By Herman F. Bozenhardt and Erich H. Bozenhardt
This two-part article on biocontainment is a companion to our discussion of potent compounds, which focused primarily on chemically derived drug substances and drug components. While analogous to chemical potent compounds, biologically derived ingredients, intermediates, and products are produced by human manipulation of naturally occurring lifeforms and their byproducts. The key difference between the chemical reactor and the bioreactor is that the chemical has a finite life in the vessel, while the biological agent is adaptive to our planet and humanity. The diversity and complexity of pharmaceutical products developed over the years have pushed the research to explore the enormous variety of bacteria, fungi, viruses, and animal forms (including the exotic) on the earth. We utilize cell cultures from humans, insects, plants, and animals and with impunity genetically engineer them for our therapies. We must therefore practice a very careful assessment of our biological processes and develop robust containment strategies and designs for the safety of our environment and personnel.
While biocontainment may seem like a relatively new topic for the industry, the practice of biocontainment actually goes back to the days of development of the smallpox vaccine (1796), research by Louis Pasteur (mid-1800s), and the development of the Salk vaccine (1955). It is important to recall that in 1955, the pharmaceutical industry was stunned by the “Cutter Incident,” in which a breach of containment caused thousands of children to be exposed to the live polio virus, resulting in paralysis and death for some of them.
The Cold War drove countries to develop laboratories and facilities (e.g., Fort Detrick, Pine Bluff, Porton Down, Zagorsk, Sverdlovsk, etc.) that practiced biocontainment. These facilities and their methods provided the early guidelines for the U.S.-based National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC), which continue to provide our primary guidance today. The CDC and its analogous organizations around the world have harmonized on biocontainment and have developed the concept of biosafety levels, or BSLs, to categorize the risks and threats of biological agents and methods to contain them.
The handling of any biological agent requires an understanding of the agent and the risk of exposure to personnel, the facility, and the environment. The CDC and the NIH have used risk assessment to develop four ascending biosafety levels of containment required for use with biological agents, as follows:1, 2
- BSL 1 – work or processing involving well-characterized agents not known to cause disease in healthy adult humans, and of minimal potential hazard to personnel and the environment
- BSL 2 – working with or processing agents of moderate potential hazard to personnel and the environment
- BSL 3 -- processing or handling of indigenous or exotic agents that may cause serious or potential lethal disease as a result of exposure by the inhalation route
- BSL 4 –working with or processing a dangerous and exotic agent that poses a high individual risk of aerosol-transmitted laboratory infection and life-threatening disease.
In April 2002, the NIH published guidelines specifically directed at the industry that took a similar approach, but with more detail, called NIH Guidelines on Recombinant DNA:
- Risk Group 1 (RG1) – the agents used are not associated with disease in healthy adult humans
- Risk Group 2 (RG2) – the agents are associated with human disease that is rarely serious and for which preventive or therapeutic interventions are often available
- Risk Group 3 (RG3) – the agents are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available
- Risk Group 4 (RG4) – the agents are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available
If you are designing or building facilities around the world, most countries have their own equivalent regulations, and you are required to adopt their terminology.
- European Economic Community (Directive 93/88/EEC) is very similar to the NIH guidelines, but adds the concept of hazards spreading to the community as part of the risk criteria
- The Canadian Laboratory Biosafety Guidelines use the same terminology as the U.S. NIH; however, they take a matrix approach, looking at both individual risk and community risk as equal factors.
When considering the design of a biological facility in the United States, another key agency to work with is the National Institute of Allergy and Infectious Diseases (NIAID), which requires you to declare the organism you may be using (class A, B, or C), as well as any immunological studies or studies with emerging infectious diseases and pathogens associated with the organism.
- Class A agents are of the greatest interest (and threat in the NIAID criteria), such as anthrax, plague, flaviviruses, and filoviruses.
- Class B agents include food and waterborne bacteria and mosquito-borne viruses.
- Class C agents include tick-borne viruses, yellow fever, and rabies.
Finally, the NIH provides a very specific document called “Design Requirements Manual,” developed by its division of technical resources.3 This nearly-1,000-page document (updated in 2012) details everything from spatial relationships, architectural requirements, and HVAC and structural requirements to water distribution, emergency power, etc. This is a complete document that uses common good pharmaceutical engineering practices (similar to International Society of Pharmaceutical Engineering guidelines) and overlays the agency’s requirements for a functioning risk-mitigation design basis.
NIH, CDC, And The FDA — Which Way Do I Go?
Although the above discussion has centered on the NIH and the CDC, a facility designed and built in the U.S. must satisfy all applicable agencies. As a general rule, consider the following:
- The FDA regulates the manufacture and distribution of biological products in the U.S.; ultimately, the Center for Biologics Evaluation and Research (CBER) will inspect and audit the facility and license the product. Its mandate includes observing for cross contamination, material and waste handling, and personnel gowning practices. It is tasked with ensuring that you manufacture your product in compliance with applicable laws and regulations.
- The CDC is concerned with how you handle and process your agents, organisms, and product materials to protect your personnel, the community, and the environment from a contamination or outbreak. You must declare your process to the agency and correspond with it during the design and construction. The CDC will inspect the facility at its discretion.
- The NIH is concerned with how you build the facility and integrate equipment in accordance with the goals of the CDC. The NIH will direct questions to you on the design and construction and refer you to its guidelines.
- The NIAID is concerned with what organisms/viruses/pathogens you are working with and the risk they pose to the community. Through your contact with the CDC, there will be discussions that will be forwarded to NIAID as needed so it can assess any potential threats. If you are dealing with a class A agent, the NIH will correspond with the FDA and inspect the facility along with the FDA during periodic visits and at the pre-approval inspection (PAI).
In summary, these agencies do work together, and you must work closely with each of them, as well as your local, state, and municipal authorities, fire departments, and the Occupational Safety and Health Agency (OSHA) and the National Institute of Occupational Safety and Health (NIOSH), as needed. However, getting in front of the NIH and CDC is critical in the early stages of design, as they have a profound impact on the equipment selection, facility layout, and HVAC design.
In Europe, the individual countries have their own regulations, in addition to the EEC guidelines and the EU regulatory agency (e.g., Annex 1 and Annex 2).
In part 2 of this two-part article, we will explore the practical implications of these regulations on facility design.
- Centers for Disease Control and Prevention, Biosafety in Microbiology and Biomedical Laboratories (BMBL) 5th Edition, December 2009.
- Vince McLeod, “Biosafety Levels 1, 2, 3, and 4”, Lab Manager, December 2010.
- The National Institutes of Health, Office of Research Facilities, Division of Technical Resources, Design Requirements Manual, revised December 18, 2012.
About The Authors:
Herman Bozenhardt has 41 years of experience in pharmaceutical, biotechnology, and medical device manufacturing, engineering, and compliance. He is a recognized expert in the area of aseptic filling facilities and systems and has extensive experience in the manufacture of therapeutic biologicals and vaccines. His current consulting work focuses on the areas of aseptic systems, biological manufacturing, and automation/computer systems. He has a B.S. in chemical engineering and an M.S. in system engineering, both from the Polytechnic Institute of Brooklyn.
Erich Bozenhardt, PE, is the process manager for IPS-Integrated Project Services’ process group in Raleigh, NC. He has 11 years of experience in the biotechnology and aseptic processing business and has led several biological manufacturing projects, including cell therapies, mammalian cell culture, and novel delivery systems. He has a B.S. in chemical engineering and an MBA, both from the University of Delaware.