1、 1 / 35Environmental Monitoring Risk Assessment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INTRODUCTION引言Environmental Monitoring describes the microbiological testing undertaken in
2、 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 cl
3、eanliness, gowning practices, the equipment, and cleaning operations. 环境监测描述了在洁净室或受控环境下，为了监测微生物数量和微生物群落繁殖的变化趋势而进行的微生物测试。所测结果提供关于房间结构，空调系统性能，人员卫生，更衣行为，设备和清洁操作的信息。Over the past decade, environmental monitoring has become more sophisticated in moving from random sampling, using an imaginary grid over t
4、he 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，环境监测愈发复杂，从任意取样，按照假想的房间网格进行测试，到现阶段注重风险评估并使用风险评估工具确定环境监测的最佳方法。This paper explores current trends in the applicati
5、on 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（理念、观念） 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
6、不同类型洁净室的监测周期。 Risk Assessment Tools（工具） : Applying risk assessment tools to establish methods for environmental monitoring 。 风险评估工具：运用风险分析工具确定环境监测方法。2 / 35 Numerical（数字的、数值的） Approaches: Considering a numerical approach to assess risk data using a case study of an aseptic（无菌的） filling operation 数值法：
7、使用无菌灌装操作案例分析考虑采用数值法评估风险数据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设备，大多为无菌灌装；然而，理念和工具也同样适用
8、于其他类型生产和包装操作的环境监控。DETERMINING THE FREQUENCY OF MONITORING: 确定监测频率In developing an adequate （适当的、胜任的）environmental monitoring programme, there should be a balance between using resources efficiently and monitoring at sufficiently（充分地、足够地） frequent intervals（应对资源的有效利用率和监测频率的间隔上进行平衡） so that a meaningf
9、ul 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) may not be suitable for all facilities. Some guidance can be obtained from the International Or
10、ganization for Standardizations (ISO) standards: principally ISO 14644 and ISO 14698. However, these do not always fit with regulatory guidance documents because they apply to （适用于、应用于）controlled environments across a range of （一系列、一些）industries other than pharmaceuticals, where standards can be hig
11、her (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 d
12、ifferent controlled areas can be determined based on criticality factors relevant to each specific area.在确定环境控制程序时，应在每个功能区的“临界因数”基础上，确定不同受控区域的监测频率。Criticality Factors：临界因数The establishment of a criticality scheme on which to base monitoring frequencies is designed to target monitoring of critical pr
13、ocess 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，最终配苗工序所接受的监控更多。3 / 35Using a criticality factor is a means of assigning a monitoring frequency based on t
14、he 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（暴露的） time, and the presence of water, would constitute（组成） a high risk and would attract a higher ri
15、sk rating（等级）. In contrast（相比之下）, an area of closed processing, in a cold area, would carry a substantially lower risk and associated risk rating. 使用临界因数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。风险分析与风险对产品的任何潜在影响相关。如，室温开放工艺区，长暴露时间，水的存在，这些将构成高风险，和高风险级别。相反地，封闭工艺区，温度较低区域潜在风险较低，相关风险级别也更低。Using a range of 1 to 6, with 1
16、 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 ratio
17、nale. 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”为最次要关键的，无菌灌装操作为 1 分；最终配苗为 2 分，开放式工艺为 3 分，等等。每一位使用者都必须在特定区域使用该分数体制并运用支持理论。该体制下的监测频率举例见图表 1，其应用举例见图表 2.图表 1 监测频率临界因数临界因数 监测频率1 每日或每批2 每周3
18、每两周4 每月5 每三个月或每个季度7 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 4 / 35two category areas: areas of higher weighting and areas of higher m
19、onitoring frequency. Examples of these categories follow:根据既定标准评估受控区域，根据一系列指导性问题确定监测频率。标准确定需考虑两大因素：较多监测点的区域和较高监测频率的区域。两大因素举例如下：Giving Higher Weighting to 较多监测点的区域 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
20、内进行，即便洁净活动是后期加工 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）。这将包括走廊和更衣室。 Routes of transfer 转移通道 Areas that receive in-coming goods 接受物料进入的区域 Compone
21、nt preparation activities and sites Duration of activity (such as a lower criticality for a 30-minute process compared to a six-hour operation) 材料准备活动和地点 活动持续时间（如：30min 的工序同 6hour 的操作相比，临界因数较低）Having Higher Monitoring Frequencies for 更高的监测频率 - Warm or ambient areas as opposed to cold rooms 与寒冷区域相对的温
22、暖或室温区域 Areas with water or sinks as opposed to dry, ambient areas 与干燥室温区域相对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) 与短时间敞开或封闭工序（确认产品风险暴露时间）相对的开放工序 Final formulation, purific
23、ation, secondary packaging, product filling, etc. 最终配苗，净化，分装，产品灌装，等。5 / 35图表 2 临界因数应用环境临界因数 环境对成品的影响可能性大小定义 监测频率1 非常可能 无进一步加工的无菌灌装。这里污染风险对产品有较大的影响，因为无法通过进一步加工减少或去除污染物每日或每批2 可能 最终配苗区。这可以 每周6 / 35适用于最终工序为灭菌级过滤器的区域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。这也适用于室温区域和高水分含量区域每两周4 不可能 这适用于少或无开放式工艺的低温区每月5 很不可能 不直接暴露于环境中
24、很不可能引起可能影响成品的污染。如果引入污染物，充分的下游控制和/或使用防腐剂可以很大程度上去除污染物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Once the monitoring frequency for each controlled area is determined, it should be reviewed at regular intervals. This review may invoke changes to a rooms status, and hence, its monitoring frequency,
25、 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 samp
26、les 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). 一旦确定每个控制区的监测频率，应当定期审核。审核可能导致房间临界因数变化，因而改变监测频率，或导致室内取样类型的变化。例如，一年数据审核之后，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，
27、将更多地关注清洁消毒行为和频率(Sandle, 2004b)。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 control to the process, whereas surface samples are ind
28、icators 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 cou
29、ld 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, 199
30、6).7 / 35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。这是因为空气取样直接指示工序质量并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，临界因数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)。RISK ASSESSMENT TOOLS 风险分析工具Once the status for each room has bee
31、n 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.一旦选择每个房间的临界因数，要求确立风险评估规程以确定环境监测的位置分布。ISO 14698 建议使
32、用基于风险的方法并且管理当局愈发多地询问药品生产商关于风险评估的问题。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 Ana
33、lysis (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败模式和效果分析(FMEA),错误树形分析 (FTA), 和危险分析和关键控制点(HACCP), 所有这些都要求使用计分方法。（其他方法包
34、括：失败模式，效果和临界因数分析(FMECA);危险操作分析(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,
35、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险分析和关键控制点(HACCP) ，及应用于设备工程的失败模式和效果分析(FMEA) (Whyte 和 Eaton, 2004a)。These various analytical tools are similar in that they invol
36、ve:各种分析工具的相同之处在于，它们都包括以下内容： Constructing diagrams of work flows 构建工作流程图 Pin-pointing areas of greatest risk 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 ac
37、count changes to the work process and seasonal activities 考虑工序和季节性活动变更8 / 35These 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 ensur
38、e 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 environme
39、ntal 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同用以确保设备，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。风险监测将协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
40、techniques:本文探讨 3 种不同方法举例： A simple conceptualisation of risk using a table 使用图表使风险简单概念化 HACCP 危险分析和关键控制点 FMEA 失败模式和效果分析Tabular Approach 制表法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。9 / 35图表 3 风险分析的制表法区域或设备：无菌
41、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败或情况：使用后未清洁彻底效果 使风险降到最低（减少风险）监测当不定期清洁隔离器时，可能会有微生物残留在环境中。在使用合适的消毒剂前用水去除污染物以清洁表面使用的消毒剂必须具备广谱效力，但是对隔离器材料无害隔离器本身的设计应该方便清洁环境监测项目（使用沉降培养皿，空气取样，接触培养皿，纱布或将显示出最大风险区。应当检查数据分析趋势。对于超标的环境监测结果，应当采取合适的纠偏措施。HACCP 危险分析和 关键控制点 The seven principles behind constructing an HACCP analysis cons
42、ist of: HACCP 分析的七大原则如下：1. Identifying hazards or contamination risks and assessing their severity 确认危险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 CCPs5. Establishing
43、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 k
44、ey points is a vital step in developing the risk assessment. 以下 7 点都是风险评估的关键步骤 The seven points include: 7 点包括：1. Construct a risk diagram, or diagrams, to identify sources of contamination. Diagrams should show sources and routes of contamination. 构建风险图表，以确认污染来源。图表应当显示污染的来源和路径。Examples include: 举例包
45、括： 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） Air supply and Room air 供气和房间空气10 / 35 Surfaces 表面 People Machines and Equipment 人员设备2. Assess the importance of these sources and determine whether or not they are hazards that should be controlled.
46、评估这些来源的重要性并确定是否存在应当受控的危险Examples include: 举例包括： Amounts of contamination on, or in, the source that is available for transfer 转移来源的污染数量 Ease by which the contamination is dispersed or transferred 污染扩散或转移的 Proximity of the source to the critical point where the product is exposed 来源与产品暴露关键点的接近程度 Ease
47、 with which the contamination can pass through the control method 污染物通过控制方法的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. 确认可以用来控制危险的方法。For
48、example: 例如： Air Supply: High Efficiency Particulate Air (HEPA) filters 空气供应：HEPA Dirty Areas adjacent to Cleanroom or Isolator: differential pressures, airflow movement 洁净室或隔离器相邻的有污染区域：压差，空气流动 Room Air: air change rates, use of barriers 房间空气：换气率， Surfaces: sterilisation, effectiveness of cleaning a
49、nd disinfection procedures 表面：灭菌，清洁消毒规程的有效性 People: cleanroom clothing and gloves, room ventilation, training 人员：洁净服和手套，房间通风，培训 Machines and Equipment: sterilisation, effectiveness of cleaning, exhaust systems 设备：灭菌，清洁有效性，排气系统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险或危险控制方法抑或二者。For example: 例如： HEPA filter integrity tests HEPA 完整性测试 Air supply velocity, air change rates 空气速率，换气率 Room pressure differentials 房间压差 Particle counts 微粒数 Air samplers,
