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前瞻性的环境监测和根源诊断 —— PEMM案例研究报告

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Advanced Environmental Monitoring and Troubleshooting with Bio-Fluorescent Particle Counters: 

Four Case Studies from the Process and Environmental Monitoring Methods Working Group



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Abstract


Bio-Fluorescent Particle Counters provide superior monitoring capabilities over the traditional plate count method due to their ability to monitor continuously with no sample preparation or manipulation, and also over classical particle counters due to their ability to discriminate between inert and biological particles. Resolving inert and biological particles from total particles can provide critical diagnostic information in air and water systems. This article presents four case studies illustrating the use of Bio-Fluorescent Particle Counters in resolving complex environmental monitoring investigations.

Bio-Fluorescent Particle Counters (BFPCs) are laser-based particle counting monitors used to measure inert and biological particles, referred to as Auto-Fluorescent Units (AFU), in clean water or air systems. The fact that the instruments can detect both inert and biological particles provide powerful advantages over classical particle counters, which only detect particles based on size without classifying them by type. Furthermore, the continuous as opposed to intermittent detection of biologic particles provides a distinct advantage over the traditional plate count method by offering a superior Environmental Monitoring (EM) profile of pharmaceutical manufacturing conditions for improved product quality decisions.



使用生物荧光计数器(BFPC)进行前瞻性的环境监测和根源诊断: 来自过程和环境监控方法工作组(PEMM)的四个案例研究


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摘要


生物荧光粒子计数器(BFPCs)提供了优于传统平板计数方法的监测能力,因为它们能够在无需样品制备或操作的情况下连续监测,并且由于它们能够区分惰性粒子和生物粒子,因此也优于传统粒子计数器。从总颗粒中分离惰性和生物颗粒可以提供空气和水系统中的关键诊断信息。本文介绍了四个案例研究,说明了生物荧光粒子计数器在解决复杂环境监测调查中的应用。

生物荧光粒子计数器(BFPCs)是基于激光的粒子计数监测仪器,用于测量洁净水或空气系统中的惰性和生物粒子,称为自动荧光单元(AFU)。该类仪器可以同时检测惰性和生物粒子,展现了比传统粒子计数器的巨大优势,后者只能检测出粒子的大小,无法根据类型分类。此外,与周期性检测相比,生物颗粒的连续检测提供了优于传统平板计数方法的显著优势,因为它提供了药物制造条件的优越环境监测(EM)曲线,以改进产品质量决策。


The Basis for Bio-Fluorescent Particle Counting Technology

Particle counting has a long history, stretching back to the middle of the last century, and can be applied to both air and water systems. In these classical systems, a light beam intersects a stream of air or water. As a particle travels through the beam, the physics of light scatter allows detection of the particle and classification of its size via Mie scattering. BFPCs take this principle and layer on an additional level of detection. Biologicals (bacterial and fungi) contain biomolecules that fluoresce at specific wavelengths when illuminated by specific shorter wavelengths of light. The addition of other detector(s) in BFPC systems, tuned to a specific range of wavelengths, creates a system that detects particles and assigns the particles to presumptive biologic and inert categories. In contrast to Colony-Forming Units (CFU) derived from traditional culture-based sample analyses, the unit of measure for BFPC is the AFU.


生物荧光粒子计数(BFPC)技术的基本原理

粒子计数有着悠久的历史,可以追溯到上世纪中叶,广泛的应用于空气和水系统。在这些系统中,光束与气流或水流相交,当粒子穿过光束时,通过米氏 (Mie) 散射的物理学原理检测粒子并对其粒径的大小进行辨别。BFPC采用了这一原则,并在检测级别上进行了分类。生物制品(细菌和真菌)含有生物分子,当被特定波长的激光(405nm)照射时,生物分子发出荧光。通过BFPC系统中的探测器可检验荧光的强度及分布,通过分析荧光的分布,可以探测粒子的种类,并将粒子分为假定的活性和非活性类别。与基于传统培养的样本分析得出的菌落形成单位(CFU)不同,BFPC的计量单位是AFU。


The Need for Improved/Faster 

Environmental Monitoring Methods

On-going public health risks associated with COVID-19 and the need to manufacture billions of dosage units for worldwide distribution quickly have cast a spotlight on improving or replacing slow and inefficient methods of manufacturing. Among these methods is microbial environmental monitoring, which typically requires 5-7 days of incubation to obtain a result stating whether the process stream or environment was suitable or not. BFPC-based detection provides real-time feedback on the level of inert and biological particles in an environment, allowing enhanced process understanding of the environment that can save countless days of waiting on results. BFPCs also allow for rapid troubleshooting and diagnosis of environmental excursions. This supports product and production time savings due to the accelerated path to a root cause since the detection is not dependent on colony growth.


改进和加快环境监测方法的必要性

与新冠肺炎相关的持续公共健康风险,以及为了满足在全球范围内制造数十亿个剂量单位并快速分销的需求,人们越来越关注于改进或取代缓慢而低效的生产制造方法,这些方法中包括微生物环境监测。传统的监测方法通常需要5-7天的培养以获得表明工艺流或环境是否合规的结果。基于BFPC的监测提供了环境中非活性和活性生物粒子水平的实时反馈,从而增强了对环境的过程理解,可以节省无数天的等待结果。BFPC还允许对环境偏差进行快速故障排除和诊断。由于检测不依赖于菌落生长,这有助于无菌操作的过程管理、帮助隔离污染根源。BFPC监测在缩短生产时间,稳定产品质量、降低劳动成本、提高经济效益等方面具有明显的优势。


Real-World Use of BFPC Monitoring

While BFPCs have been commercially available for more than a decade, the number of open literature reports of fi eld applications is somewhat limited. An early report showed that a BFPC-based air monitor could provide comparable results at a faster rate than conventional methods in pharmaceutical cleanrooms.1Similarly, Sandle et al. used the same model instrument to evaluate cleanroom conditions in real-time (see below details). 2In 2015, a study by Anders et al. demonstrated the utility of a BFPC water monitor for extending the hold time of a water system.3Lipko et al. published their experiences with using a BFPC water analyzer for monitoring a high purity water system in 2018.4Also in 2018, there were two studies published describing the use of BFPC analyzers (both air and water) for facilitating the re-start of production facilities.5,6


BFPC1


BFPC2


Cleanroom Air Shutdown and Recovery Study: Case Study 1


The following case study at a pharmaceutical company shows a non-GMP investigation using an air-based BFPC to determine the impact and recovery time of shutting down the HVAC system in a Grade C cleanroom. Quality Assurance wanted to assess the impact of shutting down the HVAC system on biological and dust particles, as well as recovery of the environment after restarting. Personnel stated that they often have a short period, usually around two hours that the HVAC system is stopped. If the environment can be restored simply by running the HVAC system, there is no need to do extra cleaning and reconfirmation, which will save time and labor.

 

The BFPC was installed in a 12 square meter, Grade C laundry room. The HVAC system was stopped, all personnel left the area and the BFPC sample was started at 12:20 pm. The HVAC system was restarted at roughly 2:00 pm.

 

As shown in Figure 2, after the HVAC system was turned off, the AFU and total particle (P) counts began to rise. When the HVAC system was restarted, the AFU and total particle counts began to decline dramatically. The number of particles per meter cubed dropped to zero within 20 minutes of the HVAC restarting. It was determined that if the HVAC system was suspended for two hours and then restarted, without other measures, the system could complete self-purification within 20 minutes.


生物荧光粒子计数(BFPC)技术应用的现状和前景

尽管BFPC技术出现已经有十多年了,但相关应用的公开文献报道数量非常有限。早期的一份报告显示,基于BFPC的空气监测器可以比药物洁净室中的传统方法更快的提供类似的结果。1 类似地,Sandle等人使用实时浮游菌监测系统(BAM®S)实时评估洁净室环境条件。2 2015年,Anders等人的一项研究证明了BFPC水监测器在延长水系统保持时间方面的实用性。3 Lipko等人于2018年发表了他们使用BFPC水分析仪监测高纯水系统的经验。4同样在2018年,发表了两项研究,阐述了使用BFPC分析仪(空气和水)有助于加快生产设施的重新启动。5,6


 

这些研究清楚地表明,基于BFPC的系统比传统方法具有优势,并在行业中得到有效应用。除了这些报告之外,本篇文章中的四个案例研究也增加了对这一知识体系重要性的了解。

 

 

案例研究1

洁净室HVAC关闭后重新恢复使用

监测方法:

  • BAM®S放置于12平方米的C级洗衣房内

  • 监测点为洗衣机上方,距出风和回风口约0.9米

  • 整个监测期间房间处于非使用状态

  • HVAC系统在大约在关闭90分钟后重新启动 (监测结果见下图)


结论:

  • 确定在没有其他清洁措施的情况下,房间在20分钟内恢复到零粒子和生物粒子水平

  • 如果HVAC关闭时间小于1.5小时,则无需进行额外清洁,节省了时间和成本

  • BAM®S为环境监测及解决问题提供了一种新型方法,这是当前基于传统的培养和菌落计数方法无法实现的

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更多的案例请点击:

https://www.americanpharmaceuticalreview.com/Featured-Articles/590789-Advanced-Environmental-Monitoring-and-Troubleshooting-with-Bio-Fluorescent-Particle-Counters-Four-Case-Studies-from-the-Process-and-Environmental-Monitoring-Methods-Working-Group/


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Conclusions


The case studies given in this paper and the other cited studies give clear evidence that bio-fluorescent particle counters (BFPCs) have major advantages over conventional methods in providing results in real-time and instantaneous discrimination of inert versus biological particles. These advantages provide the promise of improving or replacing slow and inefficient methods of manufacturing monitoring and environmental control.


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结论


本文中给出的案例研究和引用的相关研究清楚地证明,生物荧光粒子计数器(BFPC)在提供实时和瞬时的鉴别结果方面优于传统方法。这些优势给予了更快地改进或替代缓慢且低效传统监控方法希望。



References

1) Bolotin C, Varnau B, Nelson JR, Bhupathiraju VK, Jiang JP. Evaluation of an instantaneous microbial detection system in controlled and cleanroom environments. BioPharm International. 2007;20.

2) Sandle T, Leavy C, Jindahl H, Rhodes R. Application of rapid microbiological methods for the risk assessment of controlled biopharmaceutical environments. Journal of Applied Microbiology. 2014;116(6):1495-1505.

3) Anders HJ, Ayres FB, Bolden J, et al. Online Water Bioburden Analyzers: A Case Study for the Extension of Purified Water Hold Times. Pharmaceutical Engineering. 2015;35:119-124. 4. Lipko B, Termine B, Walter S. Case Study: Retrofitting Two New High-Purity Water Systems. Pharmaceutical Technology Biologics and Sterile Drug Manufacturing. 2017;18–26. Available at: http://files.pharmtech.com/alfresco_images/pharma/2019/04/24/afdeeb30-52a1-4b1e-b5a0-bd32528a2648/PT_Biologics-and-Sterile-Drug-Manufacturing_5-1-2017.pdf

4) Montenegro-Alvarado JM. Leveraging rapid microbiological methodology in forensic evaluation to identify elusive root cause. American Pharmaceutical Review. 2018. Available at: https://www.americanpharmaceuticalreview.com/Featured-Articles/353500-Leveraging-Rapid-Microbiological-Methodology-in-Forensic-Evaluation-to-Identify[1]Elusive-Root-Cause/

5) Montenegro-Alvarado JM, Salvas J, Weber J, Mejías S, Arroyo R. Pfizer Case Study: Rapid Microbial Methods For Manufacturing Recovery After Hurricane María. Pharmaceutical Online. 2018. Available at: https://www.pharmaceuticalonline.com/doc/pfizer[1]case-study-rapid-microbial-methods-for-manufacturing-recovery-after-hurricane[1]mar-a-0001

6) Hjorth J, Annel P, Noverini P, Hooper S. GMP Implementation of On-Line Water Bioburden Analyzers. Pharmaceutical Engineering. 2021. Available at: https://ispe.org/ pharmaceutical-engineering/january-february-2021/gmp-implementation-online[1]water-bioburden#





The Author


James Francis

Technical Director, MicronView

James11


James Francis is a member of the PEMM working group, and Technical Director at Micron View LLC. He focuses on the development and evaluation of environmental monitoring instrumentation, and specializes in real time microbial monitoring applications for both air and water.







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