P16: Fermentation Process Characterization and Up-scaling of cGMP Hyaluronic acid in Recombinant Bacillus subtilis

Monday, November 7, 2011
Capri Ballroom (Marriott Marco Island)
Susan Meijer1, John Larson2, Rasmus Devantier2, Kristoffer Tømmeraas2, Mads Albæk2 and Stuart Stocks2, (1)Fermentation pilot plant, Novozymes A/S, Bagsværd, Denmark, (2)Novozymes, DK-2880 Bagsvaerd, Denmark
At Novozymes A/S a fermentation process has been developed in which a recombinant Bacillus subtilis strain excretes the Hyaluronic acid polysaccharide into the external medium. Due to this product excretion a water based recovery process is achieved resulting in a high purity product.

In order to produce pharma-grade hyaluronic acid, the process requires a high degree of process understanding and documentation. Therefore the process development work is very extensive and consists of several phases. Firstly, during PAR (proven acceptable range) studies, single parameter experiments are performed. Secondly, during PC/NOR (process characterization/normal operating range) multiple parameter/interaction studies are done. Thirdly, scale dependent parameters are investigated at full manufacturing scale in order to get a comprehensive understanding of the full-scale production process. Finally, the process needs to be validated and shown to be robust and reproducible.

In this work, we describe the different approaches during the stages of the development process, where at first relatively simple experiments are performed for getting a basic understanding of the importance of each process parameter. Afterwards more advanced experiments are performed using a DOE (Design of Experiment) set-up, where the interaction between important process parameters is determined. And finally at scale experiments are described to show the effect of viscosity and mass transfer differences at scale that are very dependent on the tank geometry and cannot be simulated in a down-scale model.  

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