|Title:||A comprehensive analytical and process-technological toolbox for improved Penicillin production||Language:||English||Authors:||Ehgartner, Daniela||Qualification level:||Doctoral||Keywords:||Penicillium chrysogenum; bioprocess; PAT; flow cytometry; process control; morphology; spores; growth rate||Advisor:||Herwig, Christoph||Issue Date:||2017||Number of Pages:||145||Qualification level:||Doctoral||Abstract:||
A Comprehensive Analytical and Process-Technological Toolbox for Improved Penicillin Production Biosynthesis of one of the most important antibiotics - penicillin- depends on various process and morphological parameters. In several studies a link between specific growth rate (µ) and specific penicillin production rate (qp) is described. Depending on the process, the link between µ and qp differs. Furthermore, penicillin producing bioprocesses exhibit highly dynamic qp's, for which a simple link between µ and qp does not suffice for its description. Hence, an extended set of process parameters need be considered to gain predictive and robust bioprocess performance. This thesis aims providing an analytical and process-technological toolbox enabling detailed investigation of µ-qp-relations and, moreover, for the control of process parameters to achieve optimal penicillin productivity in industrial fed-batch processes. Thereby, the complexity of filamentous bioprocesses ought to be considered: Fungal morphology varies in relation to process parameters like spore inoculum concentration and power input. Via broth viscosity and mass transfer the morphology affects process performance. Furthermore, biomass segregation occurs. Especially fungal pellets (dense hyphal aggregates) are concerned. Thus, viable biomass measurements in nondisperse growing cultures are important. An analytical and process-technological toolbox for the investigation of morphology and biomass segregation applicable in all process phases was developed consisting of: At first, this toolbox allows the at-line determination of spore sub-populations and the measurement of viable spore concentration via spore germination monitoring. Thereby, reproducible starting conditions of fed-batch cultures based on comparable batch processes should be achievable. Secondly, one of the methodologies provided in the toolbox enables the online control of the specific growth rate based on viable biomass measurements. This tool is able to cope with physiological and morphological changes of filamentous fungi. Furthermore, the control strategy adapts to changing biomass yields, which is an important issue in the here presented bioprocess for penicillin production. The last tool analyses at-line fungal morphology to evaluate morphological parameters as a central variable in filamentous processes. Using this toolbox, the µ-qp-relation for a penicillin V producing and pellet growing Penicillium chrysogenum process with highly dynamic qp-trajectories was described. Thereby, the consumed glucose was found to be an important factor concerning the influence of µ on qp. This contribution highlights the importance and applicability of the presented analytical and process-technological toolbox for scientific investigations as well as for the conduction of robust and reproducible processes. The methodology for the analysis of µ-qp-interactions and other interfering mechanisms was hence created. Combining knowledge about µ-qp-relations with the presented tools provides the basis for experimental design and process control for the improvement of penicillin producing bioprocesses towards optimal qp-trajectories. Apart from process robustness by reproducible starting conditions and the control of the specific growth rate based on viable biomass measurements, at-line monitoring of fungal morphology provides an additional tool for process control.
|Library ID:||AC13772124||Organisation:||E166 - Inst. f. Verfahrenstechnik, Umwelttechnik und Techn. Biowissenschaften||Publication Type:||Thesis
|Appears in Collections:||Thesis|
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checked on Feb 18, 2021
checked on Feb 18, 2021
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