GE Healthcare Life Sciences is now Cytiva - Find out more

December 05, 2017

What you need to know about continuous processing

By Jenny Dunker, Global Product Marketing Manager, BioProcess Hardware at GE Healthcare

There is a lot of interest around continuous biomanufacturing, but could a hybrid of batch and continuous unit operations be the best solution for your process train?

Challenges and opportunities

As continuous processing is expected to have a significant impact on the biomanufacturing industry over the next few years (1), the challenges and opportunities of such technologies are intensively discussed (2). Continuous processing can help resolve many bottlenecks in biomanufacturing by streamlining operations. The high level of automation of such an approach can improve process consistency by decreasing the need of manual interaction, thereby reducing the risk of human error. Continuous processing can also have a positive impact on product quality when working with products with tight specifications or unstable targets that require short residence time or would benefit from steady-state operation in the different process steps. However, continuous processing is usually considered more complex than a batch process, and a feedback/feedforward control strategy with right automation is desired to ensure a consistent product quality. Process development in line with the quality by design initiative also becomes more complex, as there are more process parameters and time factors to consider.

In upstream operations, perfusion culturing is the choice when high viable cell densities are desired, enabling a high productivity at a small footprint. Perfusion culturing allows cells to be maintained in exponential growth phase for an extended time period, as fresh medium is constantly fed, while spent medium is removed. The target product is also constantly removed, preventing degradation/modification or aggregation of unstable targets. However, the medium consumption is significantly higher in a perfusion setup than in a batch culture.

For downstream processing, periodic counter-current chromatography (PCC) is a suitable choice. In a PCC setup, columns are switched between the sample loading step and the non-loading steps, comprising column wash, elution, cleaning in place (CIP), and equilibration, in contrast to a batch setup, where the process material needs to be detained in a hold tank while the chromatography column is subjected to cleaning and equilibration. For connection to a perfusion culture, a PCC setup could therefore be an attractive option, as process material from upstream production and harvest steps can be continuously fed onto the downstream purification column, which reduces costs related to both equipment and floorspace. Such a setup, however, requires a dynamic control functionality that allows the PCC system to adjust for variations in the incoming feed concentration. Additionally, in contrast to upstream, where several regulatory approved processes use perfusion culturing, none of the currently approved downstream processes include continuous chromatography. Compared with a batch process, the column cost might also be higher and there are more columns to pack in a PCC setup.

Need-based analysis

The choice between batch or continuous does not need to be either or for your whole process train. Depending on the prerequisites of your process, implementing one or more continuous unit operations and one or more connected steps together with more traditional batch process steps can be the best choice. Andrew Sinclair, President and Founder of BioPharm Services, confirms: “It is often stated that continuous processing requires perfusion upstream and continuous downstream. This is not the case. Manufacturing modes can be envisaged where fed-batch bioreactors feed a continuous downstream operation, and this currently looks to be an attractive option”.

Implementing an end-to-end continuous process in biomanufacturing might still be years away for most companies. For certain areas, however, continuous or connected processing can provide some real advantages. The benefits of continuous processing outweigh the risks in some situations, but it might not be practical for all bioprocesses. “In my view, it will require innovative thinking around, automation, PAT, and online release to realize its full potential”, Andrew concludes.

In the choice between continuous and batch processing, experts in continuous manufacturing can help you perform a need-based analysis of your different unit operations. Such an analysis can help you identify situations where continuous processing could improve process consistency and product quality, while reducing cost and operational bottlenecks to maximize productivity and efficiency of your whole production train.

Sign up for the next post that will discuss single-use versus stainless steel equipment in downstream bioprocessing.


  1. BioPharma survey report: State of the global biomanufacturing and bioprocessing industry 19 Oct. 2017.
  2. Galliher, P., Jagschies, G., Dua, A.R. Supplement: Continuous Bioprocessing: Is It for Everyone? GEN 37 (2017).