Barrier Isolation Technology: Out of the Incubator and into Production
Barrier isolators take sterility assurance beyond the limits of aseptic processing in traditional cleanrooms.
Jenevieve Blair Polin, Contributing Editor
|A vial filling line is equipped with an isolator from Bausch + Stroebel Machine Company, Inc.|
Flu season may not hit as hard this fall as it did last year, thanks in part to vaccines filled on a high-speed aseptic line inside a barrier isolator. Aventis Pasteur (Swiftwater, PA) is filling flu vaccine on a Mini Aseptic Filling System (MAFS) from Bosch Packaging Technology (Minneapolis) for the first time this season. The inauguration of commercial production on systems that have been in development and validation for years at many leading pharmaceutical firms ushers in a new era for barrier isolation.
Barrier isolators have been used for decades for production of small volumes of pharmaceuticals, usually for clinical trials, and for sterility assurance testing. These systems, known as closed-system isolators, are never opened during operation and therefore may be used only for batch processing. A high-throughput aseptic filling line, on the other hand, is known as an open system because components enter the system continuously and filled product exits continuously via a mouse hole during operation. Only continuous overpressure ensures separation of the environment inside the isolator from the surrounding room (See more in-depth definitions in "Doing Aseptic Filling in Barrier Isolators," Pharmaceutical & Medical Packaging News, November 2000).
As this technology moves from the experimental phase into established production models, many of the initial design hurdles have been surmounted. Much of the emphasis for companies implementing these systems now is on reaching consensus as to good manufacturing practices.
THE MARKET FOR BARRIER ISOLATORS
The pharmaceutical industry's interest in barrier technology is fueled in part by the requirements of new drugs. In the coming years, more and more products, such as protein-based products, will be introduced that require aseptic processing. Vaccines, for instance, are being produced on three of the seven MAFS units Bosch has delivered so far worldwide to Eli Lilly, Aventis Pasteur, Merck, Pharmacia, and GlaxoSmithKline.
|The Baker Co. offers a rapid access barrier that allows operators to intervene in the aseptic process without compromising asepsis. Using gloveports, personnel are able to keep all barrier panels closed and in place.|
Barrier isolators offer the promise of increased sterility assurance and lower operating costs. "Once you have it installed and it's validated and you're in operation, the cost to operate daily is like nothing compared with the cost of maintaining and operating a cleanroom," says Bill Friedheim, technical sales representative of Carlisle Barrier Systems (New Lisbon, WI).
"There is a significant advantage to the separation of people and product," says Patrice Cloué of La Calhène (Rush City, MN). But companies are often reluctant to set up a barrier isolator, he says, because the economic benefits are realized only in the long term. For a business not yet used to this technology, a big investment is required upstream in engineering and in validation.
While the spotlight may be on high-speed open lines, closed systems are also in demand for certain new pharmaceutical products. "For every high-speed line that's filling a product like insulin where you need filling capacity of 300 or 400 vials per minute, there are 10 other lines requiring only 40 to 50 vials a minute," Carlisle's Friedheim points out. "Many of these companies are handling sterile cytotoxic drugs. The quantities aren't that great when you're getting into your nastier things," he adds.
Mallinckrodt Inc. (St. Louis), for instance, has been in commercial production filling vials and lyophilizing the product since 1998 inside a suite of closed-system isolators. The firm's second closed-isolator line, for syringe filling, was approved by FDA in March 2000, and FDA approval of a third line (another syringe-filling line) is pending. "We fill about 60 vials a minute, our batch size is typically 10,000 vials a batch, and we may run only eight to ten batches a month," says Dave Foehringer, process engineer. "So we don't need a high-speed line."
A LACK OF GUIDANCE
While FDA has approved commercial production within barrier isolators, it has not issued the official guidance that many in industry await eagerly. FDA is in the process of revising the 1987 aseptic processing guideline, adding an appendix to the revision that will address barrier isolator technology. However, says Richard Friedman, compliance officer for FDA's Center for Drug Evaluation and Research, a draft of this revision will not be published for public comment until "we go through our own internal discussion first at FDA," and that discussion is still ongoing.
Other organizations have tried to fill the void by publishing their own guides on use of barrier isolator technology. These groups include the Parenteral Drug Association (PDA) and the International Society for Pharmaceutical Engineering (ISPE). FDA commented on the drafts of the newly published PDA technical report (TR-34), "Design and Validation of Isolator Systems for the Manufacturing and Testing of Health Care Products," which is available on-line at www.pda.org.
|The VHP M1000 system from Steris Corp. is designed for low-temperature biodecontamination of isolators, workstations, and filling lines. The VHP cycle operates in an open-loop configuration consisting of four phases: dehumidification, conditioning, decontamination, and aeration.|
"We have a good understanding of what PDA's positions are. It certainly has influenced our thought process in that it has given us a good idea of what the PDA considers the most important critical control points in isolation technology," Friedman explains. The PDA technical report, he adds, is a good reference for a manufacturer who is contemplating installing an aseptic processing isolator or has already installed one.
Another helpful document is ISPE's Baseline Guide, Sterile Manufacturing Facilities, published in 1999, which has a chapter devoted to the design, integration, and use of barrier isolation technology.
"Through ISPE and PDA, there has been a sharing of knowledge and experience that has advanced the understanding of this technology to a point that would not be attainable if the companies involved were not so free and open with their information," Friedman says. Jack P. Lysfjord, vice president, technology and international sales, for Bosch Packaging Technology, has been the force behind much of this communication as the cochair of ISPE's Barrier Isolation Technology Conferences.
MAINTAINING SEPARATION OF THE ENVIRONMENT
Friedman offers the following definitions to distinguish between a barrier and an isolator:
Barrier. A physical partition that affords aseptic-manufacturing-zone protection by only partially separating it from the surrounding area. That area, with few exceptions, is of lower air cleanliness. A barrier also affords protection from activities occurring near the processing line. Such partitions have been used in the pharmaceutical industry for decades.
Isolator. An isolator is an enclosed environment that provides full containment of an aseptic manufacturing line. It does not allow the ingress of air that is external to the isolator.
"Good design up front is the key issue with isolators," Friedman stresses. "After that, a manufacturer simply needs to control and maintain it well. But if the design isn't there, then the firms may have problems with leaks," he adds.
Glove ports. Glove ports and gloves themselves are a critical area of concern. Isolators on large, high-throughput open systems may have more than 100 glove ports. There are, however, a number of methods for detecting glove leaks, from pinhole on up. "I think that the most sensitive instruments feasible should be used," says Friedman. "When I say feasible, I mean not only economic feasibility but also reliability."
In the course of reviewing facility inspection reports, Friedman has found that the reliability of some glove-testing units is more questionable than their sensitivity when optimized. "Firms have occasionally claimed that the instrument does not always perform reliably, and that's a problem because FDA regulations require reliable and reproducible tests," he explains. "Any test that's used needs to be robust and reliable."
Some manufacturers, Friedman says, distrust their glove testers and require three consecutive failing tests before they remove the glove. "It is okay to retest a bad result as part of an investigation, but to require three consecutive bad results before a glove would be removed is really very questionable," he points out.
La Calhène has designed a proprietary leak tester that allows in situ glove testing so that operators may test gloves without stopping production. The glove, still attached to the isolator, is placed in a cylinder outside of the isolator. The cylinder is filled with an inert gas and is under negative pressure. The glove is inflated inside the cylinder, and the oxygen level inside the cylinder is monitored. A spike in the oxygen content of the cylinder would indicate a leak in the glove. About 30 of these stand-alone units have been shipped worldwide since their introduction 3 years ago.
Pressure variability. Not only the gloves but the entire isolator must be tested for leaks under certain circumstances. "You need to be gas tight before a sterilization cycle, because you don't want to have this aggressive, toxic product or gas escape to the room where you're working, so we would do this leak test just before sending the vapor inside the isolator," explains La Calhène's Cloué. La Calhène's latest designs incorporate an isolator leak tester based on a pressure decay system integrated to the controls of the isolator.
Real-world operating conditions can challenge the integrity of an isolator environment in ways that may not be apparent at the design phase. "There is sometimes no protection around the mouse hole, so anyone can walk right by. This is not good because it affects airflow dynamics right next to the mouse hole, and what is a very linear kind of movement of air becomes perturbed," Friedman explains. "Firms say, 'We won't let anybody walk by,' but it's easy for someone to do so, and there's not constant supervision or surveillance of the mouse hole at the end of the isolator to see whether this happened during an operation. If there's something to preclude that possibility, that would be a better design."
In the same vein, Friedman points out, if there are doors near the isolator or even somewhat close to the isolator, opening or closing a door may change local pressure dynamics in the room, and that can then affect the pressure within the isolator also. Such a change in airflow may permit the ingress of lower-quality air.
STERILIZATION, TRANSFER OF COMPONENTS
One of the primary design challenges to isolator operation is engineering a means to introduce components without breaching environmental integrity. Glassware often enters via a depyrogenation tunnel, but depyrogenation is not an option for many components, such as rubber stoppers.
One method is to place a bag or tub of sterile components, with a nonsterile outer wrapper, into a transfer isolator. The outside of the package is then sterilized, by means of UV, pulsed light, or hydrogen peroxide vapor. The transfer isolator is then docked to the main isolator, a port is opened between the two, and an operator using a glove port transfers the components into the machine feeding system.
|La Calhène's clinical filling isolator is designed to simplify small-volume batch formulation and aseptic product filling.|
La Calhène has developed a system that eliminates the need for intermediate sterilization and for manipulation of the components inside the isolator. The DPTE BetaBag system is a bag equipped with a DPTE beta flange. After the bag is filled with components and sterilized, it is mated directly to the corresponding flange on the isolator. The components are dropped directly into the hopper or bowl. The pulsed-light BetaBag system is similar but relies on pulsed light to sterilize the connection before material transfer. This pulsed-light system is more suited for high-volume systems because it is more economical. La Calhène supplies BetaBags already filled with components and sterilized.
Hydrogen peroxide vapor is the agent used for decontamination in the vast majority of barrier isolator systems. Vapor-phase hydrogen peroxide is typically not an aerosol; it is a dry process. However, turbulence is required to distribute the vapor effectively. When temperature and humidity are known, an injection rate that produces only a dry vapor concentration can be calculated. Monitors, such as the fiber-optic-based spectrophotometer from Guided Wave Inc. (El Dorado Hills, CA), are available, but companies vary in their use of monitors. Some monitor only during validation to establish parameters for operation. However, "if the firm is not monitoring whether they stay within those limits during operation, then it is unclear whether or not they are still within validated parameters," FDA's Friedman argues.
Another limitation to hydrogen peroxide–vapor monitoring has been the need to monitor at different locations within the isolator during different cycles. Most firms use a standard monitor with only one or two probes. They monitor at one or two sites on one cycle, then move the probes and monitor at new sites during another cycle. One firm is taking an innovative, more aggressive approach to hydrogen peroxide– vapor monitoring in a high-throughput open system. They are using Guided Wave's full-spectrum multi-channel spectrophotometer, Model 412, which may be configured with as many as 12 probes to potentially monitor the concentration ofthe vapor at 12 different points simultaneously.
However, Roger Schirmer, Guided Wave's president, cautions, "Our Model 412 is a full scanning spectrophotometer that is not configured nor calibrated to measure hydrogen peroxide vapor out of the box. This presents additional challenges to the user. The Model 412 does not have embedded firmware to continuously check the instrument for accuracy. A true multipoint, calibrated monitor may be available in the future."
Certain points in the isolator environment will always be tougher to reach, though. The issue is not whether all sites receive exactly the same amount of hydrogen peroxide vapor, but whether the tough-to-reach locations get enough sterilant to ensure elimination of any microorganisms that may be present on surfaces.
Claire Fritz, VHP process engineer, Steris Corp. (Erie, PA, and Mentor, OH), says that Steris—maker of the VHP (vaporized hydrogen peroxide) system—has been working closely with isolator vendors to optimize the design of the isolator and make it most suitable for the VHP process. Adding ports for better turbulence or regulating the flow of the air handler are two design modifications she has suggested.
"Sometimes with big filling lines, customers tend to have the air handler on almost too fast for the process, so that it actually breaks down the peroxide too fast," she points out. This flaw increases the quantity of hydrogen peroxide vapor required for decontamination.
To help distribute the vapor during decontamination, it is standard practice to continue to run the isolator's recirculation blowers in a unidirectional flow. Fritz suggests that it is best to actually decrease that flow rate during decontamination.
The first-generation hydrogen peroxide vapor generator was the VHP 1000, a self-contained closed-loop unit. The portability of this unit makes it particularly suited to applications, such as closed isolator systems, that consist of many individual isolators. However, when the unit's desiccant eventually becomes saturated, it must be taken off-line periodically. This year Steris unveiled a new modular system, the VHP M1000, that is able to run continuously without regeneration of the desiccant because it is piped with an external dry-air source.
Carlisle Barrier Systems offers isolators with Steris's VHP M1000 integrated into the HVAC system. They have been able to cut VHP decontamination cycle times in half, says Friedheim, by increasing airflows, adding heaters, and using a PLC to automate adjustment of all isolator valves. Oliver Bausch, vice president of Bausch + Stroebel Machine Company, Inc. (Clinton, CT), a manufacturer of filling and closing machine lines for pharmaceutical products, has also seen cycle times cut in half. He points out that cycle time "is an important consideration for the overall investment in a barrier isolator."
Biological indicators are considered the ultimate test of decontamination, but their use is a bit of an art. Some potential problems include their placement on materials and the choice of materials used for their construction.
Some firms have elected to use inoculated stainless-steel carriers almost exclusively as part of their validation of a barrier isolator, based upon results of development studies. This may be acceptable, FDA's Friedman says, if the development studies were comprehensive enough to conclude that the D-value does not vary appreciably between the worst-case material in the isolator and stainless-steel materials. A number of different materials—including Teflon and polyethylene—are used in addition to stainless steel in the construction of an isolator. Some of these materials, Friedman warns, may not be adequately studied during development to allow for the exclusion of their study during validation.
Another potentially problematic approach is the decision to hang preinoculated carriers from critical key areas within the isolator. These carriers are often constructed of materials other than that of the equipment at the test site. "When the organisms are not directly inoculated onto some type of surface that is representative of the worst-case material in the isolator, the test gets further and further away from accurately assessing whether or not those organisms really could be killed," Friedman says. Furthermore, he adds, there have been some quality control problems with some of these preinoculated carriers. One option, he points out, is for manufacturers to prepare their own biological indicators.
Not only the isolators but also the filling equipment inside has evolved. "La Calhène began to build and design isolators on filling machines in the late 1970s, so we've worked with almost all the filling companies," says Cloué, "but over the years, we've seen some filling-machine-manufacturing companies make more innovations than others." The main areas of improvement are more cleanability, better ergonomics, and what Cloué calls the "leaktightness" of the machine. What these companies have understood, Cloué says, is that design improvements prompted by barrier isolator requirements are transferable to traditional cleanrooms as well.
Bausch + Stroebel is one such innovator. For most barrier isolator projects, says Bausch, "we are the project leader and work as the integrator for the barrier isolator." Bausch + Stroebel's main partner for building the isolator has been Metal and Plastic (Radolfzell-Stahringen, Germany). Abbott, Mallinckrodt, and Baxter are some of the firm's customers.
Streamlining the design is the key to improved performance of a line within a barrier isolator. "You want to avoid too many transfers inside the barrier, from conveyors to star wheels to main transport systems, so we tried to focus more on minimizing penetrations through the base plate and also on smooth handling of the container itself," Bausch adds.
Lysfjord reports that Bosch has changed the infeed on the MAFS system, from conveyors to a disk, for similar reasons. "We were trying to stay away from the disk, primarily because of concerns about washing and dryability. If you have a flat surface, it's hard to get water to run off of it. But the conveyors had too many problems at high speeds," he says. The fact that GlaxoSmithKline's MAFS line in Europe is running in production at 750 vials a minute, he adds, attests to the benefit of this design modification.
"I've seen so many different designs," FDA's Friedman sums up. "Each time I look at a line, I see some sort of ingenious thing the firm has done. That's impressive, and I see that there is often a great amount of creativity and ingenuity in the design, all aimed toward providing better and better protection."