What the revisions to ISO 14644 may mean to your cleanroom

EU GMP and the FDA’s cGMP set the target cleanliness levels for non-viable particles in pharmaceutical cleanrooms. Both documents refer the reader to ISO 14644 for the methods to determine these cleanliness levels.

ISO 14644 is currently under revision and the ISO Technical Committee has assigned a Working Group to make recommendations as to how the inappropriate statistical analysis tools in the current document can be improved. In addition to this focus, the new ISO 14644 will direct users to use the already existing but little-known standard for calibration and verification of air particle counters, ISO 21501-4.

CLEANROOM CONTAMINATION
For decades, in an attempt to improve drug quality and protect patients’ lives, the non-viable particle cleanliness levels in pharmaceutical cleanrooms has been closely measured and monitored. In parallel the viable microbial contamination levels have also been closely measured and monitored through the use of settle plates and the subsequent detection of colony forming units.

The main risk to patients’ safety is widely considered to be viable particles, i.e. microbes that are capable of replication. The presence of one microbe may not be a threat in itself to a patient’s immune system, but a viable microbe will of course multiply in the right conditions and form a colony of microbes, potentially leading to infection and sickness in the patients who receive the infected drug dose.

Measuring and reporting viable particles provides its own challenges, not the least of which is the delay between the time the viable particle is collected on the settle plates and the time when a decision can be made as to whether there are colony forming units present or not. Different species of microbes favor different environmental conditions for growth and replication. Some species favor a low temperature environment; some prefer a higher temperature to stimulate growth. Even the acidity of the environment can have an effect and samples that are incubated and declared clear of viable particles can later be found to contain microbes that flourish when exposed to a change in pH.

One common factor that affects all microbes is the presence of water. Without water, microbes will not flourish and this gives an added challenge to the collection and incubation of microbes, i.e. the nutrient in settle plates tends to dry out when it is exposed in the cleanroom and this can be a particular issue for active air samplers where the settle plate is exposed to a forced stream of drying air.