Bioprocess and Biosystems Engineering

, Volume 34, Issue 4, pp 419–431

Multi-stage high cell continuous fermentation for high productivity and titer

  • 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
Original Paper

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.

Keywords

Multi-stage continuous fermentation High cell density Ethanol Lactic acid Antibody 

List of symbols

B

Bleed ratio (dimensionless)

D

Dilution rate (/h), Dt for MSC-HCDC system, Di for each reactor of MSC-HCDC, Df dilution rate increase by feed stream for each reactor

kd

Specific death rate (/h)

mx

Maintenance coefficient

P

Product titer (g/L)

PD

Productivity (g/L/h)

PR

Productivity ratio (dimensionless)

Q

Feed flow rate (main stream) (L/h)

q

Feed flow rate (branched stream) (L/h)

qp/x,\( \overline{q} \)p/x

Specific, average productivity of cells (g/g/h)

rP

Product formation rate (g-product/L/h)

S

Substrate concentration (g/L)

V

Reactor volume (L)

w

Volume ratio (dimensionless)

X,\( \overline{X} \)

Cell concentration, average cell concentration (g/L), X = 100 g/L (lactic acid, ethanol) and X = 40 and 60 g/L (penicillin) were used

Y

Yield value

μ

Specific growth rate (/h)

β

Flow ratio of the top effluent and filtrate (dimensionless)

γ

Filtration ratio in the cell filtering unit (dimensionless)

θ

Cycle or residence time of fermentation system (h)

Subscripts

0

Initial value

b, fb

Batch, fed-batch system

c

Continuous

f

Feed stream

hcdc

High cell-density culture

i

Number of optional stages

j

Number of optional stages

n

Number of stages

t

Total value for D, P, PD, V, Q or θ

Abbreviations

HRT

Hydraulic retention time

SRT

Solid retention time

Mab

Monoclonal antibody

C-HCDC

Continuous high cell-density culture

SSC-HCDC

Single-stage continuous high cell-density culture

MSC-HCDC

Multistage continuous high cell-density culture

PHB

Polyhydroxybutyric acid

B/FB

Batch or fed-batch

FB

Fed-batch

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Ho Nam Chang
    • 1
  • Nag-Jong Kim
    • 1
    • 3
  • Jongwon Kang
    • 1
  • Chang Moon Jeong
    • 1
  • Jin-dal-rae Choi
    • 1
  • Qiang Fei
    • 1
  • Byoung Jin Kim
    • 1
    • 4
  • Sunhoon Kwon
    • 1
    • 5
  • Sang Yup Lee
    • 1
  • Jungbae Kim
    • 2
  1. 1.Department of Chemical and Biomolecular EngineeringKAIST (Korea Advanced Institute of Science and Technology)DaejeonKorea
  2. 2.Department of Chemical and Biological EngineeringKorea UniversitySeoulKorea
  3. 3.Samsung PetrochemicalYongin-siKorea
  4. 4.Samsung Advanced Institute of TechnologyYongin-siKorea
  5. 5.BINEX, LLCSeoulKorea

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