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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.
Aseptic processing is widely used for preparing sterile products. Although regulatory authorities and industry experts emphasize the sterility-assurance advantages of terminal sterilization, the fact remains that most products being introduced today must be manufactured aseptically (1). Implicit in aseptic processing is the notion that items are first sterilized and then processed under aseptic conditions into the final product. More often than not, that assembly involves the labor of one or more appropriately gowned individuals in a pristine environment. The operators' typical activities will include the set-up, filling or assembly process, and environment monitoring of the processing area.
The evolution of aseptic processing
During the past 50 years, aseptic processing has evolved. Before the advent of the high-efficiency particulate air (HEPA) filter and cleanroom, aseptic processing was performed by operators working in gloveboxes that separated them from the sterilized materials. This approach afforded a degree of isolation between the operator and the sterilized items they were charged with handling and assembling, which helped ensure the sterility (or perhaps more accurately the safety) of the final product.
In the mid-1950s, HEPA filters became available to industry and were quickly adopted to provide large areas in which equipment could perform the majority of the aseptic processing activities. The operators, now garbed in sterilized garments, were still present to initially set up the equipment, perform any needed equipment adjustments, address component malfunctions, and collect environmental samples. Over the years, many improvements to cleanroom operations occurred. Equipment reliability improved, and air changes were increased. Sterilization processes were validated, and gowning materials became more comfortable and robust. And barriers were introduced.
Restricted access barrier systems. The most evolved cleanroom-based designs today are restricted access barrier systems (RABS) in which operator access to the aseptic environment is severely limited (2). RABS and all of the prior technological advances in aseptic processing were implemented because there was a clear understanding that personnel were the only significant source of microbial contamination in conventional cleanroom aseptic processing.
Isolators. Some 20 years ago, before the advent of RABS technology, the original gloveboxes of aseptic processing antiquity were reincarnated as isolators. Isolators were a substantial improvement over gloveboxes. The isolators were supplied with HEPA-filtered air that enabled these enclosures to be maintained at a positive pressure relative to the surrounding environment, mitigating issues with leaks and with finished-product out-feed isolators. The isolators could be reproducibly decontaminated and could be connected to other isolators and process equipment in a way that maintained separation between the internal environment and operating personnel (3, 4). These advancements were a technological breakthrough of substantial magnitude, and some two decades after their introduction, isolators continue to represent the pinnacle of aseptic processing technology.
Aseptic processing today
Although that might be the end of an interesting story, present-day operations use all of these aseptic technologies, and new cleanrooms for aseptic processing still are in the planning stages. All present-day aseptic processing systems require to some extent the direct participation of operators with sterilized materials just as they always have. Using the word sterilized rather than sterile is not a compliance hedge. It is the recognition that once any material is placed in a manned cleanroom and handled by personnel, it legitimately cannot be considered sterile no matter how much overkill was applied in its validation. Cleanroom operators use utensils in their gloved hands, and RABS and isolator operators use the equipment's gloves in much the same manner. There are truly refined aseptic processing concepts available that perform without operators. As with any new technology in the extremely conservative pharmaceutical industry, however, the implementation of these concepts, although certainly desirable, is by no means imminent and is unlikely to be universal for many years. (It should be noted that high levels of automation already are widely used in other clean and aseptic industries). Although we hope that in two decades aseptic processing in the pharmaceutical industry will have taken advantage of the numerous technological advancements that are available even today, their adoption is by no means a sure thing.
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:
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):
Improving aseptic processing along these lines requires changes in several areas. Some opportunities include:
An obvious but simple truth and perhaps the most critical truth of all is that the absence of microorganisms in any aseptic environment can never be proven. In isolators, we rarely detect microorganisms, but in cleanrooms, we rarely go more than a few days without recovering organisms despite sampling methods that have a rather poor limit of detection. The most painful truth of all, therefore, is that manned cleanrooms were never sterile, are not sterile now, and never will be sterile. We suspect it is rather obvious what that means about sterile products made in these facilities. Make no mistake; we think that by and large products made in the best manned cleanrooms are safe, maybe even safe enough. Cleanrooms that are less than the best, however, are a very different matter altogether. One last truth: There are better technologies available for aseptic processing than conventional manned cleanrooms, and we should be using those technologies. Unless we do, the truth is we will never reach the goal of having operators playing a diminishing role in aseptic operations.
James P. Agalloco* is the president of Agalloco & Associates, PO Box 899, Belle Mead, NJ 08502, tel. 908.874.7558, firstname.lastname@example.org He also is a member of Pharmaceutical Technology's Editorial Advisory Board. James E. Akers is the president of Akers Kennedy & Associates, PO Box 22562, Kansas City, MO 64113, email@example.com
*To whom all correspondence should be addressed.
Key words: aseptic processing, cleanrooms, isolators, operators, RABS, sterile.
1. PDA, "Current Practices in the Validation of Aseptic Processing–2001," PDA Technical Report 36, PDA J. Pharm. Sci. Technol. 56 (3) (2002).
2. ISPE, "Restricted Access Barrier Systems (RABS) for Aseptic Processing Definition," Aug. 16, 2005.
3. PDA, "Process Simulation Testing for Sterile Bulk Pharmaceutical Chemicals," Technical Report 28, PDA J. Pharm. Sci. Technol. 60 (s-2) suppl. (2006).
4. PDA, "Design and Validation of Isolator Systems for the Manufacturing and Testing of Health Care Products," Technical Report 34, PDA J. Pharm. Sci. Technol. 55 (5) suppl. (2001).
5. H. Avallone, "Current Regulatory Issues Regarding Parenteral Inspections," J. Parenteral Sci. Technol. 43 (1), 3–7 (1989).
6. V. Sigwarth, A. Gessler, and A. Stark, "Relevance of Physical Glove Integrity Testing to Microbial Contamination of Isolator Systems," presented at ISPE meeting, Prague, Czech Republic, 2005.
7. J. Agalloco and J. Akers, "Simplified Risk Analysis for Aseptic Processing: The Akers-Agalloco Method," Pharm. Technol. 30 (7), 60–76 (2006).