Addressing barriers to the shift to downstream continuous processing

Perfusion reactors have made continuous processes a viable, albeit still not commonly used, way of doing upstream manufacturing steps. Downstream processes are therefore the main obstacle to the fully integrated continuous production of monoclonal antibodies and other biologics.

Advances in technologies such as simulated moving bed systems have pointed to ways to move from batch to continuous processes downstream. There is still work to do if the industry is to widely use continuous downstream processes on a commercial scale, though.

Researchers at the University of Adelaide School of Chemical Engineering and Advanced Materials set out the state of the move to continuous downstream processing in a recent paper​​ in the journal, Chemical Engineering Science​. The paper identified key areas the industry still needs to address.

Process control and the handling of unsteady product streams featured prominently in the discussion of the key challenges that may limit broader use.

“Product titers may change over time and chromatographic unit operations produce product streams varying in concentration, which might influence subsequent unit operations and therefore require a continuous adaption,”​ wrote the researchers.

Towards mainstream adoption 

The industry will need to understand how to control such a process and validate and characterize a continuous process to make progress toward mainstream use of the approach. Equally, there remains a need for new knowledge about finding design spaces for robust processes and the identification and monitoring of critical control points.

As the University of Adelaide researchers see it, manufacturers will need a deeper understanding of the underlying processes if they are to resolve the remaining uncertainties. In doing so, companies may also address regulatory barriers to the switch to continuous downstream processing. 

Advocates of continuous processing argue companies that work through the outstanding challenges will be rewarded with a way of producing biologics that is faster, more productive, more flexible and cheaper overall. Yet, as the University of Adelaide researchers note, there remains a need for “reliable and easy to use models”​ to analyze “cost of goods at different scales.”​

The researchers see deeper economic analyses of continuous processing as a crucial step in winning broader acceptance in the biologics manufacturing industry. Sanofi garnered awards and plaudits for the digitally enabled, continuous manufacturing facility it opened in Massachusetts last year but it is an outlier in an industry that largely remains wedded to more established ways of making medicines.