OR WAIT null SECS
Any aseptic processing technology that allows intervention by gowned personnel during operation cannot be considered an advanced technology. Although a standardized definition of restricted access barrier systems has been developed, these systems fall well short of being classfied as advanced technologies.
For at least 20 years, the global parenteral industry has recognized that personnel are the dominant risk relative to microbial contamination in aseptically produced sterile products (1). The contamination source strength of the gowned aseptic processing operator has been estimated in several research studies. Concomitant with this awareness, we have witnessed a series of technological advances that have endeavored to mitigate this contamination risk. These advances can be roughly categorized as follows:
Each of these approaches provides some added measure of security to the process by increasing the degree of separation provided between personnel and the sterilized materials, components, and product contact surfaces required for the aseptic assembly of the sterile product from its individual elements.
Advanced versus conventional aseptic processing
To the extent that these approaches are effective, they can reduce contamination risk in aseptic processing. Designs that most effectively eliminate human-borne contamination have been identified as providing "advanced aseptic processing." The term advanced aseptic processing was perhaps first used at the USP Open Conference on Microbiology in May 2002 (2). During that conference, only two aseptic technologies were discussed under the heading of "advanced": isolators and blow–fill–seal. Over the intervening years, we have witnessed the term advanced aseptic processing come into ever wider use. Considering the goals of aseptic processing, that other technologies intended to meet the high expectations for sterile product manufacturing aseptically should emerge is unremarkable.
Several technical features distinguish advanced from conventional aseptic processing. We believe the following condition should be met for an aseptic processing technology to be considered advanced: no interventions should be conducted during aseptic operations by gowned employees. In other words, all interventions must be conducted using separative features such as isolator gloves or half-suits. Obviously, this condition also could be met if manned interventions of any type were not required—as can be the case in blow–fill–seal or gloveless isolators. The contamination potential from the human operator, even under the most ideal conditions, is such that the aseptic process may be compromised by even a single manipulation by gowned personnel in proximity to the sterile materials. At a minimum, the allowance of limited human interventions creates risk uncertainty that we believe is incompatible with the concept of advanced aseptic processing.
A historical perspective
A brief historical review of the environmental systems used for aseptic processing is useful to understand the genesis of today's processing technologies (see Figure 1).
Figure 1: Aseptic processing family tree.
Perhaps little known to many current practitioners is the previous use of gloveboxes for aseptic processing before the introduction of cleanroom technology. Clearly, the early practitioners of aseptic processing understood the risk from human-borne contamination and used physical separation between the operator and the so-called sterile field to provide greater control over microorganisms.
The emergence of the HEPA filter in the mid 1950s changed facility designs and operating practices dramatically. It was now possible to position equipment inside a room and, using gowned personnel, produce larger numbers of units with less human manipulation. This design has continued to evolve to the more advanced barrier designs we see today. Gloveboxes never became obsolete, but labor requirements, throughput limitations, decontamination constraints, and other factors limited their application in aseptic processing.
The cleanroom dominated the industry as the preferred choice for aseptic processing because it was amenable to high-speed filling, inclusion of processing equipment, and easy adaptation for various applications. Later designs included partial barriers to provide greater separation between operators and sterile materials.
In the early 1980s, isolation technology was reintroduced to the sterile-products industry as an alternative to cleanrooms. Many practitioners recognized it as an improvement in contamination control relative to even the most sophisticated cleanroom designs then available. Some in the industry were so enthusiastic as to claim that sterility assurance equivalent to terminal sterilization would be possible with this new technology. As with any new technology, its implementation took time, and missteps were made. Although some firms implementing isolation technology experienced difficulties, there were more successes than failures (3).
Frustrated perhaps by the difficulties they encountered with isolators—particularly relating to decontamination, leak testing, ergonomics, and flexibility of access—several firms endeavored to find a means to obviate the perceived inflexibility of isolators. Thus the restricted access barrier systems (RABS) concept was developed. RABS endeavor to provide the sterility assurance benefits of the isolator with fewer complications. At first, there was no standard definition for RABS and, as a result, there was no standardized minimum performance criterion. Fortunately, this shortcoming has been fully recognized, and a more standardized description of a RABS has been developed recently (4).
Chronologically, RABS emerged more or less as an offshoot of efforts to implement isolator technology in the mid-1990s. In our view, RABS were conceived not because of contamination-control shortcomings in isolators, but rather in hopes of solving validation and, perhaps most important, to allow more flexible access for repairing and adjusting equipment where necessary.
Shortcomings and perceived benefits of RABS
From the standpoint of contamination control, no claims have been made that the performance of RABS is superior to that of isolators, but rather that RABS may be easier to implement and more flexible in the manner in which it allows operator access. Of far greater importance is whether RABS represent an improvement relative to patient safety over earlier aseptic technologies.
Limitations and comparison with isolators. Clearly, RABS have the potential to improve contamination control over what might be termed limited access aseptic barriers, which have been used in cleanrooms for years. It is our opinion, however, that RABS that allow some open interventions by gowned operators fall well short of the ideal of advanced aseptic processing (see sidebar, "Advanced aseptic processing requirements").
Advanced aseptic processing requirements
Moreover, we believe RABS designs are less capable than isolators relative to their ability to exclude microorganisms for several reasons. First, isolators provide a measurable pressure differential between the enclosed environment and the operator. In contrast, RABS rely on air overspill to exclude contamination from the surrounding environment in which the aseptically gowned operator is located.
Second, isolators are subjected to a reproducible decontamination process (in some cases, this is a sterilization process) performed by a microprocessor-controlled system delivering a sporicidal agent in a consistent manner each time. The effectiveness of that process can be supported by the multiple-log kill of resistant microorganisms. Although it is true that RABS and the rooms surrounding them also can be reproducibly decontaminated by microprocessor-controlled equipment, this advantage is immediately lost if gowned operators are given free access to the critical zone at any time during production. Of course, should manual disinfection be required after such gowned interventions, comparable levels of control would be impossible to demonstrate. This treatment might be as effective as what is performed on the isolator from a chemical lethality perspective, but reliance on humans for execution makes it susceptible to occasional error or omission. Moreover, because this activity requires the operator to access the interior of RABS, there is always the contamination potential associated with any aseptic intervention.
Third, the product contact surfaces such as feeder bowls and stoppering equipment inside the isolator can be preinstalled and treated with a sporicidal agent with the isolator in the same process used to decontaminate the isolator. RABS designs allow these items to be sterilized remotely, transferred to the RABS, aseptically installed, and readied for operation. This represents a clear risk of microbial contamination that cannot be easily avoided.
Fourth, by the very nature of the RABS design, there may be areas of the installation that personnel cannot reach easily that require treatment. Consider for example a RABS installation with a large lyophilizer. The ability of the gowned operator to disinfect the interior of RABS adequately without physically entering the system is remote. This presents a potential microbial insult to RABS of such magnitude that a claim for this practice or design as being an advanced aseptic process cannot be easily supported.
Fifth, aseptic processing isolators operating under positive internal pressure are the preferred means for the filling of sterile cytotoxic products. RABS designs cannot be used for this type of product because the level of containment is minimal.
Finally, the suggestion that the doors to RABS can be opened for a major intervention, and then filling resumed after a "high-level disinfection" process seems tenuous at best. As noted previously, "high-level disinfection" by gowned personnel may not be truly reproducible nor without risk. Any intervention that requires the doors of the RABS to be opened is unacceptable within the context of advanced aseptic processing. We would have the same objection were this to occur in an isolator, but under those circumstances, no one would consider the system acceptable for continued use without a full decontamination comparable with the initial treatment.
Perceived advantages. Some perceived advantages of RABS designs have been identified as follows:
It is our strong belief that although RABS may be superior to manned cleanrooms, they cannot attain the certainty of performance demonstrated by present-day isolators. Perhaps the most appropriate application for RABS would be as retrofits to existing aseptic processing facilities. In this situation, the existing infrastructure of cleanrooms, corridors, and gowning rooms would remain largely unchanged, with RABS concepts applied solely to the filling lines. We remain highly skeptical relative to the utility of RABS in installations with large or multiple lyophilizers, given the access limitations they impose. These installations, however, while representing a potentially valuable contamination-control improvement over conventional cleanrooms, fall well short of advanced aseptic processing.
Ideal RABS for advanced aseptic processing
Improving RABS for advanced aseptic processing
We can define a RABS design that meets industry expectations for advanced aseptic processing (5). To realize that designation we believe the RABS design must possess specific attributes (see sidebar, "Ideal RABS for advanced aseptic processing"). To our knowledge, this type of design has not yet been used, but some operations have come very close to this ideal, and newer technologies may make it feasible. With this type of design, we would also impose the following additional requirements:
Future considerations for RABS implementation
If RABS are to become a useful technology in our industry, what will be required and what can we expect to occur? First, the fundamental characteristics of RABS for advanced aseptic operations as we have endeavored to define must be broadly accepted. Also, it is quite likely that the validation of RABS designs will be fairly similar to isolator validation.
As in all forms of aseptic processing, the elimination of interventions must be paramount. Advanced aseptic processing cannot exist when personnel have the ability to intervene at will. In addition, RABS designs probably offer the most direct and cost-effective route to upgrading existing aseptic facilities. Finally, elements of RABS may be an appropriate solution to some of the most common interventions in manned aseptic processing (e.g., component feed).
We doubt that any aseptic processing system, including RABS, which is tolerant of open-gowned aseptic interventions, will have a long shelf life based upon current and developing technology. We believe aseptic processing technology will continue to evolve toward the complete elimination of operator interventions of all kinds. In fact, gloveless isolators already exist and have been in use in some aseptic processing industries for about 10 years.
Therefore, technologies that are designed to allow easy intervention will lack staying power as machine automation and robotics replace operators. In our view, RABS' principal utility will be in the reduction of risk in existing facilities, but it will not be the technology of choice for new facilities. Of course, it is equally possible that separative enclosures such as isolators will suffer the fate of obsolescence as well. The authors have no technology preference regarding the elimination of human interventions and hence human contamination risk. Given the rapid advancement currently underway in flexible robotics, equipment self-diagnostics and self-correction, information technology, in-process control, and so forth, it is quite possible that human intervention can be eliminated by means other than barriers or separative enclosures such as isolators in the near future. In fact, systems that came very close to this ideal have been in operation since the late 1980s.
Validation of advanced aseptic processing is perceived to be substantially more difficult than conventional aseptic processing. Witness the claimed difficulties with isolation technology at some firms. A significant number of advanced aseptic processes, however, have been successfully validated. Risk- and science-based regulation should favor the systems that are best are reducing risk. Recently, FDA has sought to ease the validation requirements for advanced aseptic systems by reducing validation expectations where justified by risk management. We believe this is a great step forward. It seems logical to us that the greatest validation benefits should come to processes that truly eliminate human interventions and to those with the most capability for in-process control. We look forward to further definition from FDA so that industry has a clear understanding of what is possible in terms of reduced validation activity as a function of risk mitigation.
We believe that a definition for advanced aseptic processing much like that proposed at the USP Open Conference in 2002 is most appropriate. Thus, advanced aseptic processes are those that eliminate direct intervention by personnel. For RABS to be an appropriate technological solution, it must be very isolator-like. Systems that tolerate any form of direct intervention by gowned personnel are nothing more than highly evolved conventional cleanrooms with gowned personnel.
As validation requirements are based more on in-process control (e.g., process analytical technology), process knowledge, and risk mitigation, the more advanced aseptic technologies will be easier to validate than they are today. RABS may have their greatest utility in the reduction of risk in present-day manned cleanrooms. We can certainly envision RABS installations that are a quick and relatively low-cost solution to the minimization of human intervention risk in existing cleanroom operations. We are enthusiastic about the near- and midterm future of RABS in that capacity. We must, however, offer a cautionary note in the wake of the current enthusiasm for the RABS concept as an easier route to success in advanced aseptic processing. Here we believe RABS fall short. This does not mean that isolators as they've been designed and built during the past 10–15 years are the ultimate evolution of aseptic technologies—further improvements are desirable. Certainly, isolators have a great deal of further evolving to do and, as previously mentioned, may themselves be rendered obsolete by further developments in both processing equipment and drug delivery systems.
James P. Agalloco* is the president of Agalloco & Associates, PO Box 899, Belle Mead, NJ 08502, tel. 908.874.7558. James Akers is the president of Akers Kennedy and Associates.
*To whom all correspondence should be addressed.
1. J. Agalloco and B. Gordon, "Current Practices in the Use of Media Fills in the Validation of Aseptic Processing," J. Paren. Sci. Technol. 41 (4), 128–141 (1987).
2. Proceedings of USP Open Conference on Microbiology, 2002.
3. J. Lysford and M. Porter, "Barrier Isolation History and Trends," International Society for Pharmaceutical Engineering Washington Conference: Barrier Isolation Technology, June 2, 2004.
4. J. Lysford, "The ISPE RABS Definition: An Introduction," Pharm. Eng. 26 (10), 116,120 (2005).
5. J. Akers, J. Agalloco, and R. Madsen, "What is Advanced Aseptic Processing?" Pharm. Manufacturing 4 (2), 25–27 (2006).