Barrier isolators make inroads on aseptic filling lines
Survey surprises pharmaceutical industry with tally of 84 filling line isolators worldwide — a count dramatically higher than expected — and shows Europe leading the U.S. in implementation.
By Sheila Galatowitsch
Ask pharmaceutical professionals how many aseptic filling line isolators are in the world today — either on order, under approval, or operational — and most would guess maybe 10 to 20 systems. But according to a survey conducted by Jack Lysfjord, vice president of technology and international sales for TL Systems/Bosch Group (Minneapolis, MN), and Michael Porter, senior project engineer in the Vaccine Sterile Process Technology Group of Merck & Co. (West Point, PA), more filling line isolators exist than anyone had imaged: a surprising 84 lines, with 34 in operation.
And these are not manual filling operations, either. “They are slow- or high-speed production systems for various packages: vial, syringe or ampule,” Lysfjord says. “The magnitude is quite large, more than what we or the FDA suspected. It is an indication of how far the technology has come.”
Europe leads the U.S. in implementing isolators, according to Lysfjord and Porter. “The U.S. lags because of fear of the FDA and fear of change,” Lysfjord says. Approximately six filling lines have received FDA approval to date, and Porter expects the number of FDA-approved lines to double in the next 18 months. The survey also found that most companies with isolators are installing them in Class 100,000 cleanrooms.
Lysfjord, whose company manufactures isolation and pharmaceutical manufacturing equipment, and Porter, who has helped implement several isolators at Merck, are members of an industry user group that was one of the first to develop and attempt to gain FDA acceptance of the technology. Both were conference leaders at the International Society for Pharmaceutical Engineering (ISPE)`s barrier isolation technology conference held in Arlington, VA, in June. The two men presented the survey results to conference attendees and will publish an article on the survey in this month`s issue of the ISPE journal, Pharmaceutical Engineering.
Both men caution that while isolation technology is making inroads in aseptic processing applications, it is still evolving and several years away from maturity. “One of the trends identified by the survey was the pure number of differences from design to design. Standardization is a long way off,” Porter says.
And the industry still has plenty to learn about the technology. “A lot of learning occurs once you have an isolator,” Lysfjord says. “You just don`t buy it and start it up. There are different learning curves, and depending on how many new technology steps you introduce with your isolator, it compounds the complexities from running and sterility standpoints. There are many factors to evaluate, and you need different people and training skills in your organization,” he says.
But barrier isolation is the technology of the future, he says. Resisting change will only postpone the inevitable. “A lot of companies are saying `we are going to wait until so-and-so is in production` or until the FDA blesses it,” Lysfjord says. “The fact is that numerous companies have committed to 84 isolator projects, either recently or a long time ago, as far back as 1985. The industry is definitely going in the direction of isolation technology. However, there is hesitation on the part of others, so the question becomes: When are they going to start their learning curve?”
FDA approvals
With seven filling line isolation systems either installed or on order, Novartis Pharma AG (Basel, Switzerland) is the highest-use company to date, according to the Lysfjord/Porter survey. Companies that have received FDA approval of filling line isolators include Evans Medical (Liverpool, UK); Accutane Pharma Inc. (API) (Pau, France); Pharmacia & Upjohn (Kalamazoo, MI); Baxter International (Round Lake, IL); Merck; and Mallinckrodt Medical Inc. (Maryland Heights, MO)
After five years of work, Mallinckrodt is “excited to be one of the first” to receive FDA approval, says Thomas Freund, microbiological control supervisor. The $11 million project included construction of 12 isolators, a Class 10,000 cleanroom surrounding the isolators, and Class 10,000 and Class 100,000 staging rooms. The filling line was approved by the FDA in April, and operation will begin this year.
“It`s nice to be one of the first companies inspected for this new technology, because in a way, we set the standards — instead of just meeting standards set by others,” says Ron Bartnick, quality and regulatory compliance manager.
Mallinckrodt manufactures parenteral radiopharmaceuticals, drugs that are injected into patients to diagnose and treat bone and organ diseases. The question five years ago was whether to build a new cleanroom to replace one constructed in 1977 or look into the new technology.
“We wanted to establish a barrier between the product and the individuals manufacturing it since people are the primary source of microbial contamination,” Bartnick says. “We also felt that isolators would eventually be the standard somewhere down the line, and we wanted to get involved upfront.”
The cleanrooms were constructed first, then the isolators were installed, qualified and eventually validated. “The real success story is the validation of the line. It went very smoothly, in part, because we interacted with the local FDA compliance office from the start of the initial concept,” Bartnick says. “But there were times we weren`t sure if it was going to work or not,” says Freund.” There wasn`t any clear-cut guidance available on validation or using hydrogen peroxide vapor to sanitize an isolator system.”
Similarly, there was no guidance available on the surrounding room classification, so the project team made a conservative decision to house the isolators in a Class 10,000 environment. “The local FDA inspector felt good about the decision at that time,” Freund says. As a side benefit, the room can be converted to conventional Class 100 aseptic filling, if necessary. And since all the air that`s taken into the isolator is from the surrounding room air, “we are providing the isolator with some very clean air to start with,” Freund says.
Filling line configuration
Mallinckrodt used an existing warehouse for the new cleanrooms and filling line. Materials advance from the warehouse into the Class 100,000 staging area, where all cardboard and paper is removed.
Materials then proceed to the Class 10,000 staging room, where the vials are washed and loaded into a depyrogenation oven. Stoppers are loaded into a stopper processor, and other product equipment, such as tubing, filters and glassware, is loaded into an autoclave. All of these materials are sterilized and then unloaded into the isolators, located in the Class 10,000 filling room. The 40-foot-long filling line processes 60 vials a minute or one lot of 9,400 vials at one time. The system was validated on 9,400-vial media fills that took four to five hours to complete.
Of the system`s 12 isolators, three are mobile transfer units. Each isolator is a self-contained unit. The system is considered a “closed” barrier isolator because it does not have any mouseholes — small openings at the end of the line to remove vials. It is also a “continuous” system. Once the vials, stoppers and equipment are sterilized, they are maintained and transferred in complete isolation. Six half-body suits and 40 glove ports give personnel access to the system. Calumatic (Dongen, Holland) built the filling line and filling line isolator, and La Calhene Inc. (Rush City, MN) built the other isolators associated with the system.
Recirculated HEPA-filtered air provides unidirectional flow in the filling line isolators, where pressure, non-viable particulates, temperature and relative humidity are continuously monitored. (Unidirectional flow is not the same as laminar flow, isolator experts point out. Isolators operate at slower velocities than traditional laminar flow, and the two should not be confused.)
Ensuring that the filling line complied with both U.S. and European aseptic processing requirements was one of the most important design considerations, Bartnick says. Other criteria included no particles greater than 5 microns in size; maintenance of Class 100 conditions during production operations; smooth interior surfaces; and a minimum number of moving parts.
In addition, because of the complex interactions between the filling machine and filling isolator, the company required that the fill line equipment manufacturer be responsible for the fill line isolator, says project leader and validation supervisor Dave Foehringer.
Hydrogen peroxide vapor (HPV) is used to sanitize the isolators, with emphasis on the word “sanitize.” The project team decided not to treat isolators like autoclaves, where it is easy to demonstrate very high sterility assurance levels using heat penetration data and biological indicators.
“There is a higher cleanliness with isolators, but it is hard to equate this level of cleanliness to the sterility assurance levels of an autoclave,” Freund says. “If we had to treat isolators like autoclaves, it would have been very hard or impossible to prove sterility. And we don`t have those type of requirements for conventional cleanrooms. We were worried that a sterility assurance level of 10-6 would be the standard for isolators.”
The difficulty in proving sterility in an isolator arises from the HPV sanitizing method, according to Freund. “At the time we did our validation work, there was no easy way to measure HPV concentration in isolators. There were also limitations in the quality and availability of spores used to validate the HPV process,” he says.
Another reason the project team opted for sanitizing over proving sterility is because it didn`t want to set unduly high expectations that it would then be forced to meet. “If you tell the FDA you are going to do something, you must do it. If you require a 10-6 sterility assurance level, you have to demonstrate that,” Freund says. “Our approach can be done by any facility. We didn`t want to set the bar too high to start with.”
Still, the filling line isolators are providing an excellent manufacturing environment, according to the company. Of the 60,000 vials filled with media during validation, there were no vials positive for microbial growth.
Validation
Key to this year`s FDA approval was a master validation plan developed by Foehringer in 1993. The 80-page document outlined the scope of the validation work to qualify equipment and utilities, and described critical systems supporting the new manufacturing area.
The plan also compared how Mallin ckrodt manufactured radiopharmaceuticals in the old cleanroom versus how they would be manufactured in the new filling line isolators. “We looked at the manufacturing processes in both areas to substantiate that there were no manufacturing differences that would affect product chemistry,” Bartnick says. “The only thing that was changing in our manufacturing process was the use of a barrier isolator system. Everything else was the same except for a few minor things.”
In 1996, the team wrote a media fill validation protocol and sent it to FDA officials in Washington prior to a meeting between the officials and the project team. For routine production, Mallinckrodt planned to use the line for 15 days to produce up to seven lots of product after running one HPV sanitization cycle. Therefore, the company proposed a validation schedule of sanitizing the isolators one time with HPV, then running one 15-day cycle consisting of three media fills and four simulated production runs.
But the FDA insisted on two media fills and five simulated runs three times — a huge undertaking that took 45 days of line validation work. “We have to give the FDA credit. In those three 15-day cycles, we learned a lot,” Freund says.
During the first cycle, pin hole leaks were discovered in the gloves. As a result, the team has now implemented a procedure to test the integrity of all gloves before each 15-day production cycle.
During the second cycle, the filling line required extensive changes because the vials were not feeding into the line properly. “We decided to go ahead with the validation while the changes were being made. We did a full 15-day cycle and had no microbial contamination. That showed us we were able to maintain the integrity of the line,” Freund says.
Ultimately, 110 different protocols were written and executed to validate facility equipment and utilities. Prior to the media fill validation, each isolator was validated, as were the kill cycles for the peroxide, the air handling system, the HEPA filters and numerous other components. “The media fill was the last step in the whole validation process. It was proof that everything else we did worked.”
300-vial-per-minute filling line
But the project team would do some things differently, including using fewer half-body suits. The suits are small, which limits the personnel that can use them, and they require a lot of twisting to reach inside the line. In addition, the team would have built a mockup to test ergonomics.
A mockup was also on the wish-list of Novo Nordisk Engineering A/S (Bagsvaerd, Denmark). The company is implementing a new vial filling line isolator for Glucagen, a hormone drug, and other drugs that will be sold worldwide. The line, which processes 300 vials per minute, is currently undergoing process qualification.
Because the filling line was being designed at the same time as the isolation enclosure, the project team was unable to construct a satisfactory evaluation mockup of the final, complete system. Instead, a compromise was reached, says Dr. Charlotte Enghave, project engineer with the company responsible for project design and engineering.
Skan (Basel, Switzerland) delivered the finished isolator with a temporary plexiglass installed in the isolator in place of glass. That gave end users a month to test the ergonomics and change glove port positioning before the glass viewing windows and glove ports were permanently installed.
If a mockup had been available earlier in the project, Enghave says she probably would chosen to make a few additional ergonomic enhancements. “If we had had all the time in the world, we would have made the filling line first and built the isolator around it,” she says.
Housed in a Class 100,000 cleanroom, the vial filling line has two isolators, angled to each other in a 12-meter-long configuration. The stainless steel isolators feature 25 glove ports and glass double doors for return air. The nearly identical isolators take makeup air from the surrounding air through an inlet HEPA filter. The unidirectional airflow is recirculated through a HEPA filter.
Novo Nordisk Engineering relied on its equipment vendors for help in system design, Enghave says. Bosch (Crailsheim, Germany) and Amsco Finn Aqua (Hurth, Germany and Helsinki, Finland) supplied the filling line, freeze dryer, sterilizer and loading equipment, and sub-supplier Skan provided the two isolators.
“The glass double doors were a main requirement,” Enghave says. “We felt the doors would give a good unidirectional airflow over the total area of the isolators. Otherwise, if you have the returning air in one corner, there might not be a unidirectional flow in that area.” The company also specified windows angled at about 10 degrees for better operating comfort, and after much discussion, opted for round over oval glove ports.
Enghave says the most critical factor to a successful project — even more important than a mockup — is having project engineers with experience and ensuring that the conceptual design phase is addressed appropriately. “It is very important that project engineers work close together with the end users who are going to use the equipment and the vendors who are constructing the equipment. Vendor design reviews are extremely important,” Enghave says.
Process flow
The company`s process begins with washing and sterilizing the vials before they enter the filling machine in the first isolator. A check-weighing station inside the isolator uses a gripper to take certain vials out of the transport system for weighing, then returns the vials. The same vials are weighed again after filling.
The filling line can produce either the solvent for the freeze drying products or the freeze-dried product itself. When producing solvent, a snap-off cap is placed on the vials after the vials are filled, and then they are closed on an inline capper. These vials are then transported through the second isolator and out to an automatic loading system for the autoclave.
When producing freeze-dried products, a stopper is placed in the vials, and they are transported straight through the inline capper (without capping) and into the second isolator. They are automatically loaded into the freezedryer, which is connected to the isolator.
Getting the product into the first isolator was complicated because the preparation area is located on a floor above the cleanroom, Enghave says. The solution was to provide the filling tank in the preparation room with direct access to a smaller buffer tank in the isolator.
In addition, the processing equipment for washing and sterilizing the stoppers and caps is located on the floor above. To solve that problem, the stoppers and caps, after sterilization in a closed container, are lowered down a long pipe through the floor and ceiling and into the isolator.
One of the biggest challenges on the project was the surrounding technologies, such as the transfer of components and HPV sterilization equipment. “Isolators have come a long way in the last couple of years, but there is still a lot of work to be done in adjacent technologies,” Enghave says. “At the beginning of a project you don`t see all the challenges that will come.”
This filling line is Enghave`s third isolator project. “It`s very important that you have a conceptual design upfront, and that you take a lot of things into account that you wouldn`t automatically think of,” she says. “Isolators are not like conventional cleanrooms. You need to rethink the whole concept of contamination control when introducing an isolator.”
Although the filling line`s sterility assurance levels have yet to be measured, Enghave is certain there will be an improvement over conventional processing. “It`s a situation where you are removing the most disruptive and contaminating factor in aseptic processing — the human being. Operators contribute the most to contamination in a cleanroom.”
Both Mallinckrodt and Novo Nordisk Engineering project teams advise keeping isolator design simple. “With isolators, you have restricted access to the filling lines. It`s just not as good with glass doors and glove ports. You need to take that into account and keep everything as simple as possible,” Enghave says.
Additional isolator projects are in the works for both companies. Next up for Mallinckrodt is a syringe-filling isolator system, while Novo Nordisk Engineering is performing installation and operational qualification on a high-speed cartridge-filling line installed earlier this year. CR
Readers can contact Mallinckrodt at [email protected] and Novo Nordisk Engineering A/S at [email protected].
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The new vial filling line isolator at Novo Nordisk. The stainless steel isolator features 25 glove ports and glass double doors for return air.
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Guideline help on the way
In the decade-long evolution of barrier isolation technology for aseptic processing, early implementers have been on their own with no officially sanctioned guidance for help. But help is on the horizon, with several guidelines scheduled for release later this year and next year.
The earliest that will be available is a guide on aseptic/sterile processing, part of the ISPE`s series of 10 facility-engineering guidelines. The guide is currently undergoing FDA review, and ISPE hopes to have it available by the association`s annual meeting in November.
The guide will have a 14-page chapter devoted to barrier isolation, which will feature a general discussion of isolator types, equipment design and background environments, and cover some critical issues, such as cleaning and surface sterilization, ergonomics and transfer systems.
The Parenteral Drug Association is developing a technical report on advanced aseptic processing that will also cover barrier isolation technology. Publication is scheduled for early 1999.
Meanwhile, those waiting for a revision of the FDA`s 1987 Guideline on Sterile Drug Products Produced by Aseptic Processing, which will have a section on barrier isolators, will have to wait a little longer. An FDA spokesperson said the guideline was in the process of being revised and may be issued next year.
Users got an indication of the FDA`s thoughts on the technology in an article published earlier this year in the ISPE journal, Pharmaceutical Engineering. The article, written by Richard Friedman, a compliance officer with the FDA`s Center for Drug Evaluation and Research (CDER), is apparently the first full-length article by the FDA on the subject. Friedman says he wrote the article to provide a review of the technology and identify critical control points.
“Barrier isolation seems to be a promising technology, but it has some potential weak links,” Friedman says. “If a barrier isolator is properly designed, maintained and controlled, it appears to offer a tangible advantage over classic aseptic processing.”
The article focused on positive pressure isolators, the type that show the most potential for substantially reducing contamination rates, according to Friedman. Critical control points include design of the transfer ports; gloves; surface sterilization cycle development; design of the equipment in the isolator; and routine maintenance and control.
Friedman advises manufacturing facilities to begin working with the FDA “when they are at the stage where their design concept has coalesced enough that they can talk about some specific GMP issues.” Users should meet with the CDER review divisions and the Office of Compliance, as well as district offices.
Tracking isolation technology
From laboratory to manufacturing plant, isolation technology is taking the concept of a cleanroom to the smallest possible level. This month`s Special Report is CleanRooms` fourth in-depth article on the topic in as many years.
In the November 1995 Special Report, isolation technology was part of a broader theme on trends in biotech manufacturing. That article traced the history of the concept, defined the terminology and basic components, and discussed some of the obstacles hindering implementation.
The November 1996 Special Report, “Isolators: The future of aseptic processing,” discussed how the technology could help cut facility production and maintenance costs and give aseptic processing a substantially higher level of sterility assurance.
July 1997`s Special Report, “Implementing isolators: Advice and lessons learned from the early users of isolation technology,” focused solely on case studies and practical advice. Each user profiled gave one key bit of advice, such as “invest in a mock-up,” “use pre-engineering technology where possible,” and “partner with your vendor.”
An accompanying article offered some “do`s and don`ts” of isolator projects from equipment vendors, consultants and engineers. A year later, the most salient tip bears repeating:
Designing and implementing an isolator system is different from designing and constructing a traditional cleanroom. The bad news is that there are several mistakes you can make if you haven`t done your homework. The good news is that once you make these mistakes, you aren`t likely to make them again. — SG