"BSL-3 and -4 research facilities can be some of the most complicated and expensive buildings in the world. Regardless of whether it's a remodeling project or a new facility, it's essential to conduct a risk assessment at the beginning of the planning process," says Jeff Schantz, senior vice president of Science + Technology at Hellmuth, Obata + Kassabaum (HOK) in Atlanta.

Conducting a risk assessment not only determines what measures need to be taken for overall safety and security, but what specific protocols are required for handling the intended pathogens. Protocol dictates many key design elements including the need for shower in/out capability, gowning in/out zones, autoclaves and sterilization equipment, decontamination techniques, HEPA filtration, double door airlocks, and mechanical support considerations.

"Facilities working with select agents are subject to the security provisions of the Patriot Act, but that is not the complete story. You have to look at what is really required in the current regulatory environment for the type of research being conducted. That’s why site security and risk assessment plans should be done first," he says.

For example, expensive pressure-sealed doors, liquid effluent decontamination, and chemical shower facilities are not required for every BSL-3 facility. They are only required in certain BSL-3+, BSL-3AG or BSL-4 rated facilities, and come with a host of other logistical issues.

"If your facility is designated BSL-3Ag or BSL-4, protocol dictates that you install pressurized doors and create pressure-tested primary containment. That means you have to work through all the issues of specialized concrete construction associated with the room as primary containment," says Schantz.

Commissioning is critical to the creation of a successful BSL-rated facility. It is essential to bring the commissioning agent on board the design team early in the process to take full advantage of this approach. This will allow the creation of an operational intent document that will serve as a guide to the field tests required for certification. Exact design specifications have to be met throughout every stage of the construction process and the commissioning process provides a method to assure the facility works as intended.

"I think that you cannot overstate the value of commissioning. Organizations that are not commissioning their facilities should find a way to do it, even if they self-commission. It is something that has to be done," he says.

Airflow + Integration

Pathogen containment in all BSL-3 and -4 facilities is achieved using negative pressure gradients combined with controlled directional airflow, but there are a variety ways this can be achieved. Users and designers should carefully consider their options based on the protocol and research techniques that are planned for the space.

For example, biosafety cabinets are required for all BSL-3 lab work, but with BSL-3AG—the rating for large animal holding facilities—the room must function as the primary containment.

"In this situation, you have to think about containment design in relation to the room, as well as the equipment," says Schantz. "The room as a primary containment requires particular attention to construction details related to sealing the room. This includes sealing all penetrations, seams, and joints."

Recently, the trend has been to co-locate animal holding and research space within common barriers or containment, as close together as possible, often with integrated workflow in mind.

"It's a matter of choosing where to draw the barrier or containment line around your facility. Is it going to be an entire zone, a suite, or a single room? There are some definite advantages to having an integrated containment facility,” he says. “There are also cost advantages to making the footprint of that zone as small as possible."

The components of integrated lab space include providing air-locks for entry and exit, a method of gowning in and out, an animal holding area, sterilization equipment, and a place to do procedures.

Recent advances in cage rack and ventilation design have revolutionized the layout and operation of animal holding rooms and increased the potential for integrated research space. In many facilities, the primary barrier or containment has shifted from the room to the cage. In this environment, it is important to review transfer methods and protocols to insure that the barrier or containment environment is maintained throughout the procedure cycle.

"The technology of caging systems is really starting to catch up to research now. We are seeing systems that can be barrier or containment, with positively and negatively pressured environments at the cage level, and cage racks that are capable of supporting the cage as its own containment or barrier device. When using these systems, it is very important to think through what the protocol is. It becomes about the transfer. What happens to the animal when you take it out of the box? Is it done in the safety cabinet, or in some other form of containment?" asks Schantz.

Integrated research labs increase space efficiency, improve workflow, and allow researchers to save steps in gowning and animal transport time. Additionally, all-in-one containment reduces construction and operating costs.

"Planners shouldn't underestimate the amount of time it takes people to integrate into the environment, especially in facilities with multiple pathogens and protocols. Just the gowning time between environments can slow things down." says Schantz.

Workflow + Equipment

A major consideration in the design of all animal facilities, whether under barrier or containment protocols, is material flow and the processing of contaminated materials. A clean/dirty two-corridor system provides a safer one-way workflow and is generally preferred, but is not mandatory. The decision to go with a dual corridor design is typically based on space constraints, cost, and research protocols.

"If you have the option of having a dual corridor design it increases flexibility, but if you don't have that option, it is not the end of the world. A good compromise can be struck using a single corridor design with suites," says Schantz.

Decontamination of cages, equipment, and the space itself also presents significant cost and operational issues.

"The primary decontamination method is the use of steam sterilization such as autoclaves, but there are lots of other methods that can be used, especially with BSL-3AG and ABSL-3. Vaporized hydrogen peroxide (VHP) or paraformaldehyde systems are available. VHP doesn't degrade equipment, but may not be effective under all conditions. It is important to remember that VHP is a surface decontaminant, and does not penetrate." says Schantz.

In some cases, the use of fumigation rooms to sterilize contaminated equipment before it is moved can ease transport difficulties and lower the cost of equipment by allowing a shared cagewash outside of the primary containment.

"Fumigation rooms are useful because they allow you to transport bulkier equipment, like cage racks, out of the containment zone to places where they can be washed. They leave the containment zone in a sterile but dirty condition so they can be safely transported," he says.

Modules + Equipment

Space flexibility is maximized through the use of modular designs that can accommodate a variety of instrumentation, procedure techniques, equipment, caging systems, and floor plans.

"If you configure rooms in such a way that they only serve a single purpose or protocol, you are stuck with that design in perpetuity. Flexibility is greatly enhanced when the module dimensions are planned to handle multiple types of equipment and protocols so the space can adapt as the science evolves or the mission changes," says Schantz.

In regards to animal facilities and BSL labs, HOK prefers an 11 x 11-foot module as a starting point for design.

"It is an odd dimension, but 11 feet seems to work well in terms of getting the proper space between cage racks and different equipment sizes,” says Schantz.

Schantz also recommends the use of interstitial floors or corridors to accommodate HVAC equipment and maintenance. He also emphasizes that, regarding interior surfaces, it is very important to specify the right materials and make sure that they are installed properly.

"You want to avoid creating conditions that will cause materials to fail. For instance, if you have multiple compound corners that have to be sealed, that is a problem. You really want to do things with smooth surfaces," he says.

Protocols + People

The high cost of creating BSL facilities drives a need for flexibility. The ability to work with multiple pathogens and protocols or change research emphasis enhances flexibility, but increases logistical complexity and cost by layering the required number of protocols.

"In terms of flexibility, it’s important to consider what will be necessary to accommodate multiple pathogens and procedures. If you have the budget, including shower in/out capability in your ABSL or BSL-3 design significantly increases flexibility, as it allows the implementation of protocols necessary for the use of riskier agents" says Schantz.

Researchers considering work with avian pathogens under ABSL-3 or BSL-3 protocols will have special considerations. The housing and control of avian subjects requires specialized caging, especially in handling infected birds. It is advisable to use isolation chambers specifically designed for birds to avoid cross-contamination and to protect lab personnel from emerging infectious diseases. Handling avian species with emerging infectious diseases also requires the extension of protocols beyond the lab. For instance, lab personnel with potential exposure to avian pathogens should not have any contact with birds outside the lab for a prescribed period of time to avoid the transfer of emerging infectious diseases to domestic or wild avian populations.

"As we have seen with avian flu, these pathogens spread very quickly in avian populations and along migratory routes," says Schantz.

Another important consideration is the integration of personal protective equipment (PPE) into the protocol, and how it will affect facility plans. Those protocols that require extensive gowning, the use of PAPRs, or pressurized suits will need to accommodate the storage and decontamination of this equipment within the containment. The use of chemical showers, pressurized pass-throughs, and access to autoclaves on exit may be required to meet more stringent protocols. Designers should also think carefully about the storage and disposal or recycling requirements for PPE, especially for environments that may cross over into clinical uses related to vaccine production, cell transplantation, or other biologicals. This would include adopting cGLP/cGMP protocols as required by the FDA under CFR 21.

Regardless of size or complexity, Schantz emphasizes that the most important thing is understanding specifically what pathogens will be used and what research techniques are being conducted. The design and implementation of proper and effective protocols are in many ways as important as the facility design.

"You have to know what you are working with. If you are on the facility planning or operations side, it's important to get to know the researchers. Find out what they are doing, how they are doing it, and what equipment and protective gear they are going to use. A successful safety paradigm includes the building design, the people, and the protocols all working together," he says.

By Johnathon Allen