. Aseptic processing performance certainly has improved over the years, yet at the same time, the pharmaceutical industry
has accepted its limitations. The operator is still allowed to interact with materials using a flexible glove system to perform
many tasks as outlined below:
Set-up: Very few pieces of aseptic processing equipment, regardless of the background environmental technology, are able to begin
operation at the push of a button. An operator is typically required to adjust fill weights, conveyor rails, and closure-feed
systems before the process can begin.
Operation: The operator serves as a support to the equipment by clearing jams, wiping up spills, replenishing components, and other supportive
activities during the process.
Monitoring: Operators take environmental and product samples, check and adjust fill weights, and generally oversee the process.
Each of these activities requires some intervention with the sterilized equipment and components. The pharmaceutical industry
has become largely tolerant of interventions. The current practice is to ensure routine (process-inherent) and nonroutine
(process-corrective) interventions are closely aligned between routine operation and aseptic process simulation. This situation
may seem reasonable in the interim; however, it is wholly unsatisfactory in the long term. The pharmaceutical industry's tendency
to believe that gowned people can work in sterile environments often leads it to misidentify risks. HEPA-filtered air, for
example, recently was advanced as a source of contamination as significant as personnel, which is not only absolutely wrong,
but essentially precludes aseptic processing in its entirety.
. In developing our recent position on aseptic processing risk assessment, we were influenced by things we learned from experienced
professionals when we began working in this industry at the dawn of the validation era. The simple message we learned is that
people spread contamination, and that all interventions are risky. The following quote from Hank Avallone, a former US Food
and Drug Administration inspector and long-time industry authority dates to 1988:
It is useful to assume that the operator is always contaminated while operating in the aseptic area. If the procedures are
viewed from this perspective, those practices which are exposing the product to contamination are more easily identified (5).
It is universally acknowledged that personnel are the source of microbial contamination in cleanrooms (1). Our concerns for the capability of RABS and isolators center on glove
sterility and integrity because the failure of glove sterility and integrity is the greatest weakness of these very capable
systems. A recent communication highlighted the limitations of a variety of glove-integrity test methods and ultimately acknowledged
that glove integrity cannot be ensured by any current means. This effort focused on gloves for RABS and isolators, and these
gloves are substantially more robust than those relied upon in cleanroom operations (6). The integrity of aseptic gowning
systems is superior in every way to what existed 40 years ago, but it is still orders of magnitude away from what is necessary
to consider aseptically gowned operators as anything close to sterile.
A simple solution to further improve aseptic processing is to accept that the operator must play a diminishing role in aseptic
operations. The basic tenets are quite simple (7):
- Interventions are to be avoided at all times in aseptic processing.
- Interventions always mean increased risk to the patient.
- There is no truly safe intervention.
- The perfect intervention is the one that does not happen.
Improving aseptic processing along these lines requires changes in several areas. Some opportunities include:
Environment: isolators and barrier systems that reduce the impact of interventions;
Equipment: remote adjustment, tool-less set-up, and steam-in-place capable designs;
Components: tightened acceptance quality levels and validated preparation processes that eliminate jams;
Personnel: robotics and improved gown- and glove-systems;
Process: use sterilized assemblies and sample intelligently to avoid interventions.