Concentrated fed-batch cell culture increases manufacturing capacity without additional volumetric capacity

Yang, William; Minkler, Daniel F.; Kshirsagar, Rashmi; Ryll, Thomas; Huang, Yao‐Ming

doi:10.1016/j.jbiotec.2015.10.009

Cited by 95 publications

(72 citation statements)

References 35 publications

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“…Medium exchange rate was kept the same for all three repeats. Glucose feed rate was maintained at a lower level in Run#1 to maintain a lower glucose level would be less challenging compared with densities at even higher levels, where mass transfer may be limited in the bioreactors [14].…”

Section: Productivity Comparison Between Different Operational Modesmentioning

confidence: 99%

“…Perfusion cultures could be operated at different cell densities (ranging from 10-20 to [100 9 10 6 cells/mL) with different perfusion rates and cell bleed rates, and their productivity has been incrementally improved in recent years, thanks to the advancements in cell line, media, and perfusion technology [9][10][11]. Recently, another operational mode, concentrated fed-batch (CFB), has been re-introduced as an effective approach to significantly increase product titer in the bioreactor [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…The CFB process duration could be similar to that in a typical fed-batch process (e.g., 12-18 days), which is much shorter than that in a perfusion culture (e.g., 30-60 days). As a result of the high cell density and product accumulation from process intensification, high titer (10-25 g/L) has been reported for Chinese Hamster Ovary (CHO) cultures using this operational mode [13,14]. This level of high titer is attractive in reducing batches required for clinical/commercial supply and minimizing manufacturing footprint using smaller bioreactors.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Improving lactate metabolism in an intensified CHO culture process: productivity and product quality considerations

Hoshan

Chen

2016

Bioprocess Biosyst Eng

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In this study, we discussed the development and optimization of an intensified CHO culture process, highlighting medium and control strategies to improve lactate metabolism. A few strategies, including supplementing glucose with other sugars (fructose, maltose, and galactose), controlling glucose level at <0.2 mM, and supplementing medium with copper sulfate, were found to be effective in reducing lactate accumulation. Among them, copper sulfate supplementation was found to be critical for process optimization when glucose was in excess. When copper sulfate was supplemented in the new process, two-fold increase in cell density (66.5 ± 8.4 × 10(6) cells/mL) and titer (11.9 ± 0.6 g/L) was achieved. Productivity and product quality attributes differences between batch, fed-batch, and concentrated fed-batch cultures were discussed. The importance of process and cell metabolism understanding when adapting the existing process to a new operational mode was demonstrated in the study.

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Section: Productivity Comparison Between Different Operational Modesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Improving lactate metabolism in an intensified CHO culture process: productivity and product quality considerations

Hoshan

Chen

2016

Bioprocess Biosyst Eng

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“…Recently, mammalian cell perfusion cultures have regained attraction as an alternative to traditional fed‐batch processes for the production of therapeutic proteins, like monoclonal antibodies (mAbs; Clincke et al, ; Karst, Serra, Villiger, Soos, & Morbidelli, ). Perfusion cultures have been used for the production of unstable proteins (Bödeker, Newcomb, Yuan, Braufman, & Kelsey, ; Warikoo et al, ), and are in general a promising tool for the intensification of protein production processes (Hiller, Ovalle, Gagnon, Curran, & Wang, ; Moulijn, Stankiewicz, Grievink, & Górak, ; Subramanian, ; Xu, Hoshan, & Chen, ; Yang, Minkler, Kshirsagar, & Ryll, ). Particular interest has been directed to their application in the frame of continuous end‐to‐end integrated production processes (Godawat, Konstantinov, Rohani, & Warikoo, ; Karst, Scibona, et al, 2017; Karst, Steinebach, & Morbidelli, ; Karst, Steinebach, Soos, & Morbidelli, ; Steinebach et al, ; Warikoo et al, ).…”

Section: Introductionmentioning

confidence: 99%

Development of a shake tube‐based scale‐down model for perfusion cultures

Wolf

Lorenz

Karst

et al. 2018

Biotech & Bioengineering

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The use of benchtop bioreactors (BRs) for the development of mammalian cell perfusion cultures is expensive and time consuming, given its complexity in equipment and operation. Scale-down models, going from liter to milliliter scale, are needed to support the rapid determination of suitable operating conditions in terms of viable cell density (VCD), perfusion rate, and medium composition. In this study, we compare the performance of steady-state perfusion cultures in orbitally shaken tube and BR systems for a given Chinese hamster ovary cell line. The developed scale-down model relied on a daily workflow designed to keep the VCD constant at specific target values. This includes: cell count, removal of excessive cells (bleeding), spin down of remaining cells, harvest of cell-free supernatant, and resuspension in fresh medium. Steady-state cultures at different VCD values, medium exchange rates and working volumes were evaluated. Shake-tube perfusion cultures allowed the prediction of cell-specific growth, glucose consumption, ammonia, and monoclonal antibody production rates for much larger BRs, but not lactate (LAC) production rates. Although charge variant profiles remained comparable, different glycosylation patterns were obtained. The differences in LAC production and glycosylation probably resulted from the discontinuous medium exchange, the poor carbon dioxide removal, and the deficient pH control. Therefore, if requested by the specific process to be developed, product quality has to be fine-tuned directly in the BR system. Altogether, the developed strategy provides a useful scale-down model for the design and optimization of perfusion cultures with strong savings in time and media consumption.

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“…As the biomass in high density and “concentrated” fed‐batch cultures takes up a significant part of the culture volume, the effective liquid volume can be significantly lower than the bioreactor working volume …”

Section: Methodsmentioning

confidence: 99%

Recommendations for Comparison of Productivity Between Fed‐Batch and Perfusion Processes

Bausch

Schultheiss

Sieck

2018

Biotechnology Journal

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Due to the growing interest in integrated continuous processing in the biopharmaceutical industry, productivity comparison of batch-based and continuous processes is considered a challenge. Integrated continuous manufacturing of biopharmaceuticals requires scientists and engineers to collaborate effectively. Differing definitions, for example, of volumetric productivity, may cause confusion in this interdisciplinary field. Therefore, the aim of this communication is to reiterate the standard definitions and their underlying assumptions. Applying them to an exemplary model scenario allows to demonstrate the differences and to develop recommendations for the comparison of productivity of different upstream processes.

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Concentrated fed-batch cell culture increases manufacturing capacity without additional volumetric capacity

Cited by 95 publications

References 35 publications

Improving lactate metabolism in an intensified CHO culture process: productivity and product quality considerations

Improving lactate metabolism in an intensified CHO culture process: productivity and product quality considerations

Development of a shake tube‐based scale‐down model for perfusion cultures

Recommendations for Comparison of Productivity Between Fed‐Batch and Perfusion Processes

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