Rigorous Model-Based Design and Experimental Verification of Enzyme-Catalyzed Carboligation under Enzyme Inactivation

Enzyme catalyzed reactions are complex reactions due to the interplay of the enzyme, the reactants, and the operating conditions. To handle this complexity systematically and make use of a design space without technical restrictions, we apply the model based approach of elementary process functions (EPF) for selecting the best process design for enzyme catalysis problems. As a representative case study, we consider the carboligation of propanal and benzaldehyde catalyzed by benzaldehyde lyase from Pseudomonas fluorescens (PfBAL) to produce (R)-2-hydroxy-1-phenylbutan-1-one, because of the substrate dependent reaction rates and the challenging substrate dependent PfBAL inactivation. The apparatus independent EPF concept optimizes the material fluxes influencing the enzyme catalyzed reaction for the given process intensification scenarios. The final product concentration is improved by 13% with the optimized feeding rates, and the optimization results are verified experimentally. In general, the rigorous model driven approach could lead to selecting the best existing reactor, designing novel reactors for enzyme catalysis, and combining protein engineering and process systems engineering concept

Metabolic Regulatory Network Kinetic Modeling with Multiple Isotopic Tracers for iPSCs

The rapidly expanding market for regenerative medicines and cell therapies highlights the need to advance the understanding of cellular metabolisms and improve the prediction of cultivation production process for human induced pluripotent stem cells (iPSCs). In this paper, a metabolic kinetic model was developed to characterize underlying mechanisms of iPSC culture process, which can predict cell response to environmental perturbation and support process control. This model focuses on the central carbon metabolic network, including glycolysis, pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, and amino acid metabolism, which plays a crucial role to support iPSC proliferation. Heterogeneous measures of extracellular metabolites and multiple isotopic tracers collected under multiple conditions were used to learn metabolic regulatory mechanisms. Systematic cross-validation confirmed the model's performance in terms of providing reliable predictions on cellular metabolism and culture process dynamics under various culture conditions. Thus, the developed mechanistic kinetic model can support process control strategies to strategically select optimal cell culture conditions at different times, ensure cell product functionality, and facilitate large-scale manufacturing of regenerative medicines and cell therapies.Comment: 26 pages, 16 figure

Thermal Stability Analysis of Hydroprocessing Unit

Thermal stability is one of the most critical safety issues in the hydroprocessing units. Runaway reactions in the units can lead to catastrophic consequences as the reactors are being operated at high temperature and pressure, and the reactor effluent is a highly explosive mixture which contains hydrogen and hydrocarbons. For example, a fire and explosion due to a runaway reaction in a hydrocracking unit caused one death and forty-six injuries in 1997, in California. While the temperature runaway is the topic which has been studied extensively, most of the studies worked on simple reactions and little focused on the complex reactions such as hydroprocessing reactions. Also, in the studies on the hydroprocessing reactions, a lumping kinetic model was used which is less accurate and requires experiments for each application. In this research, the thermal stability of a naphtha hydrotreater will be analyzed by using a commercial process simulator ProMax where a novel mechanistic kinetic model, Single Event Kinetics has been integrated. Also, a simplified model will be established by using the data provided by ProMax for further analysis. The continuity and energy equations and parametric sensitivity equations will be solved by Matlab based on the methodology presented by Morbidelli and Varma

Model-based medium optimization methodologies in high-cell density perfusion culture

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KINETIC MODELING AND ITS APPLICATION IN THE BIOPHARMACEUTICAL INDUSTRY

It has been well recognized that biologics are efficient for cancer and immune disease treatment. Kinetic modeling is to mathematically model or to quantitatively illustrate how reactions occur in a biological or chemical process. A systematic study and understanding of kinetic model and its application in the biopharmaceutical industry are important for both scientific research and industrial technology development. This work consists of six chapters. First, a review of kinetic modeling and its application for cell culture was introduced. Second, the current status of biologics development and screening strategies of biomarkers and indications were discussed. Third, one experimental and kinetic modeling study for the temperature effects and temperature shift strategy development was presented. Forth, novel kinetic models were built up and applied to elucidate lactate dehydrogenase catalyzed reactions, which is a crucial metabolic process within tumor cells and Chinese hamster ovary cells. In the fifth chapter, strategies of biologics quality control via process development were briefly summarized. And finally, summary and outlook were made based on the above five chapters. Though kinetic modeling is not a FDA request tool, kinetic data are required for regulation approval of new drug discovery and process development. These data are applicable for a rapidly screening of the best biologics and the optimized manufacturing process with little extra cost via kinetic modeling. This work is potentially beneficial for speeding up and better understanding of the current biologics development in biopharmaceutical industry

Biogas production according to the waste categories

The aim of the present work is to model the production of a biogas according to the different categories of the biodegradable materials. The simulation model that predicts biogas production from a plug-flow anaerobic digester is developed. This model is based on the kinetic equation of the methanization. A first-order kinetic model is used to predict the chemical reactions in the digestion process. A model prediction is validated against Numerical simulation measured biogas production and data which are obtained from the literature

Comprehensive multiphysics modeling of photocatalytic processes by computational fluid dynamics based on intrinsic kinetic parameters determined in a differential photoreactor

AbstractThis work describes the procedure for the simulation of the operation of a photocatalytic reactor by using a multiphysics computational fluid dynamics (CFD) model based on the determination of the intrinsic kinetics parameters in an optically differential photoreactor. The model includes the rigorous description of the hydrodynamics, radiation transfer, mass transport and chemical reaction rate based on a mechanistic kinetic model. Possible existence of dead and recirculation zones has been identified from the flow field, showing a non-uniform flow through the reactor domain. The theoretical laminar profile is not reached due to the short length of the annular core and the departure from the ideal models has been quantified. The predicted velocity field has been experimentally validated with good agreement by injecting a tracer. The radiation field was simulated for slurry TiO2 suspensions with concentrations between 0.005 and 5g·L−1, showing an optimum catalyst loading around 0.1–0.2g·L−1. Above this value, the increase in the absorption of radiation is negligible, whereas a more non-uniform radiation profile develops, keeping the most external regions of the reactor in the dark. The results of photocatalytic activity, using methanol oxidation as test reaction, showed good agreement between model predictions and experimental data, with errors between 2% and 10% depending on the catalyst concentration. The successful validation confirms not only the scientific background of the model, but also supports its applicability for engineering purposes in the design and optimization of large scale photocatalytic reactor to overcome some of limitations hindering the industrial development of this technology