SAIC Frederick is the current prime contractor for the National Cancer Institute (NCI) at Frederick, Md., providing a range of research and development services to the National Institutes of Health, the Department of Defense (DOD), and other federal government agencies. Approximately 3,000 people and 100 buildings are located on the Fort Detrick, Md., campus, with more than one million sf of usable floor space.

In late 1997, the DOD asked SAIC Frederick to produce a new vaccine against Venezuelan equine encephalitis (VEE). The vaccine—which is an attenuated form of the live virus, with a 12-genome deletion—had been developed by researchers at another lab on the Fort Detrick campus. Initial data from experiments with non-human subjects were promising, and the DOD now needed additional quantities for the next stage of testing.

"This is typical of a vaccine that has no real commercial value," says Randall Morin, director of Environment, Health and Safety on the NCI-Frederick campus. "There aren't enough folks out there worried about VEE for any of the biopharm companies to really want to make something like this. So they will usually come to our facility because we have a full fledged biopharm plant that is GMP certified."

VEE—It's Not Just for Horses Any More

Venezuelan equine encephalitis (VEE) is an acute, mosquito-borne viral disease that produces fever, aches, and other flu-like symptoms in humans, sometimes progressing to encephalitis in severe cases. VEE also causes serious disease in horses and their biological cousins (donkeys, mules, etc.).

Endemic to northern South America, Central America, and some parts of southern North America, VEE belongs to a group of infectious agents that could be used in biological weapons, and, therefore, are of particular concern to government researchers and regulators. Although human mortality rates from VEE infection are low—less than one percent—almost all those who become infected show symptoms; a malicious release could thus cause significant social and economic disruption.

Because it is a threat to both humans and animals, VEE and its derivatives are regulated by both the Centers for Disease Control and the United States Department of Agriculture. As an arbovirus—a shortened reference to "arthropod-borne virus"—it requires special handling, including HEPA filtration on exhaust air. Given its potential use in bioweapons, security requirements include background checks on personnel and round-the-clock monitoring of the virus and the vaccine, in addition to sound building security systems.

Facility Conversion—Main Challenges

To house the vaccine production program, SAIC Frederick scientists chose Building 459, opened in 1996 as a GMP facility mainly for production of materials created through recombinant DNA research. As a GMP facility, the building was designed to operate under positive pressure, not negative; it was never intended to house production of live viruses, and certainly not at the BSL-3 level.

The company began renovation work shortly after receiving the DOD request. Morin and his team identified a suite within the building for renovation, consisting of two lab spaces and an anteroom, with roughly 800 sf of space. The project stopped and started several times due to competing priorities and various problems with the facility, and was eventually completed in December 1999. Start-up of vaccine production was also delayed, mainly due to changes in staffing and the time requirements associated with vaccination of new employees. Preparatory work began in May 2001, and active production of the virus was initiated in August 2002. The completed vaccine was delivered in August 2003.

"Our task was to upgrade this space from existing BSL-2 to BSL-3, while retaining GMP qualities for production. So we had to upgrade the exhaust air, enhance the spill containment abilities within the suite, and seal a lot of penetrations," says Morin.

Because the space was already built to BSL-2 specifications, the basic air-handling infrastructure was in place. With some new fans and some tweaking and rebalancing of existing fans, the facility engineering staff was able to essentially reverse the ventilation in this area and turn it into a BSL-3 suite while maintaining the GMP qualities.

Supply air was already HEPA-filtered; exhaust air is now HEPA filtered as well (a specific requirement due to the nature of the agent being produced). Biosafety cabinets are ganged together, with redundant blowers, allowing the cabinets to continue to operate if one blower stops working. The filter system itself was upgraded to a "bag-in-bag-out" (BIBO) system.

The entire ventilation system is computer-controlled, and supply and exhaust are interlocked, with emergency cutoff dampers, so that if for some reason the exhaust air fails, the supply will shut down automatically, maintaining negative pressure inside the suite. The lab space undergoes 30 air changes per hour.

The renovated suite also features a pass-through autoclave, which allows satisfaction of FDA requirements for GMP, since materials don't have to be brought back into the lab after autoclaving. The team had originally thought they would face a challenge dealing with disposal of potentially infectious waste, but the autoclave solved this. Morin describes the actual autoclave as a "dinosaur:" the vessel itself is about 25 or 30 years old.

"It still works, though. We obtained it from the Army and outfitted it with all new controls. These are big, expensive, highly specialized pieces of equipment, and we were very fortunate to get one that the Army had designated surplus," he says.

Utilities, Spill Containment, Personnel Protection

Utility connections in the suite are sealed using a system designed by one of the facility maintenance staff. The utility coupling is first sealed to a sheet of Plexiglas, which is then sealed to the wall. The system provides excellent sealing and isolation, while permitting easy removal for repair or replacement as necessary.

The facility's emergency generator was already oversized, with enough surplus capacity to handle the utilities added to the BSL-3 suite.

Poured epoxy floors within the suite feature an integral three-inch cove. A raised door sill provides additional assurance that any spills are contained within the space.

The suite also features a hands-free sink with ANSI-approved eyewash. A safety shower is located in the hall; not the ideal arrangement, Morin admits, but a workable solution under tight time and space constraints.

One of the major issues the project team faced was protecting employees who would be working on the vaccine production program.

"Since SAIC generally doesn't work with infectious agents of this type, few of its employees are vaccinated. And since they're civilians, you can't exactly order them to take an experimental vaccine," says Morin.

The team discussed using personal protection equipment (PPE) in lieu of vaccination for those who chose not to be vaccinated, and even agreed with DOD representatives on an acceptable alternative: a Tyvek suit equipped with a purified air-powered respirator, which provides HEPA filtered air under the face shield. In the end, everyone except maintenance personnel agreed to be vaccinated, so that no one actually used this alternative approach.

As another way to limit the number of people who would have to be vaccinated to work inside the suite, video cameras in the lab permit additional researchers to observe the work from outside the BSL-3 suite.

To provide security, Building 459—like all buildings on the Fort Detrick campus—is protected through electronic cardkeys. Front-desk sign-in provides a second level of security, and a punch-code system on the door into the suite serves as tertiary security.

Morin also had to address issues of transportation and material management, as the completed vaccine had to be moved to another facility for storage until the DOD could take delivery of it. Given the sensitivity of the agent, chain-of-custody issues are paramount, and both security and sterility must be assured each time the material changes hands.

"Concerning security, we are fortunate, being on Fort Detrick, since there is a fence around the place with guards carrying machine guns," says Morin.

VHP Decontamination

The refit also provides new connections for vapor-phase hydrogen peroxide (VHP), so that the suite can be decontaminated without using formaldehyde, which is generally not suited to use in a GMP environment, as its residue can compromise product purity.

During decontamination, VHP is pumped into the room until it reaches a predetermined concentration; that concentration is maintained while the VHP is re-circulated for the required amount of time. At the end, the remaining vapor is essentially "vacuumed" out of the room.

Costs and Future Prospects

Morin figures that the upgrade cost $200/sf. When added to the original building cost of $450/sf, this means that the 800-sf enhanced BSL-3 GMP suite cost roughly $650/sf total.

"I think that is a little bit low, to be honest with you," says Morin. "I don't think that captures all of the costs. But we did almost all of the work using our own engineering staff, with very little involvement by outside contractors, so we saved money that way."

Now that the facility exists and is capable of supporting GMP production at the BSL-3 enhanced level, other clients have expressed interest in contracting with SAIC Frederick for specialized production activities. The company currently has several other projects coming on line, including production of vaccines against polio virus and herpes virus.

By John Treat