Modeling of Biopharmaceutical Processes—Part 1: Microbial and Mammalian Unit Operations - Process-modeling tools can ensure smooth technology transfer of microbial and mammalian processes from b

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Modeling of Biopharmaceutical Processes—Part 1: Microbial and Mammalian Unit Operations
Process-modeling tools can ensure smooth technology transfer of microbial and mammalian processes from bench to commercial scale.


BioPharm International
Volume 21, Issue 6

HEAT AND OXYGEN TRANSFER IN BIOREACTORS FOR HIGH CELL DENSITY MICROBIAL PROCESSES

Oxygen update rate (OUR) is defined as the rate of oxygen that is consumed by a given volume of fermentation broth, and this variable fluctuates over the course of a fermentation process depending on many factors such as the metabolic state of the cells, the level of oxygen saturation in the culture, and the volume of the culture itself relative to the cell density. Carbon dioxide evolution rate (CER) is defined as the rate of CO2 evolution from a carbon nutrient source (usually glucose in fermentation processes) and can be used to determine the level of glucose utilization in the culture relative to cell density and the state of cellular metabolism through comparison with OUR. For most fermentation processes, the desired ratio of CER to OUR (RQ) is approximately 1.0. This correlates to six CO2 molecules produced for every six oxygen (O2) molecules that are consumed during the aerobic metabolism of a six-carbon sugar such as glucose. An RQ value that is noticeably lower than 1.0 indicates that the cells are using a different nutrient source for energy. In most industrial fermentation situations, it is desirable to maintain the RQ above 0.75 for the duration of the culture to ensure that the metabolic state of the cells is consistent. OUR and CER can be readily calculated using the following expressions:18–21




in which QO2 is the volumetric flow rate of O2 into the fermenter in standard liter per minute (SLPM); QAir is the volumetric flow rate of air into the fermenter in standard liter per minute (SLPM); VO2 is the molar volume of O2 in the inlet O2 (L/mol); VAir is the molar volume of Air in the inlet air (L/mol); XO2,in is the mole fraction of O2 in the inlet air (mmolO2/mmolAir); XO2,out is the mole fraction of O2 in the outlet gas (mmolO2/mmolExhaust); XN2,in is the mole fraction of N2 in the inlet Air (mmolN2/mmolAir); XN2,out is the mole fraction of N2 in the Outlet Gas (mmolN2/mmolExhaust); XCO2,in is the mole fraction of CO2 in the inlet air (mmolCO2/mmolAir); and XCO2,out is the mole fraction of CO2 in the outlet gas (mmolCO2/mmolExhaust). The inlet gas flow rates and the molar concentrations of the outlet gases can be measured by a volumetric gas flow meter or an in-line mass spectrometer. Derivation of equations 6 and 7 is based on the assumption that the water content in the gas does not affect the composition of the gas or the accuracy of the mass spectrometer reading.


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