Approximation of continuous fermentation by semicontinuous cultures

Westgate, Paul J.; EMERY, ALDEN H.

doi:10.1002/bit.260350502

Cited by 9 publications

(1 citation statement)

References 15 publications

(2 reference statements)

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“…Compared to fully continuous operation in bioreactors, a scale-down of semi-continuous cultures can be easily achieved for studying the impact of process parameters on cell growth and virus propagation. In addition, semi-continuous cultures can be set to medium exchange regimes that can approach continuous cultivations [ 25 ]. To name one recent example, semi-continuous cultivations using shake flasks have been used for propagation of the rat hybridoma cell line TFL-P9 [ 26 ] to evaluate to what extent semi-continuous cultures approach growth kinetics in continuous cultivations.…”

Section: Introductionmentioning

confidence: 99%

Efficient and stable production of Modified Vaccinia Ankara virus in two-stage semi-continuous and in continuous stirred tank cultivation systems

Tapia

Jordan²,

Genzel

et al. 2017

PLoS ONE

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One important aim in cell culture-based viral vaccine and vector production is the implementation of continuous processes. Such a development has the potential to reduce costs of vaccine manufacturing as volumetric productivity is increased and the manufacturing footprint is reduced. In this work, continuous production of Modified Vaccinia Ankara (MVA) virus was investigated. First, a semi-continuous two-stage cultivation system consisting of two shaker flasks in series was established as a small-scale approach. Cultures of the avian AGE1.CR.pIX cell line were expanded in the first shaker, and MVA virus was propagated and harvested in the second shaker over a period of 8–15 days. A total of nine small-scale cultivations were performed to investigate the impact of process parameters on virus yields. Harvest volumes of 0.7–1 L with maximum TCID50 titers of up to 1.0×109 virions/mL were obtained. Genetic analysis of control experiments using a recombinant MVA virus containing green-fluorescent-protein suggested that the virus was stable over at least 16 d of cultivation. In addition, a decrease or fluctuation of infectious units that may indicate an excessive accumulation of defective interfering particles was not observed. The process was automated in a two-stage continuous system comprising two connected 1 L stirred tank bioreactors. Stable MVA virus titers, and a total production volume of 7.1 L with an average TCID50 titer of 9×107 virions/mL was achieved. Because titers were at the lower range of the shake flask cultivations potential for further process optimization at large scale will be discussed. Overall, MVA virus was efficiently produced in continuous and semi-continuous cultivations making two-stage stirred tank bioreactor systems a promising platform for industrial production of MVA-derived recombinant vaccines and viral vectors.

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Section: Introductionmentioning

confidence: 99%

Efficient and stable production of Modified Vaccinia Ankara virus in two-stage semi-continuous and in continuous stirred tank cultivation systems

Tapia

Jordan²,

Genzel

et al. 2017

PLoS ONE

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Approximation of continuous growth of Cephalotaxus harringtonia plant cell cultures using fed‐batch operation

Westgate

Curtis

EMERY

et al. 1991

Biotech & Bioengineering

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In Cephalotaxus harringtonia plant cell cultures, periods of batch growth that are limited by hexose uptake are too short to make an accurate estimate of the Monod saturation constant. Continuous cultures are infeasible on a laboratory scale, and semicontinuous cultures require too frequent sampling. Fed-batch operation, consisting of intermittent removal from a culture that is fed continuously, was investigated as a possible solution to these problems. For a constant feed rate, computer simulations showed that a steady state can be achieved which is useful for studying growth at different specific growth rates. In terms of the dilution rate it was confirmed that the operation is essentially equivalent to continuous culture when the samples represent a small fraction of the total culture volume. Experiments with glucose or fructose as the carbon source were carried out in shake flasks fed by a multichannel syringe pump. Results indicate that Monod kinetics based on medium glucose levels cannot adequately describe growth under these conditions. Monod's expression for specific growth rate using internal glucose concentration gives an improved correlation.

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Simpler noninstrumented batch and semicontinuous cultures provide mammalian cell kinetic data comparable to continuous and perfusion cultures

Henry¹,

Kwok²,

Piret³

2008

Biotechnology Progress

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Perfusion culture optimization in multiple noninstrumented small-scale flasks allows reduced expense and time associated with process development. These cultures normally use a different process mode because at small scales it is not practical to retain the cells for medium perfusion. In this work, the kinetics of growth, nutrient consumption, metabolite, and product formation were compared in spinner cultures operated in batch, semicontinuous, chemostat, and perfusion modes. Fed-batch was also included to provide an added comparison. Using logistic fitting for more reliable specific rate estimates in transient conditions, the growth phase of batch cultures predicted similar kinetics to fed-batch and continuous processes. For daily medium exchange rates up to 50%, the semicontinuous mode also predicted the perfusion process kinetics. Differences between the chemostat and semicontinuous culture results were only observed at higher exchange rates with the greatest daily culture perturbation. Overall, the batch or semicontinuous cultures were shown to readily provide results similar to the far more complex to operate chemostat or perfusion cultures.

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Approximation of continuous fermentation by semicontinuous cultures

Cited by 9 publications

References 15 publications

Efficient and stable production of Modified Vaccinia Ankara virus in two-stage semi-continuous and in continuous stirred tank cultivation systems

Efficient and stable production of Modified Vaccinia Ankara virus in two-stage semi-continuous and in continuous stirred tank cultivation systems

Approximation of continuous growth of Cephalotaxus harringtonia plant cell cultures using fed‐batch operation

Simpler noninstrumented batch and semicontinuous cultures provide mammalian cell kinetic data comparable to continuous and perfusion cultures

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