Underpin your GMP programme with passive, active or real-time air monitoring
Manufacturing facilities follow the guidelines stipulated within Good Manufacturing Practises (GMP) Annex 1 to demonstrate that they are appropriately designed. Are heating, ventilation, and air conditioning (HVAC) systems installed? Are differential room pressures implemented? Are appropriate contamination control strategies being used that encompass all possible factors, including personnel, instruments and processes.
The effectiveness of such factors, achieved through cleanroom design and cleaning regimes, can be complemented with data collected through microbiological environmental monitoring; a process that usually involves air sampling.
There are three main methods of air sampling in cleanroom environments: active, passive and real-time. There are, however, considerable differences between them, and a variety of factors to consider.
Passive air monitoring
A simple, low-cost solution
When passive air sampling is used for environmental monitoring of cleanroom facilities, particles are collected on exposed growth agar plates – commonly known as “settle plates” – over a specific time, usually four hours. This process takes advantage of natural phenomena such as gravity, electrostatic forces or turbulent dispersion, and any bacteria or fungi to “settle” on the agar.
This is a low-cost and easy to set-up way to monitor your cleanroom, and potentially detect any microbial contamination that may occur. A further advantage is that maintenance costs are not an issue due to the disposable nature of settle plates. Yet despite its low cost, this method provides quantitative measurement, and identification of contaminant in line with regulatory requirements.
In an appropriate environment, passive air sampling using settle plates could be sufficient. And if you have specific requirements for the agar to use in settle plates for passive air sampling, here at Cherwell, we’re able to produce custom growth media to meet your specifications.
Less expensive, more time-consuming
There are disadvantages to passive air sampling, however. For example, it’s necessary to use different agar depending on the requirements: Tryptone Soya Agar (TSA) to detect bacteria, and Sabouraud Dextrose Agar (SDA) for fungus. Plates also need to be incubated at an appropriate temperature to give any bacteria or fungi that may be captured time to grow. This delays the results, which means that contamination could result in greater losses than when using other rapid air sampling methods.
A further disadvantage of passive air sampling is that the result is an indication of the point in time the sample was taken: any contamination occurring even shortly afterwards may not be detected. The plates must also be positioned correctly, and the results may be compromised if they’re physically damaged. It’s also important to remember that storage space is necessary for the incubation period, and that personnel need the necessary skills to interpret results.
Finally, Viable but Non-culturable (VBNC) bacteria won’t be detected using passive air sampling, so consider whether this is needed.
Active air sampling
A faster and more versatile alternative to passive air monitoring
Active air sampling has benefits over the passive method, but also has limitations and bears additional cost. With active air sampling, a known amount of air – usually 1,000 litres, or 1m3 – is drawn into an air sampler, and collected in either liquid, solid growth media or filter materials. A liquid sample or filter material will need to be transferred to a suitable agar plate, such as TSA or SDA, prior to incubation.
An advantage of active air sampling is versatility. This method offers the possibility of various setups to fit different locations, for example when the air sampler is in an isolator rather than a cleanroom. The instruments used, such as Cherwell's SAS 180 air sampler, are portable, user-friendly and quick: the SAS 180 can sample 1,000 litres of air in under six minutes, for example. Even in this short time, a quantitative measure (cfu/m3) can be taken, and identification of any contaminant achieved that aligns with regulatory requirements.
Active air sampling comes at a cost
Although active air sampling has advantages over passive air monitoring, there are nonetheless disadvantages. One of the most obvious is that active sampling is more expensive: initial outlay is required to buy a sampling device, and annual instrument calibration is recommended to maintain the accuracy of results.
Unless disposable daily heads are being used, active air sampling also requires the sterilisation of sampler heads. This sterilisation, usually by autoclaving can be time consuming and is a potentially costly process, especially if the necessary equipment has to be acquired. And the results of active air sampling are not instantaneous, requiring specific incubation facilities, and trained personnel to interpret the results. Active air monitoring is also just a snapshot of the time when the sample is taken; any contamination occurring even shortly afterwards may not be detected.
A further consideration is biological efficiency: D50 – microorganism impaction and survival after impaction at high flow rate – can affect results. D50 is described as the cut-off aerodynamic or equivalent particle diameter size, whereby 50% of particles from the sampled airstream can be effectively collected and impacted onto the media. And like passive air sampling, active sampling won’t indicate the presence of VBNC microorganisms.
Real-time air monitoring
Continuous air sampling that delivers instantaneous results
Real-time air sampling tackles many of the shortcomings of passive and active monitoring. A significant difference is the continuous nature of the air sampling. Machines used for real-time air monitoring continuously draw a known volume of air into a particle counter, which can measure a range of particle sizes, for example, ≥0.5-≥5 micrometer. Results are generated instantly, with a level indicator system available to set an alarm when irregularities are detected.
Although the devices used to detect contamination in real-time, such as BioAerosol Monitoring System (BAMS), offered by Cherwell, come at a premium compared with passive and active methods, their ability to alert users to contamination issues instantaneously can significantly reduce any losses in the event of an incursion; over time this could potentially offset the initial investment in the device. And unlike other air monitoring methods, BAMS does not use consumables, offering the potential for long-term savings.
Unlike passive and active air sampling methods, some real-time air monitoring machines also offer the ability to distinguish between viable and non-viable particles, and have the potential to enumerate VBNC microorganisms. In addition to the instant data output, data collected using the real-time monitoring devices can also be exported for better data integrity. For example, BAMS can export its results in PDF and Excel formats. This enables continuous data collection for analysis, meaning action can be taken should a recurring irregularity be detected.
Immediate alerts could offset greater cost
The most obvious disadvantage to real-time monitoring is the relatively high initial outlay required to purchase such a device. However, this could easily be offset by the savings made, as instantaneous contamination alerts enable issues to be tackled quickly, significantly reducing potential losses.
BAMS is a relatively small, portable real-time air monitoring device capable of fitting into a variety of locations, but this isn’t true of all instruments of this type. A larger unit could require additional restructuring and reorganisation of the location. It’s also important to note that the ability of real-time air monitoring units to meet regulatory requirements varies, and is dependent on cleanroom grading.
Due to their complexity and the potential impact on performance, annual calibration of real-time monitoring instruments is recommended.
Passive, active, real-time air monitoring – solutions for a variety of applications
Why use passive, active or real-time air monitoring? Each has advantages and disadvantages, so the method you choose will depend on your specific setup, requirements and budget. At Cherwell, we offer a range of products in every category, as well as support services such as calibration, so contact us to determine your ideal passive, active, or real-time air monitoring solution.
References:
Napoli, C., Marcotrigiano, V. & Montagna, M.T. (2012) Air sampling procedures to evaluate microbial contamination: a comparison between active and passive methods in operating theatres. BMC Public Health 12, 594. https://doi.org/10.1186/1471-2458-12-594
Tan, H., Wong, K.Y., Nyakuma, B.B., Kamar, H.M., Chong, W.T., Wong, S.L. and Kang, H.S. (2022) Systematic study on the relationship between particulate matter and microbial counts in hospital operating rooms. Environ Sci Pollut Res 29, 6710–6721. https://doi.org/10.1007/s11356-021-16171-9
Sandle, T (2023) New ISO14644-21:2023 Addresses Reducing Sampling Errors with Airborne Particle Counters. Bioprocess online. https://www.outsourcedpharma.com/doc/new-iso-14644-21-2023-addresses-reducing-sampling-errors-with-airborne-particle-counters-0001
Sinsuwanrak, S., Premanoch, P., Manakasettharn, S. and Adulyaritthikul, P. (2023). Environmental Microbial Monitoring and Risk Assessment of Cleanrooms-A Case Study in Medical Device Pilot Plant. Thai Environmental Engineering Journal, 37(1), pp.1-12.
Sehulster, L.M., Chinn, R.Y.W., Arduino, M.J., Carpenter, J., Donlan, R., Ashford, D., Besser, R., Fields, B., McNeil, M.M., Whitney, C., Wong, S., Juranek, D. and Cleveland, J. (2004) Guidelines for environmental infection control in health-care facilities. Recommendations from CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC). Chicago IL; American Society for Healthcare Engineering/American Hospital Association. https://www.cdc.gov/infectioncontrol/pdf/guidelines/environmental-guidelines-p.pdf
Stålfelt, F., Malchau, K.S., Björn, C., Ardebili, M.M. and Erichsen, A.A. (2023). Can particle counting replace conventional surveillance for airborne bacterial contamination assessments?–A systematic review using narrative synthesis. American Journal of Infection Control. https://www.sciencedirect.com/science/article/pii/S0196655323003607
