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Abstract

Our aim is the design and optimisation of equine influenza vaccine production processes for the ameloriation of virus yields and batch-to-batch reproducibility [1]. In previous works we investigated the replication of virus particles [2]. Now we focus on cultivation and scale-up of adherent animal cells (Madin Darby Canine Kidney, MDCK) using microcarrier-systems to describe the entire process and combine both, the description of cell growth and virus replication. For a better understanding of the process we first developed a simple unstructured, nonsegregated cell growth model. The model consisted of five ordinary differential equations with eleven parameters. It allowed predicting the increase in cell numbers, the uptake of glucose and glutamine as well as the release of ammonia and lactate. However, it did not take into account the attachment phase of the cells onto microcarriers during the start of cultivation. A comparison with experimental data showed drawbacks of such a basic model. Therefore we improved the existing model to include the attachment phase to describe the growth behaviour of the cells. At first we used a general mathematical description of lag phase at the beginning of cultivation. Secondly, for a more realistic biological description, we have separated the cell population into balances such as cells in suspension and on microcarriers. Furthermore we used an unstructured, segregated model to handle an inhomogeneously distributed cell population on the surface of the microcarriers. Finally we compared all modelling approaches for cell growth considering different cultivation experiments of large-scale microcarrier culture together with the corresponding model parameters specific for MDCK-cells. [1] Y. Genzel; I. Behrendt; S. König; H. Sann; U. Reichl; Metabolism of MDCK cells during cell growth and influence virus production in large-scale microcarrier culture, Vaccine 2004, 22(17-18), 2202- 2208. [2] L. Möhler, D. Flockerzi, H. Sann and U. Reichl; A Mathematical Model of Influenza A Virus Production in Large-Scale Microcarrier Culture; Biotechnology and Bioengineering; expected for publication sep 2004