Large-Scale Biosafety

There are unique considerations that must be addressed in order to ensure worker and environmental protection when working with biological agents in large-scale quantities.  Large-scale biological production facilities should use the laboratory scale principles of risk assessment set forth in BMBL Section 11, and by ISO 35001, Biorisk Management for Laboratories.  The utilization of larger equipment and volumes of chemicals or raw materials should also be considered.

With careful planning and a robust risk assessment of the unique requirements of a large-scale facility, it is possible to design and operate a facility that protects the product, workers, and the environment. 

Hazard Identification

  • Unique strains utilized primarily for research or manufacturing processes (e.g., producing high titers of a toxin);
  • High volumes (>10 liters) and high concentrations of product;
  • Specialized equipment and processes with unique risk points require a Hazard Analysis of Critical Control Points and/or Hazard and Operability studies;
  • Pressurized vessels and lines for biological and chemical reactions pose a risk for aerosol generation (e.g., bioreactors, fermenters, thermal inactivation tanks); and
  • Atypical routes of transmission (e.g., inhalation of biological agents or toxins not normally transmitted via the aerosol route).
  • Non-Biological Hazards
    • Hazardous chemicals: formaldehyde or similar for inactivation, large quantities of detergents, disinfectants and caustics, adjuvants, preser­vatives, solvents for down-stream processing, allergens or toxins, and asphyxiants;
    • Physical hazards: noise, steam, heat, cold, and radiation including UV and lasers;
    • Life-safety hazards: confined space, working at heights, line breaking, and pressurized systems;
    • Ergonomics;
    • Process safety-relevant controls (e.g., fire/explosions; pressurized systems);
    • Preventative maintenance (PM): solid and process effluent waste streams and control measures employed, including PM of relevant equipment;
    • Processes to control release of material (i.e., human and environmental risks), including corresponding emergency procedures; and
    • Risk points associated with equipment.

Hazard Evaluation

  • Increase in biological agent concentration
    • Increased growth
    • Vessel size
    • Aerosol generation due to enhanced aeration --Therefore, protection from aerosol transmission must be considered for agents normally transmitted by insect bite or injection. 
  • Increase in chemical risks 
    • Handling of dry powders for media preparation
    • Pumping of acid or base for pH control
    • Preparation/addition of inactivation chemicals for vaccine preparation
  • Increase risk of hazardous energy due to electrical, steam, and pressurized gases​

Exposure Control Measures

Risk mitigation strategies identified in large-scale research and production follow the same principles of the hierarchy of controls. 

  • Engineering Controls
    • Controls to prevent contam­ination spread within the facility and to the environment --Work "clean to dirty"
    • Establish donning and doffing needs and operational flow --Change rooms and barriers
    • Ensure airflow provides personnel and environmental protection --HVAC systems and airflow patterns
    • Ensure surfaces are impervious and easy to clean --Floor, wall and ceiling, door and window, and other exposed component
    • Design facility for spill containment --Consider biological, chemical, and physical processes
  • Work Practices and Administrative Controls
    • Apply good microbiological practices --Same as a biological research lab
    • Establish occupational health program --Offer workers appropriate medical surveillance/treatments
    • Establish emergency protocols --Plan for different emergency situations
    • Implement laboratory biosecurity protocols --Mitigate risk from an unintentional release and/or misuse
    • Establish an adequate training program --Review the epidemiology, signs/symptoms of infection, mode of transmission, risk-mitigating controls, emergency response procedures, and area-specific SOPs
    • Establish waste handling procedures --Consider inactivation methodologies for solid infectious waste streams as well as wastewater from production effluent
    • Offer adequate personal protective equipment --Assess PPE against physical, chemical, and biological hazards

 

Appendix K of NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) prescribes safety practices and containment procedures for large-scale (i.e., >10 liters per container) facilities. These guidelines can be applied to all large-scale work with biological materials (e.g., genetically modified organisms [GMO] and non-GMO, human, and animal/ zoonotic pathogens). 

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