Input received from the EH&S and the quality teams has to be incorporated as part of the final layout to ensure the facility meets all their criteria, and the manufactured product is safe and effective. Not involving them early in the project will be detrimental and will likely result in changes to the design and impact to the schedule. This is when discussions around containment levels and criticality of systems occur. Sophisticated clients will determine the level of risk at every step of the way. Through their risk assessment, direction is provided in regard to level of redundancy, continuity of power supply, level of primary and secondary containment, administrative protocols for people and material movement (personal protective equipment and gowning needs included). They will pay particular attention when the manufacturing processes utilize potent compounds to deliver the API. As was the case for this facility.

For this project, the layout of the facility was sectionalized taking the flow of people and material and the criticality of the space into account. Criticality was evaluated on the basis of health, safety and environment (HSE) criticality and cGMP criticality. HSE criticality involves providing the proper work environment for the handling of hazardous substances and the safety measures and protocols needed in place to protect the people in the manufacturing space and surrounding areas. cGMP HVAC criticality involved providing an adequate environment for the manufacture and protection of the API in terms of cleanliness, temperature and relative humidity of the space.

The owner had definitive criteria that applied depending on criticality levels. For areas handling potent compounds, the access to the suites was through a dedicated gowning area, which contained a gowning room for entry and a separate gowning room for exit. A shower room was provided before the exit as an added safety measure. The API handled was classified as non-sterile dry powder with processing work carried inside the isolator, which was the primary safety barrier. Owner direction was to provide 10 to 15 pascal differential pressure between rooms of different cleanliness classifications and twice as much for rooms handling potent compounds, which needed to be kept negative and with a full pressure step differential (13 pascal) in relation to corridors. Various iterations where employed to meet the added challenge of the functional requirement of a shower out with a bypass.

The overall scheme for people movement and pressure cascades are depicted below. Code requirements limit the amount of force that personnel should apply to open a door unassisted my mechanical means. That meant the pressure differential across rooms needed to stay within certain parameters (less than 30 to 35 pascal) and that the room layout had to work accordingly to allow for a proper and safe pressure cascade without the use of assisted door openers. In the end, the team arrived at a solution that used air “bubbles” for the entry and exit points as a secondary barrier for separating the critical spaces (see image below) from the common areas. The imposed pressure differential between the bubbles and the critical space was set to approximately 26 pascal.

In addition, there was a pressure differential between the corridor and the critical space that provided an extra level of protection in the event of bubble malfunction. Safety was paramount and the design reflected that imperative.