Q: Has Downstream Processing Technology Caught up with the Significantly Higher Titers Coming Out of the Current Upstream Process? If No, What Issues Remain?

Downstream Processing

Andrew Bulpin, Head of Process Solutions Strategic, Marketing & Innovation, MilliporeSigma
A: Yes, downstream technology development is advancing to accommodate higher titers via multiple chromatography approaches, utilizing resins with increased capacity and mass transport that require shorter residence time. In addition, increased volumes downstream are addressed by high-flux virus filters and ultra filters to relieve bottlenecks.

Michael Murray, Downstream Process Development, FUJIFILM Diosynth Biotechnologies U.S.A., Inc.
A: Downstream technology is lagging behind the upstream output of high-titer monoclonal antibody expression. Vendors are continually working to increase resin capacity and throughput, but we are finding incremental improvements. Gains to date are largely based on processing and cycling strategies designed to maximize throughput at each chromatography step or by combining steps, as is the case for continuous processing. In addition, the large volumes of chromatography buffers needed for mAb processes are a problem for manufacturers. Improvements in flow through membrane technology have reduced buffer amounts and process times while improving the ease of execution. 

Kimo Sanderson, VP Marketing and Client Services, Asahi Kasei Bioprocess America, Inc.
A: From Protein A to ion exchange to mixed mode, there have been significant improvements in chromatography resin binding capacities over the past several years that have enabled the use of smaller columns or higher loading. Further, recent techniques such as Single-Pass Tangential Flow Filtration (SPTFF) offer an opportunity to streamline concentration steps. Additionally, newer virus filters that are specifically designed to handle higher concentration protein feed streams have also helped to improve downstream efficiency. Finally, technology to enable just-in-time buffer production, such as Inline Buffer Dilution (IBD), has dramatically reduced one of the major downstream bottlenecks. Taken together, these incremental improvements have helped to narrow the gap between upstream and downstream productivities. Issues still persist, especially as it pertains to $/g downstream cost, which is encouraging a look at novel continuous or semi-continuous processes as opposed to classic batch approaches.


Andrew Bulpin

Andrew Bulpin is Executive Vice President of Process Solutions for the life science business of Merck KGaA, Darmstadt, Germany, and is based in Bedford, MA. He joined the organization in 2006 as Vice President of Upstream Processing and later assumed leadership of the Services and Solutions business. He has also served as Global Head of Sales for Pharmaceutical Chemical Solutions.