中国GMP中要求应根据药品品种、生产操作要求及外部环境状况等配置空调净化系统，保证药品的生产环境符合要求。对于无菌药品，生产环境的影响尤为重要。为了维护医药生产用洁净区环境的稳定性、确保药品质量安全，对洁净区的环境质量采取合理的控制措施和评价方法是非常重要的。基于此，我们整理了“环境日常监测频次要求”相关的法规和指南要求。希望对您了解这方面的内容有所帮助。上期我们总结过中国法规对此的要求，本期我们继续讲述欧盟和美国法规相关的要求。

01 欧盟篇

1. EU Annex1 Manufacture of Sterile Products

欧盟 附录1无菌产品的生产

依据欧盟附录1中的第9章节[1],环境监测应符合下列规定：

• 9.16 For the Grade A, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly.

  9.16 对于 A 级区域，应在包括设备组装在内的整个关键工艺中进行微粒监测。

• 9.17 The Grade A area should be monitored continuously (for particles ≥0.5 and ≥5 µm) and with a suitable sample flow rate (at least 28 litres (1ft3) per minute) so that all interventions, transient events and any system deterioration is captured. The system should frequently correlate each individual sample result with the limits in Table 6 at such a frequency that any potential excursion can be identified and responded to in a timely manner. Alarms should be triggered if alert levels are exceeded. Procedures should define the actions to be taken in response to alarms including the consideration of additional microbial monitoring.

  9.17 对A 级区域的微粒(≥0.5和≥5µm)进行连续监测，并采用适当的采样流量(至少每分钟28升(1立方英尺))，以便捕获所有干预、瞬时事件和任何系统老化情况。系统应经常将每个样本结果与与表 6 中的限值相关联，以便及时发现和响应任何潜在的偏差。如果超过警报水平，则应触发警报。程序应规定针对警报采取的行动，包括考虑额外的微生物监测。

• 9.18 It is recommended that a similar system be used for Grade B area although the sample frequency may be decreased. The Grade B zone should be monitored at such a frequency and with suitable sample size that the programme captures any increase in levels of contamination and system deterioration. If alert or action levels are exceeded, alarms should be triggered.

  9.18 建议对 B 级区域采用类似的系统，尽管采样频率可能会减少。对B 级区域应按一定的监测频率和适当的取样量进行监测，以确保监测计划能捕捉到污染水平的增加和系统老化。如果超过警戒水平，应触发警报。

  
  

• 9.24 Continuous viable air monitoring in grade A (e.g. air sampling or settle plates) should be undertaken for the full duration of critical processing, including equipment (aseptic set-up) assembly and critical processing. A similar approach should be considered for grade B cleanrooms based on the risk of impact on the aseptic processing. The monitoring should be performed in such a way that all interventions, transient events and any system deterioration would be captured and any risk caused by interventions of the monitoring operations is avoided.

  9.24 在关键工艺操作的全过程，包括设备组装（无菌装置）和灌装操作期间，均应在A级区域内进行连续的微生物监测（如浮游菌或沉降菌）。对于 B 级洁净室，应根据对无菌工艺操作影响的风险，考虑采用类似的方法。监测的方式应能捕捉到所有干预、瞬时事件和任何系统老化情况，并避免因监测操作的干预带来的风险.

  
  

• 9.25 A risk assessment should evaluate the locations, type and frequency of personnel monitoring based on the activities performed and the proximity to critical zones. Monitoring should include sampling of personnel at periodic intervals during the process. Sampling of personnel should be performed in such a way that it will not compromise the process. Particular consideration should be given to monitoring personnel following involvement in critical interventions (at a minimum gloves, but may require monitoring of areas of gown as applicable to the process) and on each exit from the grade B cleanroom (gloves and gown). Where monitoring of gloves is performed after critical interventions, the outer gloves should be replaced prior to continuation of activity. Where monitoring of gowns is required after critical interventions, the gown should be replaced before further activity in the cleanroom.

  9.25 风险评估应根据所执行的活动以及与关键区域的接近程度，对人员监测的位置、类型和频率进行评估。监测应包括在工艺过程中定期进行人员监测采样。人员监测采样应以不影响工艺过程的方式进行。对于人员监测，参与关键干预操作后（至少包括手套，但可能需要监测适用于工艺的洁净服区域）以及每次离开B级洁净室时（手套和洁净服），应特别考虑。如果在关键干预操作后监测手套，则应在继续活动之前更换外层手套。如果在关键干预操作后需要监测洁净服，则应在洁净室进一步活动之前更换洁净服。

02 美国篇

1. US FDA Sterile Drug Products Produced by Aseptic Processing

美国FDA的无菌工艺生产的无菌药品指南

在本指南[2]的第四章节建筑和设施中相关环境监测方面的内容指出：

• We recommend that measurements to confirm air cleanliness in critical areas be taken at sites where there is most potential risk to the exposed sterilized product, containers, and closures. The particle counting probe should be placed in an orientation demonstrated to obtain a meaningful sample. Regular monitoring should be performed during each production shift. We recommend conducting nonviable particle monitoring with a remote counting system. These systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters.

  我们建议在关键区域中，对于暴露的无菌产品、容器和密封组件存在最大的潜在风险的位置，进行监测来确认其空气洁净度。粒子计数探头的放置方向应能获得有意义的样本。每个生产班次都应进行常规监测。我们建议使用远程计数系统进行悬浮粒子监测。这些系统能够收集更全面的数据，而且通常比便携式粒子计数器的侵入程度更小。

在本指南[2]第五章节人员培训、确认和监测上指出：

• C. Monitoring Program

  Personnel can significantly affect the quality of the environment in which the sterile product is processed. A vigilant and responsive personnel monitoring program should be established. Monitoring should be accomplished by obtaining surface samples of each operator's gloves on a daily basis, or in association with each lot. This sampling should be accompanied by an appropriate sampling frequency for other strategically selected locations of the gown. The quality control unit should establish a more comprehensive monitoring program for operators involved in operations which are especially labor intensive (i.e., those requiring repeated or complex aseptic manipulations).

  
  

  C. 监测系统

  人员会严重影响无菌产品工艺操作所在的环境质量。应建立一个谨慎且反应迅速的人员监测系统。监测应每天或每批次采集对每个操作人员的手套进行表面取样。与此同时，还应对洁净服基于策略选定的其他位置进行适当频次的取样。质量控制部门应为从事频繁操作（即需要重复或复杂的无菌操作）的操作员制定更全面的监测计划。

2. USP-NF Microbiological Control and Monitoring of Aseptic Processing Environments

美国药典 无菌工艺环境的微生物控制和监测

在本指南[3]制定取样方案和取样区域的章节中讲述到：

• Table 2 suggests frequencies of sampling in decreasing order of frequency and in relation to the criticality or product risk of the area being sampled. This table distinguishes between aseptic processing where personnel are aseptically gowned and those where a lesser gowning is appropriate. Environmental monitoring sampling plans should be flexible with respect to monitoring frequencies, and sample plan locations should be adjusted on the basis of the observed rate of contamination and ongoing risk analysis. On the basis of long-term observations, manufacturers may increase or decrease sampling at a given location or eliminate a sampling location altogether. Oversampling can be as deleterious to contamination control as undersampling, and careful consideration of risk and reduction of contamination sources can guide the sampling intensity.

  表 2 根据取样区域的关键性或产品风险，按频率递减顺序列出了对应的取样频率。该表区分了人员需要穿无菌服的无菌工艺操作和需要穿较少无菌服的无菌工艺操作。环境监测采样计划在监测频率方面应具有灵活性，采样计划的位置应根据观察到的污染率和持续的风险分析进行调整。根据长期观察结果，制药企业可以增加或减少特定地点的采样，或完全取消某个采样位置。采样过多和采样不足一样，都会对污染控制产生不利影响，因此，仔细考虑风险和减少污染源可为采样强度提供指导。

  
  

3. PDA TR13 Fundamentals of an Environmental Monitoring Program

美国注射剂协会 TR13 环境监测程序原理

在本指南[4]的表3.0-2环境监测指南原则中对全球主流权威机构的环境监测要求进行了对比，如下：

小结：从上述分享中我们可以看出欧美对于A和B级的洁净区环境监测要求大同小异，也指明需要定期进行监测，这也只能作为一个基础的参考。最终我们还是应当基于我们生产药品的品种、生产操作要求及外部环境状况进行评估，得出来合适的频次。

相关文章

1. 【中国篇】环境日常监测频次的要求（一）

参考资料

[1] EU Annex1 Manufacture of Sterile Products

[2]US FDA Sterile Drug Products Produced by Aseptic Processing

[3]USP Microbiological Control and Monitoring of Aseptic Processing Environments

[4]PDA TR70 Fundamentals of Cleaning and Disinfection Programs for Aseptic Manufacturing Facilities