Location, Location, Location
Facilities play a substantial role in streamlining or bottlenecking bioprocess workflows. “Designers of new facilities have the luxury of designing everything from the ground up, with upstream and downstream processes in mind,” says Dave Wareheim of Integrated Project Services.
“Greenfield” facilities may even incorporate room to expand or bring in new equipment. But when retrofitting the building is the starting point,“cramming a process into an existing shell requires slightly different judgment regarding interstitial spaces, whether the process will stand on the ground floor or higher floor, how to deal with drainage. Here facility and services can get in the way,” Wareheim explains.
Rising protein titers in mammalian cell culture bring higher upstream productivity and, potentially, lower cost of goods. The negatives are underutilization of upstream space and overtaxing downstream areas that were designed for less-productive cultures. In some situations, Wareheim reports that biomanufacturers have simply abandoned these facilities—not because of bottlenecks but because the plants have become too big for the process. “Utilization of 70 to 80 percent is fine, but when it gets down to 40 or 50 percent people start to worry.”
Where upstream and downstream processing mismatches result in bottlenecks, adopting new separation technologies can help, provided these methods are adopted early enough in process development. An obvious option is high-capacity resins, but these are expensive and, many believe, approaching their theoretical capacity. Similarly, companies might consider ultra high-throughput virus filters, but processors have long complained about the cost and time involved—up to 15 hours per batch.
Wareheim mentions several separation methods that might help. One is fluidized bed chromatography that combines cell removal with affinity-based purification. The advantage, besides a smaller footprint due to replacement of two processes (filtration or centrifugation plus protein A chromatography) with one, is de-bottlenecking of the centrifugation/filtration step.
Wareheim also likes simulated moving bed techniques employing multiple (but smaller) chromatography columns. “This technique takes longer but provides a two- to threefold reduction in resin costs.” Finally, he suggests in-line buffer dilution to minimize the number of storage tanks. “One or two companies are using this and doubling their productivity during buffer dilution with minimal added footprint.”