In the summer of 2004, six men met at a Princeton, N.J. hotel to brainstorm a new aseptic filling facility for the University of Kentucky’s Center for Pharmaceutical Science and Technology (CPST): CPST managing director, an expert in business turnarounds, Frank Manella; Mark Gilbert, an expert in potent drugs who would manage the facility; and consultants Troy Fugate, Michael Perciali, David Matsuhiro and James Agalloco.
They emerged four days later with an ambitious plan: a sterile filling suite that could accommodate both potent and non-toxic compounds, in the same room at the same time. “We all hated corridors and walls,” says Manella. “It was all wasted space as far as we were concerned.”
Their vision will take shape this fall, when the new CPST facility, which was dedicated May 1, will open for business at the Coldstream Research Campus in Lexington. Sure, the facility may have a few corridors and walls, but it’s unlike any filling suite you’ve ever seen. The key to the design is mobile isolator technology, which allows product to be shuttled back and forth between contained process equipment via transfer boxes on wheels.
|View from the front: Kentucky's Center for Pharmaceutical Science and Technology’s (CPST) new sterile clinical drug manufacturing facility.
Mobile isolator technology has only been around for three or four years, and has only been implemented at a handful of sites, notably Therion Biologics (Cambridge, Mass.), notes Hank Rahe, technical director for Indianapolis-based EnGuard Systems, which designed and manufactured the mobile isolator network used at the CPST. “It’s a technology for existing facilities and smaller companies that don’t have hundreds of millions of dollars,” he says.
Filling goes something like this: Product enters the suite within one of the transfer isolators, whose doors are closed in a sealed attachment that has been decontaminated with vaporized hydrogen peroxide (VHP). The transfer box is docked with another isolator, such as that surrounding the vial filler, and the area within is disinfected via VHP before the internal doors are opened and product transferred.
Once complete, the doors are again shut and sealed, prompting another decontamination cycle. A single transfer takes approximately 40 minutes, and is repeated from station to station — as stoppers are ferried from autoclave to filler, for example, or vials moved from filler to capper or, for freeze-dried products, to the lyophilizer. Once product is sealed and capped properly, a discharge isolator carries it outside the aseptic core for labeling and secondary packaging.
Transfers are the hardest part of using the technology, says Rahe. Before mobile isolators were developed, the only way that manufacturers could link isolators was through rapid transfer ports (RTPs). “But RTPs doors must be round to work,” says Rahe, “and the [pharmaceutical] world we live in isn’t round.”
The vial filler, autoclave, depyrogenation oven and lyophilizer are the most critical pieces of equipment on Kentucky’s fill/finish line. Each presented its own containment challenges, since conventional isolators and standardized equipment could not be used for this project.
With the filler, the challenge was to ensure that the mounting table could accommodate the isolator, Rahe notes. The table had to be expanded and the surfaces made smooth for easy cleaning. EnGuard had worked with OEM Chase-Logeman Corp. (Greenville, N.C.) to design and build such a table at Therion so that, at Kentucky, it could provide detailed specifications to filler-maker Bosch Packaging Technology (Minneapolis).
The filler isolator has two chambers, Rahe notes, one above the mounting table and one below, which houses the equipment’s mechanics. The upper chamber has a positive pressure, the lower negative. Should a rotating shaft or other piece of mechanical equipment leak, the pressure differential assures that contaminants will flow toward the negative pressure, maintaining the ISO Class 5 environment above.
The autoclave, manufactured by Steris Corp. (Mentor, Ohio), presented challenges as well. The door to the equipment slides behind a fascia, so the Kentucky team worked with Steris to ensure that the fascia was sealed properly and that VHP could access all surfaces during cleaning.
To fit within its isolator, the Hull (Warminster, Pa.) lyophilizer was outfitted with a narrow, horizontal “pizza door” — something Rahe had worked with Eli Lilly to develop several years ago — into which vial trays are slid and then indexed up or down on a chain system. The trays may be placed several deep, making them hard to reach and presenting an ergonomics issue. Operators will use glove ports to access a variety of reaching tools — such as a stainless steel rod and hook — to maneuver the back trays.
Drawings and specs weren’t enough
Vendors were given strict guidelines on how their equipment should integrate with the other pieces on the line. Drawings and specifications were not enough. The OEMs used wooden templates as guidelines for sizing and bolt placement. One company would mark up a template, then ship it on to the next. For all of the equipment, Kentucky personnel joined in on factory acceptance tests (FATs).
“What’s on drawings is never what ends up on the equipment,” says Gilbert. “You can’t be off even an eighth of an inch.” Much to his surprise, it all worked. “We did not have to do any customizing on the floor,” he says.