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1、Zhulikou431 作品 丁香园首发 Zhulikou431 作品 丁香园首发 无菌制药 A 级区环境监控布点 疑难问题技术论证 无菌制药 A 级区环境监控布点 疑难问题技术论证 2010 版 GMP 是目前中国制药企业面临的很大技术难关，大部分企业都积极准备，厉兵秣马，准备认证。因为 2010 版 GMP 对于无菌药品的要求，提到一个新的历史高度，很多技术疑难问题，让中国制药企业困惑不已。 其中， 非最终灭菌药品生产需要的 A 级区的环境监控问题，一直是行业关注的热点区域。 本技术论证资料，结合最新欧美法规、PDA 技术指南、法规问答和技术简章、科技文献、和国外专家的私人信函等资料撰写而
2、成。 即使这样，笔者仍然认为，对于科学技术的追求和探索，人类从来都没有停止脚步。任何宝贵意见，2010 版 GMP 是目前中国制药企业面临的很大技术难关，大部分企业都积极准备，厉兵秣马，准备认证。因为 2010 版 GMP 对于无菌药品的要求，提到一个新的历史高度，很多技术疑难问题，让中国制药企业困惑不已。 其中， 非最终灭菌药品生产需要的 A 级区的环境监控问题，一直是行业关注的热点区域。 本技术论证资料，结合最新欧美法规、PDA 技术指南、法规问答和技术简章、科技文献、和国外专家的私人信函等资料撰写而成。 即使这样，笔者仍然认为，对于科学技术的追求和探索，人类从来都没有停止脚步。任何宝贵意
3、见，请致函 请致函 。 。 1. 【问题问题】针对非最终灭菌产品的环境监控，A 级区布点问题 1.1 在 A 级区中，至少布点多少个？ 1.2 布点位置 （高度、 平面距离、 和操作工位距离） 如何设置最科学？ 要回答如上疑难问题，开始如下调查和论证工作： 2. 【法规依据法规依据】 2.1中国GMP2010版附录1无菌药品中国GMP2010版附录1无菌药品： 第十条 应当按以下要求对洁净区的悬浮粒子进行动态监测： （一）根据洁净度级别和空气净化系统确认的结果及风险评估，确定取样点的位置并进行日常动态监控。 第十一条 应当对微生物进行动态监测， 评估无菌生产的微生物状况。监测方法有沉降菌法、定
4、量空气浮游菌采样法和表面取样法（如棉签Zhulikou431 作品 丁香园首发 Zhulikou431 作品 丁香园首发 擦拭法和接触碟法）等。动态取样应当避免对洁净区造成不良影响。成品批记录的审核应当包括环境监测的结果。 分析：在中国 GMP 中，只是提到原则要求，具体 A 级区内如何布点进行环境监控，没有更多有价值信息。既然中国 GMP 附录基本翻译自欧盟 GMP 附录 1，核实欧盟 GMP 附录 1. 2.2 EU GMP 附录 1 无菌药品（20090301 版） EU GMP 附录 1 无菌药品（20090301 版） 4. Clean rooms and clean air dev
5、ices should be classified in accordance with EN ISO 14644-1. Classification should be clearly differentiated from operational process environmental monitoring. 5. For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on t
6、he class limit of the largest considered particle size and the method of evaluation of the data collected. 8. Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classifica
7、tion of rooms and/or clean air devices. 9. For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a hazard, e.g. li
8、ve organisms and radiological hazards. In such cases monitoring during routine equipment set up operations Zhulikou431 作品 丁香园首发 Zhulikou431 作品 丁香园首发 should be undertaken prior to exposure to the risk. Monitoring during simulated operations should also be performed. The Grade A zone should be monitor
9、ed at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. It is accepted that it may not always be possible to demonstrate low levels of 5.0 m particles at the point
10、of fill when filling is in progress, due to the generation of particles or droplets from the product itself. 11. Airborne particle monitoring systems may consist of independent particle counters; a network of sequentially accessed sampling points connected by manifold to a single particle counter; o
11、r a combination of the two. The system selected must be appropriate for the particle size considered. Where remote sampling systems are used, the length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing. The selection of the monitor
12、ing system should take account of any risk presented by the materials used in the manufacturing operation, for example those involving live organisms or radiopharmaceuticals. 分析：关于A级区域内环境监控布点问题，EU GMP附录1也没有提供更详细的信息。但是给出一个线索，就是ISO14644这一系列标准。 2.3 EU GMP 附录 1 注释 EU GMP 附录 1 注释 PIC 发布的 EU GMP 附录 1 注释，对
13、于研究欧盟 GMP 和无菌药品生产，是一份很关键的文献，核实情况如下： Zhulikou431 作品 丁香园首发 Zhulikou431 作品 丁香园首发 Section 8: New text: Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of roo
14、ms and/or clean air devices. Interpretation: Frequency, location and number of monitoring locations should be based on a formal risk assessment and not on ISO 14644-1. Data obtained during classification and previous monitoring data should be considered. Critical locations should be covered. Section
15、 9: New text: For grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a hazard, e.g. live organisms and radiological
16、 hazards. The grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. Interpretation: In critical areas with exposed product continuous monitoring, covering the duration of the operations is expected. Continuous means that the system must be able to pick
