For most of the last three decades, there has been a tacit understanding that one simply had to accept some level of contamination in any aseptic processing environment. The reasons for this begrudging acceptance are easily understood.
First, for most of those three decades gowned human operators have been an absolutely essential requirement in aseptic processing. Second, the very presence of personnel necessitates a human-scale clean room—one that allows people to conduct the work of moving components and supplies to points-of-use, set up equipment, and make the necessary (and risk-intensive) interventions that have been necessary to the conduct of aseptic processing. Third, although less significant than people working in close proximity to the process and product, human-scale clean rooms need points of entry and exit for personnel and also rely on manual disinfection of materials that may enter the aseptic operations area through airlocks of various design.
Although in the modern human-scale clean room these entry points are typically fastidiously designed and carefully controlled, they remain a secondary source of contamination and, while rather minor in comparison to human-borne contamination, can still cause contamination problems that are difficult to detect and can put product at risk.
Of course, as the years have progressed regulations for the aseptic production of pharmaceutical products labeled sterile have continued to tighten. A perusal of either the current FDA guidance regarding aseptic processing or Annex 1 of the EU GMP regulations clearly confirms that regulatory expectations are much higher than they were even a decade ago. The authors believe that this ongoing escalation in regulatory requirement for aseptic processing originates, at least in part, from the perceived need of the authorities to encourage firms to make the closest approach possible to an absolute proof of sterility. Certainly, while it is clear from a scientific perspective that an absolute proof of sterility will always elude us, it nevertheless seems unlikely that the regulatory trajectory of the last three decades will change.
That being said, the wise course in strategic planning for aseptic processing operations must include consideration of not only current but future regulatory requirements as well as product liability. Thus, it is prudent to consider not only contamination risk to the product, but also producer’s risk in the event that contamination issues that are difficult to detect and resolve should arise. It seems safe to suggest that a production system that has an exceedingly low likelihood of contamination risk in terms of media fill, sterility test or environmental monitoring would provide the greatest abatement of producer’s risk in terms of both compliance and increasingly legal liability.
Production Ease and Efficiency vs. Contamination Risk
In our experience, the strategic decision regarding the production environment for aseptic processing these days most commonly hinges on a trade-off between state-of-the-art contamination control and production ease and efficiency. Since at least the early 1990’s, it has been recognized that isolator technology affords contamination control advantages over conventional human-scale clean rooms. However, although there have been numerous examples of successful implementation of isolator technology, the perception among firms conservative in adopting this technology is that it was difficult to design, hard to validate, and could result in severe compromises in terms of operating efficiency.
Among the most prevalent concerns relating to efficiency have been difficulty in making adjustments to correct operational faults, ergonomic concerns, problems in supply and component movement into and out of the isolator. Additionally, there have been fears regarding cumbersome (and lengthy) changeover from one container size or configuration to another.
These issues ultimately led to some isolator systems actually being decommissioned, and restricted access barrier systems (RABS) being considered a means of achieving most of the contamination control isolators offer while retaining some, or perhaps even most, of the human-machine interface advantages of a clean room. RABS, though (unless it is the closed variety, which is operationally very much the same as an isolator), does not diminish contamination or producer’s risk as effectively as isolators. So-called open-door RABS certainly was the subject of considerable enthusiasm within industry a few short years ago. However, at present it is possible (perhaps likely) that this approach is best suited to the improvement of existing aseptic processes.
So, while nearly all new installed aseptic pharmaceutical production systems embody some form of what can be called separative technologies such as isolator technology, RABS or even some combination thereof; the selection of environmental technology continues to be a major, perhaps even the major, point of discussion and debate during the conceptual design phase of aseptic production projects.
A Relevant Case Study from Another Industry
A widely held view in the pharmaceutical industry is that the technologies employed in this industry sit at the pinnacle of aseptic processing. Certainly, the authors do not mean to suggest that the knowledge base and professional capability in the pharmaceutical industry is anything other than outstanding. However, based upon our experience, we believe that the pharmaceutical industry can learn from the directions taken by the aseptic beverage industry over the last 15 or so years.
In the beverage industry, there is no debate at the present time regarding aseptic manufacturing environments. All such environments are separative enclosures similar if not identical in all respects to what are known in pharmaceutical aseptic processing as isolators. Of course, since the regulations are different, some important differences exist, perhaps the most noteworthy of which is the use of turbulent air flow systems instead of unidirectional (“laminar”) airflow. However, air entering the enclosure is always filtered through HEPA or in some cases ULPA filters. As one would expect given this level of air filtration, there is no difference in contamination risk arising from the use of turbulent air flow rather than unidirectional flow.