Model‐Based Monitoring and Control of a Monoclonal Antibody Production Process a

A structured mathematical model describing the dynamics of hybridoma growth and monoclonal antibody (mAb) production in suspension cultures is presented. The model fits well to experimental data obtained from batch, fed-batch, and continuous cultures with hybridoma cells. Applications of the model for process control are demonstrated. 1. An extended Kalman filter (EKF) was designed to estimate the state of the process. The oxygen consumption rate of the cell culture is monitored on-line and is used as the only measurement information for the EKF. This EKF is able to provide good estimates for living and dead cell densities and the medium composition. 2. The mathematical model can be applied for the optimization of fed-batch cultures.

[1]  M. Butler,et al.  Glucose and glutamine metabolism of a murine B-lymphocyte hybridoma grown in batch culture , 1993, Applied biochemistry and biotechnology.

[2]  L. Hartwell,et al.  Twenty-five years of cell cycle genetics. , 1991, Genetics.

[3]  K. K. Frame,et al.  Kinetic study of hybridoma cell growth in continuous culture. I. A model for non‐producing cells , 1991, Biotechnology and bioengineering.

[4]  G. Truskey,et al.  Kinetic studies and unstructured models of lymphocyte metabolism in fed‐batch culture , 1990, Biotechnology and bioengineering.

[5]  R. Mutharasan,et al.  Cell cycle‐ and growth phase‐dependent variations in size distribution, antibody productivity, and oxygen demand in hybridoma cultures , 1990, Biotechnology and bioengineering.

[6]  D F Ollis,et al.  Glutamine‐limited batch hybridoma growth and antibody production: Experiment and model , 1990, Biotechnology and bioengineering.

[7]  D F Ollis,et al.  A flow‐cytometric analysis of hybridoma growth and monoclonal antibody production , 1990, Biotechnology and bioengineering.

[8]  D. Kompala,et al.  A structured kinetic modeling framework for the dynamics of hybridoma growth and monoclonal antibody production in continuous suspension cultures , 1989, Biotechnology and bioengineering.

[9]  W M Miller,et al.  Transient responses of hybridoma cells to nutrient additions in continuous culture: I. Glucose pulse and step changes , 1989, Biotechnology and bioengineering.

[10]  R F Geoghegan,et al.  Kinetic modelling of hybridoma cell growth and immunoglobulin production in a large-scale suspension culture. , 1988, Biotechnology and bioengineering.

[11]  A J Sinskey,et al.  Reduction of waste product excretion via nutrient control: Possible strategies for maximizing product and cell yields on serum in cultures of mammalian cells , 1986, Biotechnology and bioengineering.

[12]  J. Lehmann,et al.  Inhibitory Substance(s) Secreted in Cell Culture Media of Recombinant CHO and a Hybridoma Cell Line , 1994 .

[13]  Michel Perrier,et al.  Optimization of fed-batch culture of hybridoma cells using dynamic programming: single and multi feed cases , 1992 .

[14]  W M Miller,et al.  The transient responses of hybridoma cells to nutrient additions in continuous culture: II. Glutamine pulse and step changes , 1989, Biotechnology and bioengineering.

[15]  H. R. Zielke,et al.  Glutamine: a major energy source for cultured mammalian cells. , 1984, Federation proceedings.