Pharmaceutical and Medical Packaging News Magazine
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Originally Published January 1998

PHARMACEUTICAL

Barrier Isolation Technology Takes the Next Step

While Lilly, Merck, and Pharmacia & Upjohn move toward validation, other breakthroughs are occurring.

by Jim Wagner, Editor at Large

Common wisdom holds that barrier isolation technology will revolutionize sterile filling and packaging. As yet, the promise of filling vaccines and biotech products in an enclosed environment is unfulfilled. Eli Lilly (Indianapolis), Merck (West Point, PA), and Pharmacia & Upjohn (Kalamazoo, MI) (the LUMS group) took delivery of barrier isolation systems within the past two years and are cautiously preparing for validation. But it could be another year before these systems are operational. Until recently, it seemed the industry could only wait to see what these systems could do.

Prototype of the barrier isolation system undergoing validation by the LUMS group. Photo courtesy of TL Systems Corp./Bosch Group.

The big news is that the wait may be over sooner than anticipated. While Lilly, Merck, and Pharmacia & Upjohn continue to work on their systems, another company may have the first large-scale barrier isolation system for vaccines up and running by the end of this year.

Another development that is moving the technology closer to commercialization is that FDA appears to be warming to barrier isolation. The companies working on isolator systems have dealt openly with the agency and, in return, the agency has publicly stated that it believes the technology has potential and has discussed the requirements of system validation.

In addition, new technology to support barrier systems is continuing to evolve. A major pharmaceutical company is reported to be employing ready-to-use stoppers to eliminate time-consuming, cumbersome steps on the filling line.

FIRST APPLICATION

Most likely, the first company to have a fully operational isolator system will be Pasteur Merieux Connaught (Swiftwater, PA). A maker of pediatric and adult vaccines, Pasteur Merieux delved into barrier technology three years ago, according to Ron Filipski, director of filling, packaging, warehousing, and distribution. "We felt it had potential for the future," he says.

That future may be right around the corner. In December 1996, the company acquired a system for 2—30-ml vials from TL Systems/Bosch Group (Minneapolis). Validation was initiated in February 1997 and will be completed within the coming months if all goes as expected.

Prior to acquiring the equipment, Pasteur Merieux's engineering team spent two years evaluating systems. "It truly was a global effort," says Filipski. "We tapped experts from Europe and the United States before deciding to purchase the equipment from TL Systems/ Bosch. The team included people from engineering, quality assurance, quality control, and manufacturing."

Pasteur Merieux purchased the system for several reasons, with quality being the primary concern. "Vaccine products cannot be terminally sterilized," Filipski explains. "Therefore, we evaluated a technology that provides for greater sterility assurance levels than traditional aseptic processing."

SYSTEM CAPABILITIES

The system will handle approximately 300 vials per minute throughout one shift per day, and once the line operators become familiar with the system it will be running during two shifts. Sterilization will be accomplished with vaporized hydrogen peroxide. The system itself will be located in a controlled Class 100,000 area.

A centrifugal stoppering station with vacuum stoppering wheel employed in barrier isolation filling. Photo courtesy of TL Systems Corp./Bosch Group.

Stoppers will be transferred into the system via a UV port, and Pasteur Merieux will steam-sterilize stoppers in double bags, which will connect to the port. Vials will be sterilized by first passing through a TL Systems rinser and then a Despatch Systems hot-air tunnel before entering the isolator.

Pasteur Merieux enhanced the system to meet its specific needs. "Many of our products are suspensions and need special attention," says Filipski. "The product feed system transfers product from the tank to the filler and back to the tank. The turbulent flow keeps everything in suspension." The company also modified the system by enclosing the pump table in laminar airflow. "If the pumps develop a leak, we can shut down and maintain the integrity of the system," says Filipski.

FDA VIEWPOINT

Like other packaging technologies, barrier isolation must be validated. Early in the design phase, FDA adopted a wait- and-see attitude. The agency recognized that barrier systems technology could improve product quality and also significantly reduce the risk that line operators could be exposed to biotech products. But the agency wanted solid documentation that the systems going into Lilly, Merck, Pharmacia & Upjohn, and others would perform as designed. Consequently, preparations for validation are covering all the bases and progressing slowly.

FDA's position on barrier isolation has evolved since the technology first was discussed by the LUMS group. FDA has watched the systems develop and has a few ideas about validation. FDA compliance officer Richard Friedman is closely monitoring barrier isolation. He says there are three critical issues to watch—gloves, inlets and discharge ports, and structural integrity (including gaskets and seals).

"We applaud the people who are pioneering the technology," Friedman says. "They are the first ones and are working on it very carefully. But it's a new paradigm vis-a-vis aseptic processing, and there are engineering, maintenance, and control issues. They aren't impossible to surmount, but they need to be addressed."

One specific issue is FDA's position that there is no such thing as a fully sealed isolator. "None are completely sealed. Absolute barrier is a misnomer," says Friedman. "All positive-pressure isolators have measurable leak rates."

Also, gloves are considered the weakest part of the system. "Some companies replace gloves as frequently as daily, some weekly," says Friedman. "They at least need to specify the frequency of glove replacement in their written procedures."

Another glove-related issue is the definition of pinholes. "There is no standardization of what a pinhole really is," says Friedman. "What would constitute an 'objectionable hole' needs to be decided. We expect a daily check on gloves. Also, being of elastic materials, gloves can develop holes that some consider to be self-sealing, but self-sealing goes out the window when someone flexes the glove. You should use sterile gloves inside the fixed gloves." Further, there is also concern regarding the brittleness caused by resterilizing gloves by radiation.

An additional area FDA will be monitoring is gaskets and seals. The structural integrity of the system and material breakdown are the biggest issues. "Remember, even those units termed 'closed units' are not truly fully sealed," Friedman says.

Companies are waiting for the first applications to see what the contamination rate specification will be. An aseptic process typically operates with a contamination rate of 10^—3. However, individual specs will be set for each barrier system. Friedman reports that studies are under way. "I have seen a number of isolators, and I know that they can vary widely. The expected contamination rate will be based on the soundness of the isolator design, the maintenance, and the control program."

The risk factor of the isolator is determined in large part by the access ports. Direct contact with an autoclave or a dry heat pyrogenation tunnel are the preferred methods. "The design must be such that the vials, stoppers, and other materials go in sterile," explains Friedman. "A UV port, for example, is a marginally sterilized port."

Friedman also says FDA will be looking closely at design, validation, maintenance, decontamination and sterilization, and environmental monitoring.

STOPPER TECHNOLOGY

One of the holy grails of barrier isolator technology is ready-to-use stoppers for vials, which can save companies time and an enormous amount of labor. The West Co. (Lionville, PA) is about to introduce ready-to-use stoppers and is now preparing a tray system for gamma-irradiated, presiliconized, ready-to-use stoppers. "It's hot news, not commercial yet, but patent pending," says Val Romberg, director of Westar (produced by The West Co.) and multimaterial development.

A tray system is designed to allow gamma-irradiated presiliconized stoppers to be removed without violating the isolator environment. Photo courtesy of The West Co.

"The tray transfer system is a thermoformed rigid polyethylene terephthalate-glycol [Eastman Chemical Eastar PETG copolyester] tray and will be available empty or packaged with ready-to-use stoppers," explains Paul Norton, manager, advanced systems engineering for The West Co. "The tray holds 1000 20-mm or 5000 13-mm stoppers."

The sides of the tray are corrugated to promote dispensing, and the bottom is knurled to accommodate a label on the outer side.

To introduce the stoppers into a barrier system, the tray is placed in a window frame on the outside of the isolator. An operator uses a heat-seal parting device to open the tray. When the stoppers have been removed, a window pane inside the tray is lifted and turned 90 degrees to seal the port. The tray can then be removed without violating the isolator environment.

The West Co. also introduced an autoclavable package for ready-to-use stoppers. Called SteamPac, the package consists of a Central Research Laboratories (Red Wing, MN) beta flange attached to a double bag. The inner bag is made of Tyvek, and the outer bag is autoclave-resistant plastic. The inner bag is filled with stoppers, sealed, and then sterilized with steam. The outer bag is heat sealed, preventing any contact with the inner bag. To empty the stoppers into an isolator, the bag is attached to a corresponding alpha port. SteamPac holds 25,000 13-mm serum or 20,000 13-mm lyo stoppers.

CONCLUSION

Improvements such as tray systems with ready-to-use stoppers will make it easier for barrier isolation technology to progress. Combined with FDA's openness and new, promising applications such as the one at Pasteur Merieux Connaught, this may be the year that barrier systems finally achieve their potential.