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Performance testing and computer simulations have promising applications in Quality by Design approaches. The objectives of these studies were to investigate the performance of the disintegration test using different setups in addition to comparing the performance of the disintegration test with the rupture test using soft gelatin dietary supplements capsules. Classifying common herbs according to the Biopharmaceutical Classification System approach was also investigated using ADMET predictor TM. The final objective was evaluation the predictive power of computer simulations of in vitro dissolution in different media. The studies concluded that the disintegration test is robust only if firm specifications were applied. However, this test has no advantage over the rupture test. In silico methods can be used to classify herbs according to the BCS. Computer simulations of dissolution in vitro can be also a potential tool to estimate the dissolution behavior. These tools facilitate prediction of quality desired in a product. / Pharmaceutical Sciences

Les files d'attente fluides sont des processus markoviens à deux dimensions, où la première composante, appelée le niveau, représente le contenu d'un réservoir et prend des valeurs continues, et la deuxième composante, appelée la phase, est l'état d'un processus markovien dont l'évolution contrôle celle du niveau. Le niveau de la file fluide varie linéairement avec un taux qui dépend de la phase et qui peut prendre n'importe quelle valeur réelle. Dans cette thèse, nous explorons le lien entre les files fluides et les processus QBD, et nous appliquons des arguments utilisés en théorie des processus de renouvellement pour obtenir la distribution stationnaire de plusieurs modèles fluides. Nous commençons par l'étude d'une file fluide avec un réservoir de taille infinie; nous déterminons sa distribution stationnaire, et nous présentons un algorithme permettant de calculer cette distribution de manière très efficace. Nous observons que la distribution stationnaire de la file fluide de capacité infinie est très semblable à celle d'un processus QBD avec une infinité de niveaux. Nous poursuivons la recherche des similarités entre les files fluides et les processus QBD, et nous étudions ensuite la distribution stationnaire d'une file fluide de capacité finie. Nous montrons que l'algorithme valable pour le cas du réservoir infini permet de calculer toutes les quantités importantes du modèle avec un réservoir fini. Nous considérons ensuite des modèles fluides plus complexes, de capacité finie ou infinie, où le comportement du processus markovien des phases peut changer lorsque le niveau du réservoir atteint certaines valeurs seuils. Nous montrons que les méthodes développées pour des modèles classiques s'étendent de manière naturelle à ces modèles plus complexes. Pour terminer, nous étudions les conditions nécessaires et suffisantes qui mènent à l'indépendance du niveau et de la phase d'une file fluide de capacité infinie en régime stationnaire. Ces résultats s'appuient sur des résultats semblables concernant des processus QBD. Markov modulated fluid queues are two-dimensional Markov processes, of which the first component, called the level, represents the content of a buffer or reservoir and takes real values; the second component, called the phase, is the state of a Markov process which controls the evolution of the level in the following manner: the level varies linearly at a rate which depends on the phase and which can take any real value. In this thesis, we explore the link between fluid queues and Quasi Birth-and-Death (QBD) processes, and we apply Markov renewal techniques in order to derive the stationary distribution of various fluid models. To begin with, we study a fluid queue with an infinite capacity buffer; we determine its stationary distribution and we present an algorithm which performs very efficiently in the determination of this distribution. We observe that the equilibrium distribution of the fluid queue is very similar to that of a QBD process with infinitely many levels. We further exploit the similarity between the two processes, and we determine the stationary distribution of a finite capacity fluid queue. We show that the algorithm available in the infinite case allows for the computation of all the important quantities entering in the expression of this distribution. We then consider more complex models, of either finite or infinite capacities, in which the behaviour ff the phase process may change whenever the buffer is empty or full, or when it reaches certain thresholds. We show that the techniques that we develop for the simpler models can be extended quite naturally in this context. Finally, we study the necessary and sufficient conditions that lead to the independence between the level and the phase of an infinite capacity fluid queue in the stationary regime. These results are based on similar developments for QBD processes.

Os protetores solares (PS) são os grandes responsáveis pela proteção da pele quando exposta à radiação solar, por isso a importância sanitária de se otimizar o desenvolvimento deste cosmético tipo II e monitorar para que seja eficaz em seu propósito. O principal objetivo deste trabalho é aplicar os conceitos de Qualidade por Design (QbD), ferramentas estatísticas de desenho experimental (DoE - Design of Experiments) e o conceito de tecnologia analítica de processo (PAT - Process Analytical Technology) para desenvolver uma formulação e processo produtivo de um PS de modo a modernizar os processos da indústria cosmética, fazendo as análises durante o processo e eliminando o controle de qualidade final. Trata-se de um sistema de desenvolvimento sistematizado, onde se executa as ferramentas de QbD para avaliar os dados obtidos ao longo da fase experimental. Para a fase experimental, empregou-se o desenho fatorial e desenho do compósito central (CCD - Central Composite Design) como ferramenta estatística, para a execução do planejamento de experimentos (DoE - Design of Experiments). As respostas foram analisadas através da metodologia de superfície resposta (RSM - Response Surface Methodology). Tais ferramentas são fundamentais para a determinação do desenho de concepção (design space), para se obter o PS com as melhores características físico-químicas e de processo dentro do escopo delineado. Para o desenvolvimento da metodologia de análise in line, optou-se pela utilização da espectrometria UV, utilizando-se ferramentas como análise de regressão dos mínimos quadrados (PLS) devido a praticidade em transforma-la em uma ferramenta PAT, para isto, a quimiometria foi empregada para modelar sistemas que são desconhecidos e complexos, como um PS, e trazendo respostas diretas como a aprovação do produto antes de ser embalado, por exemplo. A abordagem apresentada baseia-se na construção da qualidade ao longo do desenvolvimento e otimização de PS e torna possível o monitoramento da qualidade em tempo real. / The sunscreens are great responsible for the skin protection when it is exposed to direct sunlight, so it means a great importance of health to optimize the development of type II cosmetic and monitor for it to be effective in its purpose. The objective of this work is to apply the concepts of Quality by Design and statistical tools of experimental design (DoE - Design of experiments), as well as applying the process analytical technology (PAT - Process Analytical Technology) concept for formulation and manufacturing process development of a topical sunscreen being able to modernize the cosmetic industry processing, including real time analyses and eliminating quarantine step, which waits analysis approval performed by the quality assurance, and then release the product for sale. As it is a systematic development, where critical quality attributes and risk assessment were performed to evaluate over obtained data. During experimental phase, the factorial design was used as a statistical tool for design of experiments implementation, and the responses were analyzed by response surface methodology (RSM - Response Surface Methodology). This mapping is critical to determination of the product design (design space), i.e. get sunscreen with the best physical and chemical characteristics and processing within the outlined scope. For in line methodology development, UV spectrometry was opted to be used due to less effort in sample preparation and due to great easiness to turn it into a PAT tool. For this, chemometrics was used, which brings together chemical and statistical elements to obtain three main elements: empirical modeling, multivariate modeling and chemical data, making it able to model systems that are unknown and complex, as a sunscreen, getting direct answers as product release approval before being packed, for example. The presented approach was based on the construction of quality throughout the sunscreen development and optimization making possible the real time quality monitoring.

Os protetores solares (PS) são os grandes responsáveis pela proteção da pele quando exposta à radiação solar, por isso a importância sanitária de se otimizar o desenvolvimento deste cosmético tipo II e monitorar para que seja eficaz em seu propósito. O principal objetivo deste trabalho é aplicar os conceitos de Qualidade por Design (QbD), ferramentas estatísticas de desenho experimental (DoE - Design of Experiments) e o conceito de tecnologia analítica de processo (PAT - Process Analytical Technology) para desenvolver uma formulação e processo produtivo de um PS de modo a modernizar os processos da indústria cosmética, fazendo as análises durante o processo e eliminando o controle de qualidade final. Trata-se de um sistema de desenvolvimento sistematizado, onde se executa as ferramentas de QbD para avaliar os dados obtidos ao longo da fase experimental. Para a fase experimental, empregou-se o desenho fatorial e desenho do compósito central (CCD - Central Composite Design) como ferramenta estatística, para a execução do planejamento de experimentos (DoE - Design of Experiments). As respostas foram analisadas através da metodologia de superfície resposta (RSM - Response Surface Methodology). Tais ferramentas são fundamentais para a determinação do desenho de concepção (design space), para se obter o PS com as melhores características físico-químicas e de processo dentro do escopo delineado. Para o desenvolvimento da metodologia de análise in line, optou-se pela utilização da espectrometria UV, utilizando-se ferramentas como análise de regressão dos mínimos quadrados (PLS) devido a praticidade em transforma-la em uma ferramenta PAT, para isto, a quimiometria foi empregada para modelar sistemas que são desconhecidos e complexos, como um PS, e trazendo respostas diretas como a aprovação do produto antes de ser embalado, por exemplo. A abordagem apresentada baseia-se na construção da qualidade ao longo do desenvolvimento e otimização de PS e torna possível o monitoramento da qualidade em tempo real. / The sunscreens are great responsible for the skin protection when it is exposed to direct sunlight, so it means a great importance of health to optimize the development of type II cosmetic and monitor for it to be effective in its purpose. The objective of this work is to apply the concepts of Quality by Design and statistical tools of experimental design (DoE - Design of experiments), as well as applying the process analytical technology (PAT - Process Analytical Technology) concept for formulation and manufacturing process development of a topical sunscreen being able to modernize the cosmetic industry processing, including real time analyses and eliminating quarantine step, which waits analysis approval performed by the quality assurance, and then release the product for sale. As it is a systematic development, where critical quality attributes and risk assessment were performed to evaluate over obtained data. During experimental phase, the factorial design was used as a statistical tool for design of experiments implementation, and the responses were analyzed by response surface methodology (RSM - Response Surface Methodology). This mapping is critical to determination of the product design (design space), i.e. get sunscreen with the best physical and chemical characteristics and processing within the outlined scope. For in line methodology development, UV spectrometry was opted to be used due to less effort in sample preparation and due to great easiness to turn it into a PAT tool. For this, chemometrics was used, which brings together chemical and statistical elements to obtain three main elements: empirical modeling, multivariate modeling and chemical data, making it able to model systems that are unknown and complex, as a sunscreen, getting direct answers as product release approval before being packed, for example. The presented approach was based on the construction of quality throughout the sunscreen development and optimization making possible the real time quality monitoring.

Dans le contexte écologique actuel, les équipementiers automobiles européens sont dans l’obligation de développer des systèmes innovants afin de réduire les rejets de gaz à effet de serre des véhicules. Les nouvelles applications électroniques micro-hybrides exigent le développement de stratégies quant à l’intégration des systèmes et la réduction des pertes. Ainsi, une proposition a consisté à réaliser des modules de puissance constitués de transistors MOSFETs basse tension fort courant. L’application de type alterno-démarreur plus communément nommée « Stop & Start »exige des composants toujours plus robustes et fiables du fait de la sollicitation en mode d’avalanche sous des températures pouvant atteindre 175°C.Les travaux de recherche présentés dans cette thèse portent donc sur l’aspect d’optimisation de la robustesse et de la fiabilité des composants. Tout d’abord, il était essentiel de comprendre l’avalanche et ses enjeux pour la technologie. Ensuite dans ce contexte, le procédé notamment autour de l’oxyde de grille a été amélioré afin de garantir la tenue en mode de sollicitation grille-source et grille-drain pour satisfaire les exigences de fiabilité. En outre, le développement d’un test innovant de la puce, dérivé du QBD, a permis d’évaluer précisément les modifications apportées sur le procédé de fabrication et d’être corrélé avec les résultats des essais de fiabilité. Enfin, le cycle de vie d’un MOSFET nécessite un suivi qualité précis qui se compose de deux aspects essentiels. En premier lieu, le suivi des paramètres électriques et de leur dérive par une analyse statistique « postprocessing». En second lieu, la mise en place d’un outil de traçabilité du module à la puce pour traquer les éventuels rejets dans l’application finale et remonter à la cause d’origine. Toutes les innovations présentées, dans ce mémoire, s’inscrivent dans une démarche novatrice de l’amélioration continue de la qualité des composants de type MOSFET de puissance / In the current ecologic context, the European automotive suppliers have to develop innovating systems inorder to reduce greenhouse gas rejects produce by vehicles. The new mild-hybrid electronic applications require the development of new strategies due to their integration and the reduction of power losses.Thereby, a proposition consisted in creating power modules constituted by MOSFETs characterized by alow blocking voltage under high current. The starter alternator reversible application also named “Stop &Start” requires robust and reliable components in order to support a high current solicitation in avalanche mode for temperatures up to 175°C.Research work presented in this thesis concerns the robustness and reliability enhancement of MOSFET components. First of all, the important part is about avalanche mode understanding and their issues. Inthis context, the fabrication process is a main part for quality and reliability requirements. Then, the workis focused on gate oxide process quality in order to hold gate-source and gate-drain stress modes.Moreover, the development of an innovating test at wafer level derivate from QBD test, allowed the precise evaluation of process modification thanks to the correlation with reliability campaign results. Finally, theMOSFET life cycle needs a quality monitoring constituted by two main steps. The first one is the monitoring of electrical parameters in time with a post-processing statistical analysis. The second one is the use of a traceability tool between the power module and the silicon die in order to highlight possible defects in the final starter alternator application, and understand failure root causes. The innovations presented in this thesis are included in the continued improvement approach for MOSFETs quality and robustness enhancement.

[pt] Este trabalho apresenta a estratégia híbrida das abordagens Quality by Design e Failure Mode and Effects Analysis para aplicação no desenvolvimento de tecnologia biomédica. A qualidade e a gestão de riscos precisam evoluir com o avanço do desenvolvimento farmacêutico e tecnológico na saúde, permitindo um maior controle dos processos de fabricação de cada dispositivo biomédico. A Análise de Modo e Efeito de Falha (FMEA) tem sido amplamente utilizada na saúde para garantir a qualidade dos produtos fabricados. Ela se dedica a prevenir eventos ou incidentes adversos, identificando falhas para priorizar o risco e otimizando recursos, para uma melhor qualidade em dispositivos ou equipamentos médicos. A Qualidade por Projeto (QbD), por sua vez, tem sido aplicada na indústria farmacêutica para garantir a qualidade dos produtos desde a fase de desenvolvimento. Os resultados obtidos com a estratégia híbrida desenvolvida determinaram os atributos da qualidade e os parâmetros do processo mais críticos para aplicação no desenvolvimento de sistema de medição para localização de corpo estranho metálico em pacientes. A abordagem QbD-FMEA contribuiu para a determinação mais adequada e abrangente dos elementos críticos mais relevantes e associadas ações preventivas do que o emprego dessas sistemáticas isoladamente. / [en] This work presents the hybrid strategy of Quality by Design and Failure Mode and Effects Analysis approaches for application in biomedical technology development. Quality and risk management need to evolve with the advancement of pharmaceutical and technological development in healthcare, allowing greater control of the manufacturing processes of each biomedical device. Failure Mode and Effect Analysis (FMEA) has been widely used in healthcare to ensure the quality of manufactured products. It is dedicated to preventing adverse events or incidents, identifying failures to prioritize risk, and optimizing resources for better medical devices or equipment quality. In turn, Quality by Design (QbD) has been applied in the pharmaceutical industry to ensure product quality from the development phase. The results obtained with the developed hybrid strategy determined the most critical quality attributes and process parameters for application in developing a measurement system for metallic foreign body location in patients. The hybrid QbD-FMEA approach contributed to a more adequate and comprehensive determination of the most relevant critical elements, associating with preventive actions, than the isolated use of these approaches.

Regenerative medicine (RM) represents a promising enabling technology to revolutionize healthcare. This said there are still major gaps between the commercial promise and the reality of the cell therapy sector of regenerative medicine. There is consensus to develop high through-put, automated technologies for the manufacture of RM products. Imaging methods will have the capacity to contribute to this technological gap for cell therapies and are particularly attractive to provide non-destructive monitoring with high spatial and temporal resolution. This work applied an automated, non-invasive phase contrast imaging platform (Cell-IQ) to measure, analyse and ultimately quantify image derived metrics for human embryonic stem cells (hESCs) and haematopoietic stem cells (HSCs) as part of the colony forming unit (CFU) assay. This work has shown through thresholding and machine vision identification technology, imaging has the ability to improve the precision of current evaluation methods for cell culture, providing novel information regarding culture state and show image derived metrics to be predictive of future culture state. Building on this, differentiation through the addition of a growth factor cocktail highlighted how in-process monitoring enables protocol optimisation. After equilibrating the Cell-IQ incubator to a standard incubator, the progress of the CFU assay was monitored and image metrics representative of colony phenotype were analysed. Cell count, distance between cells and cell migration within individual colonies were identified to be informative and provide a degree of colony phenotype separation. Quantitative, novel, image derived metrics were identified that improve reliability through computer automation, cost by removing user verification and time by reducing the assay time from 14 days to 7 days. Non-invasive imaging provides a fantastic opportunity to create bespoke sampling frequencies to achieve desired precision for manufacturing cell therapies, this work has developed and shown improvement and a level of control to current culture process for ESCs and HSCs.

No description available.

Yes / The present study demonstrates the application of decision tree algorithms to the co-crystallization process. Fifty four (54) batches of carbamazepine-salicylic acid co-crystals embedded in poly(ethylene oxide) were manufactured via hot melt extrusion and characterized by powder X-ray diffraction, differnetial scanning calorimetry, and near-infrared spectroscopy. This dataset was then applied in WEKA, which is an open-sourced machine learning software to study the effect of processing temperature, screw speed, screw configuration, and poly(ethylene oxide) concentration on the percentage of co-crystal conversion. The decision trees obtained provided statistically meaningful and easy-to-interpret rules, demonstrating the potential to use the method to make rational decisions during the development of co-crystallization processes. / Commonwealth Scholarship Commission in the UK (ZMCS-2018-783) and Engineering and Physical Sciences Research Council (EPSRC EP/J003360/1 and EP/L027011/1)