Jens Vogel, Ph.D., global CMC development team leader at Bayer, believes the downstream capacity crunch is somewhat overblown. “Downstream bottlenecks do occur in existing facilities producing very high-dose monoclonal antibodies for multiple indications. But based on our experience, for most products and indications, existing unit operations are sufficient if you optimize and scale them properly and work on process intensification and scheduling.”
The real bottleneck for companies like Bayer, Dr. Vogel says, is bringing larger numbers of molecules through the pipeline as quickly as possible. Here, he says, downstream bottlenecks can occur for non-mAb therapeutic proteins for which platform purification processors do not exist.
Bayer is seriously considering negative chromatography to simplify downstream operations, improve quality, and reduce costs. “Negative chromatography becomes more attractive when your upstream platform produces very high titers,” Dr. Vogel says. With high masses of target proteins, he says, it sometimes makes more sense to bind the relatively smaller amounts of impurities. Like most biotech firms, Bayer already uses disposable membrane adsorbers for polishing, a practice Dr. Vogel says will expand as newer generations of membranes emerge.
Bayer’s interest in alternative separations arises in part from its diverse product pipeline that includes complex, highly potent, nonantibody molecules. But if adopted, techniques like negative chromatography must be applied early in process development—not just to mitigate potential regulatory hurdles but to avoid delays in getting drugs into the clinic.
Bayer is investigating negative chromatography with third-party partners and considers the effort evolutionary. “If it comes too late for a particular molecule, at least we have taken it to proof-of-principle stage and can plug it in when the next project comes along.” Dr. Vogel believes that Bayer could eventually develop a purification process based on one packed bed affinity column and two disposable membrane steps—one for capture and one for polishing. Such a system would work particularly well with highly potent, labile proteins but not with large-volume products like antibodies.
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.”