From a business perspective, many pharmaceutical manufacturers have begun considering multimodal facility design to diversify their pipeline and help bring commercial-stage products to market.
While it may be important to a company’s profitability, multimodal facility design becomes a sophisticated puzzle, complicated by regulatory requirements, materials costs, and the realities of the processes required for each mode of operation.
Typically, cGMP sites will have one focus, with additional research opportunities that are not as intensive from a capital investment and utility standpoint. Bringing in multiple modalities for clinical and commercial production simultaneously adds the additional effort of supplying multiple unique process utilities, cleanroom strategies, and complex personnel and material flow paths that must interact with each other without the risk of cross-contamination across product lines.
Is it possible to fit several very different operations into one cohesive facility? What compromises must be made within the shared spaces to allow full manufacturing capability within each product mode? ?
Easy in concept, complex in execution
Multimodal facility design is not a hard problem to understand: You’re effectively trying to compress multiple different facilities into the space typically taken by one. The difficulty lies in the realities of making that happen. Supporting utilities, shared spaces such as media and buffer prep, and warehousing—each of which might otherwise need its own complete set of designs—must instead be accommodated in a single design while still offering capacity for every mode to be undertaken.
It all makes for a lot of mathematics. On the process side, it becomes a complex decision to determine how many different modalities at different scales will be operating concurrently. You have to combine your assumptions on equipment utilization and utility diversity to determine which equipment will need to run simultaneously. With those calculations, you can understand how a particular application might tax a standard set of utilities. That’s important because it enables you to build in capacity for other applications at a very high level.
The architectural issues can be complex, with differing segregation levels depending on the modality mix. When considering how much square footage you have in a room, a shared space room must wear multiple hats. You can no longer have a storage room for one product when it may have to accommodate five products. It’s a matter of efficiency in maximizing a design footprint in any way you can.
That’s true not only for the in-suite spaces, but for all of the “above the ceiling” elements that nobody sees. HVAC, mechanical and electrical systems all have to be streamlined in design; there’s little room in the construction phase to find out you’ve run out of space. Fortunately, 3D modeling and BIM coordination in a typical engineering design approach can address many of those issues—but only if they’re built into the process from the start.
Similarities and differences in modalities
Of course, some unit operations do share some common ground. For example, let’s consider oligonucleotide, mRNA/LNP, and AAV. These all have similar requirements: ISO8/ISO7 cleanrooms, clean compressed gasses, and (from a generic point of view) some warehouse and inventory requirements.
However, their differences can be stark—the oligonucleotide portion requires bulk flammable solvent usage, generating flammable waste. That, in turn, requires high-hazard space development, the potential for tank farms and solvent handling strategies, and additional protection measures. Depending on the scale, much of this can be delivered in an automated, closed process, limiting some risk and potential for hazardous exposure.
The LNP process has a similar hazard profile, albeit typically at a much smaller scale. It introduces a new hazard set—manual operations and flammable material handling in a ballroom-type environment.
Finally, AAV, being a viral manufacturing process using human cell lines and with a BSL-2 rating, needs complete segregation from other processes. Separate locker rooms, air locking requirements, and unidirectional flows take up additional space that cannot be shared with other modalities, increasing the required footprint of a multimodal site.
Key considerations: regulatory and cost
Ultimately, the biggest challenges of multimodal facility design fall into two main categories: regulatory issues and cost. Let’s look briefly at each.
Regulatory issues. On paper, it’s not the most difficult thing to discuss design: A product here, another there, a third elsewhere, add doors, corridors, HVAC, and electric, and you’re done, right?
But it’s when dealing with viral products that require close monitoring by the FDA, the challenges become extremely demanding. Viral products, for example, need to be segregated and have their own independent systems. Design criteria may be accommodated well on paper, but—to take one example—the FDA may not allow a utility service to supply two separate production processes without some level of segregation. Biosafety level is also a concern when producing viral vector products, with considerations around the handling of both solid and liquid biowastes streams to be addressed during design.
Other considerations may include the handling of hazardous materials. Oligonucleotide processing, for example, can be chemically hazardous, using flammable solvents and corrosive chemicals on a much larger scale than required for the same capacity of product used in an R&D lab.
Consequently, it’s not just the cleanroom labs that must be considered in designing multimodal facilities. Thousands of gallons of flammable solvent being stored on-site carries its own set of permitting and hazard issues. The storage rooms may now be rated as hazardous rooms, requiring electrical classifications, HVAC, and fire protection measures not typical of “ordinary” facilities. Procedures for moving aqueous solutions, pure solvent, and other flammable materials open clients up to concerns they may have previously not had to worry about. These issues then creep into the other design modes because it is now a site-wide issue.
Multimodal design often boils down to a fine-line interpretation that requires regulatory and engineering experts to work together closely. The design must be feasible for the company and meet the complex regulatory requirements that the FDA or other governing authorities impose to ensure product safety.
Cost. We all hope that current supply chain challenges will eventually resolve, but in today’s world, we’re finding that everything is nearly twice as expensive as it might have been a year ago. Clients that arrive with conceptual designs as recent as six months old may be shocked to realize material costs have already doubled since the project’s inception.
A prime example is stainless steel. Compared to projects completed in 2020, today’s projects may see the cost of steel doubled. This has ramifications for both building construction and equipment costs. In the example of stainless-steel facilities, that means the process portion of the entire project may have doubled.
The industry is not far enough out of the COVID-19 crisis to know whether the prices will correct themselves to pre-pandemic rates; at the moment, it’s difficult for suppliers to stand by even 30-day price guarantees. Historically, in cases like this, industry trends have shifted towards single-use manufacturing to alleviate these concerns. Current supply chain challenges have also influenced single-use distributors, meaning the decision isn’t as straightforward—clients have to weigh and evaluate their options in these (still) unprecedented times.
It is true that, from a business perspective, multimodal facilities may enable companies to research and bring to market more varied types of treatments and therapies than they might have otherwise. But the considerations at play in the cost and regulatory compliance of multimodal facility design and construction may be out of the comfort zone of companies previously used to manufacturing a single product.
Organizations looking to expand into multimodal projects would do well to work with design, engineering, and construction companies with previous experience in such work. They can orchestrate a design that doesn’t compromise an individual modality while maximizing efficiency by considering shared overlap wherever possible.