Jonathan Romero, Ph.D., senior engineer III at Biogen Idec, believes that some of the upstream-downstream capacity-mismatch is self imposed. “It’s when downstream says, ‘ok, let’s process it all’ that bottlenecks occur, particularly in older facilities designed for lower-titer processes.” And, absent market demand, overproducing introduces logistical issues related to cold chaining, storage, and, in a worst case, product expiration.
Dr. Romero suggests processing the batch to the clarification step and freezing half for later purification. Clarification is a good endpoint since for proteins the big purification cost is entailed at the capture step. Another option is to precipitate the product and store it as a salt.
Bottlenecks don’t usually arise around unit operations but from auxiliary operations like buffer mixing and storage. “Before you know it tanks become larger than the production vessels.” Expanding these areas, Dr. Romero says, involves huge capital outlays. “These bottlenecks are far more troublesome than capacity issues for resins or viral filters. People deal with those. You can still process when they occur.”
Dr. Romero’s group is actively pursuing what he terms “disruptive” technologies such as precipitation, expanded bed, and simulated moving bed chromatography, as well as squeezing as much productivity as possible from existing equipment and facilities. Those new technologies include precipitation, simulated moving bed, and expanded bed.
None have yet reached production levels at Biogen Idec. Dr. Romero cites time, space, up-front capital costs, production-scale validation, and suitability to platforming as the major challenges. “We’re always running the facility, so finding the right time to implement some of these technologies is difficult.”
An even greater concern is the degree to which, say, simulated moving bed chromatography will work with all or most of the company’s proteins, which include antibodies, fusion proteins, interferons, and others. “We’re reluctant to bring in technologies that may only work on one-third of our molecules. So at this point we’re looking for more of a stepwise improvement in the new operations, while squeezing as much productivity as we can from existing technologies.”