Very High Cell Density in Perfusion of CHO Cells by ATF, TFF, Wave Bioreactor, and/or CellTank Technologies – Impact of Cell Density and Applications

Chotteau, Véronique; Zhang, Ye; Clincke, Marie-Françoise

doi:10.1002/9783527673681.ch13

Cited by 9 publications

(11 citation statements)

References 23 publications

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“…The purpose of this step is to grow the cells to certain density and viability before transferring them to a production bioreactor. From the literature, inoculation cell density ranges between 0.2 × 10 6 and 1 × 10 6 cells/mL. ,,− Some publications show that the density can reach as high as 2 × 10 6 –3 × 10 6 cells/mL . In this paper, 1.5 × 10 6 cells/mL is considered as the peak cell density in an inoculation bioreactor.…”

Section: Methodsmentioning

confidence: 99%

Comparison between Batch and Continuous Monoclonal Antibody Production and Economic Analysis

Prabhu

Ierapetritou

2019

Ind. Eng. Chem. Res.

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This work aims to evaluate the benefits of the continuous process in biopharmaceutical manufacturing of monoclonal antibodies (mAbs). An integrated continuous process is designed and built using a process simulator and compared with a fed-batch process production line. The comparisons are based on cost of goods (COG/g) calculation and sensitivity analysis. The fed-batch process results in operating COG/g of $99/g in mAbs production, whereas the continuous process accounts for $51/g. Because of the smaller footprint and fewer storage tanks required in the continuous process, the facility cost reduced by 66%, compared to the fed-batch process. In continuous production, there is a better utilization of the primary capture resin, which leads to a reduction in consumables cost by 68%. Sensitivity analysis is used to evaluate the process in different manufacturing scales (50–1200 kg/yr), upstream titers (1.5–5.5 g/L), and downstream yield (70%–80%). Cost savings can be observed through the entire range.

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Section: Methodsmentioning

confidence: 99%

Comparison between Batch and Continuous Monoclonal Antibody Production and Economic Analysis

Prabhu

Ierapetritou

2019

Ind. Eng. Chem. Res.

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“…We performed a series of experiments in a wave bioreactor connected to an ATF2 using a MAb producing CHO-K1 DHFR À cell line (Clincke et al 2011(Clincke et al , 2013aChotteau et al 2014a). We developed and studied this system in several runs maintained at 20 Â 10 6 cells/mL by cell bleeding during up to 2 weeks.…”

Section: Atfmentioning

confidence: 99%

Perfusion Processes

Chotteau

2014

Cell Engineering

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The interest for perfusion is increasing nowadays. This new focus has emerged from a synergy of a demand for disposable equipment and the availability of robust cell separation device, as well as the need for higher flexibility and lower investment cost. The cell separation devices mostly used today are based on filtration, i.e. alternating flow filtration, tangential flow filtration, spin-filter, or acceleration/gravity, i.e. inclined settler, centrifuge, acoustic settler. This paper gives an introduction to the basic concepts of perfusion and its practical implementation. It reviews the actual cell separation devices and describes the approaches used in the field to develop and optimize the perfusion processes.

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“…Perfusion cell culture requires equal volumes of fresh media continuously added and spent media removed, while retaining the cells in the bioreactor by use of perfusion equipment, such as alternating tangential flow (ATF) devices, cross-flow filters, centrifuges, or settlers. 14 , 15 Due to the complexity of process development and automation control, process intensification through perfusion production cell culture has not been widely used in manufacturing of proteins such as monoclonal antibodies (mAbs). 6 , 16 - 18 A notable exception is in the production of unstable complex proteins/enzymes usually with very low titers.…”

Section: Introductionmentioning

confidence: 99%

Biomanufacturing evolution from conventional to intensified processes for productivity improvement: a case study

Huang

et al. 2020

mAbs

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Process intensification has shown great potential to increase productivity and reduce costs in biomanufacturing. This case study describes the evolution of a manufacturing process from a conventional processing scheme at 1000-L scale (Process A, n = 5) to intensified processing schemes at both 1000-L (Process B, n = 8) and 2000-L scales (Process C, n = 3) for the production of a monoclonal antibody by a Chinese hamster ovary cell line. For the upstream part of the process, we implemented an intensified seed culture scheme to enhance cell densities at the seed culture step (N-1) prior to the production bioreactor (N) by using either enriched N-1 seed culture medium for Process B or by operating the N-1 step in perfusion mode for Process C. The increased final cell densities at the N-1 step allowed for much higher inoculation densities in the production bioreactor operated in fed-batch mode and substantially increased titers by 4-fold from Process A to B and 8-fold from Process A to C, while maintaining comparable final product quality. Multiple changes were made to intensify the downstream process to accommodate the increased titers. New high-capacity resins were implemented for the Protein A and anion exchange chromatography (AEX) steps, and the cation exchange chromatography (CEX) step was changed from bind-elute to flow-through mode for the streamlined Process B. Multi-column chromatography was developed for Protein A capture, and an integrated AEX-CEX pool-less polishing steps allowed semi-continuous Process C with increased productivity as well as reductions in resin requirements, buffer consumption, and processing times. A cost-of-goods analysis on consumables showed 6.7-10.1 fold cost reduction from the conventional Process A to the intensified Process C. The hybrid-intensified process described here is easy to implement in manufacturing and lays a good foundation to develop a fully continuous manufacturing with even higher productivity in the future.

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Very High Cell Density in Perfusion of CHO Cells by ATF, TFF, Wave Bioreactor, and/or CellTank Technologies – Impact of Cell Density and Applications

Cited by 9 publications

References 23 publications

Comparison between Batch and Continuous Monoclonal Antibody Production and Economic Analysis

Comparison between Batch and Continuous Monoclonal Antibody Production and Economic Analysis

Perfusion Processes

Biomanufacturing evolution from conventional to intensified processes for productivity improvement: a case study

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