Automation Key to Clean Freeze-Drying

By Sheila Galatowitsch

The days of gowned pharmaceutical personnel transferring product from fillers to freeze dryers via stainless steel trays may be on the way out. The latest advancements in lyophilization replace people–the “number one” source of particulate contamination–with automated, enclosed alternatives. The result is a product with near-zero defects, a lower rejection rate, continuous uniformity and better pharmaceutical “elegance.”

But there are still plenty of human personnel transferring materials in the traditional way. Only a small number of companies–mostly giant corporations and small, forward-thinking firms–have installed automated loading systems, the people-free alternative to traditional material handling. Still fewer have attached their freeze dryers to a barrier isolator. It`s not for lack of interest, though. The new technologies require a significant capital investment and increased costs in the short-term–and they`re not for all applications.

“What`s driving this discussion is the need to eliminate sources of contamination,” says Bill Roedel, systems application engineer at Hull Corp. (Hatboro, PA), a freeze dryer manufacturer. “A second driving force is the option of alternative sterilization technologies, such as the use of a chemical sterilization process as opposed to steam pressure.”

Two approaches are emerging in the industry, Roedel says. The first is installing an automated loading system into a traditional cleanroom area and using it, instead of personnel, for material transfer. For example, Hull has installed a fully automatic loading system, designed to run unattended, at Nexstar Pharmaceuticals (San Dimas, CA). The second approach redefines the sterile core itself by attaching an isolator to the door of the freeze dryer, allowing the freeze dryer and isolator to be chemically sterilized.

Unfortunately, automated loading systems may be difficult, and possibly cost prohibitive, to retrofit to an existing facility. It`s far easier to start with an empty building and then develop a material flow layout from scratch.

Five years ago, when Pharmacia Upjohn Inc. (Albuquerque, NM) was adding on to an existing facility, engineers decided to install one of the first fully automated loading systems available. The company became one of the pioneers in testing the technology, and today it is in the final stages of validating the loader for several cancer drugs, according to Tom Romig, director of engineering.

Pharmacia`s loader, manufactured by Serail Freeze Drying Systems (Phoenixville, PA), is a batch system that occupies 20 square meters of floor space. The loader consists of three major pieces of equipment: a working table, a lifting rack for storage, and a loading cart. After the working table has accumulated three square meters of product, the system automatically transfers this pack of vials onto the lifting rack, which will accumulate 10 shelves of three square meters each, for a total of 30 square meters of shelf area and product volume.

After filling, the loading cart docks against the lifting rack and retrieves the entire 30 square meters of product at once. Then it rotates and travels along a pathway directly in front of the freeze dryer, where it docks and gently pushes the entire product into the freeze dryer. A second rear door on the freeze dryer allows another system to remove the product and transfer it to the capping equipment. The system is installed in a Class 100 cleanroom with full HEPA ceiling.

Pharmacia`s primary reason for installing the new technology was to minimize the number of people in the room and the opportunity for microbial contamination, Romig says. Engineers had also hoped that the loader would let a batch be filled while the chamber was finishing its sterilization-in-place cycles, thus allowing a faster turnaround. That advantage didn`t materialize with this early system, and the company had to use “trial-and-error” to get other kinks out. Romig says the loader runs smoothly now. “We have even validated the potential to handload, but we have never had to handload.”

For the past 10 years, BOC Edwards Calumatic (Buffalo, NY) has been selling both semiautomated and automated loading systems to companies worldwide. Two systems have recently been installed in Japan and Europe. The system in Japan was installed two years ago and is making product. The system in Europe was installed in early 1995.

The loaders, operating in Class 100 conventional cleanrooms, are completely integrated with the freeze dryers. One loader serves four freeze dryers, loading a single shelf at a time, and the system is fully automated. No people are in the cleanroom. All loading and unloading is triggered remotely and done without trays.

“We are finding that 50 percent of new inquiries are about a loading system,” says Malcolm Forrest, operations manager for the company`s freeze dryer division. “We see quite a fast movement in this direction because the benefits are recognized, and we can demonstrate that the technology is working.” Automated loaders have another advantage, according to Forrest: By eliminating people from the process, less space is required, so the cleanroom itself can be smaller and is, therefore, easier to keep clean.

In the five years since the Pharmacia installation, 80 percent of loader manufacturer Serail`s sales volume has included automated loaders, according to vice president John Connor. Now the company offers four different models and loading methods. Its systems have been installed at Smithkline Beecham SA – Biologicals of Belgium and Ciba-Geigy AG in Switzerland. The Smithkline Beecham system measures 60 square meters and has been validated. This year, the company will complete installation on multiple 20-square-meter automated dryers at Bayer Pharmaceuticals in North Carolina.

The cost of an automatic loader varies widely for each application. Vendors say the price tag for a large industrial loader begins at approximately $500,000 and goes up, depending on what options are selected. Options can include various loading techniques, special doors, automatic doors, HEPA filters and automatic clean-in-place systems.

Freeze Dryers in Isolators

The freeze dryers best suited for automation are the large industrial dryers used in pharmaceutical production. For the smaller dryers used by the biotech industry, measuring up to 15 ft2 in shelf space, automated loaders are impractical. These dryers handle small fill volumes and small vials and are used mainly for research and clinical trials. But in the past few years, users are becoming more interested in enclosing these freeze dryers in isolators, according to Cynthia Reiter, division manager for the life science division at FTS Systems, Inc. (Stone Ridge, NY).

Alkermes Inc. (Cambridge, MA) has installed a 10 ft2 FTS freeze dryer, which has been attached to a La Calh&#232ne workstation isolator. The integrated system is being used for preclinical pharmacology and animal studies in a general laboratory, not a cleanroom.

Alkermes` director of manufacturing technology, Dennis Croll, says the drug company actually brought the freeze dryer and isolator vendors together to build the system. “La Calh&#232ne made the aperture and port for it, and FTS made a modification in their freeze dryer so that they would have the bracket to attach the isolator,” says Croll. The project team originally got together in February 1995. The drawings were approved in April, and Alkermes received the system in July and started using it immediately.

Croll says the freeze dryer can maintain -80C in the chamber, allowing the company to store product there. The isolator can maintain a relative humidity of less than 20 percent and a temperature of 65 to 75F. “We felt it was an economical, and also a more advanced, technology over a traditional cleanroom,” Croll says. “It certainly cost a fraction of what it would cost for a cleanroom, and the timeframe to build it was faster. It will also be cheaper to maintain.” About the only support equipment needed is a small dehumidifier on the isolator to condition room air for use in the system.

While these smaller dryers can benefit from isolators, no one is aware of a large freeze dryer or automated loader attached to an isolator. “Putting a loading system in an isolator” is an industry dream, according to BOC Edward`s Forrest. Cost and technology logistics are significant hurdles, although a few vendors report they are working on the concept.

Chemical Sterilization

Alkermes` freeze dryer and isolator are both sterilized with vaporized hydrogen peroxide (VHP). “We can maintain sterility throughout loading, freeze drying and unloading,” Croll says.

Using VHP sterilization methodologies over traditional steam sterilization is attractive to many users and vendors. “People are looking for alternatives to steam,” Reiter says. “Steam puts freeze dryers under incredible stress, because freeze dryers have to go to low temperatures and low pressure ranges. Then, in the presence of steam, they have to go to high temperatures in a high pressure condition. It`s probably safe to say that this variance subjects those units to stresses, and any way to eliminate that stress would be considered an advantage.”

VHP is more friendly in terms of wear and tear on refrigeration equipment, and the cycle is about the same length of time–three to four hours from start to finish, Reiter says. FTS has eight units in the field that are VHP sterilized.

Validating VHP-sterilizable units is another question altogether, according to Larry Ulfik, regional manager, eastern division, of VirTis (Gardiner, NY), a freeze dryer manufacturer. “The bottom line is that the FDA inspectional guide states unequivocally that steam sterilization of the interior of a freeze dryer is an acceptable methodology, and it is a validated and proven process. So if one is investing in the future short-term, one would go for steam,” Ulfik says. Moreover, the cost of VHP for a freeze dryer is the same as steam sterilization, and since validation of VHP is chancy, “you are better off going with steam,” he says. VirTis has one freeze dryer in the field that is VHP sterilized and installed in a cleanroom.

VHP may or may not prove to be the best way to sterilize the inside of a freeze dryer, Ulfik says. Other methodologies may also be developed, such as steam hydrogen peroxide and ozone. n