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Interviewing experts on DSP intensification

  • by Ypso-Facto
  • September 12, 2022
Interviewing experts on DSP intensification

Process intensification allows biomanufacturers to produce more product, often more quickly, using fewer raw materials and smaller equipment in less space. While there has been much focus on upstream process intensification, this approach can have significant impacts for downstream processing as well. We interviewed Kilian Kobl (project manager at Ypso-facto), Yohann Le Guennec (Project manager at Ypso-Facto) and Lucrèce Nicoud (Head of Product Portfolio at Ypso-Facto) on the subject. Discover the interview below !


According to you, why is increasing the efficiency of downstream processes so important today?

Downstream operations in bioprocesses are challenging because of the extreme complexity of the mixtures to be purified. Crude solutions indeed contain a very high number of impurities, some of them being very similar to the product. 

In the last decades, major improvements have been achieved in upstream processing, in particular thanks to advances in cell engineering, cell culture media development and bioreactor design. As a consequence, the bottleneck has shifted from upstream to downstream processing, the latter representing now the major part of the production costs.  


What are the areas within downstream processing where process intensification can have the greatest impacts? 

The purification of biomolecules by chromatography consumes about 1000 kg of eluent per kg of product – this is enormous and we have to change this! Eluent consumption has direct implications in terms of cost, safety and of course environmental impact. I believe process intensification efforts should aim at reducing raw materials consumption and the associated generation of wastes. This will lead to greener, safer and cheaper processes - cheaper not only thanks to a decrease of operating costs but also thanks to a decrease of the footprint coming along with the reduction of storage units.  


What are the approaches available today to achieve process intensification in downstream bioprocessing? 

There are 3 main approaches: 

  • Fully experimental – either “trial and error” or testing all possible combinations. It appears rapidly that the latter approach is bound to failure. Consider as an example a simplified downstream process with 3 purification steps (e.g., Protein A, IEX1, IEX2), each step affected by 5 key operating parameters (e.g., column length, loading volume, buffer concentration, buffer pH, flowrate), each of this parameter possibly taking 3 values (low, medium, high). If you consider that 1 experiment takes 1 week, one would need several tens of thousands of years to test all possibilities! 
  • Statistical models. Mathematical relations (e.g., linear, quadratic) are used to correlate operating parameters (e.g., pH, flowrate) with responses (e.g., purity, recovery). This has the advantage of allowing to reduce the number of tested conditions and being applicable to any type of process. However, this suffers from a lack of predictive capability (e.g., if the experiments were performed in a single column in an isocratic mode, there is no possibility to predict what would happen in a multicolumn process or using a gradient elution). 
  • Mechanistic models. The physico-chemical phenomena at stake (e.g., acid-base equilibria, diffusion in the pores, interactions with the chromatographic medium) are identified and described by a set of equations solved numerically. This approach requires a certain level of understanding of the underlying separation mechanisms but is extremely powerful. Once the model parameters have been determined, the model can be used to predict new conditions “outside the box”. 


Do you think that intensified downstream processing can become the norm any time soon? What is still needed to make that a reality? Are any solutions under development that you can discuss? 

Process intensification is by essence the willingness to improve existing processes. Due to a constant pressure to develop cheaper, safer and greener processes, intensifying processes will always remain of major importance for the industry!  

A key aspect to process intensification is a close collaboration between all the teams involved in the development of a process, be they (bio)chemists or process engineers, at lab, pilot or production scales. Software tools can be extremely valuable to ease communication between stakeholders, in particular through the structuration of data to ensure the completeness and reusability of the information through various services and functions. 

 Author : Lucrèce Nicoud, Yohann Le Guennec and Kilian Kobl

Do you have any questions or comments on this? Contact us to discuss : 

Ypso-Facto is a service company helping industrial firms to develop, optimize and secure their chemical processes and bioprocesses.

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