Downstream Processing

To assess current trends in separation and purification, BioPharm International turned to Mandar Dixit, head of product management–filtration technologies, Sartorius Stedim Biotech; Günter Jagschies, senior director of strategic customer relations, life sciences, biotechnologies, GE Healthcare; Richard Pearce, program director of purification, Millipore Corporation; and Jon Petrone, global technical director, Pall Life Sciences.

Q: What are the most important trends now emerging in the downstream processing of biopharmaceuticals?
Dixit: Disposable small-scale chromatography.
Jagschies: The need for higher capacity, especially with large mass production, namely MAbs. People are realizing where the much-discussed bottlenecks actually are: in the facility layout and in particular, the tankage capacity, not so much in the methods used for purification where modern tools exist that can take production a long way.
Pearce: How to manage and reduce costs through better plant and process operation efficiency.
Petrone: Increased bioreactor titers and the resulting greater protein loads to be processed require large chromatographic columns. The process of transferring large volumes of resin and packing large-scale columns can be a challenge.

Q: What application area do you see growing the fastest?Dixit: Membrane chromatography for contaminant removal from partially purified product.
Jagschies: MAbs are still the fastest growing field including some of the followers, such as antibody fragments and fusion proteins. Insulins and certain vaccines are growing fast too.
Pearce: Virus-removal processes.
Petrone: Process development groups are screening chromatographic sorbents and loading conditions for higher capacity. High-capacity sorbents offer the ability to reduce column sizes and thus reduce costs.

Q: What important breakthroughs have you seen in this area?
Dixit: Small, single-use resin-based pre-packed columns, membrane chromatography, and virus clearance technologies such as UVC.
Jagschies: More than a decade ago, Protein A chromatography was a breakthrough for manufacturing MAbs. This has enabled the platform concept for downstream processing MAbs and led to significant cost reductions. The increasing implementation of two-step purification schemes may become another one.
Pearce: Higher-capacity filters.
Petrone: The introduction of high-capacity ion exchange sorbents offers the ability for process development scientists to create more cost-efficient processes.

Q: Upstream titers are continuing to increase. Where do you think the solution lies to the downstream bottleneck? What obstacles stand in the way of the potential solutions?
Dixit: Increasing titers are creating larger quantities of cell debris to remove, so novel separation technologies could be needed along with existing ones to solve the downstream bottleneck.
Jagschies: Existing downstream technology of the current generation can handle processes up to 5 g/L. Whether higher titers make sense is part of the discussion right now, because it is difficult to see that anyone really needs them. If they make sense in case studies, one can assume that is in the context of smaller bioreactors; when the scale is smaller, there is no technical downstream bottleneck. Definitely, successful and economical manufacturing of the future is not dependent so much on high titers, but much more so on the flexibility of the manufacturing facilities. There are still areas for improvement in downstream technology: increasing the capacity of purification resins, decreasing membrane areas, and making virus filtration robust and less costly (single-use!).
Pearce: The solution lies in better plant operation and planning. Most plants have the potential to manage the higher titers; however, they need to be redesigned for faster turnaround.
Petrone: As titers increase, there is a possibility that a process won't fit in existing plants. The intermediate process and buffer tanks, and WFI supply may not have enough capacity to accommodate the process requirements. In-line concentration steps and the use of buffer concentrates with point-of-use buffer dilution are potential solutions.

Q: What is the future of downstream processing?
Dixit: Hybrid processes involving single-use and re-usable tanks.
Jagschies: [The future of downstream processing is] Bright to very bright as long as that remains true for biologics as therapies, for vaccines, and even future types of medicines. Purification will be needed for all approaches on the horizon. With all the technical improvements under development, and the manufacturing scenarios requiring producers to operate at smaller scale and with greater flexibility, we will see more standardized equipment solutions, and more use of disposable or ready-to-process tools.
Petrone: The combination of process steps as well as the use of continuous processing will lead to reduced processing times, greater plant throughput, and reduced costs.