October 2025 marks the 12th anniversary of National Biosafety and Biosecurity Month, an event sponsored by the American Biological Safety Association (ABSA) International. This is a great time to review all aspects of your biosafety program, including new initiatives that may be taking place, such as expansion into large-scale biological research or production.
Large-scale biological work is defined as using culture volumes greater than 10 liters per container by the National Institutes of Health (NIH) in Appendix K of the Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines). Per Appendix M—Large-Scale Biosafety of the CDC/NIH publication Biosafety in Microbiological and Biomedical Laboratories (BMBL), 6th Edition, the same volume threshold can be applied to non-recombinant work.
Based on guidance in the BMBL’s Appendix M, large-scale biological production facilities should use the laboratory-scale principles of risk assessment outlined in Section II of the BMBL and, as applicable, in the International Organization for Standardization’s (ISO 35001), Biorisk Management for Laboratories and Other Related Organizations. In addition to following the risk-based biosafety practices established for laboratory work, large-scale operations introduce unique hazards that must be considered to ensure the protection of both the employees and the environment. These include, but are not limited to, the hazards described below:
- Biological: Greater biological agent growth and at a higher concentration; increased vessel size and pressurization; and enhanced aeration magnify the aerosol generation risk. This also applies to agents normally transmitted only by other routes of exposure (e.g., ingestion, percutaneous).
- Chemical: Exposure risk is increased from the use of larger quantities of hazardous materials such as detergents, disinfectants, acids and bases for pH control, other caustics for bioreactor cleaning, and solvents for downstream processing.
- Physical: The operation of equipment such as batch mixers, reactors, pumps, and compressors can present a wide range of physical hazards including over-pressurization; exposure to excessive noise, heat, and cold; as well as those attributed to confined spaces.
- Ergonomic: Materials handling often involves moving bulky or heavy items that present a greater risk of ergonomic injury. Controls may need to be implemented to mitigate risk such as by mechanical means (e.g., lifts, hand trucks), work area modifications (e.g., automation to replace manual transfer of materials), task adjustments (e.g., rotating and/or varying work), and employee training (e.g., on proper lifting techniques).
- Energy-related: The risk due to hazardous energy sources (e.g., electrical, hydraulic, pneumatic) is often increased related to the equipment used. Therefore, hazardous energy control procedures may be more complex and require additional training for both authorized and affected employees.
In addition to the hazards unique to large-scale work, there are also special considerations for other aspects of the environmental health and safety (EHS) program such as waste management and spill response.
- Waste management: Larger amounts of waste often require different procedures and equipment such as effluent decontamination systems (e.g., kill tanks) to treat liquid waste streams. Solid waste management may necessitate implementing procedures for processing used bioreactor bags containing infectious agents (e.g., autoclaving or packing for transport and incineration).
- Spill Response: Large-scale spills can cause significant personnel exposure, facility contamination, and accidental release into wastewater systems and the environment. Engineering controls that can contain large volumes of liquids, such as berms, dikes, spill decks, and sloped/sunken floors may be needed to help confine unintended releases. Specialized and/or additional spill supplies may also be required, and adequate training, such as HAZWOPER First Responder Operations Level (FROL), must be provided.
When large-scale biological work is being conducted, the consequences of a deficient EHS program can be significant. By conducting a comprehensive risk assessment that takes into consideration its unique hazards and EHS requirements, the appropriate engineering, administrative, and work practice controls can be put in place to ensure both employee and environmental protection.
Whether your company is just getting started or is already conducting large-scale biological research or production, we can help you establish and maintain a robust EHS program that aligns with your company’s current good manufacturing practice (cGMP) standards—contact us!
This blog was written by Beth Graham, Safety Partners’ Director of Quality, Research, and Training.
