Bioprocess and Biosystems Engineering

, Volume 26, Issue 1, pp 1–10 | Cite as

Improvement of a mammalian cell culture process by adaptive, model-based dialysis fed-batch cultivation and suppression of apoptosis

Original Paper


Both conventional and genetic engineering techniques can significantly improve the performance of animal cell cultures for the large-scale production of pharmaceutical products. In this paper, the effect of such techniques on cell yield and antibody production of two NS0 cell lines is presented. On the one hand, the effect of fed-batch cultivation using dialysis is compared to cultivation without dialysis. Maximum cell density could be increased by a factor of ~5–7 by dialysis fed-batch cultivation. On the other hand, suppression of apoptosis in the NS0 cell line 6A1 bcl-2 resulted in a prolonged growth phase and a higher viability and maximum cell density in fed-batch cultivation in contrast to the control cell line 6A1 (100)3. These factors resulted in more product formation (by a factor ~2). Finally, the adaptive model-based OLFO controller, developed as a general tool for cell culture fed-batch processes, was able to control the fed-batch and dialysis fed-batch cultivations of both cell lines.


Process control Fed-batch Apoptosis bcl-2 overexpression NS0 cells 



membrane area (dm2)


glucose concentration in nutrient feed (mmol L−1)


glucose concentration in dialysis feed (mmol L−1)


glucose concentration in inner reactor chamber (mmol L−1)


glucose concentration in outer reactor chamber (dialysis chamber) (mmol L−1)


lactate concentration in dialysis feed (mmol L−1)


lactate concentration in inner reactor chamber (mmol L−1)


lactate concentration in outer reactor chamber (dialysis chamber) (mmol L−1)


limiting substrate concentration in dialysis feed (mmol L−1)


limiting substrate concentration in inner reactor chamber (mmol L−1)


limiting substrate concentration in outer reactor chamber (dialysis chamber) (mmol L−1)


monoclonal antibody concentration (mg L−1)


feed rate of dialysis feed (L h−1)


feed rate of nutrient concentrate feed (L h−1)


maximum death constant (h−1)


death rate constant for limiting substrate (mmol L−1)


monod kinetic constant for glucose uptake (mmol L−1)


monod kinetic constant for lactate uptake (mmol L−1)


monod kinetic constant for limiting substrate uptake (mmol L−1)


cell lysis constant (h−1)


monod kinetic constant for glucose (mmol L−1)


monod kinetic constant for limiting substrate (mmol L−1)


cell-specific growth rate (h−1)

µ d

cell-specific death rate (h−1)

µ d,min

minimum cell-specific death rate (h−1)

µ max

maximum cell-specific growth rate (h−1)


membrane permeation coefficient for glucose (dm h−1)


membrane permeation coefficient for lactate (dm h−1)


membrane permeation coefficient for limiting substrate (dm h−1)


cell-specific glucose uptake rate (mmol cell−1 h−1)


maximum cell-specific glucose uptake rate (mmol cell−1 h−1)


cell-specific lactate uptake/production rate (mmol cell−1 h−1)


maximum cell-specific lactate uptake rate (mmol cell−1 h−1)


cell-specific limiting substrate uptake rate (mmol cell−1 h−1)


maximum cell-specific limiting substrate uptake rate (mmol cell −1 h−1)


cell-specific antibody production rate (mg cell−1 h−1)


maximum cell-specific antibody production rate (mg cell−1 h−1)


time (h)


volume of inner reactor chamber (culture chamber) (L)


volume of outer reactor chamber (dialysis chamber) (L)


total cell concentration (cells L−1)


viable cell concentration (cells L−1)


kinetic production constant (stoichiometric ratio of lactate production and glucose uptake) (−)



This project "Suppression of programmed cell death in industrial scale biological production systems", contract number QLK3-CT-2000-00076, is kindly financed by the European Union (framework V).


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Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Bioprozess- und BioverfahrenstechnikTechnische Universität Hamburg-HarburgHamburgGermany
  2. 2.Institut für Technologie und BiosystemtechnikBundesforschungsanstalt für LandwirtschaftBraunschweigGermany

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