Facility design and control considerations for mitigating viral contamination risk is a holistic approach to facility design and controls, considering all potential routes of viral introduction and spread. A living risk management approach should be taken to identify vulnerabilities and implement appropriate mitigation measures.

Facility Considerations

• Segregation of areas: Separate areas for cell banking, small-scale and large-scale upstream cell culture/fermentation, downstream processing, media/buffer preparation, materials management, corridors, and ancillary rooms (e.g. cold rooms, freezer rooms, storage areas).
• Traffic flow: Control and minimize traffic flow of materials, personnel, equipment, and air within and between areas and corridors. Implement room segregation strategies.
• Air handling systems: Design HVAC systems to maintain appropriate air quality and prevent cross-contamination between areas. Use HEPA filtration where needed.
• Room Classifications
  • For open operations:
    • Open sterile and aseptic operations must be performed in an environment where the probability of contamination is acceptably low, i.e. an environment meeting the bioburden requirements for a Grade A space.
    • Open bioburden-controlled processing may be performed in an ISO Grade 8/EU Grade C or EU Grade D environment as appropriate for the unit operation.
    • Open aseptic operations require a Grade A environment. Maintaining a Grade A cleanroom for large bioreactors is not feasible.
  • For closed operations:
    • Closed systems do not require cleanroom environments. ICH Q7 states that closed or contained systems can be located outdoors if they provide adequate protection of the material.
    • When all equipment used to manufacture a product is closed, the surrounding environment becomes less critical. The cleanroom requirements should be based on a business risk assessment and could be categorized as unclassified.
    • Housing a closed aseptic process in a Grade C or Grade B cleanroom would not mitigate contamination risk compared to an unclassified environment.
    • For low bioburden closed operations, the manufacturing environment can be unclassified.

Equipment Considerations

Closed vs. open processing: Utilize closed processing operations where possible to prevent introduction/re-introduction of viruses. Implement additional controls for open processing steps.

Closure Level	Description
Closed Equipment	Single use, never been used, such as irradiated and autoclaved assembles; connections are made using sterile connectors or tube wielders/sealers
Functionally closed equipment: cleaned and sterilized	Open vessels or connections that undergo cleaning and sterilization prior to use and are then aseptically connected. The connection is then sterilized after being closed and remains closed during use.
Functionally closed equipment: cleaned and sanitized	Open vessels or connections that are CIPed including bioburden reducing flushes, but not sterilized before use and remain closed during use
Open	Connections open to the environment without subsequent cleaning, sanitization or sterilization prior to use

Operational Practices

• Personnel controls: Implement rigorous training programs, safety policies and procedures for personnel working in critical areas.
• Cleaning and sanitization: Establish frequent and thorough cleaning protocols for facilities, equipment, and processing areas using appropriate cleaning agents effective against viruses.
• Material and equipment flow: Define procedures for disinfection and transfer of materials and equipment between areas to prevent contamination spread.
• Storage practices: Implement proper storage procedures for product contact materials, intermediates, buffers, etc. Control access to cold rooms and freezers.

Additional Controls

• Pest control: Implement comprehensive pest control strategies both inside and outside facilities, including regular treatments and monitoring.
• Water systems: Design and maintain water systems to prevent microbial growth and contamination.
• Process gases: Use appropriate filtration for process air and gases.
• Environmental monitoring: Establish environmental monitoring programs to detect potential contamination early.