Tech Visor

Rationale for clean rooms

Finding a rationale for cleanrooms seems to be a catch 22 situation at every stage. Monisha Narke, Director Klenzaids GMP Academy advises that one way of avoiding the irrational tech-trap is to focus on operator protection and protection of the proximity ambient

Monisha Narke

As intravenous therapy becomes increasingly complex, potent recombinant therapeutics are being favoured. The chance of lapses in manufacturing, preparation or administration naturally increases, with a consequent risk of adverse effects to patients. Can that be adequate rationale for falling into the irrational tech-trap? When technology is overridden by technicality? When are originality and creativeness sacrificed on the altar of technique and doctrinaire conformance?

Disregarding application needs, in accordance with regulations, separate or defined areas of operation in an aseptic processing facility should be appropriately controlled to attain different degrees of air quality. These clean rooms must satisfy microbiological and particle criteria as predicated by the equipment, components, and products exposed, as well as the operational activities conducted in the area.

The cleanroom itself is presumed to be a contamination vector. That's what the US Food and Drug Administration (FDA) focuses on, which is why specifications are becoming more stringent. That is the weirdest part of the state-of-the-art, which never reflect the actual application requirement, which today must be operator protection and protection of the proximity ambient.

Instead, cleanroom control parameters are supported by microbiological and particle data obtained during qualification studies. Also initial cleanroom qualification includes, in part, an assessment of air quality under as-built, static conditions.

For operator protection, it is important for area qualification and classification to place most emphasis on data generated under dynamic conditions ie. with personnel present, equipment in place, and operations ongoing. An adequate aseptic processing facility monitoring programme also will assess conformance with specified clean area classifications under dynamic conditions on a routine basis.

There are basic differences between the production of sterile drug products using aseptic processing and production using terminal sterilisation, which is not only preferred by FDA but also virtually enforced.

Terminal sterilisation usually involves filling and sealing product containers under high-quality environmental conditions. Products are filled and sealed in this type of environment to minimise the microbial and particulate content of the in-process product and to help ensure that the subsequent sterilisation process is successful. In most cases, the product, container, and closure have low bio-burden, but they are not sterile. The product in its final container is then subjected to a sterilisation process such as heat or irradiation.

In an aseptic process, the drug product, container, and closure are first subjected to sterilisation methods separately, as appropriate, and then brought together. Because there is no process to sterilise the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment of a cleanroom.

Aseptic processing involves more variables than terminal sterilisation. Before aseptic assembly into a final product, the individual parts of the final product are generally subjected to various sterilisation processes. For example, glass containers are subjected to dry heat; rubber closures are subjected to moist heat; and liquid dosage forms are subjected to filtration.

Any manual or mechanical manipulation of the sterilised drug, components, containers, or closures prior to or during aseptic assembly poses a bio-hazard to operators and the proximate ambient and thus necessitates careful review of random exposure, besides regulatory cleanroom specifications.