For Dirk Müller, Dr-Ing, manager media and process development at Sartorius, cost reduction is the underlying motivation for scale-down modeling and process intensification.
“Biopharma firms are interested in process intensification for several reasons: intensification can help to increase product output of existing facilities by either shortening required process duration and/or higher productivity per production run, often by two- to four-fold,” he tells GEN.
“This, in turn, helps to reduce Cost of Goods (CoGs) and provides greater scheduling flexibility in multi-product facilities, especially if intensification enables switching from stainless steel to single-use systems with simpler switch-over protocols. Moreover, process intensification provides a convenient way of producing a required amount of product with a significantly smaller facility footprint, thus lowering investment cost.”
Drug companies that want to intensify processes face technical challenges, according to Müller, who says preparation begins on the factory floor.
“Intensification usually goes along with higher volume requirements of media and buffers, so suitable concentrates and handling infrastructure like inline dilution need to be developed further to maintain the footprint advantage and environmental process sustainability,” he points out. “You need to handle much higher cell densities and—for continuous processes like perfusion—also larger media and harvest liquid volumes. This necessitates to have the right equipment and a well-developed fluid handling logistics in place when making the switch.”
Fortunately, Müller says, such solutions are available ranging from single-use reactors for growing cells to around 100 million cells/mL to devices able to harvest from high-density cell broths to multi-column product capture technologies.
In other areas, more is needed, notes Müller.
“The industry would profit from progress on technologies for different process steps. For example, scalable solutions for frozen high cell density seed cultures in bags can further shorten seed train duration and enhance flexibility,” he says.
The best way of intensifying a process is to model each step in miniature, states Müller, who outlined such an approach using “scale-down” models in a recent study.
“An intensified process only works if all elements play together well. This starts with the cell line, but also involves the right media system, cultivation equipment and purification strategy,” he explains. “Scale-down models can help us to efficiently test different clones or different process variants in parallel in a short time frame.
“Importantly, we can have a more nuanced look at different cell line aspects beyond mere productivity already at this stage if we know what is relevant for a stable intensified process, like long-term viability or stability of critical product quality attributes. Thus, this tool can greatly speed up process development timelines and avoids delays in speeding to he clinic.”
Scale-down modeling is already widely used in fed-batch based production processes, and this experience is likely to encourage its adopting for process intensification, continues Müller.
“We consider this key because people in the industry can test intensified process variants in early development, build trust and optimize settings to see if it works in their hands,” he says. “This makes it much easier to adopt an intensified process strategy.”