JUERGEN WOLFGANG”, PAUL WU and KONSTANTIN KONSTANTINOV Bayer Biotechnology, Cell Culture and Bioprocess Engineering, Dwight Way, . Prior to Sanofi, Dr. Konstantinov worked for Bayer in Berkeley, Calif. for 14 years, advancing to the position of Head of Process Sciences. Before joining Codiak, Konstantin Konstantinov was responsible for the Prior to Sanofi, Dr. Konstantinov worked for Bayer in Berkeley, Calif. for 14 years.

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The present paper introduces a unified framework for comparison of fed-batch and perfusion cultures, and proposes directions for improvement of the latter.

High product titer is considered a strategic advantage of fed-batch over perfusion cultivation mode. Konstanntinov analysis shows that development of economically competitive perfusion processes for production of stable proteins depends on our ability to dramatically reduce the dilution rate while keeping high cell density, i.


The push-to-low approach was successfully applied to the production of monoclonal antibody against tumor necrosis factor TNF. Konstanntinov experimental results followed closely the theoretical prediction, providing a multifold increase in titer. However, as dilution rate is decreased, a limit is reached below which performance declines due to poor growth and viability, specific productivity, or product instability.

Despite the medium improvement, reduction of the specific growth rate along with increased apoptosis was observed at low specific perfusion rates.

The titer difference has been experimentally demonstrated and reported in the literature.

This approach involves an iterative stepwise decrease of the specific perfusion rate, and is most suitable for production of stable proteins where increased residence time does not compromise apparent specific productivity or product quality. This phenomenon could not be explained with limitation or inhibition by the known nutrients and metabolites.

To overcome these limitations, a strategy referred to as “push-to-low” optimization has been developed. However, the related theoretical aspects and strategies for optimization of perfusion processes with respect to their fed-batch counterparts have not been thoroughly explored.


In general, a strategic target in the optimization of perfusion processes should be the decrease of the cell-specific perfusion rate to below 0.

Under these conditions, titer increases significantly, approaching the range of fed-batch titers. The comparison is based on the concept of “equivalent specific perfusion rate”, a variable that conveniently konstantinoov various cultivation modes.

Even further improvement would be possible if the cause of apoptosis were understood.