Without measurement there is no control 3rd Annual Cleanroom Design and Engineering Forum Frequently Asked Questions This FAQ paper is a follow up to the webinar, “3rd Annual Cleanroom Design and Engineering Forum” presented by Anna Campanella. Many thoughtful questions were asked about non-viable particle counting requirements in cleanrooms and sampling placement pertaining to process design. Questions submitted during and after the webinar are answered by Anna Campanella, below. If you have any additional queries for our experts, submit them directly here. When is an investigation required for NVPC excursion? How do we set alert and action limits? Investigations must be carried out when an out of action limit occurs or in the event the alert limit is exceeded several times consecutively. The environmental monitoring data follows a non-normal trend (they do not follow a Gaussian trend). Therefore, the definition of the alert and action limits requires an appropriate statistic. ∙∙∙ For the ORABS system filling machine, what is the correct sequence of activities? Installation of gloves or keeping microbial monitoring plate inside the filling machine cabinet? Monitoring should be done wearing gloves and without opening the RABS. ∙∙∙ Is it required to perform a smoke study for installation of a NVPC sensor in a Grade A zone? If the isokinetic probe is installed in a new position, it could impact the machine’s design, and therefore any turbulence must be verified by the smoke study. ∙∙∙ info@pmeasuring.com | +1 800 238 1801 Page 1 of 4 Cleanroom Design and Engineering Forum FAQ Is it required to monitor particle counts near a vibratory bowl of the aseptic filling machine? Due to vibration, particles may generate. The sampling positions must be defined through a risk assessment. The stoppering area inside the filling machines is certainly a critical area. The vibrating effect can be mitigated by proper installation of the isokinetic probe (steel tube and bev-A-line tube inside). ∙∙∙ What is the air classification of a vial sealing/capping area and what is the right location for a non-viable counter? If the capping area is inside the insolator or it is part of the filling line, this area must be classified as Grade A. If the crimping machine is in Grade C with unidirectional flow, the classification is Grade A supply. Annex 1 states that Grade A air supply is air which is passed through a filter qualified as capable of producing Grade A non-viable quality air. However, there is no requirement to perform continuous non-viable monitoring or meet Grade A viable monitoring limits and the area itself is not classified. The area is specifically used for the protection of fully stoppered vials where the cap has not been crimped and the equipment and engineering systems have a direct impact on product quality. The correct position should be assessed by QRM based on the process and area design. ∙∙∙ According to the newest Annex 1 draft, the CNC rooms should be specified as ISO 8, ISO 9 or lower. Does that mean we should qualify them as part of the cleanroom? If so, which test qualification should be used? The manufacturer should used the QRM approach to define microbial control levels according to their process. The level, type, and frequency of both the cleaning program and the environmental monitoring program (including contamination limits) should be based on a formal risk assessment (captured within the wider contamination control strategy). It should be commensurate with the specific risks all processes and product manufactured within each CNC area. Different CNC areas within the same facility may have different methods to control and monitor based on the risks to processes and products. ∙∙∙ info@pmeasuring.com | +1 800 238 1801 Page 2 of 4 Cleanroom Design and Engineering Forum FAQ From your experience, does CCS risk management using FMEA depend on historical data or experience and expectations? If the CCS is issued for an existing facility the FMEA must be based on the historical data and scientific knowledge of the team. ∙∙∙ Do you use SPC data in quality control? Yes, SPC is used, but only for the normal data that follows a gaussian trend (i.e., pH, TOC, etc). I have never used it for environmental monitoring data, as these do not follow a normal trend and require appropriate statistics. ∙∙∙ What is the efficiency of counters able to monitor viable and particle concurrently? The counting efficiency of these particle counters should be assessed based on the technical data provided by the supplier. Above all, the real efficiency (in comparison to actual standard methods) must be evaluated for your production process, which allows you to build a performance qualification and perform comparability studies with traditional methods that verify the real efficiency in the field. You can then define alert and action levels designed specifically for the process. Additionally, you can use ISO 21501-4 for industry recommendations on counting efficiency. ∙∙∙ How we classify the LAF (UDAF) zone surrounded by Grade C for viable and nonviable monitoring? My suggestion is to classify these unidirectional airflows (UDAFs) in “operational state” as Grade C, as their purpose is to clean and avoid the accumulation of particles during non-sterile operations but which could have an impact on critical processes. Introducing non-sterile material into these UDAFs, it makes no sense to classify them as Grade A. ∙∙∙ info@pmeasuring.com | +1 800 238 1801 Page 3 of 4 Cleanroom Design and Engineering Forum FAQ What is your opinion on particle counters able to monitor viable particles in real time? Monitoring viable and non-viable particles in real-time is excellent for controlling the production process at every stage. It allows for quick intervention when deviations occur, which protects the product. These new technologies require a great effort to validate and define the correct alert and action levels based on the process to be monitored. Trusting new technology to provide the critical data on aspetic core status comes with additional risk. Improving the expertise surrounding such important environments will help manufacturers make those decisions to use this technology. As with any new technology, you need to establish continuity to what has been done previously. This will require months of gathering data for comparison before relying on the technology for real-time process decisions. ∙∙∙ Anna Campanella, PhD Global Sterility Assurance Advisor, Particle Measuring Systems In Anna’s role at PMS, she uses her industry experience to collaborate and consult with pharmaceutical companies to develop and implement science-based strategies, principles of monitoring, and controlling and improving the chemical, physical, and microbiological state of various production processes. Anna has a diverse background in the pharmaceutical field including a PhD in Molecular Medicine, expertise in QA & QC processes, validation of chemical and microbiological methods, validation of sterile production processes and experience in microbiological aspects of aseptic production processes. © 2021 Particle Measuring Systems, Inc. All rights reserved. Reproduction or translation of any part of this work without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to Particle Measuring Systems, Inc. at 1-800-238-1801. App Note 297 210203 info@pmeasuring.com | +1 800 238 1801 Page 4 of 4
