The Truth about Interventions In Aseptic Processing - Pharmaceutical Technology

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The Truth about Interventions In Aseptic Processing
Aseptic processing has advanced over the past several decades, yet the pharmaceutical industry is still accepting of its limitations, particularly as it relates to human intervention as a source of contamination. The authors explain the importance of further diminishing the role of operators in aseptic processing and the approaches and technologies needed to achieve that goal.

Pharmaceutical Technology

Performance . 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.

Human intervention . 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.


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