Look Within Downstream Itself
Despite the fact that downstream technology is out there and regulators are more open to it than ever, most processors are reluctant to deploy an entirely new process. For them, incremental improvements are more comfortable and familiar.
Dave Wareheim, subject matter expert in biotechnology at Integrated Project Services, believes that streamlining downstream processes can be achieved without significant changes to individual unit operations. Wareheim has worked with GE Healthcare on a system for adjusting pH in-line between columns, for example between capture and ion exchange. The technique works with bind-elute/bind-elute as well as bind-elute followed by flow-through chromatography. “It eliminates a collection vessel dedicated to pH adjustment,” Wareheim says.
A second, related technique involves in-line buffer mixing directly in front of the chromatography skid, which reduces buffer storage volumes. Warheim has co-invented (and applied for a patent on) a method linking chromatography and filtration steps directly, with no hold step, through in-line buffer dilution. As with any process, the slow step dictates overall throughput, but Wareheim says under optimal conditions throughput may improve up to sixfold.
In-line dilution and pH treatment save not only materials and time, but can help avoid costly alterations to a facility to accommodate higher throughput.
More complex is the application of SMB chromatography to the capture step, which can reduce costs associated with the “million dollar column.” Wareheim mentioned technology from Tarpon Biosystems, BioSMB™, which claims to outperform conventional chromatography by a factor of five while reducing purification costs by up to 50%.
Efficiencies can often be achieved simply by replacing expensive unit operations with much less expensive ones, which may be less risky.
The protein A capture step has been a target for cost improvement for a long time. In 2010, Bio-Rad introduced a cation-exchange resin, Nuvia™ S, with a dynamic binding capacity of up to 200 g/L—significantly higher than the best protein A resins available.
“A number of companies are actively exploring ways to replace protein A with cation-exchange capture,” says Randy Jacinto, Ph.D., senior product manager. “The question is who will implement it first at large scale.” One of Bio-Rad’s customers has, in fact, done so.
The resin lacks the specificity of protein A but provides other benefits, like removing aggregates and the ability to load the column directly from the clarification step. Cationic-exchange resins do not require conditioning, at least on the scale of protein A. Another benefit is price. Nuvia resins cost about $2,000 per liter compared with $12,000 per liter for protein A resins, Dr. Jacinto says.
So why isn’t Bio-Rad selling 50 tons per year of this resin? It’s hard to disagree with Dr. Jacinto that inertia plays a large role. “Companies stick with what’s worked in the past.”
The regulatory hurdle is also significant, as no company wants to be first to petition regulators for their blessing on new technologies. For now, unless a compelling business case can be made for switching, adopters will be companies producing mostly for preclinical or Phase I studies. Dr. Jacinto says one of Bio-Rad’s customers is considering Nuvia S in Phase III because “that traditional process is not delivering the economics they were hoping for.”
For whatever the reason, and despite opportunities to employ second- and third-generation separations methods, downstream experts continue to lament about bottlenecks. While technologies allowing full utilization of downstream capacity are readily available, one can easily construct economic models that justify staying put.
“It is sometimes profitable to revisit the whole purification process, when the regulatory burden is very high”—or perceived to be—“change is perhaps not worth it,” observes Dr. Holzer.