It is suggested upstream technologies have improved faster than those downstream. But the idea of a “downstream bottleneck” is something of a misnomer

Gareth Macdonald

August 1, 2019

2 Min Read
Bemoaning bottlenecks? Put a cork in it! Downstream techs better than ever

Innovative methods and techs have reshaped downstream operations says an industry expert.

If you Google “biopharma” and “bottleneck” most results will be articles suggesting upstream technologies have improved faster than those downstream.

But the idea of a “downstream bottleneck” is something of a misnomer says Tom Ransohoff from BDO. Instead he argues the upstream gains reflect where innovation efforts have focused.


“When antibody and protein titers in mammalian cell culture systems were less 1 g/L several decades ago, the capacity limitations were almost exclusively defined by bioreactor scale, i.e. upstream. As a result the focus of improvement for many in the industry was disproportionately on the USP side for a decade or more” Ransohoff said.

Less to gain

In contrast, downstream processes have not been a focus because there was less room for improvement Ransohoff says.

“Most antibody processes have overall downstream process yields of ~70%; for recombinant proteins, this number is a bit lower.

“The ceiling on recovery for downstream processes is 100%, so the opportunity for gains is limited to ~2x. On the upstream side, titers have increased from <1 g/L to approaching 10 g/L over the past two decades, so the realized gains there are several orders of magnitude.

“As a result, the perception is that USP technologies have “improved more,” but I’m not sure that is a really fair comparison,” Ransohoff said.

Downstream innovation

Innovation in downstream technologies is not about yields – although efforts continue in this area. Instead, the focus is on cost reduction and general efficiency improvements.

Chromatography and ultrafiltration are among the most common downstream processing techniques. They are effective and a wide range of technologies are available.

But neither approach is very efficient, which is a major driver for technology developers says Ransohoff.

“One of the shortcomings is the relatively high cost of chromatography media and the inherent inefficiencies of batch processing.”

He added, “There are a number of exciting improvements in DSP technologies that are in various stages of implementation by manufacturers.

“One is continuous processing for all DSP unit operations, which has great potential to improve capital utilization and volumetric productivity.

“Another is continued improvements in affinity technologies, both improving the capacity and stability of existing resins as well as the ability to discover novel affinity ligands where needed, Ransohoff said.

Real-time monitoring systems – process analytical technologies – are also becoming more common downstream.

Ransohoff told us “the integration of analytical technologies into DSP operations promises continued movement towards better product quality control and shorter product QA release times.”

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