MRI is one of the nation's leading independent, not-for-profit research institutes conducting work in the areas of life sciences, pharmaceutical product development, national security and defense, agriculture and food safety, engineering, and energy research. Headquartered in Kansas City, MRI has additional laboratories in Florida and Maryland. MRI also has managed the National Renewable Energy Laboratory in Colorado for the Department of Energy since 1977.

Building a lab for vaccine development support was a natural progression of the organization's capabilities, says Yolanda Arriaga, senior scientist and biotechnology lab director at MRI. The organization has a long history of pharmaceutical product testing, and has had experience working in BSL-3 labs. MRI wanted to be able to use small animals in the Kansas City facility, as well as BSL-3 pathogens, including select agents, and pathogens listed in the Appendix D of the Biosafety in Microbiological and Biomedical Laboratories (BMBL) manual.

"The infrastructure was already in place," says Arriaga. "We had a biosafety plan, safety procedures, security protocols, work practices, and tracking and inventory systems for select agents.

"We planned to build this laboratory as an expansion of our BSL-3 complex," she explains. "We already had a pass-through autoclave in place. We had our plans remaining from the facility. Most importantly, we had the same contractors that had built and continued to service and maintain our BSL-3 facility. We also had the same consultants."

In order to pursue the renovation, the organization faced a dizzying array of federal regulations that spell out not only how the lab is designed, but how it operates. MRI typically follows NIH and CDC guidelines listed in the BMBL. Because the organization wanted to use certain restricted pathogens, it also had to adhere to USDA guidelines for lab design. The USDA required MRI to double-HEPA-filter the exhaust from the lab, to weld all ductwork rather than taping it, and to decontaminate all effluent.

The overarching regulation, which was undergoing a major revision as this project got underway, is the Code of Federal Regulations issued by the Inspector General of the Department of Health and Human Services. The revised code assigns civil and legal liability to a company's handling of select agents, subjecting employees to fines and potential jail time for violations. Finally, because the lab is used for vaccine development, much of its work falls under the Joint Vaccine Acquisition Program, which is regulated by the Department of Army. The Army requires even more oversight and documentation than other federal agencies, including daily audits.

Although some of the renovations are required to comply with federal regulations, others are included for much more mundane reasons: The researchers requested two showers instead of one, for example, in order to reduce the amount it time it takes for them to leave the lab for lunch and at the end of the day.

Keeping on Track

The lab suite originally contained two radioactive labs and five BSL-3 rooms with a pass-through autoclave between them. The renovation construction team assigned the task of turning the radioactive labs into ABSL-3 labs was anchored primarily by MRI facility staff and long-time vendors, with additional suppliers, contractors, and distributors who could provide what MRI needed in the time required.

"The distributors really prioritized our work," says Arriaga. "They understood our timeline, and they managed their inventory accordingly. This was post-9/11 and after the anthrax events in October. The construction team was quite motivated, really out of a sense of patriotism, to try and do something in the biodefense effort."

The project required a great deal of oversight to maintain that motivation and stick to the rigorous timeline:

Week 1: The radioactive labs are decommissioned in accordance with Nuclear Regulatory Commission regulations.

Week 2: The labs are gutted, and work begins on the plumbing, electrical, and ductwork. The equipment is ordered, and the air handling unit is built locally.

Week 3: The stud work begins, the concrete is poured, and the ductwork is 50 percent completed.

Week 4: The ductwork, steel studs, block walls, plumbing, piping, and rough electrical work are completed.

Week 5: Controls, humidifiers, ceiling steel, and fan drives are installed.

Week 6: Showers, doors, ceilings, controls, walls, rooftop air-handling unit, and exhaust fan are installed; duct pressure test is completed.

Week 7: The lab is painted and finished; testing is done on the air-handling unit, exhaust fan, controls, and air balancing.

Week 8: Flooring is begun; leak testing is conducted; HVAC is tested.

Week 9: Biosafety cabinets are installed and certified; flooring is completed; leak testing is conducted; final adjustments are made; balance tests are reported.

Week 10: Labs are furnished, cleaned, and certified.

Week 11: CDC registers the labs.

"Starting with the second week, our construction team worked six days a week, and an average of twelve hours a day," says Arriaga. "Our construction manager was required to check on things twice a day to make sure we had enough labor and supplies, and to coordinate everyone so that we had sufficient space for our contractors to work."

In order to meet its deadlines, MRI went $80,000 over budget—a cost creep of about 25 percent—bringing the total project cost to $600 per square foot.

"This was a calendar-driven project, so we made some choices we might not otherwise have made, that we consider suboptimal," says Arriaga. "But our laboratories did pass all of their audits very well, and are CDC-registered and USDA-permitted. They are in use and are quite useful to us."

Space and Time Limitations

The rigorous government regulation and tight time constraints sometimes worked against each other. For example, USDA regulations require the lab to decontaminate all effluent it produces from the showers, sinks, and eye washes. At $270,000, however, a commercial system was too expensive and would have taken 12 weeks to deliver. So MRI's own facilities staff developed a system in one week at a cost of $6,000.

"It is inexpensive; it was fast to construct; but it has a lot of limitations," admits Arriaga.

Located one floor below the lab, the decontamination system consists of a flow-through retention tank with one incoming immersion pipe, one effluent pipe, a chemical disinfectant supply container, a pump, sensors, and a HEPA-filtered plumbing vent on top. Because the space is so tight, the pipes have to be vertical, so there is no way to measure the flow from the lab to the tank. Instead, sensors are installed throughout the lab to measure the flow of water as it goes into the sinks, eye washes, and showers. The flow of water is significant, because it determines the amount of chlorine that needs to be added to kill the pathogens before the effluent is pumped into the sanitary sewer. The limitation is that the tank is so small, it takes just 6 minutes and 48 seconds for the effluent to pass through the tank and into the sewer, giving very little time for decontamination.

The layout of the lab space also presents challenges with the air balancing system. To prevent pathogens from leaving the lab, the most hazardous areas of the lab—the animal holding rooms and the "dirty" side of the autoclave—must be kept at the highest negative air pressure. The lab contains three differential pressure zones, which is not difficult to design if the pressure changes occur in sequence along with the natural flow of traffic. In this lab, however, spaces with the lowest negative pressure—the "clean" spaces—are adjacent to those with the highest negative pressure. That means that the entrance and egress doors can never be open at the same time.

The air balancing issue within the new lab exists also between the ABSL-3 side and BSL-3 side, where researchers go to use a second, larger autoclave. They currently have to cross the entire suite to clean their larger animal cages, which necessitates that access to the "clean" spaces be limited during transport of waste. MRI plans to eliminate this inconvenience by constructing a corridor leading to the new autoclave.

Several features have already been added to the labs after the official renovation was completed, including carbon dioxide piping (to eliminate the need to bring in tanks); the larger autoclave in the BLS-3 labs; thermocouples dropped down through the ceiling into the cold units so that the service staff can work with the lab staff to calibrate the freezers and refrigerators without entering the laboratory; and an emergency generator for the entire building. In addition, timers were added to the biosafety cabinets to afford the animals the proper amount of light and dark time.

"We balance our air pressures with all of the biosafety cabinets running," explains Arriaga. "But to turn off the light in our new biosafety cabinets, you have to close the sash, which then turns off the biosafety cabinet air. So we have added a timer to coordinate the timing of the lights with our light and dark cycles in those rooms and still allow the air flow to continue circulating."

The facilities staff also has had trouble regulating the humidity level in the new lab, and has replaced its humidistats several times.

"We are bringing in some temperature and humidity control software to help us handle that," she says.

Operational Regulations

Since 9/11, government regulators are looking more closely at their contractors' security procedures. MRI had many of the practices in place already, such as requiring at least two people in a lab at all times, requiring them to use a badge to enter the lab, and to sign in and sign out. The company has strengthened its procedures by requiring staff to use a security badge to exit, as well. In addition, the Code of Federal Regulations requires contractors to designate a person to track the use of select agents, and local criminal background checks have been replaced by nationwide checks conducted by the Department of Justice.

The Army also requires MRI to do a more formal hazard analysis and daily internal audits of the select agents, in addition to the weekly and monthly audits required previously. Finally, proficiency observations previously conducted by the scientific analyst, the trainer, now must be performed by the biosafety officer.

"At MRI, we continue to do renovations with our facilities," says Arriaga. "We will take the lessons learned on our future renovations, and do everything we can with our operations to accommodate project-specific needs and procedures."

By Lisa Wesel

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