no / Batch and semi-batch reactors are widely used for fine chemical productions. The target in the fine chemical industry is to produce a high quality product and operational optimization is the key-element to match it. This work investigates how batch and semi-batch reactors can be optimized in order to increase the yield of a desired product. Optimization problem is formulated and applied to calculate the optimal operating parameters such as the reactor temperature and the feed flow rate. Comparison and considerations on the two reactor configurations are given.

Animal cell culture is widely used as a platform for the production of a variety of biopharmaceuticals. The development of an efficient and productive cell culture requires a deep understanding of intra-cellular mechanisms as well as extra-cellular conditions for optimal synthesis. Mathematical modeling can be an effective strategy to predict, control, and optimize cell performance under different culture conditions. This research presents the evaluation of Chinese hamster ovary (CHO) cell culture secreting recombinant anti-RhD monoclonal antibody (MAb) through different processing modes, namely batch, fed-batch and perfusion operations. The ultimate objective of this study was to establish a comprehensive dynamic model which may be used for model-based optimization of the cell culture for MAb production in both batch, fed-batch or perfusion systems. In analyzing process performance, the key potential cause of cell growth inhibition was attributed to lowering of pH in the culture possibly due to the accumulation of dissolved carbon dioxide. The most important finding in this regard was the significantly different observed maximum total viable cell density in two identical cultures differing in culture volume only (250mL and 500mL). However, the other byproduct metabolites such as lactate and ammonia and glucose depletion were also capable affecting growth adversely causing growth arrest, viability reduction, apoptosis initiation and progress. Employing the experimental results of nutrient consumption, metabolite and biomass production, a metabolic flux based methodology was developed for modeling the metabolism of a CHO cell line. The elimination of insignificant fluxes resulted in a simplified metabolic network which was the basis for modeling the significant extracellular metabolites. Using kinetic rate expressions for growing and non-growing subpopulations, a logistic model was first developed for cell growth and dynamic models were formulated to describe culture composition and monoclonal antibody (MAb) secretion. The viable cell population was assumed to consist of normal growing, normal non-growing and apoptotic cell subpopulations. The rate of apoptotic cell formation was assumed to have a second order dependence on the normal cell concentration. The proposed mathematical model for metabolites included distinct terms that reflected the metabolic rates of growing and non-growing cell populations. The model was validated for a range of glutamine and glucose concentrations. Good agreement was obtained between model predictions and experimental data. In subsequent steps the attempt was to correlate the growth kinetics to significant variables of the culture. The regulatory effects identified through each culture condition were combined for a rational design of a dynamic model constructed for the viable cell subpopulation. A Tessier-based model was applied for defining the fraction of growing cells as a function of a growth inhibitor, presumably dissolved carbon dioxide. Although only few variables appeared in the biomass model, all equations were solved simultaneously. The parameters were estimated using the Metropolis-Hastings algorithm and the fmincon function in MATLAB. The final model adequately predicted the effect of significant variables on the metabolic behavior of CHO cells in batch, fed-batch and perfusion systems.

Animal cell culture is widely used as a platform for the production of a variety of biopharmaceuticals. The development of an efficient and productive cell culture requires a deep understanding of intra-cellular mechanisms as well as extra-cellular conditions for optimal synthesis. Mathematical modeling can be an effective strategy to predict, control, and optimize cell performance under different culture conditions. This research presents the evaluation of Chinese hamster ovary (CHO) cell culture secreting recombinant anti-RhD monoclonal antibody (MAb) through different processing modes, namely batch, fed-batch and perfusion operations. The ultimate objective of this study was to establish a comprehensive dynamic model which may be used for model-based optimization of the cell culture for MAb production in both batch, fed-batch or perfusion systems. In analyzing process performance, the key potential cause of cell growth inhibition was attributed to lowering of pH in the culture possibly due to the accumulation of dissolved carbon dioxide. The most important finding in this regard was the significantly different observed maximum total viable cell density in two identical cultures differing in culture volume only (250mL and 500mL). However, the other byproduct metabolites such as lactate and ammonia and glucose depletion were also capable affecting growth adversely causing growth arrest, viability reduction, apoptosis initiation and progress. Employing the experimental results of nutrient consumption, metabolite and biomass production, a metabolic flux based methodology was developed for modeling the metabolism of a CHO cell line. The elimination of insignificant fluxes resulted in a simplified metabolic network which was the basis for modeling the significant extracellular metabolites. Using kinetic rate expressions for growing and non-growing subpopulations, a logistic model was first developed for cell growth and dynamic models were formulated to describe culture composition and monoclonal antibody (MAb) secretion. The viable cell population was assumed to consist of normal growing, normal non-growing and apoptotic cell subpopulations. The rate of apoptotic cell formation was assumed to have a second order dependence on the normal cell concentration. The proposed mathematical model for metabolites included distinct terms that reflected the metabolic rates of growing and non-growing cell populations. The model was validated for a range of glutamine and glucose concentrations. Good agreement was obtained between model predictions and experimental data. In subsequent steps the attempt was to correlate the growth kinetics to significant variables of the culture. The regulatory effects identified through each culture condition were combined for a rational design of a dynamic model constructed for the viable cell subpopulation. A Tessier-based model was applied for defining the fraction of growing cells as a function of a growth inhibitor, presumably dissolved carbon dioxide. Although only few variables appeared in the biomass model, all equations were solved simultaneously. The parameters were estimated using the Metropolis-Hastings algorithm and the fmincon function in MATLAB. The final model adequately predicted the effect of significant variables on the metabolic behavior of CHO cells in batch, fed-batch and perfusion systems.

The present study consists of the development of a MATLAB version of computer program (FORTRAN) developed by Papanicolaou (1992) to solve the governing small strain consolidation equation of second order non-linear transit partial differential equation of parabolic type. This program is modified to integrate the settling and consolidation processes together in order to provide continuous results from start to end of the process in a single run of MATLAB program. The study also proposes a method to calculate the batch curve by considering the variation of solids concentration in the suspension region. Instead of the graphical approach available in the literature, the program uses numerical approach (Newton-Raphson method) to calculate the solids concentration in suspension region at the interface of suspension and sedimentation regions. This method uses the empirical relationship between solids flux and solids concentration. The study also proposes a method to calculate the solids concentration, throughout the settling column, using the concept of characteristic. The present work also simulates the large strain consolidation model (Gutierrez, 2003). The results of present work closely match with the results of small strain model (Diplas & Papanicolaou, 1997) available in literature. / Master of Science

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Le vin est un milieu peu propice à la croissance de la levure mais il est néanmoins possible de la faire croître sur base de vin enrichit en nutriments et dilué pour diminuer la concentration en éthanol. En vue de l’élaboration des vins effervescents par une seconde fermentation, produire la levure Saccharomyces cerevisiae dans ces conditions est indispensable pour l’acclimater mais il s’agit d’un enjeu complexe qui doit prendre en compte de nombreux paramètres physico-chimiques mais aussi économiques. En effet, les paramètres opératoires peuvent induire des conditions de croissance pouvant affecter le développement de la levure. Seule la levure S. cerevisiae (Fizz+) a été utilisée car elle est spécialement sélectionnée pour cette seconde fermentation en vase clos. Le principal enjeu était donc d’obtenir une bonne adaptation de la levure à croître dans un milieu hydro-alcoolique, conditions contraignantes pour elle, mais aussi d’obtenir une production maximale.Nous avons tout d’abord étudié en fioles Erlenmeyer (250 mL) l’influence de divers paramètres : conditions physico-chimiques, concentrations en nutriments, concentration minimale en levure sèche active nécessaire à une bonne activité ainsi que son temps de réhydratation.Dans un deuxième temps, nous avons effectué des propagations en mode batch dans un bioréacteur (5 L) pour valider les conclusions réalisées à la suite de l’étude en Erlenmeyer et ainsi étudier l’influence de différentes aérations sur la production de S. cerevisiae. Les données obtenues ont servi de base pour comparer les améliorations apportées par le procédé développé en mode fed-batch. Les concentrations en levures obtenues suite à l’optimisation des conditions du milieu de culture en cinq litres sont supérieures d’un facteur cinq à celles obtenues dans la pratique en cave.Ensuite l’étude s’est concentrée sur le développement d’un nouveau procédé d’alimentation en nutriments pour cultiver S. cerevisiae en métabolisme respiratoire dans des cuves réalisées par la société partenaire du projet, OEno Concept. La nouveauté réside dans la façon de réguler la température de la culture qui se fait simultanément à l’apport des nutriments suite au dégagement de chaleur lors de la croissance de S. cerevisiae. Un brevet a été déposé sur cette technologie. Ce nouveau procédé a permis une augmentation de la productivité cellulaire, d’un facteur supérieur à quatre, car il a permis aux levures de s’adapter à cet environnement stressant et a favorisé l’oxydation du glucose au détriment de la fermentation. / Wine is an aggressive/stressful growth medium; it is depleted of micronutrients, rich in ethanol and very poor in assimilable nitrogen. Despite all these difficulties, it is possible to grow yeast in a medium largely based on wine by diluting the ethanol concentration and enriching the medium with micronutrients, a carbon source and assimilable nitrogen. It is, desirable to propagate Saccharomyces cerevisiae in such environment in order to produce a culture of yeast adapted to a second fermentation of alcoholic beverages. Production of microorganism in wine growing environment, is a complex issue that must take into account many, physicochemical and economic parameters. Indeed, the operating parameters can affect the development of yeast in a bioreactor. Therefore, it is important to know the most influential parameters on growth. The strain S. cerevisiae (Fizz+), a commercial strain that has been selected for the second fermentation in bottles, was used during this project. The propagation process served to increase the amount of yeast as well as to adapt the yeast to grow in an alcoholic environment. We first studied in shake-flasks cultures various physicochemical conditions such as nutrients concentration, the rehydration time and the minimum concentration of active dry yeast necessary for good yeast activity.In a second step, we performed batch fermentations in bioreactors (5 L) to confirm the conclusions from the shake-flask cultures and additionally to study the influence of aeration on S. cerevisiae production. The data obtained served as a basis for performing fed-batch cultures. The yeast concentrations obtained as a result of the optimization of the conditions of the culture medium in five liters were five times greater than those obtained in actual industrial production processes. The next step was to develop an automated fed-batch culture to grow S. cerevisiae respiratively in partnership with the industrial partner of the project, OEno Concept. The novelty of the process is the way in which the growth medium feed-rate is linked to the heat produced by the growing S. cerevisiae.This research has allowed an increase in cell productivity, by a factor greater than four, thanks to the novel process in stressful growth environment promoting respiration with regard to fermentation.

Abstract The objective of this study was to investigate the possibility of using maize tassel as an alternative adsorbent for the removal of chromium (VI) and cadmium (II) ions from aqueous solutions. The effect of pH, solution temperature, contact time, initial metal ion concentration and adsorbent dose on the adsorption of chromium (VI) and cadmium (II) by tassel was investigated using batch methods. Adsorption for both chromium (VI) and cadmium (II) was found to be highly pH dependent compared to the other parameters investigated. Obtained results gave an adsorption capacity of 79.1 % for chromium (VI) at pH 2, exposure time of 1h at 25 ºC. Maximum capacity of cadmium of 88 % was obtained in the pH range of 5-6 at 25 ºC after exposure time of 1 h. The adsorption capacities of tassel for both chromium (VI) and cadmium (II) were found to be comparable to those of other commercial adsorbents currently in use for the removal of heavy metals from aqueous wastes. These results have demonstrated the immense potential of maize tassel as an alternative adsorbent for toxic metal ions remediation in polluted water and wastewater.

ABSTRACT: The objective of this study was to investigate the possibility of using maize tassel as an alternative adsorbent for the removal of chromium (VI) and cadmium (II) ions from aqueous solutions. The effect of pH, solution temperature, contact time, initial metal ion concentration and adsorbent dose on the adsorption of chromium (VI) and cadmium (II) by tassel was investigated using batch methods. Adsorption for both chromium (VI) and cadmium (II) was found to be highly pH dependent compared to the other parameters investigated. Obtained results gave an adsorption capacity of 79.1 % for chromium (VI) at pH 2, exposure time of 1h at 25 ºC. Maximum capacity of cadmium of 88 % was obtained in the pH range of 5-6 at 25 ºC after exposure time of 1 h. The adsorption capacities of tassel for both chromium (VI) and cadmium (II) were found to be comparable to those of other commercial adsorbents currently in use for the removal of heavy metals from aqueous wastes. These results have demonstrated the immense potential of maize tassel as an alternative adsorbent for toxic metal ions remediation in polluted water and wastewater.

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