Dr. Jochen B. Sieck, Lab Head of Cell Culture Media R&D, Process Solutions R&D, at Merck KGaA shares insight on his presentation "Optimization, Simplification and Intensification of Cell Culture Processes" to be featured at the upcoming Optimizing Cell Culture Technology conference being held in Boston.

Q. How do cell culture media impact productivity?

The function of cell culture media and feeds is to provide the cells with the optimum concentrations of nutrients for a given process phase. The cellular requirements in terms of nutrition depend on the cell line, the process mode (e.g. batch, fed-batch or perfusion) and the process phase (e.g. growth phase, production phase, steady-state operation…). In addition, the media have to provide a good physical-chemical environment for the cells e.g. in terms of osmolality and pH. All these impacts may influence the overall and the cell specific productivity of cell culture processes.

Jochen has 10 years of experience in bioreactor operation and characterization, specifically for cell culture and shear sensitive model systems. After his PhD on Scale-Down Modelling of CHO fed-batch processes in Novartis Bioprocess R&D, in collaboration with ETH Zürich, he started working on perfusion processes as Postdoc researcher, also in Novartis, setting up a novel perfusion processing platform. 2 years ago he moved on to Merck KGaA, Darmstadt, Germany where he started a new lab focusing on medium development aspects of perfusion processes.

Q. What are the benefits of the chemically modified amino acids for cell culture media?

Some of the challenges which you encounter when working work cell culture media are the chemistries of L-Tyrosine and L-Cysteine. With cysteine there is primarily a stability issue due to the cysteine’s biochemical role of forming disulphide bonds. This is a redox reaction, and impacts the redox balance of the medium, which is a delicate one. Tyrosine is only well soluble at extreme pH values, which is why it is frequently added in the form of a separate, caustic feed, often together with cysteine. As this additional and caustic feed adds complexity, we have been investigating alternative possibilities to overcome the solubility and stability issues of these amino acids. One successful method is chemical modification of both cysteine and tyrosine, leading to the elimination of the separate feed for these, as well as improved productivity of the cell culture. These projects also improved our understanding of the complexity of cell culture medium chemistry and the root cause of some poorly understood phenomena occurring in CCM.

Q. How are perfusion media different from fed-batch media?

In batch or fed-batch media, most of the nutrients required for cell growth and protein production have to be included in the basal medium from the start. Thus, the maximum solubility can be a limiting factor for the productivity of these processes. Growth will stop when nutrient limitations or inhibitions by metabolite accumulation occur. Both aspects only play a minor role in perfusion, because of the continuous influx of fresh medium and continuous outflow of spent medium. In perfusion the focus is on achieving the ideal balance of all components to achieve maximum productivity and lowest cell specific perfusion rate (CSPR).

Q. Besides perfusion media, what aspects of continuous bioprocessing are you currently working on?

We are investigating all aspects required for successful perfusion operation, including single-use bioreactors, cell retention devices and different perfusion related process strategies (e.g. steady-state perfusion, ‘dynamic’ perfusion processes, perfused N-1 bioreactors etc.). The combination of single-use and perfusion enables the envisioned flexible factories of the future by increasing plant capacity. We also have various activities for continuous capture, virus inactivation and purification ongoing to facilitate the next generation of bioprocesses.


Optimization, Simplification and Intensification of Cell Culture Processes

Fed-Batch processes are the standard cultivation method for the manufacturing of biopharmaceuticals with CHO cells today. Besides the production organism, cell culture media and feeds have a great impact on process productivity optimization. Our recent introduction of chemically modified amino acids for cell culture media allow for a significant simplification of CHO fed-batch processes by eliminating the second, typically caustic feed. Furthermore, increases in productivity were observed, resulting in more productive fed-batch as well as highly intensified perfusion processes.

To learn more about this conference and The Bioprocessing Summit, visit Bioprocessingsummit.com/Cell-Culture


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