Stirred Tank Models

Reuß, Matthias; Bajpai, R.

doi:10.1002/9783527620852.ch10

Cited by 19 publications

(3 citation statements)

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“…The presence of DOT gradients, a prevalent problem in large-scale fermenters, can be predicted through regime analysis (Oosterhuis and Kossen, 1984;Sweere et al, 1987). DOT gradients are likely to occur when the characteristic time constant for oxygen consumption (t OC ) is lower or within the same order of magnitude than the characteristic circulation time (t c ) (Amanullah et al, 2004;Oosterhuis, 1984;Palomares and Ramírez, 2000;Reuss and Bajpai, 1991;Sweere et al, 1987). The range of mean t c for a variety of large-scale fermenters, when operated with low-viscosity Newtonian fluids and under conditions typical of E. coli cultures is between 3 and at least 60 s (Amanullah et al, 2004;Schügerl, 1993;Sweere et al, 1987;Vrábel et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional and metabolic response of recombinant Escherichia coli to spatial dissolved oxygen tension gradients simulated in a scale‐down system

Lara

Leal

Flores

et al. 2005

Biotech & Bioengineering

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Escherichia coli, expressing recombinant green fluorescent protein (GFP), was subjected to dissolved oxygen tension (DOT) oscillations in a two-compartment system for simulating gradients that can occur in large-scale bioreactors. Cells were continuously circulated between the anaerobic (0% DOT) and aerobic (10% DOT) vessels of the scale-down system to mimic an overall circulation time of 50 s, and a mean residence time in the anaerobic and aerobic compartments of 33 and 17 s, respectively. Transcription levels of mixed acid fermentation genes (ldhA, poxB, frdD, ackA, adhE, pflD, and fdhF), measured by quantitative RT-PCR, increased between 1.5- to over 6-fold under oscillatory DOT compared to aerobic cultures (constant 10% DOT). In addition, the transcription level of fumB increased whereas it decreased for sucA and sucB, suggesting that the tricarboxylic acid cycle was functioning as two open branches. Gene transcription levels revealed that cytrochrome bd, which has higher affinity to oxygen but lower energy efficiency, was preferred over cytochrome bO3 in oscillatory DOT cultures. Post-transcriptional processing limited heterologous protein production in the scale-down system, as inferred from similar gfp transcription but 19% lower GFP concentration compared to aerobic cultures. Simulated DOT gradients also affected the transcription of genes of the glyoxylate shunt (aceA), of global regulators of aerobic and anaerobic metabolism (fnr, arcA, and arcB), and other relevant genes (luxS, sodA, fumA, and sdhB). Transcriptional changes explained the observed alterations in overall stoichiometric and kinetic parameters, and production of ethanol and organic acids. Differences in transcription levels between aerobic and anaerobic compartments were also observed, indicating that E. coli can respond very fast to intermittent DOT conditions. The transcriptional responses of E. coli to DOT gradients reported here are useful for establishing rational scale-up criteria and strain design strategies for improved culture performance at large scales.

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Section: Introductionmentioning

confidence: 99%

Transcriptional and metabolic response of recombinant Escherichia coli to spatial dissolved oxygen tension gradients simulated in a scale‐down system

Lara

Leal

Flores

et al. 2005

Biotech & Bioengineering

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“…Circulation times are not of fixed duration but follow a distribution characterized previously for a range of stirring conditions as log‐normal (e.g., Refs. ) (Supporting Information C).…”

Section: Methodsmentioning

confidence: 99%

Bioreactor scale‐down studies of suspended plant cell cultures

2018

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The effect of dissolved oxygen fluctuations on suspended plant cells was investigated using a scale‐down stirred bioreactor system to simulate the heterogeneous conditions found in large‐scale vessels. Transgenic Nicotiana tabacum cells expressing IgG1 antibody and Thalictrum minus cells producing berberine were subjected to gas switching cycles based on a stochastic model of log‐normal circulation time distributions. Because pumping severely damaged the cells, the scale‐down approach was restricted to a single‐vessel system. Dissolved oxygen oscillations of amplitude about ±5% air saturation were achieved in the N. tabacum cultures; however, most simulations produced highly damped fluctuations due to oxygen transfer limitations and no significant effect on the cultures was observed. In contrast, berberine production by T. minus cells was reduced when fluctuations of ±10–15% air saturation were superimposed on mean dissolved oxygen tensions of 25 and 35% air saturation. This work demonstrates that dissolved oxygen gradients such as those found in large‐scale mixing vessels can be detrimental to plant cell cultures even when sufficient average dissolved oxygen levels are provided. © 2018 American Institute of Chemical Engineers AIChE J, 64: 4281–4288, 2018

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“…This was unlikely to affect the behavior of the fermentation as the process was found to be insensitive to the effect of pH between 4.5 and 7.0 with respect to metabolism, growth (Pollard et al, 2002b), and rheological behavior (Pollard et al, 2002a). While a number of authors have proposed correlations for estimation of mixing time and circulation times from system configuration and operational parameters (Khang and Levenspiel, 1976;Mooyman, 1987;Reuss and Bajpai, 1991), the diversity of experimental conditions (many of which are based on fully-turbulent systems) suggests that a simpler correlation based on measured data in a representative system may prove at least as accurate. Mean circulation times, t C , have been correlated with mixing times through a linear relationship with mixing time for unaerated, single phase systems:…”

Section: Mixing Time Measurementmentioning

confidence: 99%

Scale up of a viscous fungal fermentation: Application of scale‐up criteria with regime analysis and operating boundary conditions

Pollard

Kirschner

Hunt

et al. 2006

Biotech & Bioengineering

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The scale up of the novel, pharmaceutically important pneumocandin (B(0)), from the filamentous fungus Glarea lozoyensis was successfully completed from pilot scale (0.07, 0.8, and 19 m(3)) to production scale (57 m(3)). This was accomplished, despite dissimilar reactor geometry, employing a combination of scale-up criteria, process sensitivity studies, and regime analysis using characteristic time constants for both oxygen mass transfer and bulk mixing. Dissolved oxygen tension, separated from the influence of agitation by gas blending at the 0.07 m(3)-scale, had a marked influence on the concentrations of pneumocandin analogs with different levels of hydroxylation, and these concentrations were used as an indicator of bulk mixing upon scale up. The profound impact of dissolved oxygen tension (DOT) (low and high levels) on analog formation dictated the use of constant DOT, at 80% air saturation, as a scale-up criterion. As a result k(L)a, Oxygen uptake rate (OUR) and hence the OTR were held constant, which were effectively conserved across the scales, while the use of other criterion such as P(g)/V(L), or mixing time were less effective. Production scale (57 m(3)) mixing times were found to be faster than those at 19 m(3) due to a difference in liquid height/tank diameter ratio (H(L)/D(T)). Regime analysis at 19 and 57 m(3) for bulk mixing (t(c)) and oxygen transfer (1/k(L)a) showed that oxygen transfer was the rate-limiting step for this highly shear thinning fermentation, providing additional support for the choice of scale-up criterion.

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Stirred Tank Models

Cited by 19 publications

References 50 publications

Transcriptional and metabolic response of recombinant Escherichia coli to spatial dissolved oxygen tension gradients simulated in a scale‐down system

Transcriptional and metabolic response of recombinant Escherichia coli to spatial dissolved oxygen tension gradients simulated in a scale‐down system

Bioreactor scale‐down studies of suspended plant cell cultures

Scale up of a viscous fungal fermentation: Application of scale‐up criteria with regime analysis and operating boundary conditions

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