Multi-stage high cell continuous fermentation for high productivity and titer |
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Authors: | Ho Nam Chang Nag-Jong Kim Jongwon Kang Chang Moon Jeong Jin-dal-rae Choi Qiang Fei Byoung Jin Kim Sunhoon Kwon Sang Yup Lee Jungbae Kim |
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Institution: | (1) Department of Chemical and Biomolecular Engineering, KAIST (Korea Advanced Institute of Science and Technology), Daejeon, 305-701, Korea;(2) Department of Chemical and Biological Engineering, Korea University, Seoul, 136-701, Korea;(3) Present address: Samsung Petrochemical, Yongin-si, 446-712, Korea;(4) Present address: Samsung Advanced Institute of Technology, Yongin-si, 446-712, Korea;(5) Present address: BINEX, LLC, Seoul, 121-815, Korea |
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Abstract: | 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. |
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