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中国生物工程杂志

China Biotechnology
China Biotechnology
China Biotechnology  2018, Vol. 38 Issue (8): 69-75    DOI: 10.13523/j.cb.20180809
    
High-Throughput Micro Bioreactor Development for Biopharmaceuticals
Yu-lei GUO1,Liang TANG2,Rui-qiang SUN2,You LI2,Yi-jun CHEN1,*()
1. College of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
2. Wuxi Biologics, Shanghai 200131, China
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Abstract  

The development of biologics based on mammalian cell culture technologies has increasingly rapid advances for the pharmaceutical markets in the recent years. Economic concerns and time constraint as the critical factors and the driving force have accelerated bioprocess development of delivery of new biopharmaceutical drugs to market. Dramatically, advancement of semi-high-throughput micro-bioreactors in bioprocess development has shown a significant alternative for the conventional approaches due to automation, increased capability of throughput, and excellent parallel level compared to costly and laborious bench-top bioreactors. There are several commercially available micro scale bioreactors, such as Simcell TM, Ambr 15 TM and Ambr 250 TM, being applied in different stages of cell culture development to enhance throughput. This research reviewed and summarized the strengths and challenges of high-throughput bioreactors for the mammalian cells culture, showing the potential as scale-down models for process development and further improvement in the future.



Key words： Mammalian cell      Cell culture process development      Bench-top bioreactor      Micro-bioreactor     
Received: 13 March 2018      Published: 11 September 2018
ZTFLH:  Q81  
Corresponding Authors: Yi-jun CHEN     E-mail: yjchen@cpu.edu.cn
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Yu-lei GUO
Liang TANG
Rui-qiang SUN
You LI
Yi-jun CHEN
Cite this article:

Yu-lei GUO,Liang TANG,Rui-qiang SUN,You LI,Yi-jun CHEN. High-Throughput Micro Bioreactor Development for Biopharmaceuticals. China Biotechnology, 2018, 38(8): 69-75.

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https://manu60.magtech.com.cn/biotech/10.13523/j.cb.20180809     OR     https://manu60.magtech.com.cn/biotech/Y2018/V38/I8/69

Fig.1 Simplified flow diagram showing biologics development and cell culture process development
Items Bench-top B
ioreactors (1~3L)		 Shake flasks SimcellTM Ambr 15TM Ambr 250TM
Mode Manual Manual Automated Automated Automated
Quantities* 8 24 1260 48 24
Volume 1~3L 50~1000ml 7000ml 10~15ml 200~250ml
Capital cost Large footprint
Very high capital		 Moderate footprint
Low capital		 Large footprint Very
high capital		 Low footprint
Moderate capital		 Low footprint
Moderate capital
Temperature control Individual Incubator control Controlled in units
of 252		 Controlled in units
of 12		 Individual
pH control Real-time NA Periodic Real-time Real-time
DO control Real-time NA Periodic Real-time Real-time
Gassing Overlay + Sparger Surface Surface Sparger Overlay + Sparger
Oxygen KLa 2~10h-1 NA 7h-1 2.6~6.0h-1 2.5~8.5h-1
Agitation 200~300r/min 100~125r/min 20r/min 300~1500r/min 200~800r/min
P/V values 30~70W/m3 40W/m3 NA 3.9~419W/m3 10~445W/m3
Agitator blade Three-blade
propeller		 NA NA Two-blade
propeller		 Three-blade
propeller
Mixing time 10~100s 2~5s 20s 5~25s 5~40s
Table 1 Parameters comparison between high-throughput mini-bioreactors and bench-top bioreactors [5,17,22]
Fig.2 SimcellTM micro-bioreactor array and agitation scheme [10]
Fig.3 Ambr 15TM system contains mini-bioreactors (a) and work station (b)
Fig.4 Ambr 250TM system contains mini-bioreactors (a) and work station (b)
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