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).