Continuous and Intensified Bioprocessing: An Interview with Dr. Gerben Zijlstra

What is the difference between intensified and continuous bioprocessing?

Dr. G. Zijlstra: A fully continuous biomanufacturing process consists of interconnected continuous unit operations, without intermediate holding tanks, through which the product travels into the containers for Drug Substance in a seemingly constant flow.

Continuous unit operations represent an extremely intensified form of processing and have short downtimes relative to the amount of time they are used for production. A fully continuous biomanufacturing process might have a perfusion bioreactor coupled to a multi-column chromatography capture step, followed by flow-through virus inactivation, multi-column intermediate purification, a flow-through membrane adsorber polishing step, continuous virus filtration and a final ultrafiltration step operated in continuous mode. K.B. Konstantinov and C. Cooney have written an excellent review on this subject.

Some companies are adopting a hybrid approach to continuous biomanufacturing, such that only the upstream or part of the downstream process is operated continuously. I have seen companies operate a perfusion bioreactor in combination with a batch purification process and others that operate a fed-batch bioreactor with a continuous chromatography capture step.

The objective of process intensification, however, is to optimize the productivity of unit operations. Engineers can achieve this by using more concentrated process streams or optimizing process schedules to reduce downtime. Companies are intensifying upstream processes by increasing cell densities. They can intensify purification steps by increasing binding capacities or switching to flow-through modes that reduce processing time.

What are the relative merits of intensification versus continuous?

Dr. G. Zijlstra: Both intensified and continuous bioprocessing can be used to increase productivity, reduce facility footprints and reduce costs.

Engineers may decide to intensify processes without switching to full continuous processing to retain the batch nature of a unit operation or entire process. The relatively short batch cycles allow more flexibility especially in multi-product facilities. Moreover, the batch definition is very clear and companies can keep their traditional strategies for intermediate product release. In some ways, we can consider hybrid continuous bioprocessing with concentrated fed-batch upstream processes and continuous or intensified downstream processes to be the ultimate form of process intensification that allows the retention of the batch cycle.

However, continuous upstream bioprocessing has benefits because it can result in the product spending less time in the bioreactor and near steady-state production. This can give better product quality, less variation and reduce the opportunity for product degradation. Continuous downstream is probably the most productive processing scenario. Using counter current chromatography technologies, engineers can achieve good separation of product isotypes from very similar isoforms, which may be needed during the production of biosimilars.

In your experience, which of these process scenarios is the industry adopting the most frequently?

Dr. G. Zijlstra: Currently process Intensification and hybrid continuous processing are predominating. Companies are implementing process intensification strategies in state-of-the-art manufacturing platform technologies. To give some examples, some firms are using high volume and cell density seed stocks to reduce the length of the pre-culture phases prior to the inoculation of the production bioreactor. Others are using perfusion seed bioreactors to inoculate a fed-batch production bioreactor at the maximum working cell density. The use of concentrated fed-batch processing is reported increasingly.

In downstream processing, continuous capture steps are gaining momentum with the advent of new multi-column chromatography equipment suitable for commercial manufacturing. Scalable Membrane Adsorber technology is making large-scale single-use flow-through and bind-and-elute chromatography more feasible than ever.

Fully continuous processes are still mostly under development in the advanced bioprocessing centres of large pharma companies. However, we may see these in a manufacturing setting, for the production of labile products, sooner rather than later.

Which companies have experienced success with continuous or intensified bioprocessing?

Dr. G. Zijlstra: Many large pharma companies, CMO’s, and several smaller biotech companies are actively working on intensified and continuous bioprocessing. Companies such as Sanofi-Genzyme, Merck, Sandoz, Bayer, Shire, Amgen, Janssen and Pfizer have all reported some form of intensified or continuous activity.

Companies with a relatively small installed asset base, but a large product pipeline, are especially interested in developing these concepts. Companies with substantial installed base are mostly interested in improving their asset utilization by applying process intensification principles.

What kind of benefits are companies seeing?

Dr. G. Zijlstra: The benefits of intensification and continuous processing relate primarily to the reduced need to invest in the traditional, highly expensive production facilities especially when firms can use single-use and intensification synergistically. These approaches can also improve the quality of labile biologics and enable greater flexibility to run different molecule formats in the same facility. Finally, intensified and continuous biomanufacturing could allow more localised manufacturing strategies with companies operating many identical facilities with small-footprint across the globe.

What does the industry need in order to realise the potential of continuous or intensified bioprocessing?

Dr. G. Zijlstra: Intensified and several formats of hybrid continuous bioprocessing are ready for implementation right away. Perfusion seed bioreactors and concentrated fed-batch bioreactors can be implemented today. In downstream processing multi-column capture chromatography and intensified membrane absorber chromatography are coming within reach.  

Most importantly, the industry needs reliable supply partners that not only have robust high quality products and a solid supply chain, but also offer real process understanding and the engineering capabilities to translate the industries bioprocessing needs into turnkey process solutions that work.

Process development and scale-up tools, process and equipment design, automation concepts, facility layout, disposable design, are all fundamental ingredients that the supply partners should be able to offer.