Barrier/Isolation Systems Pressure Cleanrooms Industry
By Susan English
Rockville, MD–Last December, over 200 people attended a 2 1/2-day seminar on barrier isolation technology sponsored by the International Society of Pharmaceutical Engineers (ISPE). In addition to 12 case studies and numerous technology updates, a representative from the FDA`s CDER (Center for Drug Evaluation & Research) presented that organization`s position on the use of barrier isolators. The consensus–“1996 will be the year barrier/isolation technology comes into its own.”
Product cleanliness, operator safety, cost savings, the development of genetically created drugs, and escalating regulatory demands are all factors influencing the pharmaceutical industry`s shift away from the use of cleanrooms toward barriers and isolators. Barrier and isolation systems–terms which tend to be used interchangeably–offer some companies significant advantages over conventional cleanroom filling operations. Experts predict this will have a major impact on the cleanrooms market over the next five to fifteen years. Patrick Oles, vice president of U.S. operations (Westtown, NY) for the European-based firm, La Calhene, says the company has seen “tremendous growth” in demand over the last two or three years for its barrier/isolation systems. The company had sales of almost $10 million last year and with a steady growth rate of 30 to 40 percent per year.
Barrier/isolation technology provides for both advanced aseptic processing and process containment, with initial data indicating that barrier technology provides a higher level of sterility assurance than cleanrooms. Also, with the shift from chemically-based drug to gene therapies, and operator protection becoming more of a factor (with about 50 percent of new drugs falling into the “potent” classification), Jack Lysfjord, vice president of sales and marketing for TL Systems (Brooklyn Park, MN), says that separation of the operator from the actual filling line is going to be “imperative.” TL Systems manufactures the isolator-equipped mini-aseptic filling system (MAFS), which was incorporated into Eli Lilly`s unit, which he says, is close to receiving the FDA`s approval
Although the technology is not new, it has gained momentum because of rising costs and shrinking margins. According to a leading healthcare product supplier, when government-mandated cost levels “put the squeeze” on hospitals back in the early 80s, pharmaceutical companies began to feel its effects. As a result, about five years ago, a group of engineers from Eli Lilly (Indianapolis, IN), Pharmacia Upjohn (Kalamazoo, MI) and Merck (West Point, PA) formed a consortium that included TL Systems. The group`s task was to build a sterile filling system that could operate without requiring a Class 100 cleanroom. Merck is now in the process of receiving its barrier system, Lilly is installing its line at its Indianapolis facility, and Upjohn is expected to take delivery in early 1997. Other companies are expected to follow in short order.
Lilly is expected to be the first to obtain FDA validation for its barrier isolator–a fill line for veterinary products ranging from 50 to 500 ml using vapor-phase hydrogen peroxide as a sterilant. Significantly, the company is seeking approval to operate the line in a “controlled but unclassified” environment. If the FDA approves Lilly`s system, other companies will no doubt follow suit, potentially pushing out the envelope even further. According to senior engineer, Ken Weerts, one advantage of the technology is the dramatically higher air turnover rate inside the barrier. “Whereas cleanrooms might have air change rates of 40-60 air changes per hour,” says Weerts, “our barrier gives up to 400-600 per hour.”
Weerts conducted tests of typical pharmaceutical cleanroom facilities by calculating the percentage of the buildings dedicated to cleaning air and keeping it clean. In comparing a 200,000 ft2 facility to a barrier system, it was found that air handling costs could be cut by 40 to 60 percent and the footprint could be reduced by 25 to 40 percent. “A typical cleanroom might have between a 50 and 100 horsepower motor on it to supply air,” he says. “We have a 10 horsepower motor. Where a cleanroom might have dozens of HEPA filters, we have two.” Weerts sees controlled environments of the future corresponding more to ASHRAE guidelines than Federal Standard 209. Right now, Federal Standard 209 doesn`t define any classification levels beyond 100,000. But once one or two companies get FDA approval, says Weerts, “everyone will jump on the bandwagon. In fifteen years, the pharmaceutical industry won`t be building cleanrooms.”
Containment vs. contamination
Despite the appeal of barrier/isolation technology, many observers see a continuing need for cleanrooms in the pharmaceutical industry, although perhaps considerably fewer and scaled-down versions. Ken Dixon, president of Air Control, Inc. (Hendersonville, NC) points out that “in the pharmaceutical industry, it`s still a twofold issue–containment vs. sterilization. If you just want clean conditions for products, technologically, you can pull it off in a garage with softwall, modular and portable cleanrooms. But, if you also need containment–protection of people, then this (isolator technology) is something you just can`t jump into–you have to be sure. There can`t be any leaks.”
Pharmacia Upjohn`s Dave Mulder agrees. “The isolator I`m working in is negative pressure to maintain containment, but because of the possibility of a leak, I also have to be fully gowned up with a respirator, and the air around me must be Class 100 to prevent contamination. Therefore, I still need to operate it in a cleanroom environment.” Mulder cautions the industry not to develop a false sense of security and believe that an isolator is the ultimate barrier. “We don`t need isolators for everything,” he adds, “cleanrooms will still have a place in the industry.”
Baxter Healthcare`s Archie Woodworth says that with the removal of many of the controls inherent in cleanrooms, the HEPA filter will become an even more critical barrier. “If you have a redundant HEPA filter system, theoretically you can put an isolator in a warehouse, but generally, nobody wants to do that. The FDA`s only real regulatory issue in approving the first European barrier system was that the company monitor the environment. They said, `you don`t necessarily have to classify it, but we`d like to know that these filters are not overchallenged on a regular basis.` “
The FDA`s Ken Muhvich made his agency`s reservations clear at the December ISPE meeting, citing the following concerns: validation of barrier isolator filling lines in “unclassified, but controlled” areas; maintenance of sterility inside the barrier itself; barrier interface requirements; validation of the sterilizing method for the area/equipment inside the isolator; and the use of barrier isolator technology as a substitute for terminal moist heat sterilization. Says Muhvich, “Were I going to be making a sterile product, I wouldn`t want to be using the family garage for it. Some say they want to run operations in these uncontrolled environments, but what`s going to be the impact on the HEPA filters, how long will they hold up before they fail?” Muhvich suggests companies calculate their true cost benefit “when they`re using HEPA filters to beat the band and putting their product at risk instead of using a Class 100,000 facility.”
Others have reservations as well. They cite industry inertia to adopt new technology because of the new products/equipment redesign and process modifications involved. Austin McDonald, director of barrier technology at engineering and consulting firm, John Brown (Bridgewater, NJ), says the U.S. companies pursuing the technology are doing so because they are processing aseptic toxic entities or citotoxins, while European companies are more concerned with the cost benefits of replacing cleanrooms. For these reasons, he doesn`t see barrier/isolation technology pushing out cleanrooms in the near future. Instead of unilaterally installing isolators everywhere, he advocates a more incremental approach–a mixture of isolators, process technology improvements and SOPs. Rarely, he says, is it necessary to use isolators alone. “All too often, people are trying to sell technology to the pharmaceutical industry, but the industry doesn`t want technology (for technology`s sake). They want to make products better, faster, cheaper,” says McDonald.
A pivotal year
Even given the difficulties of adjusting to a new technology or new application, the transition could take place more quickly than some anticipate. La Calhene`s Oles already sees more and more people questioning the strategic benefit of going to cleanrooms. “When I go to conferences, I hear speakers saying that people who invest in cleanrooms technology today might wish, in five years, that they had gone to barrier technology instead.” On the other hand, John Brown`s McDonald qualifies his overall endorsement of barrier technology by pointing out that “the greatest benefit from isolators won`t be seen until people start developing the technologies to work with them. Currently, all the technologies are space oriented–towards cleanrooms–where operators can move freely around. The future will have to see a more integrated approach,” he says.
TL Systems` Lysfjord sums up the advocates` view. “I think this is going to be a turning point year, with Lilly`s pushing the envelope by seeking operation in a “clean manufacturing” surrounding room environment for their barrier isolator. This will allow the equipment to operate in the least costly environment, while providing improved sterility levels. And that`s what we`re trying to accomplish.” n