Isolators: The Future of Aseptic Processing
Early users report that isolation technology will help cut facility production and maintenance costs, and give aseptic processing a substantially higher level of sterility assurance, even when operated in nonclassified environments.
By SHEILA GALATOWITSCH
Only a tiny fraction of U.S. companies with aseptic processing lines have implemented isolation technology, but industry insiders predict that in the next 10 years, almost all lines will be enclosed in isolators. Leading the charge are five major pharmaceutical companies that have quietly worked with the FDA to develop and gain acceptance of the technology. These seminal users, several of whom are currently validating production lines with isolators, report a higher level of sterility assurance and reduced production costs using isolators.
The technology encapsulates processes in a smaller, enclosed space, completely segregating people and product to maintain a germ-free, clean or contained environment. It has been used for many years for sterility testing, animal handling and dispensing pharmaceuticals in clinical environments. But the drive to apply the technology to aseptic manufacturing and filling lines began only in this decade as the industry improved its understanding of cleanroom concepts and the technology itself progressed.
“There`s going to be a high level of activity within the industry over the next three to four years, with the primary focus by contract manufacturers and with major companies installing additional lines,” says Hank Rahe, director of technology at Contain-Tech Inc. (Indianapolis, IN) and vice president of the International Society for Pharmaceutical Engineering (ISPE). “It`s going to happen rapidly, but you have to get the first four to five lines out there and get approval, and the FDA is in the process of looking at the first several lines.”
The small industry group responsible for building prototypes and working with the FDA is the Barrier Users Group Symposium (BUGS), comprised of representatives from Merck, Pharmacia & Upjohn, Eli Lilly, Bayer Corp. and Sanofi Winthrop; as well as equipment suppliers TL Systems Bosch Group (Minneapolis, MN) and Despatch Industries (Minneapolis, MN); and Dr. Irving Pflug, an expert in sterility technology for the food and pharmaceutical industries. Gary Hoffman, Merck`s director of sterile product engineering, came up with the idea for the group at an isolation technology conference sponsored by TL Systems in 1992.
All five company members have either installed isolators or are in the process of building systems for liquid, nonpotent applications. As part of the development process, the companies tested prototypes in dirty environments with excellent results. Their early data shows that isolators maintain sterility even when operated in nonclassified environments, a conclusion that has led some to question the need for conventional cleanrooms for nonpotent aseptic processing applications when isolators are used. Placing isolators in nonclassified rooms would help companies save even more in production and maintenance costs, but few think the industry is ready to take that step or that the FDA will sanction it.
The seminal work of BUGS
The goal of BUGS was to get a group of market-leading, yet noncompetitive companies to share information and the expense of designing and implementing the first few isolator systems. The group started meeting in October 1992 to plan the projects that each of the companies would pursue. Ultimately, they would meet for two days every two months for two years–representing a tremendous commitment from each company`s management.
“One of the big issues we faced was how do we deal with FDA? How do we educate the FDA on this new technology? What class of surrounding room would the agency say we had to have?” notes Jack Lysfjord, TL Systems` vice president of sales and marketing. “There were questions on terminal sterilization: Would barrier isolation be a substitute for that? How do you transfer product in and out while maintaining sterility levels? How far can you advance sterility levels by using barrier isolation technology?”
The opportunity to meet with the FDA came after Lysfjord presented a paper at a Parenteral Drug Association (PDA) meeting and an FDA representative agreed to meet with the group. In April 1993, BUGS members had their first meeting with the FDA in Rockville, MD, where they discussed a steam and hydrogen peroxide sterilization process for isolators. Meeting face-to-face with the FDA to answer questions and address concerns about a new technology was something that hadn`t been done before, Lysfjord says. “We were asking for their opinions and fears. We could design a test and come back later and answer their questions. It was a unique opportunity for pharmaceutical companies, equipment manufacturers and the FDA to discuss problems and potential solutions, and test methods that might be done. It was refreshing.”
In the spring of 1993, Lilly, Upjohn and Merck formed a subgroup called LUMS. The LUMS companies planned to design open production systems and purchase fillers, the base machinery that would be enclosed in isolators, from TL Systems. (Open systems allow continuous transfer of components, such as bottles to be filled, into and out of the isolator during operation. Closed systems, used for the production of small components or batches, remain sealed during operation.) Sanofi Winthrop planned to build an open cartridge isolator, while Bayer undertook a closed syringe fill isolator.
The first prototypes built by LUMS included a system that tested both hydrogen peroxide vapor and the steam hydrogen peroxide sterilization process and a vial filling unit that simulated production. Merck placed the latter in its mezzanine above the filling suite for testing. Another prototype, a representative production system, performed media fill tests on a machine shop floor at TL Systems in 1994-1995. The data from those tests in nonclassified areas was presented to the FDA in May 1995.
Also that spring, Eli Lilly and Merck began to build production systems based on the prototype design. TL Systems shipped the first completed unit to Eli Lilly in October 1995 and a second unit to Merck in April 1996. Both companies have installed the lines and are in the process of validation. TL Systems is also building two lines for Pharmacia & Upjohn and one line for another company, Connaught Laboratories Inc. (Swiftwater, PA).
The importance of the BUGS effort lies in its cooperation with the FDA and its implementation of isolators into aseptic production systems. Although there had been a strong interest in isolators for production, there were only a few worldwide in 1992. The group helped design filling equipment that would integrate with isolators, and the preliminary data from the BUGS` prototypes helped the FDA feel better about the technology, Lysfjord says.
In addition, the group`s work showed that isolators provide extremely high levels of sterility. “We have data to show that cleanliness was significantly better than with conventional cleanroom technology–even when the isolators were placed in a dirty environment like a machine shop,” Lysfjord says. Even so, the LUMS companies have opted to place their new isolators in Class 100,000 cleanrooms.
Following are profiles of three of the BUGS companies: Eli Lilly, Pharmacia & Upjohn, and Bayer Corp. The remaining two companies, Merck and Sanofi Winthrop, have installed their isolators, and Merck is in the early stages of validation.
Eli Lilly: Validating filling isolators
Eli Lilly`s (Indianapolis, IN) isolator, a filling machine for veterinary products, was the first to be installed, and the company is in the process of validating the system, according to Ken Weerts, senior pharmaceutical engineer. Expected to be operational by next spring, the isolator was built in conjunction with the LUMS prototype.
Isolators coming out of the LUMS effort are similar in concept and design, but different to each company. Eli Lilly`s isolator is constructed of glass and stainless steel and sterilized using hydrogen peroxide vapor. Maintaining positive pressure, the isolator goes through a leak test process before sterilization. TL Systems supplied the filling equipment and Despatch Industries supplied the isolator.
The system has a remote air handling, heating and cooling unit that is filtered through double HEPA filters before entering the isolator. It has a recirculation system with a makeup air unit for pressurization. It also has a clean-in-place (CIP) system, glove ports for human manipulation of the product, and rapid transport ports (RTPs) and UV pass-throughs to get sterile components, including stoppers, into and out of the isolator. The isolator and air handling system combined occupy about 600 ft3 in volume; the isolator itself measures about 350 ft3.
Eli Lilly participated in the BUGS effort because “traditional aseptic processing requirements were getting tougher and tougher to meet,” Weerts says. Implementing a new technology is a big undertaking, he adds. “One company couldn`t do it by themselves. From a cost and technology standpoint, working together has helped us to overcome a lot of obstacles.” In addition, the most valuable part of the collaboration, according to Weerts, was building the prototype.
Eli Lilly is focusing on the operational savings of isolation technology. By placing its isolator in a Class 100,000 room as opposed to traditional aseptic filling suites with Class 100 laminar hoods, the company realizes substantial savings on garments, utilities, environmental monitoring and cleaning costs, while gaining more flexibility, Weerts says.
Weerts predicts that as the technology becomes more pervasive, the idea of what constitutes a suitable operating environment for isolators will evolve. Currently, the industry is limited to the requirements of Federal Standard 209, which extends no further than Class 100,000 levels of cleanliness. “In the future, I see bridging a gap between Federal Standard 209 and other classified environments that we can put barriers in,” Weerts says. This may also include standards that specify air handling requirements for residential and office buildings.
Pharmacia & Upjohn: Two isolators on order
Engineers at Pharmacia & Upjohn (Kalamazoo, MI) had been exploring isolation technology for some time before joining BUGS, even meeting with European and U.S. suppliers and designing a pre-BUGS prototype. While Lilly and Merck built their production machines on a tight schedule and parallel to the LUMS effort, Pharmacia & Upjohn was on a less strict time schedule, says Walt Senour, senior project engineer. Today, the company has two lines under construction, both using concepts explored with the LUMS prototype.
The two lines use isolation technology to transfer product from the fill line into the lyophilizer. The first line, expected to ship in March 1997, will fill vials that are then fed to five freeze dryers. Isolator transport and sterile docking technology will be used to get the vials from the filling line into the freeze dryers. The second line, for solutions and suspensions, will ship in July 1997. The Baker Company (Sanford, ME) is supplying the isolators and TL Systems the filling equipment. Both isolators will be placed in Pharmacia & Upjohn`s new sterile facility in Kalamazoo, which is expected to be validated and operational by April 1998.
“Our vision was that the isolator itself should be like a tank; it ought to have a continuous skin with an exoskeleton to support the skin,” Senour says. “We have very large–1.5-inch radius–corners, which makes them easy to clean and keeps them from being a dead area as far as airflows for sterilization. We also paid attention to ergonomics. Many of the isolator walls are angled at 10 degrees to improve operator access and comfort. We put a tremendous amount of effort in building full-size models before committing to the final design. We want these systems to be like the family car. You load up, close the doors, start it and go.”
One of the problems discovered in the LUMS prototype was how to make the isolator doors seal, Senour says. Isolators need openings into the system that are easy to operate, reliable and cleanable. “We [LUMS] always ended up with an exposed edge of the elastomer. It couldn`t be sterilized, which created a spot where water could collect and provide a haven for microbes.”
Pharmacia & Upjohn and The Baker Company solved this problem by developing a double-knife edge door seal design. The companies are applying for a joint patent on the design.
The two isolators are contained in one 23-foot long piece. “That means no welding will be performed in the plant when the systems are delivered,” Senour says. “It also allows us to do pressure testing at the vendor.” The lyophilizer line consists of four isolation sections. The first is a tunnel outfeed isolator, which takes the mass of vials out of the tunnel and single-files them using a Covert throughflow accumulator. That leads to the filler isolator and then to the filler outfeed isolator, and finally to the lyophilizer accumulation table isolator. All totaled, there are approximately 65 feet of connected isolator, all operating with one air handling system at the same positive pressure.
Both units feature double ULPA filtration, glove ports and UV pass-throughs, and will use hydrogen peroxide vapor sterilization. The remote air handler has the capacity to supply unlimited amounts of 60(C air for drying the isolator after CIP, Senour says.
The company will report on sterility assurance levels achieved with the isolators in 1998 after testing is completed. However, Senour says he believes the isolators will be “more robust” than traditional aseptic processing lines and that “we will get a higher quality product.”
Senour agrees that the operational savings realized by using a Class 100,000 environment are significant. “From a practical standpoint, we don`t want to run a facility with air quality greater than Class 100,000, but to go to even a Class 10,000 increases costs tremendously.”
In an project unrelated to the BUGS effort, Pharmacia & Upjohn built a sterile containment isolator for production of a cancer drug that has been approved by the FDA and is currently producing product. The fast-track schedule began in November 1994, the line was installed in August 1995, and product approval came this spring. The sterile box runs at negative pressure in a Class 1,000 cleanroom. Proponents of isolation technology point out that for some applications, including those pertaining to potent compounds, cleanrooms will always be necessary to contain the product and protect personnel.
Bayer Corporation: Syringe fill isolator
The application Bayer Corp. (Clayton, NC) settled on for its project–a production-capable syringe fill isolator–was an “ideal first candidate” for testing the technology, says John Melahn, Bayer`s project manager for plasma products, “simply because the components are small, we are doing low volumes, and all the components are sterilized and decontaminated fairly easily.”
The opportunity to design and construct the syringe fill isolator was a high point of Melahn`s career. “For 22 years I`ve been working on minimizing or attempting to eliminate people from the aseptic area to the extent possible,” Melahn says.
The syringe fill isolator, operating at below Class 1, is designed for decontamination using hydrogen peroxide vapor. The outside shell is made from 316L stainless steel and the windows from Lexan. The glove sleeves are a custom accordion pleat design. All the control systems, including the fill chamber, are external to the isolator. The air handling system inside the isolator conforms to what would be expected of a good aseptic cleanroom, Melahn says. This includes unidirectional airflow at 120 feet per minute through the chamber; ULPA intake, ceiling and exhaust filters; and catalytic converter.
Material transfers are made through the unit`s electrically driven 350-mm RTP. The RTP is a double-door system that uses alternate sealing surfaces to trap contaminated surfaces between the two door flanges to isolate for production, and to prevent the contamination of the door exterior during decontamination. The entire system can be washed down, including the PC interface and scanner. Flanders Filters (Washington, NC) supplied the isolator; F.P. Developments (Williamstown, NJ), the filling equipment; Central Research Laboratories (Red Wing, MN), the unit`s RTP; and Island Automation (Emerald Isle, NC), system integration.
A great deal of effort went into the operator interface, says Melahn. “A thousand-fold improvement in the environment should expect a thousand-fold improvement in the control of the operating system.” The isolator is also capable of complete electronic batch production records that are logged to disk and date/time stamped at one-minute intervals. It integrates data such as online particle counting, air flow velocity measurement and recording, pressure monitoring and recording, and event-driven activities such as alarms and operator interactions. Operator interaction is performed via an LCD touch-screen panel or bar code scanner.
Validation of the isolator is being performed in two steps because the building it was originally intended to be located in was under construction at the time of delivery late last year. While waiting for the facility to be completed, Bayer operated the unit in a clean manufacturing area (above Class 100,000), where it was validated to maintain below Class 1 conditions. The unit has recently been relocated to the new facility, where it will reside permanently in a Class 10,000 cleanroom. The remainder of the development and validation work will be completed there. “We are being extremely conservative as far as ensuring that all documentation is first class,” Melahn says. The unit is being placed in a Class 10,000 cleanroom because the facility was designed before the isolator, he says, but “we have demonstrated, and there is a great deal of confidence that the system itself doesn`t care. We could put it in a parking lot and there would be no difference in particle counts,” he says.
Melahn advises companies interested in building isolators to “understand exactly what you want and be totally involved in the design. There is no expert in the field in terms of design and sales.”
The next two years will prove the testing ground for isolation technology in general, and these early systems in particular. As the systems are validated and data is presented to the FDA, the industry will be able to gauge the agency`s official reception of the technology. But these early users are already sold. For them, the future of aseptic processing lies in isolation technology.
 |
 |
A backside view of the TL Systems Corp.`s LUMS prototype. Shown are the vertical wall drive components and plumbing.
The filling station overall view of TL Systems Corp.`s LUMS Prototype.
 |
Pharmacia & Upjohn and The Baker Company built this sterile containment isolator for production of a cancer drug. The isolator has been approved by the FDA and is currently producing product. The sterile box runs at negative pressure in a Class 1,000 cleanroom.
 |
 |
Bayer Corp. built a production-capable syringe fill isolator that operates at below Class 1. All the control systems, including the fill chamber, are external to the isolator. The air handling system features ULPA intake, ceiling and exhaust filters. Shown is an overview of the equipment lay-out in the environmental chamber. The cylindrical chamber mounted on the right chamber wall contains the steam sterilized product contact portions of the fill system.
A close-up view of Bayer Corp. syringe fill isolator`s deck and air return detail showing the work surface and support.