La lyophilisation est le procédé de choix dans l'industrie pharmaceutique pour la stabilisation de produits thermosensibles tels que les vaccins. Cependant, en raison du pré-conditionnement du produit dans des flacons individuels, ce processus est difficile à concevoir et aboutit souvent à des lots présentant une hétérogénéité significative dans la qualité du produit final. L'objectif principal de ce doctorat a été le développement d'un modèle mathématique pour la conception du processus de lyophilisation à un niveau de risque donné, c'est à dire un pourcentage de flacons potentiellement non conformes. Le travail a porté sur la compréhension et la quantification des sources possibles responsables de la variabilité des transferts de chaleur et de matière lors du processus. Dans un premier temps, la variabilité du transfert de chaleur entre les flacons a été étudiée en considérant les dimensions du flacon et sa position sur l'étagère de l'équipement. La variabilité des dimensions géométriques observées dans un lot de flacons (i.e., l'aire de contact entre l'étagère et le flacon et la profondeur de concavité du fond) a influencé la distribution du coefficient de transfert de chaleur entre les flacons. De plus, un modèle mathématique original en 3D a été développé dans COMSOL Multiphysics pour expliquer et prédire les transferts de chaleur atypiques observés dans les flacons situés sur les bords de l'étagère lors du processus de lyophilisation. Les phénomènes conductifs à basse pression au sein de la vapeur d'eau ont été reportés comme un mécanisme dominant expliquant ces transferts de chaleur atypiques alors que les phénomènes radiatifs liés à la présence des parois de l'équipement ont toujours été cités dans la littérature. Par ailleurs, ce modèle mathématique en 3D a été utilisé pour étudier l'effet de la configuration de chargement du lyophilisateur et des caractéristiques de l'équipement sur la variabilité du transfert de chaleur. Dans un deuxième temps, la variabilité des transferts de matière a été évaluée sur une solution de saccharose à 5 % en considérant deux paramètres, la résistance de la couche sèche au transfert de matière pendant la sublimation et le temps caractéristique de désorption. La résistance à la couche sèche a été évaluée en combinant deux approches complémentaires, les tests de remontée de pression et la méthode gravimétrique. La variabilité estimée de la résistance à la couche séchée a eu un impact plus important sur la distribution de la température du produit que la variabilité du coefficient de transfert de chaleur. La valeur et la variabilité du temps caractéristique de désorption ont été évaluées pour différentes températures et ont permis de simuler l'hétérogénéité de la teneur en eau finale entre les flacons. Dans la dernière partie du travail, les principales sources quantifiées de variabilité des transferts de chaleur et de matière ont été intégrées dans un modèle mathématique de lyophilisation. Ce modèle dynamique multi-flacons a été utilisé non seulement pour prédire l'évolution de la température et de la teneur en eau du produit pendant la lyophilisation pour un lot de 100 flacons, mais aussi pour estimer le pourcentage de flacons potentiellement non conformes. L'approche de modélisation proposée, étendue à un plus grand nombre de flacons simulés, pourrait être utilisée pour calculer les "design spaces" (espaces de travail) des étapes de dessiccation primaire et secondaire du processus de lyophilisation à un risque connu de pourcentage de flacons non conformes. / Freeze-drying is the process of choice in pharmaceutical industry for the stabilization of heat sensitive products such as vaccines. However, due the product pre-conditioning in individual vials, this process is difficult to design and often results in batches presenting a significant heterogeneity in the quality of the final product. The main goal of this Ph.D. project was the development of a mathematical model making it possible to predict the risk of failure when designing the freeze-drying process, i.e., the percentage of "rejected vials". To this end, the work focused on the understanding and quantification of the sources responsible for heat and mass transfer variability during the process. Firstly, the vial-to-vial heat transfer variability was investigated by taking the vial bottom dimensions and the vial position on the shelf of equipment into account. The variability of geometrical dimensions observed within a batch of vials (i.e., contact area between the shelf and the vial and the mean bottom curvature depth) moderately influenced the heat transfer coefficient distribution among vials (by less than 10 %). Secondly, a original 3D mathematical model was developed in COMSOL Multiphysics to explain and predict atypical heat transfer observed in vials located at the border of the shelf during the freeze-drying process. Conduction through low-pressure water vapour appeared as the dominant mechanism explaining the additional heat transfer to border vials rather than as reported in literature radiation from the walls of the drying chamber. Furthermore, this 3D mathematical model was used to investigate the effect of the vial loading configuration and of the equipment characteristics on heat transfer variability. In a second part, mass transfer variability was quantified on a 5% sucrose solution and by focusing on two parameters, the resistance of the dried layer to mass transfer during sublimation and the characteristic desorption time. The dried layer resistance was assessed by combining complementary approaches, the pressure rise test and gravimetric methods. The estimated variability of the dried layer resistance was found to have a higher impact on the product temperature distribution than the heat transfer coefficient variability. The value and variability of characteristic desorption time was evaluated for different temperatures and made it possible to simulate moisture content heterogeneity between vials in the batch. In the last part of the work, the main quantified sources of heat and mass transfer variability were integrated in a mathematical model of freeze-drying process. This multi-vial, dynamic model was used not only to predict the evolution of product temperature and moisture content during freeze-drying for a batch of 100 vials, but also to estimate the percentage of vials that could potentially be rejected. The proposed approach, extended to a greater number of simulated vials, could be applied to calculate design spaces of the primary and secondary drying steps of freezedrying process at a known risk of failure.

L’intensité concurrentielle et les évolutions technologiques n’ont jamais été aussi intenses. Aussi, les entreprises en quête de pérennité sont-elles de plus en plus confrontées à une nécessité d’exploiter leurs activités actuelles et d’explorer des activités futures. Or la gestion de ce double impératif est loin d’être évidente, générant potentiellement d’importantes tensions au sein des entreprises. Bien que la recherche en management ait permis de mieux appréhender cette tension d’Exploration/Exploitation, il reste des zones de contradiction et des espaces non explorés. En particulier, il n’y a pas de consensus sur les définitions des concepts d’exploration et d’exploitation, ne permettant pas ainsi de garantir une certaine cohérence dans la recherche (Birkinshaw & Gupta, 2013). D’autre part, la tension Exploration/Exploitation n’a que très peu été étudiée dans le contexte des jeunes entreprises de croissance - également appelées « scale-up » - qui ont la particularité d’être exposées à de forts enjeux de survie. Ainsi, afin de contribuer à une meilleure compréhension des problématiques que soulève cette tension au sein de celles-ci, un format de thèse sur travaux, comprenant trois études complémentaires, est adopté.Au préalable, afin de cadrer conceptuellement la thèse, je réponds, dans une première étude, à l’appel des chercheurs pour la clarification des concepts d’exploration et d’exploitation en proposant une typologie d’exploration. Puis, par l’intermédiaire d’une approche multi-cas longitudinale menée auprès de huit jeunes entreprises de croissance, j’explore tout d’abord, dans une deuxième étude, les facteurs influençant les orientations stratégiques des entreprises quant à leurs activités d’exploration et d’exploitation. Enfin, dans la troisième étude, je cherche à comprendre comment le fonctionnement des équipes de direction définit les rôles de chacun dans les activités d’exploration et d’exploitation. / Competition and technological change have never been as intense as they are today. To survive, companies must increasingly carry out current activities at the same time that they explore future ones. It is no easy task to operate on both of these fronts, and doing so is a potential source of tension and contradiction. Although management research has provided insight into the exploration and exploitation tension, there are still contradictions and unexplored areas. In particular, there is no consensus on the definition of the concepts of exploration and exploitation, which means the research lacks a certain level of consistency. In addition, there has been very little attention paid to the Exploration/Exploitation tension in the context of young, growing “scale-up” companies, which are particularly exposed to threats to their survival. To obtain a better understanding of the situations this tension causes in these companies, we have adopted a multi-paper dissertation consisting of three complementary studies.In the first study, to create a conceptual framework for the thesis, we answer researchers’ call for a clarification of the concepts of exploration and exploitation by proposing a typology of exploration. Then, based on a longitudinal, multi-case approach focused on eight scale-up companies, we first explore, in a second study, the factors influencing firms’ strategic orientations vis-à-vis exploration and exploitation activities. Finally, in the third study, we seek to understand how management teams define their individual roles with respect to exploration and exploitation activities.

In the last decades, miniaturized flow chemistry has promised to bring the benefits of process intensification, continuous manufacturing and greener chemistry to the fine chemical industry. However, miniaturized catalytic processes where gas, liquid, and solids are involved have always been impeded by two main drawbacks: multiphase-flow maldistribution (i.e. gas channeling) and clogging of capillary reactors. In this thesis, first principle models have been used to capture the complexity of multiphase flow in micropacked-bed reactors, which can suffer from poor and unpredictable mass-transfer performance. When the particle size ranges 100 µm in diameter, capillary and viscous forces control the hydrodynamics. Under such conditions, the gas —and not the liquid— flows creating preferential channels that cause poor radial dispersion. Experimental observations from the literature were reproduced to validate a physical-based modeling approach, the Phase Field Method (PFM). This simulation strategy sheds light on the impact of the micropacked-bed geometry and wettability on the formation of preferential gas channels. Counterintuitively, to homogenize the two-phase flow hydrodynamics and reduce radial mass-transfer limitations, solvent wettability of the support needs to be restricted, showing best performance when the contact angle ranges 60° and capillary forces are still dominant. Visualization experiments showed that ultrasound irradiation can also be used to partially fluidized the bed and modify the hydrodynamics. Under sonication, residence time distributions (RTD) in micropacked-bed reactors revealed a two-order-of-magnitude reduction in dispersion, allowing for nearly plug-flow behavior at high gas and liquid flow rates. At a reduced scale, surfaces vibrating with a low amplitude were shown to fluidize, prevent and solve capillary tube blockage problems, which are commonly found in the fine chemical industry for continuous product synthesis. The modeling and simulation strategy used in this thesis, enables a fast prototyping methodology for the proper acoustic design of sonoreactors, whose scale-up was achieved by introducing slits in sonotrodes. In addition, a patent-pending helicoidal capillary sonoreactor has shown to transform longitudinal vibrating modes into radial and torsional modes, pioneering a new range of chemistry able to handle a high concentration of particles. The contributions of this thesis made in the fields of reaction engineering and process intensification have demonstrated how computational methods and experimental techniques in other areas of research can be used to foster innovation at a fast pace.

Solvent-free extrusion emulsification (SFEE) is a recently developed process for producing submicron particles with high viscosity polymers inside a twin-screw extruder without the use of hazardous solvents. Its dependency on a catastrophic phase inversion makes the process knowingly sensitive to a variety of formulation and operational variables, causing a narrow window of production. The purpose of this thesis was to investigate and improve process stability as well as widening operational window. Transient effects of the start-up procedure was investigated by considering the process stability and particle size distribution. The transient sensitivity corresponded to the residency of material in the dispersion zone. When a sub-optimal water/surfactant fraction was allowed to produce an undesired polymer-water (thick lamella) morphology, this morphology continued to persist until the critical first half of the dispersion zone was purged of existing mass. Lot to lot variability of polyester resin was used to investigate the sensitivities of the SFEE process more deeply to better understand the mechanism involved. In this case, acid number was shown to have a significant effect on the initial amount of water needed in the dispersion zone for phase inversion, resulting in an emulsification boundary dependent on the resin acid number. In fact, a significant correlation was found between the acidic end groups of the resin and the maximum amount of water content that could be used in the dispersion zone. The effect of feed rate, screw speed, dispersion length, and surfactant concentration were studied for their individual influence on widening the emulsification boundary. The most significant improvement was observed by applying a longer dispersion length or lower feed rate because both significantly increase the residence time. The effect of residence time on the emulsification boundary was attributed to the total strain imposed on the polymer/water mixture which was related to interfacial growth in the dispersion zone. / Dissertation / Doctor of Philosophy (PhD)

No description available.

When scaling a company it is important to implement customer insights to achieve growth of revenue. Understanding and defining a suitable B2B sales process has also been shown to play an important part in enhancing sales, and traditional processes include multiple steps performed by sales representatives. One step revolves around the presentation of the offered product or service. For sales representatives to present a product or service successfully they must acquire or have deep knowledge of the customer, such as their industry trends and general business. This can be achieved by acquiring customer insights that are data driven. Adopting data driven customer insights has also been proven to increase sales. Therefore, this research investigates the connection between the B2B sales process and the generation and implementation of data driven customer insights. In particular, this research explores the steps included in a B2B sales process at a high technology scaleup and hence how data driven customer insights can enhance the presentation step in the B2B sales process.  The research is carried out through a case study at a case company labelled as a high technology scaleup. Interviews were conducted with sales representatives working in the commercial team at the case company. The result from this research finds that six steps are included in the B2B sales process at high technology scaleups. The steps are as follows: Lead generation, First meeting, Assessment, Contract proposal, Negotiation and Closed deal. The second step includes presenting the offered product or service, which this research identified as most challenging for the sales representatives to execute successfully due to the technical complexity of the product/service. Findings from this research shows that data driven customer insights can be used to simplify this step in the process. For example, data driven customer insights can help personalize presentation material and enable rapport building. In addition, data driven customer insights help align expectations between buyers and sellers during the first meeting, thus increasing the likelihood of reaching a closed deal. / När ett företag ska skalas upp är det viktigt att implementera kundinsikter för att uppnå ökad omsättning. Att förstå och definiera en passande B2B-försäljningsprocess har också visats spela en viktig roll för nå ökade intäkter, och traditionella säljprocesser innehåller flera steg som säljpersonal utför. Ett steg kretsar kring presentationen av den erbjudna produkten eller tjänsten. För att säljpersonal ska kunna presentera en produkt eller tjänst med framgång behöver de förvärva eller ha djup kunskap om kunden, såsom branschtrender och generell verksamhet. Detta kan uppnås genom att anskaffa kundinsikter som är datadrivna. Att använda datadriven kundinsikt har också visats öka försäljningssiffror. Med detta som bakgrund undersöker därför den här forskningen sambandet mellan B2B-försäljningsprocessen och generering och implementering av datadriven kundinsikt. I synnerhet undersöker denna forskning stegen som ingår i en B2B-försäljningsprocess i ett högteknologiskt scale up och därmed hur datadriven kundinsikt kan förbättra presentationssteget i B2B-försäljningsprocessen.  Forskningen utförs genom en fallstudie på ett fallföretag som räknas som ett högteknologiskt scale up. Intervjuer genomfördes med försäljningsmedarbetare som jobbar i det kommersiella teamet på företaget. Resultatet från denna forskning visar att sex steg ingår i B2B-försäljningsprocessen vid högteknologiska scale ups. Dessa sex stegen är: Leadsgenerering, Första möte, Utvärdering, Kontraktsförslag, Förhandling och Avslutad affär. Det andra steget innebär att den erbjudna produkten eller tjänsten presenteras, och detta steg identifieras som mest utmanande för försäljningsmedarbetarna att utföra med framgång på grund av produktens/tjänstens tekniska komplexitet. Vidare visar resultat från denna forskning att datadriven kundinsikt kan användas för att förenkla detta steg i processen. Datadriven kundinsikt kan till exempel hjälpa till att personalisera presentationsmaterial och möjliggöra förtroendebyggande. Dessutom möjliggör datadrivna kundinsikter att köpare och säljare delar gemensamma förväntningar på det första mötet, vilket ökar sannolikheten att uppnå en sluten affär.

<p><a href="" target="_blank">Synthetic microbial communities (SynComs) are an important focus in modern microbiology. SynComs are used for studying the dynamics of naturally occurring microbial communities ranging from soil to the human gut. Synthetic refers to the assemblage of some or all the members of these communities in a laboratory setting. SynComs allow for communities difficult to study <i>in situ</i> to be studied in a controlled environment, or they may be used to create beneficial products like biofertilizers. When SynComs are used as products, the focus shifts to optimizing a desired outcome of a culture. For biofertilizers, a high diversity is key to producing a functionally redundant product for stimulating plant growth. Media manipulation is a common approach for inducing community changes in a SynCom. Amino acids (AA) are a media supplement that soil microbes (often the components of biofertilizers) are particularly fond of to support their metabolic activities. This study took a scale-up approach to assess the changes in growth dynamics of a SynCom (Environoc© 401) when supplemented with different concentrations of commercially available AA products from plant and animal sources. Expanding from microplates, to shake flasks, then into a 4L bioreactor, Environoc© 401 cultures were compared for their maximum growth rate, time in lag phase, and final growth (optical density or viable cell density) when supplemented with these AA products at various concentrations. Furthermore, Illumina sequencing of the 16S rRNA gene was used to evaluate community-level changes from these treatments based on taxonomic, alpha (Chao 1 and Shannon indices), and beta diversity (Generalized UniFrac) of shake flask and bioreactor samples. Quantitative PCR was also used to assess the relative change of three select species of the SynCom in each AA treatment. Shake flask data revealed significant changes in the growth dynamics of the SynComs within AA treatment groups. Whether the AA was animal or plant derived, generally as the concentration of AA increased, the maximum growth rate decreased, lag time increased, and final growth readings increased. The best AA supplement and rate according to the growth metrics and <i>Curveball </i>analysis was Stimtide at a 33% supplementation rate. This was compared with the control at the bioreactor scale where it showed higher overall final growth and a higher taxonomic and alpha diversity. The scale-up approach to this study was successful at selecting the best amino acid supplement type and rate despite having less sophisticated control and monitoring compared to larger scales (i.e. the bioreactor). Use of the <i>Curveball</i> modeling program was useful for treatment group selection but did not always predict the outcomes seen in the live cultures. The use of AA as a media supplement can increase growth and diversity of a SynCom, though not all AA supplements or rates affect growth and community dynamics in the same way</a>.</p>

Historically, scale- up of technologies have been a fundamental driver for success-ful economies in enhancing performance of applications. In the context of com-bustion technologies, several scale- up approaches were developed with the aim of transferring relevant characteristics of combustion systems from laboratory- to industrial- scale system. A reasonable selection of scaling approaches is required to perform a proper scaling of a combustion system. In the current study, the development of scaling methods and their use for technical applications is pre-sented. In order to provide a guideline for the examination of combustion systems to be scaled up, common and recently published scale- up methods are compared qualitatively, as well as the investigation on scale- up of combustion chambers, is addressed. Due to the expected further technical and environmental restrictions, the focus of the implementation is directed towards NOx emissions.

Dans le contexte énergétique et climatique mondial, le coût élevé des enzymes Cellulolytiques (cellulases) freine le développement des bioraffineries lignocellulosiques, pour produire des biocarburants et composés chimiques à partir d'une matière première végétale renouvelable. L'objectif de ce travail est de caractériser et de modéliser le métabolisme du micro-organisme Trichoderma reesei, afin d'optimiser le protocole industriel de production de cellulases. Cette étude a été réalisée sur des milieux modèles représentatifs de ceux attendus à l'échelle industrielle. Tout d'abord, la stoechiométrie des réactions de croissance et de production a été établie, puis une étude cinétique a été menée pour mesurer précisément le comportement du micro-organisme à forte induction de la production de cellulases. Le modèle résultant a été utilisé pour optimiser le protocole industriel de production. Ensuite, l'intégration de cette étape dans une bioraffinerie lignocellulosique a été étudiée, avec l'effet sur le métabolisme i) des mélanges de sucres disponibles, ii) des composés inhibiteurs issus de la dégradation de la lignocellulose, et iii) du changement d'échelle. Ces travaux ont fait progresser de façon substantielle les connaissances du métabolisme de T. reesei en ce qui concerne la production de cellulases, et les modèles développés sont des outils d'aide rationnelle à la définition d'un procédé de production de cellulases intégré dans une bioraffinerie lignocellulosique. / In the global energetic and climatic context, the high cost of the cellulolytic enzymes (cellulases) postpones the development of lignocellulosic biorefineries, dedicated to produce biofuels and chemical compounds from renewable vegetable feedstocks. The aim of this work was to measure and model the metabolism of the micro-organism Trichoderma reesei, in order to optimize the industrial protocol for the production of cellulase. This study was carried out using synthetic media representative of industrial ones. First, the stoichiometries of growth and protein production reactions were determined. Then, a kinetic study was conducted to precisely measure the specific rates of T. reesei at high induction of cellulase production. The resulting model was used to optimize the industrial production protocol. Finally the integration of this step in a lignocellulosic biorefinery was studied by determining the impacts on the metabolism of i) available sugar mixtures, ii) inhibitory compounds from lignocellulosic biomass degradation, and iii) scale-up. These results significantly contributed to improve the knowledge of T. reesei metabolism on cellulase production. The developed models are rational tools for the optimization of a cellulase production protocol suited to lignocellulosic biorefineries.

O desenvolvimento de fontes de energia renováveis tem se tornado cada vez mais necessário e, nesse contexto, os biocombustíveis têm um importante papel. Este trabalho teve como objetivo otimizar a produtividade de biomassa e de lipídios da microalga Nannochloropsis gaditana, em cultivos de baixo-custo visando à produção de biodiesel. Um sistema de cultivo foi concebido com materiais acessíveis e os experimentos testaram o efeito de diferentes exposições das células ao claro-escuro, sob irradiância de 800?E m-2 s-1. Foram testadas três profundidades de cultivo (2, 4 e 8 cm) e duas taxas de aeração (0,25 e 1,00 L min-1 por L de cultivo). A penetração de luz nos cultivos e o rendimento de biomassa seca foram monitorados diariamente. Altos rendimentos de biomassa e lipídios foram alcançados. Os valores máximos foram observados no experimento com 4 cm de profundidade e maior taxa de aeração: 13,83 g m-2 d-1 de produtividade de biomassa e 20,50% de teor lipídico, resultando em uma produtividade lipídica de 2,84 g m-2 d-1. Estes resultados indicam o potencial da utilização de N. gaditana para aplicação em cultivos de larga escala, uma vez que o rendimento lipídico observado foi superior ao da soja, principal matéria-prima vegetal para produção de biodiesel. O sistema de cultivo desenvolvido pode ser inserido em um processo de scaling up em cultivos abertos de grande escala. / The development of renewable energy sources has becoming an increasing necessity and, in this context, biofuels have an important role. This study aimed to optimize the productivity of biomass and lipids of the microalgae Nannochloropsis gaditana in a low-cost system, focusing biofuel production. A culture system was designed with low-cost and accessible materials and the experiments tested the effect of different degrees of exposition of cells to light-dark, under 800?E m-2 s-1 irradiance. Three different culture depths (2, 4 e 8 cm) and two aeration ratios (0.25 e 1.00 L min-1 per L of culture) were tested. Light penetration into the cultures and the dry biomass yield were monitored daily. High yields of biomass and lipids were attained in the experiment with 4 cm depth and the high aeration ratio: 13.83g m-2 d-1 of biomass productivity and 20.50% lipid content, resulting in a lipid productivity of 2.84 g m-2 d-1. These results indicate the potential of N. gaditana for application in large-scale cultivation, since its lipid yield is higher than the soybean, the main feedstock plant for biodiesel production. The culture system developed can be inserted in a process of biomass scaling up for large-scale open microalgae cultures.