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Achim Kienle - One of the best experts on this subject based on the ideXlab platform.
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Analyzing the Impact of Heterogeneity in Genetically Engineered Cell Lines for Influenza Vaccine Production Using Population Balance Modeling
IFAC-PapersOnLine, 2016Co-Authors: Robert Durr, Mandy Bachmann, Stefanie Duvigneau, Tanja Laske, Achim KienleAbstract:Abstract: Engineering of novel cell lines for biotechnological processes, e.g. influenza virus vaccine production, can be achieved by the genetic modification of host cell gene expression. Therefore, versatile genome editing methods such as lentiviral transduction can be applied to improve the production process. However, due to random integration of lentiviral-delivered genes in the host cell genome, nonuniform, i.e. heterogeneous, gene expression within the host cell Population is expected. Within this contribution we investigate the influence of this cell-to-cell variability on important process variables like the maximum virus yield. Therefore, a multi dimensional Population Balance model is proposed which, on the one hand comprises a detailed description of the intracellular viral replication cycle and, on the other, also accounts for the expected heterogeneity in the host cell Population. The results indicate that the overall vaccine production process can be improved by enhancement or inhibition of certain steps in the viral replication cycle. Furthermore, the achieved improvements show robustness against moderate degrees of cell-to-cell variability from genetic modification of host cells via transduction.
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Population Balance Modeling of biopolymer production in cellular systems
IFAC Proceedings Volumes, 2014Co-Authors: Andre Franz, Robert Durr, Achim KienleAbstract:Abstract In this contribution we present a Population Balance Modeling approach for the production of the biopolymer poly(β-hydroxybutyrate) in Ralstonia eutropha. The Population Balance model is based on a dynamic single cell model, which accounts for cell internal regulation by means of the cybernetic Modeling approach. The change of internal coordinates is controlled by cybernetic control variables. Depending on available substrates and internal composition the Population Balance model is therefore able to switch between growth, synthesis of biopolymer and metabolization of biopolymer. The latter one was neglected in an earlier contribution, but is crucial for overall dynamic behavior. In a first step we present a extended two-dimensional Population Balance model which includes metabolization of biopolymer and considers the cell internal biopolymer and residual biomass as internal coordinates. The two-dimensional Population Balance model includes cell internal regulation by means of cybernetic control variables. Since concentration of internal biopolymer and amount of residual biomass are costly to determine, we discuss in a second step a reduction of the two-dimensional to a one-dimensional Population model by means of correlating cell size with biopolymer concentration.
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stochastic Population Balance Modeling of influenza virus replication in vaccine production processes ii detailed description of the replication mechanism
Chemical Engineering Science, 2008Co-Authors: Y. Sidorenko, Achim Kienle, Udo Reichl, Andreas Voigt, J SchulzehorselAbstract:Abstract In a recent paper a segregated stochastic model was proposed for influenza virus replication in vaccine production processes [Sidorenko, Y., Schulze-Horsel, J., Voigt, A., Reichl, U., Kienle, A., 2008. Stochastic Population Balance Modeling of influenza virus replication in vaccine production processes. Chemical Engineering Science 63, 157–169]. The model used a simple segregated, unstructured approach for the description of the virus replication. In particular, effects arising from limited internal cellular resources and detailed cell physiology were not taken into account. The degree of infection—corresponding to the number of virus equivalents per cell—was used as the only internal coordinate. The model was successful in describing the integral dynamics of the process, however, revealed some discrepancies with respect to the “internal dynamics” of the virus replication. Therefore, in a second step, a much more detailed description of the virus replication process is considered in this paper. Again, cell physiology is described in terms of global growth and death events. Limitations of the intracellular resources are not taken into account. It is shown that this type of model does not contribute significantly to an improvement of the prediction of the internal dynamics. Hence, it is concluded that limited intracellular resources or a detailed description of the cell physiology is required for a more realistic Modeling of virus replication dynamics.
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Population Balance Modeling of influenza virus replication in MDCK cells during vaccine production
Computer Aided Chemical Engineering, 2008Co-Authors: T. Mueller, J. Schulze-horsel, Udo Reichl, Y. Sidorenko, Achim KienleAbstract:Abstract In this contribution a Population Balance model of influenza A virus replication during vaccine production in Madin-Darby canine kidney (MDCK) cell cultures is developed. Differentiation on the Population level is described by a degree of infection, which is proportional to the amount of intracellular viral proteins. This can be measured directly using flow cytometry. It is shown that the model shows reasonable agreement with experimental data, although not all details of the inner dynamics can be fully reproduced.
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stochastic Population Balance Modeling of influenza virus replication in vaccine production processes
Chemical Engineering Science, 2008Co-Authors: Y. Sidorenko, Achim Kienle, Udo Reichl, Andreas Voigt, J SchulzehorselAbstract:Abstract A distributed Population Balance model of influenza A virus replication in adherent Madin-Darby canine kidney cells has been developed to reproduce and interpret flow cytometry data for virus propagation in microcarrier culture. The Population of cells is differentiated into uninfected, infected and degraded cells. As an internal coordinate the number of intracellular viral components is considered. The main focus of the model is to link the time course of intracellular virus protein accumulation monitored by flow cytometry with the total yield of virus particles measured by the hemagglutination assay. The model allows simulating the extracellular virus dynamics for multiplicities of infection in the range 0.025–3.0. Shape of predicted histograms is in general agreement with distributions obtained by flow cytometry. Differences in time course at about 12–14 and 20 h post infection indicate that additional assumptions on intracellular virus dynamics are required to fully explain experimental data. Furthermore, prerequisites for virus replication, like receptor binding sites, the number of endosomes or the demand for free amino acids and nucleotides for virus synthesis can be estimated and compared with cellular resources available. Simulation results suggest that intracellular pools of free amino acids as well as early cell death due to influenza virus-induced apoptosis can limit virus yields. It is expected that based on a better understanding of the infectivity status of cells and the spreading of viruses in Population of cells in bioreactors strategies on design and optimization of vaccine production processes can be developed.
Marco Mazzotti - One of the best experts on this subject based on the ideXlab platform.
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Population Balance Modeling of growth and secondary nucleation by attrition and ripening
Crystal Growth & Design, 2020Co-Authors: Luca Bosetti, Marco MazzottiAbstract:Secondary nucleation is ubiquitous in nature and of fundamental importance for both batch and continuous crystallization processes. Attrition is the mechanism through which fragments are formed aft...
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Population Balance Modeling of growth and secondary nucleation by attrition and ripening
Crystal Growth & Design, 2020Co-Authors: Luca Bosetti, Marco MazzottiAbstract:Secondary nucleation is ubiquitous in nature and of fundamental importance for both batch and continuous crystallization processes. Attrition is the mechanism through which fragments are formed after the collision of a crystal with a stirrer. Those fine fragments, if small enough, are considered secondary nuclei. In this work, starting from the mechanistic description of attrition by Gahn and Mersmann ( Crystallization Technology Handbook; CRC Press, 2001), two Population Balance equation models to simulate secondary nucleation processes have been derived. The first simulates attrition as a breakage term, and growth rate is the result of size-dependent solubility. The second model considers attrition as a boundary condition at zero crystal size, where the expression for secondary nucleation rate already takes into account the effect of supersaturation, while the growth rate is size-independent. The two models are proven equivalent in the growth regime, thus where secondary nucleation and growth are the do...
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Population Balance Modeling with size dependent solubility ostwald ripening
Crystal Growth & Design, 2012Co-Authors: Martin Iggland, Marco MazzottiAbstract:In this work, we present a detailed Population Balance model for Ostwald ripening. The model is based on a size-dependent growth rate expression incorporating the Gibbs–Thomson relationship between particle size and solubility, and is solved numerically. The effect of parameters such as average initial particle size, initial width of the particle size distribution, and initial mass as well as solubility are investigated in simulations. This analysis focuses on understanding how the ripening phenomenon can be exploited in a crystallization process. The simulations are compared to the predictions of classical Lifshitz, Slyozov, Wagner (LSW) theory. Using our results, we assess the advantages and disadvantages of the full numerical simulation compared to the LSW model.
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experimental characterization and Population Balance Modeling of the polymorph transformation of l glutamic acid
Crystal Growth & Design, 2009Co-Authors: Jeroen Cornel, Christian Lindenberg, Marco MazzottiAbstract:In this work, the polymorph transformation of the metastable α to the stable β polymorph of l-glutamic acid at 45 °C was monitored using in situ Raman spectroscopy. In a series of seeded transformation experiments, the effect of different operating conditions on the transformation was studied. Both increasing seed mass and increasing stirring rate decrease the transformation time, thus suggesting an attrition-based secondary nucleation mechanism of the β polymorph. Moreover, it was found that no pure seed crystals of the metastable α polymorph could be produced and that different sieve fractions of the α polymorph contained different amounts of the β polymorph, which was included within the α crystal. These inclusions had a significant effect on the transformation times meaning that in experiments with larger seeds the transformation was faster than in experiments with smaller seeds. Independent seeded batch desupersaturation experiments were conducted to determine the growth rate of the β polymorph. On t...
Andreas Voigt - One of the best experts on this subject based on the ideXlab platform.
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stochastic deterministic Population Balance Modeling and simulation of a fluidized bed crystallizer experiment
Chemical Engineering Science, 2019Co-Authors: Clemens Bartsch, Andreas Voigt, Kai Sundmacher, Viktoria Wiedmeyer, Zahra Lakdawala, Robert I A Patterson, Volker JohnAbstract:Abstract The crystallization of potassium aluminum sulfate dodecahydrate (potash alum) in a fluidized bed crystallizer is studied both with experiments and simulations. A Population Balance system with three spatial coordinates and one internal coordinate (mass) is utilized as our model. The simulations are performed with a stochastic-deterministic method with novel extensions, where the fluid dynamics of the crystallizer (flow field, temperature, concentration) are solved deterministically and the particles are simulated with a stochastic method. In experiments of 30 min duration, the average crystal diameter increases by growth and agglomeration from about 130 μm to 210 μm. This observation agrees qualitatively well with our simulation results. A quantitative difference between simulation and experiment leaves room for future improvements in Modeling.
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stochastic Population Balance Modeling of influenza virus replication in vaccine production processes ii detailed description of the replication mechanism
Chemical Engineering Science, 2008Co-Authors: Y. Sidorenko, Achim Kienle, Udo Reichl, Andreas Voigt, J SchulzehorselAbstract:Abstract In a recent paper a segregated stochastic model was proposed for influenza virus replication in vaccine production processes [Sidorenko, Y., Schulze-Horsel, J., Voigt, A., Reichl, U., Kienle, A., 2008. Stochastic Population Balance Modeling of influenza virus replication in vaccine production processes. Chemical Engineering Science 63, 157–169]. The model used a simple segregated, unstructured approach for the description of the virus replication. In particular, effects arising from limited internal cellular resources and detailed cell physiology were not taken into account. The degree of infection—corresponding to the number of virus equivalents per cell—was used as the only internal coordinate. The model was successful in describing the integral dynamics of the process, however, revealed some discrepancies with respect to the “internal dynamics” of the virus replication. Therefore, in a second step, a much more detailed description of the virus replication process is considered in this paper. Again, cell physiology is described in terms of global growth and death events. Limitations of the intracellular resources are not taken into account. It is shown that this type of model does not contribute significantly to an improvement of the prediction of the internal dynamics. Hence, it is concluded that limited intracellular resources or a detailed description of the cell physiology is required for a more realistic Modeling of virus replication dynamics.
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stochastic Population Balance Modeling of influenza virus replication in vaccine production processes
Chemical Engineering Science, 2008Co-Authors: Y. Sidorenko, Achim Kienle, Udo Reichl, Andreas Voigt, J SchulzehorselAbstract:Abstract A distributed Population Balance model of influenza A virus replication in adherent Madin-Darby canine kidney cells has been developed to reproduce and interpret flow cytometry data for virus propagation in microcarrier culture. The Population of cells is differentiated into uninfected, infected and degraded cells. As an internal coordinate the number of intracellular viral components is considered. The main focus of the model is to link the time course of intracellular virus protein accumulation monitored by flow cytometry with the total yield of virus particles measured by the hemagglutination assay. The model allows simulating the extracellular virus dynamics for multiplicities of infection in the range 0.025–3.0. Shape of predicted histograms is in general agreement with distributions obtained by flow cytometry. Differences in time course at about 12–14 and 20 h post infection indicate that additional assumptions on intracellular virus dynamics are required to fully explain experimental data. Furthermore, prerequisites for virus replication, like receptor binding sites, the number of endosomes or the demand for free amino acids and nucleotides for virus synthesis can be estimated and compared with cellular resources available. Simulation results suggest that intracellular pools of free amino acids as well as early cell death due to influenza virus-induced apoptosis can limit virus yields. It is expected that based on a better understanding of the infectivity status of cells and the spreading of viruses in Population of cells in bioreactors strategies on design and optimization of vaccine production processes can be developed.
Jitendra Kumar - One of the best experts on this subject based on the ideXlab platform.
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Population Balance Modeling of volume and time dependent spray fluidized bed aggregation kernel using monte carlo simulation results
Applied Mathematical Modelling, 2021Co-Authors: Ashok Kumar Das, Jitendra KumarAbstract:Abstract This paper seeks to extend the work of Hussain et al. (A new framework for Population Balance Modeling of spray fluidized bed agglomeration, Particuology 19 (2015) 141–154) to develop a detailed one-dimensional Population Balance Modeling (PBM) of the spatially homogeneous spray fluidized bed aggregation (SFBA) process. A new mathematical model of the volume and time dependent aggregation kernel is developed based on process specific microscopic mechanisms. In addition, the Population Balance equations of other important process related parameters (total number of available droplets and size distribution of wet particles) are presented. The developed PBM contains a new mathematical model which estimates the death rate of binder droplets due to the drying mechanism. For the verification of the developed PBM, a constant number Monte Carlo (MC) algorithm is used, which simulates important micro-mechanisms of the SFBA process (droplet addition, droplet drying, volume dependent particle collisions, aggregation, and rebound). The MC algorithm is capable of analyzing the effects of each microscopic event on the aggregation behavior. Volume dependency in particle collisions is used, while mimicking the SFBA process in the MC simulation algorithm. Furthermore, the volume and time dependent probability of successful wet position collisions is successfully extracted using the MC simulations and then transferred to the development of the PBM. Finally, the accuracy of the proposed PBM is verified by comparing its results against the predictions of the MC simulations.
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A new framework for Population Balance Modeling of spray fluidized bed agglomeration
Particuology, 2015Co-Authors: Mubashir Hussain, Jitendra Kumar, Evangelos TsotsasAbstract:Abstract Previous work (Hussain et al. (2013). Chemical Engineering Science, 101, 35) has pointed out that the conventional, one-dimensional Population Balance equation for aggregation can be expanded to accurately reproduce the results of discrete simulations of spray fluidized bed agglomeration. However, some parameters had to be imported from the discrete simulation (Monte-Carlo). The present paper shows how the expanded Population Balance can be run without importing parameters from the Monte-Carlo simulation. The expanded Population Balance still reproduces the results of Monte-Carlo simulations accurately, taking into account key micro-scale phenomena (sessile droplet drying, efficiency of collisions), but with much lower computational cost. Required input parameters are just the drying time of sessile droplets (calculated in advance), and the pre-factor of an equation that correlates particle collision frequency with fluidized bed expansion. In this way, the expanded Population Balance is, apart from autonomous, also (nearly) predictive. Its performance is demonstrated by comparisons with both Monte-Carlo results and experimental data for various operating conditions (binder mass flow rate, gas temperature). Despite formally being a one-dimensional expression, the expanded Population Balance captures additional properties, such as the number of wet particles and the number of droplets in the system, which are even difficult to measure in experiments.
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on two compartment Population Balance Modeling of spray fluidized bed agglomeration
Computers & Chemical Engineering, 2014Co-Authors: Mubashir Hussain, Jitendra Kumar, Mirko Peglow, Evangelos TsotsasAbstract:Abstract The present work focuses on the Modeling and analysis of a spray fluidized bed granulation (SFBG) process based upon the concept that particles are communicating between the two compartments at some steady state mass flow rate. A numerical technique for solving the proposed two-compartment model (2CM) is developed and validated against some newly derived analytical solutions. Moreover, the inverse technique for extracting the rate constant of one-compartment model (1CM) is extended to 2CM. A correlation of aggregation rate constant of 2CM with the rate constant of conventional 1CM under some restrictions is investigated and it is found that the 1CM cannot be used, in general, to predict results of 2CM. Furthermore, it is observed that the existence of two zones in SFBG is responsible to certain extent for time dependent behaviour of aggregation rate constant. Finally, influence of compartment sizes and particles residence times on particle size distribution is investigated.
Udo Reichl - One of the best experts on this subject based on the ideXlab platform.
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stochastic Population Balance Modeling of influenza virus replication in vaccine production processes ii detailed description of the replication mechanism
Chemical Engineering Science, 2008Co-Authors: Y. Sidorenko, Achim Kienle, Udo Reichl, Andreas Voigt, J SchulzehorselAbstract:Abstract In a recent paper a segregated stochastic model was proposed for influenza virus replication in vaccine production processes [Sidorenko, Y., Schulze-Horsel, J., Voigt, A., Reichl, U., Kienle, A., 2008. Stochastic Population Balance Modeling of influenza virus replication in vaccine production processes. Chemical Engineering Science 63, 157–169]. The model used a simple segregated, unstructured approach for the description of the virus replication. In particular, effects arising from limited internal cellular resources and detailed cell physiology were not taken into account. The degree of infection—corresponding to the number of virus equivalents per cell—was used as the only internal coordinate. The model was successful in describing the integral dynamics of the process, however, revealed some discrepancies with respect to the “internal dynamics” of the virus replication. Therefore, in a second step, a much more detailed description of the virus replication process is considered in this paper. Again, cell physiology is described in terms of global growth and death events. Limitations of the intracellular resources are not taken into account. It is shown that this type of model does not contribute significantly to an improvement of the prediction of the internal dynamics. Hence, it is concluded that limited intracellular resources or a detailed description of the cell physiology is required for a more realistic Modeling of virus replication dynamics.
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Population Balance Modeling of influenza virus replication in MDCK cells during vaccine production
Computer Aided Chemical Engineering, 2008Co-Authors: T. Mueller, J. Schulze-horsel, Udo Reichl, Y. Sidorenko, Achim KienleAbstract:Abstract In this contribution a Population Balance model of influenza A virus replication during vaccine production in Madin-Darby canine kidney (MDCK) cell cultures is developed. Differentiation on the Population level is described by a degree of infection, which is proportional to the amount of intracellular viral proteins. This can be measured directly using flow cytometry. It is shown that the model shows reasonable agreement with experimental data, although not all details of the inner dynamics can be fully reproduced.
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stochastic Population Balance Modeling of influenza virus replication in vaccine production processes
Chemical Engineering Science, 2008Co-Authors: Y. Sidorenko, Achim Kienle, Udo Reichl, Andreas Voigt, J SchulzehorselAbstract:Abstract A distributed Population Balance model of influenza A virus replication in adherent Madin-Darby canine kidney cells has been developed to reproduce and interpret flow cytometry data for virus propagation in microcarrier culture. The Population of cells is differentiated into uninfected, infected and degraded cells. As an internal coordinate the number of intracellular viral components is considered. The main focus of the model is to link the time course of intracellular virus protein accumulation monitored by flow cytometry with the total yield of virus particles measured by the hemagglutination assay. The model allows simulating the extracellular virus dynamics for multiplicities of infection in the range 0.025–3.0. Shape of predicted histograms is in general agreement with distributions obtained by flow cytometry. Differences in time course at about 12–14 and 20 h post infection indicate that additional assumptions on intracellular virus dynamics are required to fully explain experimental data. Furthermore, prerequisites for virus replication, like receptor binding sites, the number of endosomes or the demand for free amino acids and nucleotides for virus synthesis can be estimated and compared with cellular resources available. Simulation results suggest that intracellular pools of free amino acids as well as early cell death due to influenza virus-induced apoptosis can limit virus yields. It is expected that based on a better understanding of the infectivity status of cells and the spreading of viruses in Population of cells in bioreactors strategies on design and optimization of vaccine production processes can be developed.