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CFD (computational fluid dynamics) techniques were used to predict mixing and gas-liquid mass transfer in a 250 ml shake flask operating over a range of shaking frequencies between 100 and 300 rev./min, shaking diameters between 20 and 60 mm, and fill volumes between 25 and 100 ml. Interfacial area, a, volumetric mass-transfer coeffcient, kLa, and the power input per unit volume, epsilonv, of the liquid were predicted to be 300<a<800 m2 . m(-3), 10<kLa<100 h(-1) and 40<epsilonv<600 W . m(-3) respectively. These values are significantly different from the reported range for laboratory and pilot-scale bioreactors used in the fermentation of bacterial and fungal micro-organisms (100<a<300 m2 . m(-3), 100<kLa<400 h(-1) and 1000<epsilonv<3000 W . m(-3)). Our analysis showed that, at the highest shaking frequency and amplitude of operation, the specific power input in the shake flask was much lower than in laboratory bioreactors. Bacterial and fungal micro-organisms require dissolved oxygen concentrations typically in the range 50-250 mmol of O2 . h(-1) . litre(-1), corresponding to volumetric mass-transfer coefficients, kLa, in the range of 250-400 h(-1). Poor mixing and dissolved-oxygen limitation in shake flasks may limit their use in process design and media optimization in fermentation. In contrast, mammalian cells have relatively low demand for oxygen and consequently require a lower specific power input, this being typically between 1 and 10 W . m(-3), allowing efficient operation in shake flasks. Experimental data presented as part of the present study showed that mammalian cell growth in shake flasks was essentially independent of the specific power input, the maximum specific cell growth rate being 0.056 h(-1). The corresponding maximum oxygen-uptake rate was 0.74 mmol of O2 . h(-1) . litre(-1) for a viable cell count of 1.3 x 10(6) cells . ml(-1). These values are comparable with reported values for laboratory and pilotscale bioreactors. This analysis suggests that growth of mammalian cells in shake flasks (and hence in laboratory bioreactors) is not limited by the gas-liquid mass-transfer rate. In mammalian cell cultures, the requirement for good mixing is driven by other considerations, including the need for good cell suspension and reduction in heterogeneity, for example, in pH, temperature, nutrient concentration, osmolality and lactate/glucose ratio.
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PMID:Computational-fluid-dynamics (CFD) analysis of mixing and gas-liquid mass transfer in shake flasks. 1531 Feb 85

Experimentation in shaken microplate formats offers a potential platform technology for the rapid evaluation and optimization of cell culture conditions. Provided that cell growth and antibody production kinetics are comparable to those found in currently used shake flask systems then the microwell approach offers the possibility to obtain early process design data more cost effectively and with reduced material requirements. This work describes a detailed engineering characterization of liquid mixing and gas-liquid mass transfer in microwell systems and their impact on suspension cell cultures. For growth of murine hybridoma cells producing IgG1, 24-well plates have been characterized in terms of energy dissipation (P/V) (via Computational Fluid Dynamics, CFD), fluid flow, mixing and oxygen transfer rate as a function of shaking frequency and liquid fill volume. Predicted k(L)a values varied between 1.3 and 29 h(-1); liquid-phase mixing time, quantified using iodine decolorization experiments, varied from 1.7 s to 3.5 h; while the predicted P/V ranged from 5 to 35 W m(-3). CFD simulations of the shear rate predicted hydrodynamic forces will not be detrimental to cells. For hybridoma cultures however, high shaking speeds (>250 rpm) were shown to have a negative impact on cell growth, while a combination of low shaking speed and high well fill volume (120 rpm, 2,000 microL) resulted in oxygen limited conditions. Based on these findings a first engineering comparison of cell culture kinetics in microwell and shake flask formats was made at matched average energy dissipation rates. Cell growth kinetics and antibody titer were found to be similar in 24-well microtiter plates and 250 mL shake flasks. Overall this work has demonstrated that cell culture performed in shaken microwell plates can provide data that is both reproducible and comparable to currently used shake flask systems while offering at least a 30-fold decrease in scale of operation and material requirements. Linked with automation this provides a route towards the high throughput evaluation of robust cell lines under realistic suspension culture conditions.
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PMID:Microwell engineering characterization for mammalian cell culture process development. 1973 83