What are the key initial considerations and need-to-knows for yourself and client before you embark fully on a new cell and gene therapy project?
AB: Early in the design process, I need to understand where the client is at with their process. All of this is relatively new technology, and some of the technology or production platforms might be sourced from just one or two vendors. I need to get a feel for the state of their process technology and how familiar they are with it.
An issue I see with a number of clients is that they own the product and they may have carried out the basic research and development but they are subcontracting the production for clinical trials to a contract manufacturing organization (CMO), and sometimes don’t always know all the details of what that production method is.
Beyond their immediate manufacturing needs, I also want to understand what the future state of production is. Often early in development, you’re doing things that are perhaps not the way you want to do things 5 years out. So, I need to know from a client: what’s your planned technology changes? How will this process train be different in the future? And look to design their cell and gene therapy facility with that in mind.
GL: For me it’s essential to under-stand the functional needs of the facility, in order to come up with a design for a space that meets those needs. In addition to that, and perhaps more important are three things: the client’s process, their operations strategy, and business drivers. Upfront it’s critical to understand the ripple effect these three items have in how I design the overall facility.
Understanding the process down to the level of characterization of product material is essential. For instance, is there something that would qualify as BSL2 type of cells or viruses, or are there viruses that will require special containment and decontamination cycle strategies? Is there a virus reduction or clearance step that requires physical segregation? Unit operations and level of process closure are also important; all these things really point me to specific regulatory requirements, or guidelines, that will shape how I design the facility to meet proper room classifications, flows, and segregation and containment strategy.
On the operation strategy side, I need to understand the redundancy criteria and equipment utilization rates, as this can really drive up the quantity of the equipment or sometimes the number of production suites themselves, if companies want to have the capacity to have one shut down for maintenance while the other one still operates. It is also important to understand their strategies around manual operations versus automated systems, as well as shift structure. How they plan on operating the facility would have an impact on the overall facility and site; lockers rooms should be sized to avoid bottleneck during shift change, and sufficient parking spaces for employees when they arrive at work.
Lastly, the business driver, as in the projected market demand and their tolerance for business risk, really sets the dial for what level of flexibility and future expansion capabilities need to be built into the facility. In the early conceptual phase of a project, there’s usually a wide range for the projected market demand. Sometimes I hear ‘if this product takes off and we outgrow this building in 3 years, that would be a good problem to have’. But we’re also sensitive to the fact that would mean there are sick patients with unmet needs. On the flip side, there’s also a concern that maybe the market demand or approval process through clinical trial won’t go as planned, and if that’s the case, what do we do with this capital investment? Under-standing that range of market demand in both extremes helps me design the facility in ways that would meet their primary target, as well as providing them with a space that could be prepared for secondary or even tertiary plans if things don’t go quite as planned.
NK: I agree that a major concern is if the trials do not go as planned or demand is not as you expect. There’s a lot of uncertainty and variability in the processes. One of the tools we have used successfully, and I recommend very highly, is discrete event simulations. They are essentially a specialized or advanced version of a Monte Carlo simulation, so you have a Markovian chain of Monte Carlo simulations.
This allows you to characterize any uncertainty, for example any unplanned downtime of equipment, patient demand explodes tenfold, or you fail in clinical trial 3. Beside this we also use visualization models to visualize the operations and the process. The models are capable to import a layout, then overlay your operations on top of that to help visualize whether this room is adequately sized or whether you need to expand the room so that you don’t have people bumping into each other or working shoulder to shoulder.
These tools can also reveal a lot of different nuances. For example, a sample management room is usually only manned by one or two people inside the room, but at 8 o’clock in the morning everyone comes to collect samples or handover their samples, which creates a traffic or choke point in that particular corridor. This helps understand operations and overlaying those operations on the layout can visualize those areas where they need to give more attention.
Another tool we find valuable, computational flow and dynamics that, instead of modeling operations, helps model the air flows or gas flows or fluid flows, and helps understand how we want to design our HVAC systems, and locate supply and return systems, etc., to minimize the risk of cross contamination and improve air flows within spaces.