Biomanufacturing evolution from conventional to intensified processes for productivity improvement: a case study

Abstract

Process intensification has shown great potential to increase productivity and reduce costs in biomanufacturing. This case study describes the evolution of a manufacturing process from a conventional processing scheme at 1000-L scale (Process A, n = 5) to intensified processing schemes at both 1000-L (Process B, n = 8) and 2000-L scales (Process C, n = 3) for the production of a monoclonal antibody by a Chinese hamster ovary cell line. For the upstream part of the process, we implemented an intensified seed culture scheme to enhance cell densities at the seed culture step (N-1) prior to the production bioreactor (N) by using either enriched N-1 seed culture medium for Process B or by operating the N-1 step in perfusion mode for Process C. The increased final cell densities at the N-1 step allowed for much higher inoculation densities in the production bioreactor operated in fed-batch mode and substantially increased titers by 4-fold from Process A to B and 8-fold from Process A to C, while maintaining comparable final product quality. Multiple changes were made to intensify the downstream process to accommodate the increased titers. New high-capacity resins were implemented for the Protein A and anion exchange chromatography (AEX) steps, and the cation exchange chromatography (CEX) step was changed from bind-elute to flow-through mode for the streamlined Process B. Multi-column chromatography was developed for Protein A capture, and an integrated AEX-CEX pool-less polishing steps allowed semi-continuous Process C with increased productivity as well as reductions in resin requirements, buffer consumption, and processing times. A cost-of-goods analysis on consumables showed 6.7-10.1 fold cost reduction from the conventional Process A to the intensified Process C. The hybrid-intensified process described here is easy to implement in manufacturing and lays a good foundation to develop a fully continuous manufacturing with even higher productivity in the future.

Technology outlook for real‐time quality attribute and process parameter monitoring in biopharmaceutical development—A review

“…Based on our experience thus far, we envision two specific objectives for developing PAT tools in biopharmaceutical development: An analytical platform to support intensified‐process development (J. Xu et al, 2020), where major CPPs and CQAs are monitored in a real‐time or near‐real‐time fashion, providing more information than traditional offline analytics. Systematic progression of PAT tools from the development space to manufacturing to enable RTR and Industry 4.0 concepts.…”

“…An analytical platform to support intensified‐process development (J. Xu et al, 2020), where major CPPs and CQAs are monitored in a real‐time or near‐real‐time fashion, providing more information than traditional offline analytics.…”

“…Biotherapeutic manufacturers are keen to generate higher titers with high concentrations at the drug product stage as a part of process intensification (J. Xu et al, 2020). However, highly concentrated formulations are more susceptible to biomolecular aggregation, leading to highly turbid and viscous solutions (Bailly et al, 2020).…”

Overcoming challenges of improving legacy biopharmaceutical processes

“…In the upstream cell culture process, improved cell line and expression system and novel strain engineering techniques can help to improve product yield, productivity and product stability 7,8 . An intensified seed culture scheme to enhance cell densities prior to the production bioreactor, such as using enriched seed culture medium, could be an efficient strategy for increasing manufacturing capacity without modifying the production bioreactor, make fed‐batch processes highly productive and may enable flexibility of manufacturing capacity with limited volumetric capacity 9–11 . Perfusion cell culture is another process intensification strategy, with the potential to achieve higher cell density and productivity, that has also attracted increasing interest, and been adopted in biopharmaceutical manufacturing 12,13 …”

Why Is Batch Processing Still Dominating the Biologics Landscape? Towards an Integrated Continuous Bioprocessing Alternative

“…Similarly, several technological developments lowered the risk of contamination during in situ product removal as in continuous bioprocessing [18,19]. Besides resolving the risks during continuous processing, increasing the historically low upstream drug substance titer in batch biologics manufacturing (<1 g/L) has been an important underlying driver for the exploration of continuous processing in biologics [20]. A solution came with perfusion processes that kept cell counts constant while exchanging culture supernatants with fresh media at regular intervals.…”