区。适用于最终工序为灭 菌级过滤器的区域 每周 3 有一定可能 产品直接或间接地暴露在环境中可 能引起污染。也适用于室温区域和 高水分含量区域。 每两周 4 不可能 适用于少或无开放式操作的低温区 每月 5 很不可能 不直接暴露于环境中很不可能带来 可能影响产品污染。如果引入污染 物有充分的后续控制和/或使用防 腐剂可以很大程度上去除或明显降 低污染。 每三个 月或每 个季度 6 非常不可能 非受控区域或很少微生物污染可能 的区域，如冻干机房。 每六个 月或半 年 When both types of monitoring are producing low level counts, the balance of risk would be towards air samples. This is because air samples are direct indicators of the quality of the process and assign a level of Environmental Monitoring Risk Assessment 环境监测风险评估环境监测风险评估环境监测风险评估环境监测风险评估 2006 - Journal of GXP Compliance，2006 年 1 月，10 卷，2 号 翻译/编辑：谢永/http:/blog.sina.com.cn/xiedaxialaile 6666 / 20202020 内部交流，请勿转载/2013 年 3 月 6 日 control to the process, whereas surface samples are indicators of cleaning and disinfection. If the results of surface samples are generally satisfactory, as indicated by trend analysis, then either the number of samples or the frequency at which they are taken can be reduced. If subsequent data showed an increase in counts, the monitoring frequency could easily be restored. Indeed, all types of monitoring frequencies may increase as part of an investigation, as appropriate. Therefore, the criticality factor approach not only sets the requirement for a room, it can also be used to vary the sample types within a room (Ljungqvist and Reinmuller, 1996).如果两种类型的监测结果计数都较少，那么风险偏向于空气取样。这是因为空气取样是工序质量的直 接显示并可以确定工序的控制级别，而表面取样显示清洁和消毒情况。如果根据趋势分析，表面取样结果普遍令人满意， 那么要么减少取样点数，要么减少取样频率。如果之后的数据显示计数增长，则恢复原有监测频率。确实，按照调查需求， 可适当地增加各种类型取样的频率。因此，关键因子法不仅对房间做出要求，也可以用作改变房间的取样类型(Ljungqvist 和 Reinmuller, 1996)。 Environmental Monitoring Risk Assessment 环境监测风险评估环境监测风险评估环境监测风险评估环境监测风险评估 2006 - Journal of GXP Compliance，2006 年 1 月，10 卷，2 号 翻译/编辑：谢永/http:/blog.sina.com.cn/xiedaxialaile 7777 / 20202020 内部交流，请勿转载/2013 年 3 月 6 日 RISK ASSESSMENT TOOLS 风险评估风险评估风险评估风险评估工具工具工具工具 Once the status for each room has been selected, a risk assessment procedure is required to determine locations for environmental monitoring. Such risk-based approaches are recommended in ISO 14698 and regulatory authorities are increasingly asking drug manufacturers about this subject. 一旦确定了每个房间的状态，就需要使用风险评估来确定环境监测的位置。ISO 14698 推荐使用基于风险的方法，药政 当局也会增加询问制药企业这方面的问题。 Risk-based approaches include Failure Mode and Effects Analysis (FMEA), Fault Tree Analysis (FTA), and Hazard Analysis and Critical Control Points (HACCP), all of which employ a scoring approach. (Other approaches include: Failure Mode, Effects, and Criticality Analysis (FMECA); Hazard Operability Analysis (HAZOP); Quantitative Microbiological Risk Assessment (QMRA); Modular Process Risk Model (MPRM); System Risk Analysis (SRA); Method for Limitation of Risks; and Risk Profiling.) 基于风险的方法包括失效模式和影响分析(FMEA)、故障树 (FTA)和危害分析和关键控制点(HACCP), 所有这些都要求使 用打分的方法。（其他方法包括：失效模式、影响效果和关键因素分析(FMECA)、危害可操作行分析(HAZOP); 定量微 生物风险评估(QMRA); 模块化工序风险模型(MPRM); 系统风险分析(SRA); 风险限制方法；和风险概要分析。） At present, no definitive method exists, and the various approaches differ in their process and in the degree of complexity involved. However, the two most commonly used methods appear to be HACCP, which originated in the food industry, and FMEA, which was developed for the engineering industry (Whyte and Eaton, 2004a). 现在，无定义方法，不同的方法在工序和复杂程度方面有所不同。然而最常用的两种方法是应用于食品行业的危害分析和 关键控制点(HACCP)，及应用于设备工程的失效模式和影响分析(FMEA) (Whyte 和 Eaton, 2004a)。 These various analytical tools are similar in that they involve: 各种分析工具的相同之处在于都包括以下内容： • Constructing diagrams of work flows 编制工作流程图 • Pin-pointing areas of greatest risk 标出最高风险区域 • Examining potential sources of contamination 确定污染的潜在来源 • Deciding on the most appropriate sample methods 确定最合适的取样方法 • Helping to establish alert and action levels 协助确立警戒限和行动限 • Taking into account changes to the work process and seasonal activities 考虑工序和季节性活动的变化。 These risk assessment approaches are not only concerned with selecting environmental monitoring locations. They integrate the environmental monitoring system with a complete review of operations within the cleanroom to ensure those facilities, operations, and practices are also satisfactory. The approaches recognise a risk, rate the level of the risk, and then set out a plan to minimise, control, and monitor the risk. The monitoring of the risk will help to determine the frequency, locations for, and level of environmental monitoring (for example, refer to an article by Sandle [2003a], for a more detailed example). 这些风险评 估方法不仅仅和环境监测位置的选择相关。它们将环境监测系统用以确保设备、操作和行为符合规定的洁净室操作完整审 核相结合。这些方法识别风险，评估风险级别，之后确定计划以最小化，控制和监测风险。风险监测将帮助确定环境监测 的频率、位置分布和级别（如：详细举例参见 Sandle 的文章 [2003a]）。 This paper explores an example from three different techniques: 本文列举了 3 种不同方法的例子： • A simple conceptualisation of risk using a table 使用图表使风险简单概念化 • HACCP 危害分析和关键控制点 • FMEA 失效模式和影响分析 Environmental Monitoring Risk Assessment 环境监测风险评估环境监测风险评估环境监测风险评估环境监测风险评估 2006 - Journal of GXP Compliance，2006 年 1 月，10 卷，2 号 翻译/编辑：谢永/http:/blog.sina.com.cn/xiedaxialaile 8888 / 20202020 内部交流，请勿转载/2013 年 3 月 6 日 Tabular Approach 图表图表图表图表法法法法 An example using a simple table for analyzing risk in environmental monitoring situations appears in Figure 3.图表 3 为使用简单图表分析环境监测风险举例。 图表 3 风险分析的图表法 区域或设备：无菌检测隔离器 风险：隔离器环境下微生物数量增加所造成的污染 失效或情景：使用后未清洁彻底 影响 风险最小化（降低风险 的方法） 监测 1）当隔离器 不是定期清 洁时，可能会 有微生物残 留在环境中。 1）在使用合适的消毒 剂前用水清洁表面以 去除污染物或溢出物。 2）使用的消毒剂必须 具备广谱杀菌效力且 对隔离器材料无损害。 3）隔离器本身的设计 应易于清洁。 1）环境监测项目（使用沉 降碟、空气取样，接触碟， 擦拭法或手指接触碟）将 涵盖最大风险区。数据应 做趋势分析。 2）对于超标的环境监测结 果，应当采取恰当的纠正 预防措施。 Environmental Monitoring Risk Assessment 环境监测风险评估环境监测风险评估环境监测风险评估环境监测风险评估 2006 - Journal of GXP Compliance，2006 年 1 月，10 卷，2 号 翻译/编辑：谢永/http:/blog.sina.com.cn/xiedaxialaile 9999 / 20202020 内部交流，请勿转载/2013 年 3 月 6 日 HACCP 危危危危害害害害分析和关键控制点分析和关键控制点分析和关键控制点分析和关键控制点 • The seven principles behind constructing an HACCP analysis consist of: • HACCP 分析的七大原则包括： 1. Identifying hazards or contamination risks and assessing their severity。 确认危害或污染并评估其严重程度 2. Determining Critical Control Points (CCPs) 确定关键控制点(CCPs) 3. Establishing critical limits 确定关键限度 4. Establishing a system to monitor and control CCPs 确立监测系统并控制关键控制点。 5. Establishing corrective action when a CCP is not under control 当 CCP 不在控制范围内时，确定纠正措施 6. Establishing procedures for verification to confirm that the HACCP system is working effectively 建立确认规程以确认HACCP系统运行正常 7. Establishing documentation and reporting systems for all procedures 为所有的规程建立文件和报告系统 Each of these seven key points is a vital step in developing the risk assessment. 这 7 点每一点都是风险 评估的关键步骤 序 号 The seven points include: 7 点包括： Examples include: 举例包括： 1. Construct a risk diagram, or diagrams, to identify sources of contamination. Diagrams should show sources and routes of contamination. 建立风险图或图表以识别污染 源。图表应当显示污染的来源和路径。 1）Areas adjacent to Cleanroom or Isolator (e.g.: airlocks, changing rooms) 邻近洁净 室或隔离器的区域（如：气闸间，更衣室） 2）Air supply and Room air 供气和房间空气 3）Surfaces 表面 4）People Machines and Equipment 人员机器和设备 2. Assess the importance of these sources and determine whether or not they are hazards that should be controlled. 评估这些来源的重要性并确定其是否是应当控 制的危害。 1）Amounts of contamination on, or in, the source that is available for transfer 存在于 转运环节的污染物的数量。 2）Ease by which the contamination is dispersed or transferred 污染物扩散或转移的 难易程度取决于： --Proximity of the source to the critical point where the product is exposed 污染源与产 品暴露的关键点的接近程度 --Ease with which the contamination can pass through the control method 污染物穿越 控制方法的难易程度。 -The use of a scoring method can greatly help in assessing the relative importance of these contamination sources. 使用计分法可以大大有助于评估污染源的相对重要程 度。 3. Identify the methods that can be used to control these hazards. 确定可以用来控制危害的方法。 1）Air Supply: High Efficiency Particulate Air (HEPA) filters 空气供应使用高效过滤器 2）Dirty Areas adjacent to Cleanroom or Isolator: differential pressures, airflow movement 毗邻洁净室或隔离器的污染区域：压差，空气流动 3）Room Air: air change rates, use of barriers 房间空气：换气率，使用屏障 4）Surfaces: sterilisation, effectiveness of cleaning and disinfection procedures 表面： 灭菌，清洁消毒规程的有效性 5）People: cleanroom clothing and gloves, room ventilation, training 人员：洁净服和 手套，房间通风，培训 6）Machines and Equipment: sterilisation, effectiveness of cleaning, exhaust systems 机器设备：灭菌，清洁有效性，排风系统 4. Determine valid sampling methods to monitor either the hazards or their control methods or both. 确定有效的取 样方法以监测危害或危害控制方法或二者兼顾。 1）HEPA filter integrity tests 高效过滤器完整性测试 2）Air supply velocity, air change rates 风速，换气次数 3）Room pressure differentials 房间压差 4）Particle counts 尘粒数 5）Air samplers, settle plates, contact plates, etc 空气取样器，培养皿，接触碟等 5. Establish a monitoring schedule with ‘alert’ and ‘action’ levels and the corrective measures to be taken when these levels are exceeded. 建立监测计划，规定“警戒” 和“行动”限以及超出限值时应采取的纠正措施。 1）The greater the hazard, the greater the amount of monitoring required 危害越大， 需要监测的数量越多 2）Trend analysis for alert and action levels, in or out of control 控制限范围内外的警戒 限和行动限趋势分析 6. Verify that the contamination control system is working effectively by reviewing key targets like product rejection rate, sampling results, control methods, and so on. These may require modification over