Greater experience spells shorter time to commercial production. Turnkey isolators can now be validated within 18 months of delivery.
Jenevieve Blair Polin, Contributing Editor
STERILITY ASSURANCE AND COST SAVINGS
The greatest lure of isolator technology is the promise of greater sterility assurance. "Trying to save money was not part of our criteria," stresses Greg Zimmerman, a process engineer for Eli Lilly & Co. (Indianapolis). "We were looking for improved sterility assurance, getting the operator further away from the product path or critical zone."
John Barnes, manager of engineering for filling and packaging at Aventis Pasteur (Swiftwater, PA), also cites greater sterility assurance as the primary draw of isolators. "We sterilize the inside of our isolator such that our alert limit at most sites would be one colony forming unit, and we rarely get any hits. So we know that the inside of that isolator is ultraclean," he says. "Some of our products do not get sterile filtered from the bulk tank to the line, so having them in the cleanest possible environment for filling is a real plus."
"FDA looks for sound aseptic processing line design as well as maintenance and control procedures to support the design," stresses Richard Friedman, compliance officer for FDA's Center for Drug Evaluation and Research (CDER). "As long as the line is designed in a manner to prevent contamination and it's meeting CGMPs, a company doesn't necessarily have to use an isolator in order to attain the required level of sterility assurance." Traditional cleanrooms, however, are notoriously expensive to operate and hard to control. Product recalls for lack of sterility have increased. Many large pharmaceutical companies that have received warning letters from FDA regarding their traditional aseptic processing lines are making the transition to barrier isolators.
While the initial cost of a barrier isolation system is greater than that of a filling line without the isolator, operating costs are less. With greater sterility assurance, less product is wasted because of contamination. The possibility of a product recall because of lack of sterility is a cost that must be factored in for traditional cleanrooms. The overall footprint of the aseptic processing area is reduced, gowning is reduced or eliminated, the volume of air to be handled by HVAC systems is reduced, and, where appropriate, room classifications may be lowered.
Adds FDA's Friedman: "Instead of having to dismantle the line, sterilize, and aseptically assemble, firms are now able to do multiple-day campaigns, which offer another tremendous cost savings. The findings of industry when they talk about the economic benefits are that they are able to increase throughput and that they're making money on the isolator not long after they've installed and begun to run it."
Aventis Pasteur hopes to reap such additional cost savings from operational improvements. "We have plans for next year to validate the isolator to run as many as three or four days in a row without resterilization. When we get to that point, we'll start to see additional real economic advantages," Barnes predicts.
Some have proposed that having the highly automated equipment inside the isolator do more of the tasks requires fewer highly skilled personnel. "I don't agree with that," argues Jack P. Lysfjord, vice president, technology, Bosch Packaging Technology (Minneapolis). "I think the industry has downsized to the point where they are barely able to keep up with today's technology and current cleanrooms. If you throw in the complexity of a system that has its own clean environment, sterilization system, control systems, automation machinery, and microbiology requirements, as well as maintenance and general business operations, it's a more complex challenge for those who manage that operation. Maybe the actual operators themselves don't have to be as highly skilled, but they have to have some knowledge of microbiology, maybe more than what they had as a cleanroom operator."
"It's difficult to get and keep really qualified operators," says Aventis's Barnes. "One of the drawbacks to a system like that is that there are a lot of things that you can do procedurally that may cause you to lose the batch, lose sterility on either the bulk or the isolator, and throw you back hours or even a day or so. So we've worked hard to build and maintain a good, consistent crew."
BIOLOGICAL PRODUCTS
With many vaccines currently in development or in production—such as those for HIV, hepatitis C, and smallpox—protecting operators is a big concern. "These vaccines can be very dangerous to the operator," points out Oliver Bausch, vice president of Bausch + Stroebel Machine Company, Inc. (Clinton, CT). "The isolator provides greater safeguards than a conventional cleanroom."
Some unit-dose packages present an additional source of risk to operators. "We see a lot of manufacturers going toward disposable syringes, which they can market as ready-to-use products. The needle in the syringe adds an additional source of risk," Bausch says. Risk can be better controlled with isolators that provide greater separation of people and product.
The sensitivity of vaccines also makes isolators particularly invaluable. "It is more and more often the requirement to have low residual-oxygen levels within the product, or within the container together with the product," says Bausch. "With isolators, this can be better controlled, up to a level where you run the whole isolator with a nitrogen atmosphere."
Aventis Pasteur is filling 90% of its flu vaccine on an isolator line this year. Theirs is a MAFS (Mini Aseptic Filling System) unit from Bosch, running 225 to 250 10-dose vials a minute.
"There's pretty much a mandate to get the preservative out of all vaccines," Barnes adds. "Once the preservative is gone, it will be even more of an advantage to manufacture the vaccine in such an ultraclean environment."
VALIDATION
One hesitation some pharmaceu-tical manufacturers have regarding use of isolators is the fear of the seemingly never-ending validation process. Barnes says engineers at a major U.S.-based pharmaceutical manufacturer recently told him they have an isolator line that took five years to validate and never did go into commercial production. This fear of prolonged validation, however, may be based more on the experience of these hardy pioneers in this technology than on current capabilities.
Validation streamlined. "At the beginning of isolator technology, people were doing a lot of environmental monitoring," points out Patrice Cloué, director of corporate technology, La Calhène (Rush City, MN). "The trend now is to do less because it was getting very difficult to validate and now people focus on the essential. There were some data that were redundant and disturbing the validation." Particle content or air velocity, for example, he adds, are measured at one point instead of at several points within the isolator now. La Calhène provides not only isolators with integrated HVAC systems and transfer systems for getting components into the isolator, but also an extensive line of monitoring equipment.
Timeline Shortening. While early models required time-consuming custom engineering, today standardized commercial production models, such as Bosch's MAFS unit, are available for vial filling. Bosch manufactures the complete MAFS unit: the isolator, the filling system, and the air-handling units, and it has recently launched the next-generation FLM system. "That gives customers some economies of scale," Lysfjord explains. "They're working with fewer vendors, and we offer more-predictable delivery and shorter lead times." Lysfjord estimates time from order date to delivery for a MAFS unit is now at 12 months and startup through validation is at 18 months, which rivals that for traditional cleanroom-based aseptic filling installations.
"This is a very encouraging piece of information to hear, because really the lone drawback has now been essentially eliminated," Friedman says. "Isolators are getting approved; it's as simple as that. And the reason they're getting approved is because they're generally very good systems, and we've been seeing excellent results. FDA also works with these firms carefully to resolve any issues that occasionally come up in a preapproval inspection, and approval has followed rapidly thereafter."
Barnes suggests that newcomers to isolator technology consider hiring a validation group, such as Advanced Barrier Concepts. These veterans, he says, will "help with design, certainly help with validation. They'll hold your hand through the whole process."
Guidance Still Lacking. Much of the murkiness about validation requirements would be eliminated if the long-awaited revision of the aseptic processing guidelines—last revised in 1987, when barrier isolation was in its infancy—were finally made public. "At the end of September we posted a preliminary concept paper to the Internet that has all the technical commentary as a preview," FDA's Friedman says. "Following an advisory committee meeting, we will soon issue a formal guidance for public comment." (See www.fda.gov/cder/dmpq/ for more information.)
CUSTOMIZATION
Like Bosch has done with the MAFS unit, Bausch + Stroebel has also streamlined its process by standardization. Its FFV 6024/8024 vial-filling machine with a linear, continuous-motion feed interfaces with an isolator Model RRI (manufactured by Metal and Plastique, Staringen, Germany). "If the customer starts with a new facility," Bausch explains, "we can propose an ideal layout with minimal customization for a vial-filling line." If the equipment must fit into an existing facility, the vendors will customize it and make the work flow in the required direction.
The issue of component entry is key to isolator success. "Figuring out how to get things in and out of the isolator is one of the biggest challenges," Zimmerman says. Lilly uses a Getinge stopper processing system that interfaces with an RTP (Rapid Transfer Port) system. The stoppers are loaded into the system, where they can be washed, siliconized, sterilized, and dried. The system then docks with the isolator itself. This custom-engineered system was the progenitor of a similar system that is now commercially available.
The experience of B. Braun (Irvine, CA) demonstrates that it is possible to validate an isolator line and successfully launch commercial production of one of the greatest challenges: a novel drug-delivery system that is difficult to package, containing incompatible components that must be kept separate. The Duplex drug delivery system is a two-chambered bag. One chamber containing powdered antibiotic is separated by a peelable seal from the other chamber, which contains the liquid diluent that will be used for reconstitution. (See "Alternatives to PVC for IV Bags," PMP News, April 2002, for more details on this bag.) In this drug delivery system, B. Braun currently offers cefazolin and plans ultimately to offer a range of cephalosporins. These drugs are unstable as liquids at room temperature.
Manmohan Sihra, director of technical services for B. Braun, describes these challenges. "Knowing how difficult it is to automate a flexible container, I was better prepared to face the challenge of automation of this technology," he says. "And automation is the key to success with isolation technology. We had to develop the technology from scratch to engineer not only the empty container but also the isolators. You can well imagine the problems with the sensitivity of the powder. You can't have moisture with the powder, which is a highly moisture-sensitive drug. We have been able by design to accomplish all those things: to maintain a very-low-moisture atmosphere for powder filling and to immediately fill the liquid next to it in a series of isolators. We have developed automation to handle this flexible container through this series of isolators to do these operations." B. Braun uses an isolator made by Bioquell (Andover, UK) with filling equipment from IMA (Bologna, Italy).
FUTURE GROWTH
Another area of increasing demand and interest is isolation systems for aseptic potent filling applications that generally involve integrated freeze dryers as well, says Bill Friedheim, technical sales representative, Carlisle Life Sciences (New Lisbon, WI). "Due to the potency of new products in pharmaceutical development for fill/finishing, it is now absolutely essential to use isolators for containment (protection of operators) while still ensuring increased sterility assurance levels," says Friedheim.
"Furthermore, most new systems have been requiring the ability to fill and transfer vials to freeze dryers in an inert, low oxygen level atmosphere (as low as 0.25% oxygen). This requirement, along with solvent filling, leaves customers little choice other than isolation technology."
Many in the industry predict that isolators will one day be the norm for aseptic pharmaceutical filling. "One major U.S.-based pharmaceutical company has essentially mandated that any and all new filling systems that it builds and installs are going to be in isolators," says Aventis's Barnes. "That's its interpretation of where FDA is going with all this. The company feels that once the environmental data start rolling in on how clean the process of filling in isolators is, eventually FDA is going to expect isolators."
Still, despite pressures for greater sterility assurance, there appears to be a dampened demand for barrier isolator systems. Lysfjord, together with Michael Porter from Merck, has surveyed vendors and users of barrier isolators every other year since 1998. The results of this latest survey, which will be published in an upcoming issue of Pharmaceutical Engineering, show a definite downturn. Lysfjord speculates this may have to do with scarce personnel resources. "People are realizing that it takes maybe more time and energy to validate systems that are more complex, which an isolator is. And, with the issues that they're having with FDA warning letters, they're tucking their horns in on technology. They don't have resources to devote to that."
"I personally think this downturn is only a temporary reaction following the big first initial push for isolators," says Bausch. "A lot of people took a more conservative approach again, choosing rather to go with the conventional line. In the long run, however, that's going to be not the right direction."
Those who have the technology, however, are sold on it. "We're actually retrofitting our isolator with a time pressure filling system and configuring it to fill our adsorbed products," says Aventis Pasteur's Barnes. One adsorbed product is the Tripedia DPT vaccine. Because it is adsorbed with aluminum phospate, it must be kept in suspension continuously for a consistent fill. "So we're going to put more products on this isolator, and we're also considering putting an isolator in a new facility that we're working on right now," Barnes
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