Anne Weeks- Senior Field Marketing Manager BioMonitoring, MilliporeSigma, Burlington, MA, An affiliate of Merck KGaA, Darmstadt, Germany; Adele Gisselmann- Global Product Manager, BioMonitoring Environmental Monitoring, Merck KGaA, Darmstadt, Germany.
Both PDA TR 90 and the European Union’s recently revised GMP Annex 1 require manufacturers of sterile pharmaceuticals to implement and document a holistic contamination control strategy (CCS) that covers the entire manufacturing chain across the facility. Within this CCS, the environmental monitoring program is an important basic part. Where aseptic operations take place, monitoring according to part 9 of Annex 1 should be frequent, using a combination of methods such as settle plates, volumetric air sampling as well as glove, gown and surface sampling with contact plates or swabs. The sampling plan parameters to consider should be based on a risk assessment and include the locations, number and frequency of samples to take, the sampling methods and practices (including incubation conditions) and the limits to set, including alert levels. Annex 1, although an EU regulation, also affects manufacturers elsewhere insofar as their exports to the EU are concerned, so it’s worth taking a closer look at some of its changes.
Low-risk transfer of instrumentation
Moving equipment and materials is known to be a contamination risk in manufacturing. Annex 1 part 4.10 requires this risk of to be assessed, while part 4.15 calls for airflow patterns to be visualized to demonstrate there is no ingress from lower to higher grade areas. This is particularly important when using active microbial air samplers. For isolators, stationary systems specially adapted to this environment, like the MAS-100 Iso NT® sampler, are always preferable. If not an option, any sampler moved into a Grade A area should be easy to clean and disinfect and offer the option to have a HEPA filter mounted to its air outlet that retains almost all particles sized over 0.3 µm. This filter should have no significant influence on the airflow calibration and the microbial sampling efficiency.
A microbial air sampler’s basic design matters too. Specific blower units with a brushless motor, like the MAS-100 NT® sampler uses, keep particle generation well below the Grade A limits. Validation documentation to demonstrate an instrument’s suitability for controlled environments should be available from its manufacturer.
Physical separation to prevent contamination
Also relating to the transfer of equipment, Annex 1 part 4.12 states that all airlocks should be designed and used in a way that ensures physical separation and minimizes microbial and particle contamination between areas. The final stage of an airlock must, in the “at rest” state, be of the same cleanliness grade as the area to which it gives access. Annex 1 part 4.18 suggests that the entry of materials into isolators or RABS during processing (and after decontamination) be minimized and preferably supported by rapid transfer technologies or transfer isolators. Space in isolators is usually very limited, so using its 190 mm alpha port to attach a transfer bag that contains a stock of contact and settle plates is proving popular. This space-saving storage concept can reduce the number of decontamination cycles and prolong production times. A single gamma-irradiated IsoBag® DPTE BetaBag®, for example, can safely hold up to 80 ready-to-use plates for air and personnel monitoring, allowing plate transfer through multiple connections. Triple-packed plates are the ideal choice to maintain aseptic conditions in Grade A (ISO 5) cleanrooms and isolators. This allows the outermost bag to be removed on advancing into the next higher-class area.
Some measures to avoid false results
Certain practices, while not risking contamination of the critical environment, may cause false positive test results. The immediate consequences for the manufacturer are much the same: an often lengthy and costly investigation into the root cause must be launched. Contamination can occur if, for example, plates open while being transferred for incubation between the sampling area and the lab. Lockable plates (e.g. of the ICRplus range) help ensure that the lids stay safely in place.
Agar contact plates, however, are impractical for microbial testing of irregular surfaces such as equipment recesses, nooks, crevices, tubing and filling needles. Swabs that deliver a yes/no result are better suitable here. To minimize false positive results, unnecessary handling steps before and after sampling should be avoided. This is achieved by using a swab assembly that carries its own sterile growth medium and therefore has to be opened only once, like the ICR-Swab. Its medium comes into contact with the pre-moistened swab tip only after the system has been closed again.
Generally speaking, part 9.29 of the new Annex 1 calls for sampling methods and equipment to be fully understood and procedures put in place for correct operation and interpretation of results. The manufacturer of the culture media should be able to supply detailed validation data and application notes to help build the required documentation, for example on the efficiency of the media to neutralize sanitizers, the impact of air sampling on recovery, and recovery rates of dried versus fresh plates to determine the effects of water loss.
Take a closer look at our complete range of instruments, culture media and other consumables for compliant environmental monitoring in the pharmaceutical industry.
sigmaaldrich.com/environmentalmonitoring
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