Abstract
Biopharmaceutical production processes strive for the optimization of economic efficiency. Among others, the maximization of volumetric productivity is a key criterion. Typical parameters such as partial pressure of CO2 (pCO2) and pH are known to influence the performance although reasons are not yet fully elucidated. In this study the effects of pCO2 and pH shifts on the phenotypic performance were linked to metabolic and energetic changes. Short peak performance of qmAb (23 pg/cell/day) was achieved by early pCO2 shifts up to 200 mbar but followed by declining intracellular ATP levels to 2.5 fmol/cell and 80% increase of qLac. On the contrary, steadily rising qmAb could be installed by slight pH down-shifts ensuring constant cell specific ATP production (qATP) of 27 pmol/cell/day and high intracellular ATP levels of about 4 fmol/cell. As a result, maximum productivity was achieved combining highest qmAb (20 pg/cell/day) with maximum cell density and no lactate formation. Our results indicate that the energy availability in form of intracellular ATP is crucial for maintaining antibody synthesis and reacts sensitive to pCO2 and pH-process parameters typically responsible for inhomogeneities after scaling up.
Highlights
The global sales for biopharmaceuticals are constantly on the rise which is the major driving force for the optimization of industrial production processes (Walsh, 2014; Morrison and Lähteenmäki, 2017)
All cultivations were controlled at pH 6.8 after initial adaptation and diverged only after approximately 120 h when base addition was suppressed in setup no base titration process (NOB)
Until 120 h pressure of CO2 (pCO2) values of all processes conformed to about 90 mbar, showed similar tendency for 48 h and diverged again >158 h with CO2 stressed process (COP) and NOB showing maximum pCO2 values at the very end of 170 and 220 mbar, respectively
Summary
The global sales for biopharmaceuticals are constantly on the rise which is the major driving force for the optimization of industrial production processes (Walsh, 2014; Morrison and Lähteenmäki, 2017). The growing number of expiring patent protections and the subsequent emergence of biosimilar producing companies and processes has increased the urge for optimized processes even further (Mullard, 2012; Gaughan, 2016). Product titers have increased substantially over the past years (Kunert and Reinhart, 2016) and process intensification toward continuous processes (Hammerschmidt et al, 2014) as well as an increased use of singleuse bioreactors (Löffelholz et al, 2013) has taken place. Since fed-batch cultivation remains the predominant large-scale process in industry, a large number of studies focusing on fed-batch processes have been published over the past decades. Challenges occurring during scale-up can be inhomogeneities due to local
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