Continuous biomanufacturing offers the potential for more agile, flexible production with improved robustness through the elimination of process steps, including hold steps, and the use of smaller equipment and facilities.
Since product is harvested continuously, continuous, and integrated upstream/downstream systems also provide alternatives to batch-cell culture-based processing for molecules with inherent instabilities.
In describing its MaruX™ continuous biomanufacturing platform FUJIFILM Diosynth Biotechnologies (FDB) mentions its possible benefits for “products that may not have a fully-defined clinical and/or commercial forecast” through supply chain simplification.
MaruX employs perfusion-ready Chinese hamster ovary (CHO) cells continuously cultured within a 500-L single-use perfusion bioreactor, which feeds into an alternating tangential-flow filtration cell-retention device. Purification relies on “intensified batch purification” with column cycling and product pooling before final filtration and formulation.
Nick Hutchinson, EngD, business steering group lead for mammalian cell culture at FUJIFILM Diosynth Biotechnologies, describes this approach as “semicontinuous” since it exploits control and validation strategies already established for batch processes with the advantages of process intensification.
“MaruX is semi-continuous in that, following the second chromatography step, we collect a pool of intermediate purified product, and then process sub-lots of this pool through the remaining downstream steps,” Hutchinson tells GEN.
This strategy is based in part on the meager economic benefits to running the final purification steps continuously. “Our third chromatography step for monoclonal antibodies is relatively inexpensive, so there is little to be gained from operating this to high cycles,” he continues. “This isn’t the case with protein A capture, where rapid cycling offers enormous advantages in process economics, including halving the cost of consumables.”
The second benefit is that the platform uses control strategies similar to those used in fed-batch processes, and viral clearance validation is identical.
“We believe that delivering a semi-continuous process will facilitate adoption of continuous processing generally,” according to Hutchinson, who does not view “semi-continuous” as a steppingstone of any sort, or an entree to fully continuous processing.
“If there was a situation where we thought that fully continuous was a good option there is no reason, from a technical perspective, why it couldn’t be done. We don’t think it’s likely that we’ll see such scenarios, however, and we’re not planning for this.”
Platform avoids large upfront investments
FUJIFILM Diosynth offers MaruX as a more-efficient manufacturing option, and lower cost-of-goods, in a fully single-use process, explains Hutchinson, adding that the platform avoids the large upfront investments in raw materials and consumables required for large-scale manufacturing of products whose success is yet to be determined.
“MaruX works really well for recombinant proteins where stability is an issue, but we are also getting a lot of interest from clients with antibody products who are looking for innovative ways to ensure efficient manufacturing to help them defend against competition from biosimilars,” Hutchinson says. “I anticipate that customers will choose to implement the platform as part of early development, but some companies have been interested in using MaruX for commercial products, which is something I did not expect. These customers are thinking about their business continuity plans and want to have options to ensure they can always meet market demand.”
Interest in continuous biomanufacturing waxes and wanes, with regulatory uncertainty most often cited as a reason for slow uptake. “Which is why we think our semi-continuous approach is the right one,” points out Hutchinson. “I think we’ve reached a tipping point, and we’ll see a change as companies address smaller markets with more targeted therapies while experiencing greater price pressure from biosimilars.
“Firms are beginning to take a longer view and recognize that investments in technologies that make manufacturing processes more efficient add real value to their projects. That said, I think the full potential of MaruX has yet to be appreciated. It’s easy to see ways in which we can increase productivity, scale and capacity to make manufacturing ever more efficient and help biotech customers develop medicines for patients with unmet clinical needs.”