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James P. Agalloco is the president of Agalloco & Associates, P.O. Box 899, Belle Mead, NJ 08502, tel. 908.874.7558, firstname.lastname@example.org. He is also a member of Pharmaceutical Technology’s editorial advisory board.
There are few, if any, valid reasons not to install an isolator in a new aseptic processing facility.
Aseptic processing is perhaps the most critical of all production activities performed within the healthcare industry (1, 2). The risks to patients are higher for aseptic processing than any other process in current use, and the technologies used for the aseptic production of sterile products are among the most complex and costly in the industry. Regulators worldwide recognize the importance of proper practices for aseptic processing and have established several guidance documents pertaining to its application (1, 3).
James P. Agalloco
Firms that produce aseptic products, pharmaceuticals, or medical devices have attempted to reduce the microbial contamination risk associated with their assembly by using individually sterilized materials and packaging in pristine environments. Beginning in the 1950s, firms relied for years almost completely on cleanroom technology in which critical activities were performed by gowned personnel.
As product sophistication and machine automation capabilities advanced, industry increased its use of machinery to produce many aseptically processed sterile products. Despite these advances, human presence in aseptic areas, though substantially reduced, has remained a constant. Although the aseptic fill rooms of the 1960s and 1970s may have used several operators per line, that number has often been reduced to one in newer installations using the most advanced equipment. This reduction was made with the knowledge that personnel have always been the single greatest source of microbial contamination in the aseptic process, and reducing their influence on the aseptic process presence should be a high priority.
One must only visit facilities using automation, blow–fill–seal or form–fill–seal, robotics, remote particle sensors, and other technologies to understand that patients who are administered aseptic products would be at greater risk had these advances not taken place during the past 20–30 years.
This article reviews the history of isolator implementation and address why the vast majority of these obstacles are either no longer meaningful, nonexistent, or were self imposed without good reason.
The advent of isolation technology
The current pinnacle of aseptic processing capability is isolation technology, in which personnel have been removed from the aseptic environment almost entirely. In the most advanced isolator installations, operators perform only a limited number of tasks, roughly equal in number to those required with an advanced filling system in a cleanroom. The isolator makes those tasks substantially safer because the gloves are hermetically sealed to the isolator wall. This barrier provides a degree of separation between the operator and the critical operating environment that is substantially more secure than is possible in a manned cleanroom containing aseptically gowned personnel.
Designs are on the drawing board to take this concept substantially further, using robotics and advanced equipment designs inside an isolator, thus eliminating the need for gloves. The introduction of these systems is some years away. In the interim, isolators are considered the best available technology for the production of aseptic products. This rationale was acknowledged by the US Food and Drug Administration in its 2004 aseptic processing guidance, and similar perspectives were advanced by leaders in the European and Japanese regulatory communities (in which the introduction of isolators for aseptic processing has progressed at a far greater rate than within the United States) (1, 3, 4).
It was first predicted nearly 15 years ago that isolators would make the conventional manned cleanroom obsolete (5, 6). At that same time, I identified 10 obstacles to isolator implementation that had to be overcome. These obstacles included:
The transition to isolation technology from manned aseptic processing was slower than anticipated. Consequently, nearly five years after my initial prediction, I added some additional items to my list of delaying influences (7). Between 1997 and 1998 these items were added:
It is now 2006, and although many technological advances (e.g., cell phones, satellite radio, DVDs, global positioning systems) have become commonplace throughout our global society, the pharmaceutical industry has been unconscionably slow in implementing a superior technology in one of its most critical areas. Industry should be cautious with new technologies but it should not essentially ignore them or worse yet, actively oppose them, as has been the case in far too many companies. We owe our patients sterile products with the least possible potential for contamination, within the limits of the available technology, especially when the technology also may be the most cost-effective one available.
Solving the problem
Some of the aforementioned issues can be dismissed rather easily. The suggestion that an exclusionary practice such as aseptic processing could prove equivalent sterility assurance and reliability to a destructive process is patently absurd. Newer advanced aseptic processing technologies such as robotics in isolators and closed-vial filling can come very close to the same levels of sterility assurance that are achieved by terminal sterilization, however they are still exclusionary and thus must be still considered to present more of a risk to the patient. This could never be possible and it led to extraordinary measures to demonstrate that an isolator could operate at an unrealistic level of perfection.* This belief led to interminable, self-created delays as firms endeavored to satisfy them. The user requirements specification (URS) derived from this inappropriate expectation led directly to several of the obstacles.
Plugging the leaks. Every closed system has leaks, no matter how sophisticated. Manned aseptic cleanrooms rely on continuous air over-spill to purge the facility of contamination. Moreover, leaks are perhaps of greatest relevance during isolator decontamination, and even then, they are a safety issue not a true aseptic concern. A defined leak rate established by safety requirements during decontamination is now considered acceptable (8).
Pressure management. The largest openings in most filling isolators are where containers enter and exit. Relatively simple pressure management allows these ports to be managed with ease.
Absolute sterilization. Attempts to validate the absolute sterility of an isolator interior that merely provides an operating environment led to lengthy (and unnecessarily harsh) decontamination cycles with no meaningful benefit. The cycles had the concomitant result of weakening gloves and other soft parts, increasing corrosion possibility, and delaying aeration of the enclosure. Inoculating every possible material in the isolator to establish the absence of a substrate effect is perhaps the worst example of URS excess. The isolator is intended to provide an environment for aseptic processing, not administering injections to patients. Isolator decontamination now is recognized as a practical solution before aseptic processing. Sterilization of product contact surfaces during the overall decontamination (or separately) is accomplished easily. With the reduction in process expectation has come a reduction in adverse effects on the exposed materials (9).
Proper humidification. Isolator decontamination difficulties are readily overcome by proper humidification of the system. Reports of failure and difficulties are largely associated with humidity conditions outside the effective range. It should be noted that spores are rapidly inactivated by liquid H2O2, and thus concerns about the adverse effects of too much humidity (e.g., condensation) are misguided. An unfortunate outgrowth of decontamination problems is the expectation that conditions in the gas phase may be measured and the results of the measurements can be used to confirm process efficacy. Success with these vapor analysis systems is inherently limited, because they cannot measure conditions on the surface in which lethality may be derived from condensed H2O2 (10, 11).
Aseptic technique. Gloves in isolators may be necessary for aseptic setup and interventions. The use of isolation technologies does not eliminate the need for aseptic techniques at all times. Direct contact of the gloves with sterile materials is inappropriate; tools must be used at all times. The effect of minor glove penetrations has been the subject of several recent studies. The consensus is that concerns relative to their integrity and their effect on asepsis are overstated. With proper equipment design and quality components, interventions of all types can be substantially reduced, which is a desirable objective in every aseptic operation. Isolators without gloves are now possible and will make any concern for glove integrity moot (8).
*Providing a level of confidence in aseptic processing using isolation technology equivalent to a terminal sterilization treatment of a sealed container will never be possible in the absolute sense. Nonetheless, with the elimination of interventions within an isolator through the use of automation and robotics, the differences in performance may be indistinguishable. What must be acknowledged is that the isolator doesn't need to be perfect to realize a comparable capability. The key requirement is that it be able to operate with minimal (and preferably no) human activity internally.
Higher class. In general, industry agrees that the classification of the surrounding environment has little effect on the ability to provide suitable conditions for aseptic processing within an isolator, whether open or closed. ISO 8 conditions have usually been adopted as the acceptable practice and, with restricted access, make an ideal environment for isolator placement.
Material-handling concerns. Equipment manufacturers have overcome many of the perceived component handling and material-transfer concerns. Some of these are overly complex, resulting in additional problems. But simpler designs have eliminated this concern.
Sophisticated suppliers. Marketplace demands have eliminated some of the less-capable isolator manufacturers, and the remaining suppliers have increased the sophistication of their designs and control systems. Materials for construction have been upgraded as well, and through licensing agreements, rapid transfer ports will sometimes be available for interoperable configuration.
Simplified designs. Isolator designs may be substantially simplified if the need for unidirectional airflow is eliminated. Currently, this process is necessary to purge the aseptic processing environment of viable and nonviable particles typically associated with gowned personnel, but by removing personnel from within the isolator environment, unidirectional airflow is no longer beneficial or necessary. In isolator systems in which unidirectional airflow is not present, no adverse effect occurs (9).
A new perspective. Globally, regulators have shifted their perspective from one of initial caution (an appropriate consequence of their relative novelty and the excessive claims of some early practitioners) to acknowledgment that isolators offer a more secure environment for aseptic processing than other available technologies (1, 3).
Time and money
From an overall technical perspective, it should be evident that success with isolation technology is an attainable reality. The perceived difficulties with its implementation have largely been overcome. At present, there exist only two remaining objections to its broader use: time and money. A rather important duo, but even these concerns aren't all that valid.
The time required for the implementation of any project is a direct result of the difficulties associated with its implementation. Isolators were badly served early on by some of their more vocal proponents. Expectations and public statements that isolators were going to replace terminal sterilization led to unattainable goals, frustrated users, extended timelines, and bad feelings at some firms. Isolator owners established more realistic goals or met them without substantial difficulty. Industry surveys have indicated that at least two major firms operate more than 20 aseptic processing isolators each (4). I participated in a smaller project in which the purchase decision for a custom system was made in mid-May and the firm performed successful media fills in December (12). Design, fabrication, qualification, decontamination-cycle development, and validation were completed without any delay or difficulty. Numerous other projects of larger scope have experienced similar success.
Increased initial costs for systems using isolation technology have been a cause for some concern. Cost may vary but is typically in the range of 30–70% above that of a manned cleanroom. The substantially lower costs of operation for isolator systems are undisputed. Savings accrue in utility consumption, gowning materials, labor use, decontamination, and environmental monitoring. Hard numbers on comparative costs of operation are difficult to generate. Nonetheless, the numbers of isolators installed, especially by those firms with numerous installations, suggests that the real economics are more favorable than the projections would suggest.
The aseptic processing isolator has truly arrived. The earlier concerns associated with the implementation of this technology have essentially disappeared, and there is every reason to believe that early predictions regarding the replacement of cleanrooms by isolators will be proven correct. Ensuring success with isolation technology requires a realistic user requirements specification and an environment open to novelty. Those reasons alone are sufficient to realize the advantages of this technology without the tribulations of people that asked for the impossible and then complained mightily when they could not realize it. Realizing the substantial improvement in patient safety requires the recognition that there exist few, if any, valid reasons not to install an isolator for a new aseptic processing facility.
James Agalloco is the president of Agalloco & Associates, PO Box 899, Belle Mead, NJ 08502, tel. 908.874.7558, email@example.com He is also a member of Pharmaceutical Technology's Editorial Advisory Board.
1. US Food and Drug Administration, Guidance for Industry. Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Processes (FDA, Rockville, MD, 2004).
2. J. Agalloco and J. Akers, "Risk Analysis for Aseptic Processing: The Akers–Agalloco Method," Pharm. Technol. 29 (11), 74–88 (2005).
3. PIC/S, "Recommendation–Isolators for Aseptic Processing and Sterility Testing" (Pharmaceutical Inspection Convention and Pharmaceutical Co-operation Scheme, Geneva, Switzerland, 2004).
4. J. Lysford and M. Porter, "Barrier Isolators History and Trends," Pharm. Eng. 23 (2), 58–64 (2003)
5. J. Agalloco, presentation to ITUG, December 1992.
6. J. Agalloco, "Opportunities and Obstacles in the Implementation of Barrier Technology," PDA Pharm. Sci. Technol. 49 (5), 244–248 (1995).
7. J. Agalloco, "PDA Course on Principles of Validation," 1997.
8. PDA, "Design and Validation of Isolator Systems for the Manufacturing and Testing of Health Care Products," PDA J. Pharm Sci. Technol., 55 (5) suppl. (2001).
9. J. Agalloco and J. Akers, "Risk and Science in Isolator Technology," PDA Newsletter 56 (9), 8–11 (2003).
10. D. Watling, J. Drinkwater, and B. Webb, "The Implication of Physical Properties of Mixtures of Hydrogen Peroxide and Water on the Sterilization Process," presented at the ISPE Symposium, Barrier Isolation Technology, Zurich, Switzerland, Sept. 23–24, 1998.
11. V. Sigwarth and C. Moirandat, "Development and Quantification of H2O2 Decontamination Cycles," PDA Pharm. Sci. Technol. 54 (4), 286–304 (2000).
12. J. Agalloco, personal communications, 2002.