require and how you can meet this new standard.The newly added Section 9 of Annex 1 Draft discusses environmental and process monitoring for viable and non-viable cleanroom particle counting. The focus in Section 9 is routine monitoring and focuses on system design, setting action limit alert levels, and reviewing data trends. Previously, Annex 1 only addressed cleanroom qualification and cleanroom classification. Ongoing cleanroom monitoring is now emphasized as important.Section 2.2 of Annex 1 specifies that Quality Risk Management (QRM) and Science must be the base for all approaches to manage the final quality of a product:
Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Where alternative approaches are used, these should be supported by appropriate rationales and risk assessment and should meet the intent of this Annex.Regarding environmental monitoring from a general perspective, Annex 1, Rev 12 says:
Annex 1, draft rev 12, Section 2.2
Routine monitoring of cleanrooms, clean air equipment and personnel should be performed in operation throughout all critical stages, including equipment set-up.
Annex 1, draft rev 12, Section 9.5… Monitoring should be performed at locations posing the highest risk of contamination to the sterile equipment surfaces, container, closures and product. The selection of monitoring locations and the orientation and positioning of sampling devices should be justified and appropriate to obtain reliable data from the critical zones.Key takeaways from this are:
Annex 1, draft rev 12, Section 9.6Sampling methods should not pose a risk of contamination to the manufacturing operations.
Annex 1, draft rev 12, Section 9.7
- Full process monitoring
Where aseptic operations are performed, microbial monitoring should be frequent using a combination of methods such as settle plates, volumetric air sampling, glove, gown and surface sampling (e.g. swabs and contact plates). The method of sampling used should be justified within the CCS and should be demonstrated not to have a detrimental impact on Grade A and B airflow patterns.An emphasis here is that that occasional monitoring is no longer acceptable. Rather frequent (even continuous) monitoring should be considered in your Contamination Control Strategy (CCS). Also, there is no longer a standard method, rather various methods are available and should be considered in your CCS based on Quality Risk Management (QRM) principles and science. Finally, airflow patterns are called out as a key decision parameter.Section 9 goes on to specify that viable particle monitoring must include monitoring when normal operations are not happening, not just during regular operations. Also, that monitoring should not occur only in the cleanroom, but also in surrounding and associated areas to proactively manage the risk of potential incursions. Finally, when an incident occurs, extra sampling should be considered to ensure the CAPA solution was effective:
Annex 1, draft rev 12, Section 9.24
Viable particle monitoring should also be performed within the cleanrooms when normal manufacturing operations are not occurring (e.g. post disinfection, prior to start of manufacturing, on completion of the batch and after a shutdown period), and in associated rooms that have not been used, in order to detect potential incidents of contamination which may affect the controls within the cleanrooms. In case of an incident, additional sample locations may be used as a verification of the effectiveness of a corrective action (i.e. cleaning and disinfection) .
Annex 1, draft rev 12, Section 9.26
CONTINUOUS VIABLE AIR MONITORINGContinuing to section 9.27 where continuous viable air monitoring is highlighted:
Continuous viable air monitoring in the Grade A zone (e.g. air sampling or settle plates) should be undertaken for the full duration of critical processing, including equipment (aseptic set-up) assembly and filling operations. 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.In the past, “snapshot” 100 LPM monitoring was the norm – this is no longer acceptable. Rather, pharmaceutical manufacturers should find a continuous viable particle counting solution to effectively monitor critical processes.This approach does allow for settle plates, but I would argue that they are not the ideal solution for two main reasons:1. Settle plates are a measure of the surface contamination rate, not the quality of the air. There are a variety of factors that affect surface versus air contamination sampling including:
Annex 1, draft rev 12, Section 9.27
- Air speed
- Air flow patterns
- Adhesion to surfaces
- Particle size
SOLUTION: BIOCAPT® IMPACTORThe BioCapt® Single Use Microbial Impactor from Particle Measuring Systems can continuously sample up to two hours of viable air actively at 25 LPM, which provides you with more effective data than the “Snapshot” at 100 LPM.If you look at the entire manufacturing process, from preparation process through to cleaning and dismantling, continuous viable particle monitoring can be done. At 100 LPM, you only get a single snapshot, missing out on many excursions that are critical. Even increasing 100 LPM sampling 4x or at 50 LPM you will not truly cover the whole process (about 8 hours) . At 25 LPM, with multiple sampling locations, helps you get a much more complete picture of the process and what is going on regarding contamination so that you can quickly identify problematic occurrences and resolve them before they escalate:
Additionally, the BioCapt Single Use (BCSU) will decrease your overall quality costs with a high return on investment (ROI) because of reduced failures from settle plates that have false positive results. Also, it is very compatible with modern manufacturing requirements like testing and … It also has neutralizing capabilities for VHP and antibodies.Learn more about the BioCapt Single Use