Research on Applications of High-Throughput Perfusion Models in Bioprocessing Development

doi:10.13523/j.cb.2005005

China Biotechnology

2020, Vol. 40

Issue (8): 63-73 DOI: 10.13523/j.cb.2005005

Research on Applications of High-Throughput Perfusion Models in Bioprocessing Development

JIN Lu¹,ZHOU Hang^2,^*,CAO Yun²,WANG Zhou-shou²,CAO Rong-yue^1,^*(

)

1 College of Life Science and Biotechnology,China Pharmaceutical University,Nanjing　211198,China
2 Cell Culture Process Development,Wuxi Biologics,Shanghai　200131,China

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Abstract

Recently, continuous cell culture is becoming the process focus in the pharmaceutical industry due to its high volumetric productivity, stable product quality attributes, and cost- effectiveness. Compared to the traditional fed-batch culture, benchtop-scale perfusion culture requires quantities of media and labor costs due to its longer culture duration and operation complexity, thus failing to satisfy the current requirement of accelerated and efficient process development. To obtain a robust perfusion process with reduced costs, high-throughput perfusion models are utilized for batches of small-scale perfusion culture in the early-stage process development including clone screening, media selection and process parameter optimization, providing practical process data for late-stage large-scale bioprocessing. Furthermore, they are also applied to predict the phenotype and product quality attributes in large-scale culture. This article will focus on the characteristics, applications and comparisons of current high-throughput systems including shake flasks and spin tubes, parallelized automated ambr systems and microfluidic systems, and discuss the opportunities and challenges faced with high-throughput perfusion models in the bioprocessing development, then look forward to the future prospects.

Key words： Perfusion High-throughput Micro-bioreactor Ambr Microfluidics

Received: 06 May 2020 Published: 10 September 2020

ZTFLH:

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Corresponding Authors: Hang ZHOU,Rong-yue CAO E-mail: caorongyuenanjing@126.com

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Cite this article:

JIN Lu,ZHOU Hang,CAO Yun,WANG Zhou-shou,CAO Rong-yue. Research on Applications of High-Throughput Perfusion Models in Bioprocessing Development. China Biotechnology, 2020, 40(8): 63-73.

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https://manu60.magtech.com.cn/biotech/10.13523/j.cb.2005005 OR https://manu60.magtech.com.cn/biotech/Y2020/V40/I8/63

Fig.1 Bioreactor perfusion culture modules

Fig.2 Batch-refeed mode in spin tubes^[28]

Fig.3 Ambr^? 15 work station overview^①(①图片来源:www.sartorius.com.cn)

Fig.4 Ambr^? 250 perfusion system overview^①(①图片来源:www.sartorius.com.cn)

Fig.5 Examples of microfluidics employed in the cell culture process (a) The culture chamber, storage chamber, the microchannels for pH reagents and feeds in the microfluidic FlowerPlate?, Reprinted from Ref. [56] with permission of John Wiley and Sons (b) The bottom view of the microfluidic reactor containing DO (black) and pH (white) optical sensors, optical density (OD) measurement locations, optical fiber head, magnetic stirrer and micro-channels, as well as aeration layer, Reprinted from Ref. [58] with permission of Elsevier

Table 1 Comparisons of high-throughput perfusion models


[1]	Rathore A. Implementation of quality by design (QbD) for biopharmaceutical products. PDA Journal of Pharmaceutical Science and Technology, 2010,64(6):495-496. pmid: 21502059

[2]	Rathore A S, Winkle H. Quality by design for biopharmaceuticals. Nature Biotechnology, 2009,27(1):26-34. doi: 10.1038/nbt0109-26 pmid: 19131992

[3]	Bhavyasri K, Vishnumurthy K M, Rambabu D, et al. ICH guidelines-“Q” series (quality guidelines)-A review. GSC Biological and Pharmaceutical Sciences, 2019,6(3):89-106. doi: 10.30574/gscbps

[4]	Lu J, Wang J, Hollenbach M, et al. Process scale up and characterization of an intensified perfusion process. [2020-08-29].https://dc.engconfintl.org/ccexvi/222.

[5]	Butler M. Animal cell cultures: recent achievements and perspectives in the production of biopharmaceuticals. Applied Microbiology and Biotechnology, 2005,68(3):283-291. doi: 10.1007/s00253-005-1980-8

[6]	Walther J, Godawat R, Hwang C, et al. The business impact of an integrated continuous biomanufacturing platform for recombinant protein production. Journal of Biotechnology, 2015,213:3-12.

[7]	Croughan M S, Konstantinov K B, Cooney C. The future of industrial bioprocessing: batch or continuous? Biotechnology and Bioengineering, 2015,112(4):648-651.

[8]	Dorai H, Ganguly S. Mammalian cell-produced therapeutic proteins: heterogeneity derived from protein degradation. Current Opinion in Biotechnology, 2014,30:198-204.

[9]	Pollock J, Ho S V, Farid S S. Fed-batch and perfusion culture processes: economic, environmental, and operational feasibility under uncertainty. Biotechnology and Bioengineering, 2013,110(1):206-219.

[10]	Yang W C, Lu J, Kwiatkowski C, et al. Perfusion seed cultures improve biopharmaceutical fed-batch production capacity and product quality. Biotechnology Progress, 2014,30(3):616-625.

[11]	Noorman H. An industrial perspective on bioreactor scale-down: what we can learn from combined large-scale bioprocess and model fluid studies. Biotechnology Journal, 2011,6(8):934-943.

[12]	Schäpper D, Alam M N H Z, Szita N, et al. Application of microbioreactors in fermentation process development: a review. Analytical and Bioanalytical Chemistry, 2009,395(3):679-695.

[13]	Szita N, Boccazzi P, Zhang Z, et al. Development of a multiplexed microbioreactor system for high-throughput bioprocessing. Lab On A Chip, 2005,5(8):819-826. pmid: 16027932

[14]	Huang C, Lee G. A microfluidic system for automatic cell culture. Journal of Micromechanics and Microengineering, 2007,17(7):1266-1274.

[15]	Maharbiz M M, Holtz W J, Howe R T, et al. Microbioreactor arrays with parametric control for high-throughput experimentation. Biotechnology and Bioengineering, 2004,85(4):376-381.

[16]	Zhang Z, Perozziello G, Boccazzi P, et al. Microbioreactors for bioprocess development. Journal of Laboratory Automation, 2007,12(3):143-151.

[17]	Krommenhoek E E, Van Leeuwen M, Gardeniers H, et al. Lab-scale fermentation tests of microchip with integrated electrochemical sensors for pH, temperature, dissolved oxygen and viable biomass concentration. Biotechnology and Bioengineering, 2008,99(4):884-892.

[18]	Boccazzi P, Zhang Z, Kurosawa K, et al. Differential gene expression profiles and real-time measurements of growth parameters in Saccharomyces cerevisiae grown in microliter-scale bioreactors equipped with internal stirring. Biotechnology Progress, 2006,22(3):710-717.

[19]	Cervera A E, Petersen N, Lantz A E, et al. Application of near-infrared spectroscopy for monitoring and control of cell culture and fermentation. Biotechnology Progress, 2009,25(6):1561-1581. pmid: 19787698

[20]	Krommenhoek E E, Gardeniers J G E, Bomer J G, et al. Integrated electrochemical sensor array for on-line monitoring of yeast fermentations. Analytical Chemistry, 2007,79(15):5567-5573.

[21]	Voisard D, Meuwly F, Ruffieux P A, et al. Potential of cell retention techniques for large-scale high-density perfusion culture of suspended mammalian cells. Biotechnology and Bioengineering, 2003,82(7):751-765. pmid: 12701141

[22]	Jordan M, Jenkins N. Tools for high-throughput medium and process optimization//Pörtner R. Animal Cell Biotechnology. Methods in Biotechnology. Totowa: Humana Press, 2007: 193-202.

[23]	Fernandez D, Femenia J, Cheung D, et al. Scale-down perfusion process for recombinant protein expression//Kitagawa Y, Matsuda T, Iijima S. Animal Cell Technology: Basic & Applied Aspects. Berlin: Springer, 2008: 59-65.

[24]	Janoschek S, Schulze M, Zijlstra G, et al. A protocol to transfer a fed-batch platform process into semi-perfusion mode: the benefit of automated small-scale bioreactors compared to shake flasks as scale-down model. Biotechnology Progress, 2019,35(2):e2757. doi: 10.1002/btpr.2757 pmid: 30479066

[25]	Villiger-Oberbek A, Yang Y, Zhou W, et al. Development and application of a high-throughput platform for perfusion-based cell culture processes. Journal of Biotechnology, 2015,212:21-29. pmid: 26197419

[26]	Wolf M K, Lorenz V, Karst D J, et al. Development of a shake tube-based scale-down model for perfusion cultures. Biotechnology and Bioengineering, 2018,115(11):2703-2713. pmid: 30039852

[27]	Gomez N, Ambhaikar M, Zhang L, et al. Analysis of tubespins as a suitable scale-down model of bioreactors for high cell density CHO cell culture. Biotechnology Progress, 2017,33(2):490-499. pmid: 27977914

[28]	Wolf M K F, Muller A, Souquet J, et al. Process design and development of a mammalian cell perfusion culture in shake-tube and benchtop bioreactors. Biotechnology and Bioengineering, 2019,116(8):1973-1985.

[29]	Moses S, Manahan M, Ambrogelly A, et al. Assessment of AMBRTM as a model for high-throughput cell culture process development strategy. Advances in Bioscience and Biotechnology, 3(7), 918-927.

[30]	Delouvroy F, Siriez G, Tran A-V, et al. Ambr TM Mini-bioreactor as a high-throughput tool for culture process development to accelerate transfer to stainless steel manufacturing scale: comparability study from process performance to product quality attributes . BMC Proceedings, 2015,9:P78.

[31]	Janakiraman V, Kwiatkowski C, Kshirsagar R, et al. Application of high-throughput mini-bioreactor system for systematic scale-down modeling, process characterization, and control strategy development. Biotechnology Progress, 2015,31(6):1623-1632. pmid: 26317495

[32]	Hsu W, Hsu W, Hsu W, et al. Advanced microscale bioreactor system: a representative scale-down model for bench-top bioreactors. Cytotechnology, 2012,64(6):667-678.

[33]	Kelly W J, Veigne S, Li X, et al. Optimizing performance of semi-continuous cell culture in an ambr15 TM microbioreactor using dynamic flux balance modeling . Biotechnology Progress, 2018,34(2):420-431. pmid: 29152911

[34]	Kreye S, Stahn R, Nawrath K, et al. A novel scale-down mimic of perfusion cell culture using sedimentation in an automated microbioreactor (SAM). Biotechnology Progress, 2019,35(5):e2832.

[35]	Draoui N, Feron O. Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatments. Disease Models & Mechanisms, 2011,4(6):727-732. doi: 10.1242/dmm.007724 pmid: 22065843

[36]	Qian Y, Xing Z, Lee S, et al. Hypoxia influences protein transport and epigenetic repression of CHO cell cultures in shake flasks. Biotechnology Journal, 2014,9(11):1413-1424.

[37]	Gagliardi T, Chelikani R, Yang Y, et al. Development of a novel, high-throughput screening tool for efficient perfusion-based cell culture process development. Biotechnology Progress, 2019,35(4):e2811. pmid: 30932357

[38]	Kim H S, Lee G M. Differences in optimal pH and temperature for cell growth and antibody production between two Chinese hamster ovary clones derived from the same parental clone. Journal of Microbiology and Biotechnology, 2007,17(5):712-720.

[39]	Velugula-Yellela S R, Williams A, Trunfio N, et al. Impact of media and antifoam selection on monoclonal antibody production and quality using a high throughput micro-bioreactor system. Biotechnology Progress, 2018,34(1):262-270.

[40]	Zoro B, Ahmad A, Rees-Manley A, et al. Developing new perfusion capabilities for ambr (R) micro and mini bioreactors. [2020-08-29].https://dc.engconfintl.org/biomanufact_iv/10.

[41]	Robin J, Bandow N, Barrett S, et al. Scale-down high-throughput perfusion development with ambr 250. [2020-08-29].https://dc.engconfintl.org/ccexvi/10.

[42]	Lowry A. Single-use systems advance upstream processing.[2020-08-29]. http://www.biopharminter-national.com/single-use-systems-advance-upstream-processing.

[43]	Walls P L L, Mcrae O, Natarajan V, et al. Quantifying the potential for bursting bubbles to damage suspended cells. Scientific Reports, 2017,7(1):15102. pmid: 29118382

[44]	Terry S C, Jerman J H, Angell J B. A gas chromatographic air analyzer fabricated on a silicon wafer. IEEE Transactions on Electron Devices, 1979,26(12):1880-1886.

[45]	Harrison D J, Manz A, Fan Z, et al. Capillary electrophoresis and sample injection systems integrated on a planar glass chip. Analytical Chemistry, 1992,64(17):1926-1932.

[46]	Manz A, Graber N, Widmer H á. Miniaturized total chemical analysis systems: a novel concept for chemical sensing. Sensors and Actuators B: Chemical, 1990,1(1-6):244-248.

[47]	Hegab H M, Elmekawy A, Stakenborg T. Review of microfluidic microbioreactor technology for high-throughput submerged microbiological cultivation. Biomicrofluidics, 2013,7(2):021502.

[48]	Kirk T V, Szita N. Oxygen transfer characteristics of miniaturized bioreactor systems. Biotechnology and Bioengineering, 2013,110(4):1005-1019.

[49]	Jaccard N, Griffin L D, Keser A, et al. Automated method for the rapid and precise estimation of adherent cell culture characteristics from phase contrast microscopy images. Biotechnology and Bioengineering, 2014,111(3):504-517.

[50]	Lu S. Microfluidic Assays for perfusion culture and chemical monitoring of living cells. Michigan:University of Michigan, 2017.

[51]	Du G, Fang Q, Den Toonder J M. Microfluidics for cell-based high throughput screening platforms-a review. Analytica Ahimica Acta, 2016,903:36-50.

[52]	Wohlgemuth R, Plazl I, Žnidarsicplazl P, et al. Microscale technology and biocatalytic processes: opportunities and challenges for synthesis. Trends in Biotechnology, 2015,33(5):302-314.

[53]	Marques M P, Szita N. Bioprocess microfluidics: applying microfluidic devices for bioprocessing. Current Opinion in Chemical Engineering, 2017,18:61-68.

[54]	Bjork S M, Joensson H N. Microfluidics for cell factory and bioprocess development. Current Opinion in Biotechnology, 2019,55:95-102. pmid: 30236890

[55]	Buchenauer A, Hofmann M, Funke M, et al. Micro-bioreactors for fed-batch fermentations with integrated online monitoring and microfluidic devices. Biosensors and Bioelectronics, 2009,24(5):1411-1416. pmid: 18929478

[56]	Blesken C, Olfers T, Grimm A, et al. The microfluidic bioreactor for a new era of bioprocess development. Engineering in Life Sciences, 2016,16(2):190-193.

[57]	Funke M, Buchenauer A, Schnakenberg U, et al. Microfluidic biolector-microfluidic bioprocess control in microtiter plates. Biotechnology and Bioengineering, 2010,107(3):497-505.

[58]	Schapper D, Stocks S M, Szita N, et al. Development of a single-use microbioreactor for cultivation of microorganisms. Chemical Engineering Journal, 2010,160(3):891-898.

[59]	Paik S-M, Sim S-J, Jeon N L. Microfluidic perfusion bioreactor for optimization of microalgal lipid productivity. Bioresource Technology, 2017,233:433-437.

[60]	Kwon T, Prentice H, Oliveira J, et al. Microfluidic cell retention device for perfusion of mammalian suspension culture. Scientific Reports, 2017,7(1):6703. pmid: 28751635

[61]	Kwon T. Novel micro/nanofluidic system for separation and monitoring of cells and proteins in perfusion. Massachusetts: Massachusetts Institute of Technology, 2019. doi: 10.1142/S2339547815500016 pmid: 26161433

[62]	Grünberger A, Wiechert W, Kohlheyer D. Single-cell microfluidics: opportunity for bioprocess development. Current Opinion in Biotechnology, 2014,29:15-23.

[63]	Super A, Jaccard N, Marques M P C, et al. Real-time monitoring of specific oxygen uptake rates of embryonic stem cells in a microfluidic cell culture device. Biotechnology Journal, 2016,11(9):1179-1189. pmid: 27214658

[64]	Gernaey K V, Baganz F, Franco-Lara E, et al. Monitoring and control of microbioreactors: an expert opinion on development needs. Biotechnology Journal, 2012,7(10):1308-1314.

[65]	Sandner V, Pybus L P, Mccreath G, et al. Scale-down model development in ambr systems: an industrial perspective. Biotechnology Journal, 2019,14(4):1700766.

[66]	Campbell A M, Brieva T, Raviv L, et al. Concise review: process development considerations for cell therapy. Stem Cells Translational Medicine, 2015,4(10):1155-1163. pmid: 26315572

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