Multi-stage high cell continuous fermentation for high productivity and titer.
We carried out the first simulation on multi-stage continuous high cell density culture (MSC-HCDC) to show that the MSC-HCDC can achieve batch/fed-batch product titer with much higher productivity to the fed-batch productivity using published fermentation kinetics of lactic acid, penicillin and ethanol. The system under consideration consists of n-serially connected continuous stirred-tank reactors (CSTRs) with either hollow fiber cell recycling or cell immobilization for high cell-density culture. In each CSTR substrate supply and product removal are possible. Penicillin production is severely limited by glucose metabolite repression that requires multi-CSTR glucose feeding. An 8-stage C-HCDC lactic acid fermentation resulted in 212.9 g/L of titer and 10.6 g/L/h of productivity, corresponding to 101 and 429% of the comparable lactic acid fed-batch, respectively. The penicillin production model predicted 149% (0.085 g/L/h) of productivity in 8-stage C-HCDC with 40 g/L of cell density and 289% of productivity (0.165 g/L/h) in 7-stage C-HCDC with 60 g/L of cell density compared with referring batch cultivations. A 2-stage C-HCDC ethanol experimental run showed 107% titer and 257% productivity of the batch system having 88.8 g/L of titer and 3.7 g/L/h of productivity. MSC-HCDC can give much higher productivity than batch/fed-batch system, and yield a several percentage higher titer as well. The productivity ratio of MSC-HCDC over batch/fed-batch system is given as a multiplication of system dilution rate of MSC-HCDC and cycle time of batch/fed-batch system. We suggest MSC-HCDC as a new production platform for various fermentation products including monoclonal antibody.
Department of Chemical and Biomolecular Engineering, KAIST (Korea Advanced Institute of Science and Technology), Daejeon, Korea. hnchang@kaist.edu
Ho Nam
HN
Chang
Nag-Jong
NJ
Kim
Jongwon
J
Kang
Chang Moon
CM
Jeong
Jin-dal-rae
JD
Choi
Qiang
Q
Fei
Byoung Jin
BJ
Kim
Sunhoon
S
Kwon
Sang Yup
SY
Lee
Jungbae
J
Kim
D000911:Antibodies, Monoclonal / Q000737:chemistry; D018533:Biomass; D019149:Bioreactors; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003198:Computer Simulation; D003470:Culture Media; D000431:Ethanol / Q000737:chemistry; D005285:Fermentation; D005947:Glucose / Q000737:chemistry; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry; D015233:Models, Statistical; D010406:Penicillins / Q000737:chemistry; D013379:Substrate Specificity; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors
D000911:Antibodies, Monoclonal; D003470:Culture Media; D010406:Penicillins; D019344:Lactic Acid; D000431:Ethanol; D005947:Glucose