Thesis (doctoral)--Lund University, 1997.

Thesis (doctoral)--Lund University, 1997.

The aim was to analyze processes selected SMEs (small and medium enterprises) and to suggest possible improvements in the selection processes. In the initial stage, I deal with study of professional literature Czech and foreign authors. I used the information to write a review of the literature. The Part of my work is devoted to the description of the company and also describe the key processes. The findings gave me the possibility of a comprehensive perspective on the issue and used to create a design of the possible improvements in selected processes.

Submitted by Maike Costa (maiksebas@gmail.com) on 2016-05-16T13:15:08Z No. of bitstreams: 1 arquivo total.pdf: 6619153 bytes, checksum: ab30577da64fe07f90d28f172fea6661 (MD5) / Made available in DSpace on 2016-05-16T13:15:08Z (GMT). No. of bitstreams: 1 arquivo total.pdf: 6619153 bytes, checksum: ab30577da64fe07f90d28f172fea6661 (MD5) Previous issue date: 2015-04-06 / Statistical process control is becoming increasingly important in the pharmaceutical industry, since it can act on the product quality assurance and monitoring of production efficiency. Regulatory agencies worldwide already include multivariate statistical process control on their recommendations. In this work we perform three applications of multivariate control charts to detect small variations in monitoring pharmaceutical process. The studies were performed in the Laboratório Farmacêutico do Estado de Pernambuco Governador Miguel Arraes - LAFEPE using process data and addressing real problems of the industry routine. The first one consists in the elaboration of the Annual Product Review using multivariate control charts based on Principal Component Analysis, accompanied by a simple and unique methodology for identification of multivariate signal out of control, which was performed by decomposition of T2 statistics based on the loadings of VARIMAX rotation. The method developed has allowed the sector responsible for the Quality Assurance industry to verify the variables that most impact the process. The second application consists in monitoring of the degradation of captopril in tablets by High Performance Liquid Chromatograph measurements. For this aim multivariate control charts based on residuals of principal component analysis were built. The weighting of the retention time of the chromatogram in the region of captopril disulfide highlights the residual chart for revealing slight changes in the chromatographic standards. The third and last application consists in monitoring of the degradation of captopril in tablets by near infrared and middle infrared measurements. For this aim T2 control charts were built by using a variable selection method and a CUSUM-COT scheme. Both the techniques showed to be able for detection of expired samples and Middle infrared was able to identify slight changes during degradation process. Keywords: Monitoring of Process, Multivariate Control Charts, Annual Prod / O controle estatístico de processos vem ganhando importância na indústria farmacêutica, uma vez que pode atuar na garantia da qualidade do produto e no monitoramento da eficiência da produção. Agências regulatórias no mundo já incluem o controle estatístico de processos multivariado em suas recomendações. Neste trabalho realizamos três aplicações de cartas de controle multivariadas para detectar pequenas variações em processos na indústria farmacêutica. Os estudos foram realizados no Laboratório Farmacêutico do Estado de Pernambuco Governador Miguel Arraes - LAFEPE, empregando dados do processo e abordando problemas reais da rotina da indústria. A primeira aplicação consiste na elaboração da Revisão Periódica de Produtos empregando cartas de controle multivariadas baseadas em Análise de Componentes Principais, acompanhada de uma metodologia simples e original para identificação do sinal multivariado fora de controle por meio da decomposição da estatística T2 com base nos pesos da rotação VARIMAX. O procedimento desenvolvido permitiu monitorar e diagnosticar os desvios no processo produtivo, além de permitir ao setor responsável pela Garantia da Qualidade verificar as variáveis que mais impactaram o processo. A segunda aplicação é demonstrada em estudos de estabilidade de medicamentos empregando Cromatografia Líquida de Alta Eficiência. No estudo de estabilidade a carta de resíduos das componentes principais permitiu monitorar o processo de degradação de comprimidos de captopril. A ponderação do cromatograma na região do dissulfeto de captopril sensibiliza a carta de resíduos para revelar alterações sutis no padrão cromatográfico. A terceira aplicação envolve estudos de estabilidade empregando a espectroscopia no infravermelho próximo e médio. Nesta aplicação, conclui-se que ambas as técnicas são eficientes em detectar amostras vencidas. O Processo de degradação do captopril pode ser acompanhado pela carta de resíduos baseada nos espectros do infravermelho próximo. No infravermelho médio, a carta T2 construída com um método de seleção de variáveis e um esquema CUSUM-COT também foi eficiente em detectar as pequenas alterações durante o processo de degradação.

En aéronautique, l’élaboration via des pré-imprégnés n’est pas toujours adaptées àla fabrication de nouvelles pièces de formes complexes ou de grandes dimensions. Desprocédés directs existent, dénommés Liquid Composites Molding (LCM), tels que leResin Transfer Moulding (RTM) ou les procédés d’infusion de résine, comme le LiquidResin Infusion (LRI) et le Resin Film Infusion (RFI). Actuellement, environ 5 à 10%des pièces composites sont fabriqués par ces procédés directs. Avec le procédé RTM,les tolérances dimensionnelles et la porosité peuvent être maîtrisées et on peut atteindredes pièces haute qualité, mais son industrialisation est complexe et les modèlesmécaniques doivent être améliorés pour réaliser des simulations représentatives. Parcontre, les procédés d’infusion peuvent être utilisés dans des conditions plus flexibles,par exemple, dans des moules ouverts à sac vide en nylon ou silicone, à faible coût. Parconséquent, les procédés de LRI et RFI sont particulièrement adaptés pour les petites etmoyennes entreprises car les investissements sont plus faibles par rapport à d’autresprocédés de fabrication.Les procédés par infusion de résine LRI ou RFI sont basés sur l’écoulement d’unerésine liquide (pour RFI, après le cycle de température, la résine solide obtenir son étatliquide) à travers l’épaisseur d’un renfort fibreux sec dénommé préforme.L’optimisation du procédé est difficile à réaliser car le volume de la préforme changefortement pendant le procédé car elle est soumise à une pression extérieure et qu’il n’ya pas de contre-moule. Pour optimiser les paramètres de fabrication des matériauxcomposites par infusion de résine, il est nécessaire de mettre en oeuvre un modèlenumérique. Récemment, une modélisation de l'écoulement d’un fluide isotherme dansun milieu poreux compressible a été développée par P. Celle [1]. Avec ce modèlenumérique, nous avons simulé des cas test en 2D pour des géométries industriellesclassiques. Pour valider ce modèle numérique, des essais d’infusion d’une plaque par leprocédé LRI dans des conditions industrielles ont été réalisés. D’une part, la simulationnumérique permet de calculer le temps de remplissage, l’épaisseur de la préforme et lamasse de la résine durant l’infusion. D’autre part, nous avons suivi de procédéexpérimentalement par des micro-thermocouples, la fibre optique et la projection defranges. Un des points clefs de l’approche expérimentale est que l’écoulement de larésine et le comportement de la préforme dépendent intrinsèquement de paramètres quiévoluent pendant l’infusion de la résine, tels que la variation de l’épaisseur, le temps deremplissage et le taux volumique de fibres, via la perméabilité. Enfin, une comparaisonentre les résultats expérimentaux et la simulation numérique permet de valider lemodèle numérique. Cette confrontation des résultats permettra de mettre en lumière lesdifficultés et les limites de ce modèle numérique, afin d’améliorer les futurs modèles.De plus, ces deux approches constituent un bon moyen d’étudier et d’approfondir nosconnaissances sur les procédés d’infusion de résine, tout en développant un outil desimulation indispensable à la conception de pièces composites avancées. / Weight saving is still a key issue for aerospace industry. For instance 50% in weightof the B787 and A350 aircraft structures is made of CFRP, so it is necessary to makelighter thick and complex parts. Direct processes called Liquid Composite Molding(LCM), such as Resin Transfer Moulding (RTM) or Resin Infusion Process (LRI, RFI).At the present time, around 5 to 10% of the parts are manufactured by direct processesand the current trend is clearly to go ahead. In RTM process, the dimensional tolerancesand porosity fraction can be kept under control and high quality parts produced, but itsindustrialisation is complex and refined models are still needed to perform simulations.On the contrary, the resin infusion process can be utilized in flexible conditions, such asin low cost open moulds with vacuum bags in nylon or silicone. This type of processonly requires low resin pressure and the tooling is less expensive than RTM rigidmoulds. Therefore LRI and RFI processes are particularity suitable for small andmedium size companies because the investments are rather low compared to othermanufacturing process.Liquid Resin Infusion (LRI) processes are promising manufacturing routes toproduce large, thick or complex structural parts. They are based on the resin flowinduced across its thickness by pressure applied onto a preform / resin stacking.However, both thickness and fibre volume fraction of the final piece are not wellcontrolled since they result from complex mechanisms which drive the transientmechanical equilibria leading to the final geometrical configuration. In order tooptimize both design and manufacturing parameters, but also to monitor the LRIprocess, an isothermal numerical model has been developed by P. Celle [1], whichdescribes the mechanical interaction between the deformations of the porous mediumand the resin flow during infusion. With this numerical model, we have investigated theLRI process with classical industrial piece shapes. To validate the numerical model andto improve the knowledge of the LRI process, the researcher work details a comparisonbetween numerical simulations and an experimental study of a plate infusion testcarried out by LRI process under industrial conditions. From the numerical prediction,the filling time, the resin mass and the thickness of the preform can be determined. Onanother hand, the resin flow and the preform response can be monitored bymicro-thermocouples, optical fibre sensor and fringe projection during the filling stage.One key issue of this research work is to highlight the major process parameterschanges during the resin infusion stage, such as the preform and resin temperature, thevariations of both thickness and fiber volume fraction of the preform. Moreover, thesetwo approaches are both good ways to explore and improve our knowledge on the resininfusion processes, and finally, to develop simulation tools for the design of advancedcomposite parts.