An aphorism from the world of chess is applicable to biomanufacturing: “You’ve found a good move—now look for an even better one.”
Having achieved leaps-and-bounds improvements in volumetric efficiencies through optimization of cell lines, media, and feeds, bioprocessors continue to look for “better moves.”
Presentations from the recent CHI Bioprocessing Summit in Boston illustrated how improving, tweaking, and applying process understanding can lead to even greater productivity, even in the age of multigram-per-liter cell cultures.
Media and feed now receive most of the credit for cell culture productivity jumps, to the point where they remain an area of focus. Brandon Pence, global marketing director at Thermo Fisher Scientific, noted that the analytical tools employed by media designers and manufacturers to develop their products are now employed, inline, to bioprocessing.
“These techniques—HPLC, mass spectrometry, and others—provide real-time feedback on the state of the culture by monitoring the consumption of nutrients,” Pence said, “to the point where they are even driving various formulation and feed strategies.” Process analytic technology enables processors to approach manufacturing in a more controlled fashion, to drive volumetric productivity without the risk of overfeeding, or overengineering formulation design.
Thermo Fisher has dovetailed its strong instrument/PAT capabilities with media offerings and single-use bioreactors, and developed strategies, processes, and protocols around the integration of analytics into disposable processing.
The success of PAT in cell culture depends on scale. In-line analysis is cumbersome in shaker flasks because of sampling and analysis logistics, and in some instances, sample size. Single-use bioreactors already at production scale can incorporate feed lines, removing samples in real time, and delivering them to an automated system for prep and analytical work. Moreover, these operations can occur without disrupting the culture, continuously, in real time.
It has been almost a decade since the FDA issued its guidance on PAT. To describe progress as slow would be an understatement. Implementations remain principally within the domain of process development, with a few instances in full-scale manufacturing and even fewer in legacy processes. The reasons for low uptake are many and varied.
Pence believes that the Thermo Fisher approach has as good a shot as any in being widely adopted at manufacturing scale. “There’s growing comfort at development stages with the presence of real-time analytics, and with the ability to integrate PAT into a bioprocessing workflow.” With successful applications behind them, engineers will be more confident, as processes scale, to employ analytic techniques at larger and larger scale. “I expect them to apply analytical technologies much more aggressively.”
Still, no one can be certain that large-scale biomanufacturing will employ comprehensive PAT, no matter how well it performed during development, at the 500 or 1000 L scale. In one scenario, bioprocessors will use PAT to gain process knowledge and understanding during development, design an optimized process, then migrate only a few PAT components forward.
“The key will be controlling bioreactor production in such a way that does not inhibit the process itself,” Pence said.