Making The Leap From Micro To Macro Scale
Long ago – more years than I care to remember – I gave a presentation at BIO 2004 sharing work executed while at Millennium and Xcellerex regarding the development of a high throughput cell culture medium and feed screening platform (Glacken M-High throughput biopharmaceutical process development). We were proud of this plate-based platform since we used it to formulate a very serviceable serum-free medium in just one experiment and to develop a feed that doubled the titer from a fed-batch bioreactor also in just one experiment.
However, this plate-based system was just a crude screening tool – there was no way it could be considered even remotely representative of a commercial scale bioreactor process. Our team attempted to develop a high throughput bioreactor system that could be sufficiently representative of a large-scale system but this proved a tougher nut to crack than. It was abandoned. At that time, a now defunct company (Bioprocessors Corp.) was promoting a highly miniaturized, highly automated, and in my view, highly complex, high-throughput bioreactor system for process development which also proved too expensive and too complicated to be practical.
About 5 or 6 years later our team tested out a beta version of a simpler high-throughput bioreactor platform from Applikon. While promising, the system had technical issues that needed to be resolved. As a result, we lost interest in pursuing it and other high-throughput bioreactor platforms and remained content continuing to use 2 L laboratory bioreactors for process development and process characterization as a stepping stone to large-scale manufacturing.
This has remained the standard approach — until now. At the recent BPI-West conference, Patheon, KBI, and Novartis all presented data suggesting that the Sartorius AMBR 15 high-throughput bioreactor system might finally be a useful high throughput scaled-down model (SDM) that allows direct scale-up to production scale bioreactors without the need for intermediate testing in small scale bioreactors.
The feasibility of such scale-up from the AMBR 15 micro-scale system to process scale bioreactors was shown by Mathew Zustiak from Patheon who used the AMBR 15 system to optimize a legacy process, removing animal-derived components from the cell culture media while tripling the product titer. The optimized process was scaled-up directly to large-scale bioreactor process without any intermediate scale-up testing.
In the same vein, Abhinav Shukla presented data showing how the AMBR 15 system enabled KBI to shorten their process characterization timelines. Shukla presented data showing that for a given process, growth curves and lactate profiles, as well as gas transfer and pCO2 profiles were comparable between the AMBR 15 system and the large-scale bioreactor.
The engineering details of how critical parameters as tip speed, power per unit volume, headspace aeration, and light protection can be mimicked in a micro-scale high throughput system were discussed by Ben Neunstoecklin of Novartis. Neunstocklin also presented a myriad of metabolic time profiles such as glucose, glutamine, ammonia, lactate and pCO2 demonstrating suitable equivalence between the SDM and large-scale process enabling the use of the AMBR 15 for DOE studies supporting process characterization.
I left the conference encouraged that the journey we began some 15 years ago may have reached its destination with the AMBR 15. It is a significant step toward the development of a truly representative high-throughput bioreactor system supporting and enabling rapid process development, scale, and characterization.
Blog article by: Mike Glacken