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As Boas Práticas de Fabricação de Medicamentos (BPFM) enfatizam que a indústria farmacêutica deve dirigir seus esforços no sentido de compreender a variação do processo, incluindo as fontes, o grau de variação e o impacto dessa variação nas características de qualidade do produto. O processo de fabricação de medicamentos tem apresentado significativas mudanças, em especial no que se refere à introdução de tecnologias analíticas que permitem o controle do processo em tempo real. A abordagem baseada na análise de risco e no novo Sistema de Qualidade Farmacêutica constitui ponto central das BPFM para o século XXI. Os órgãos regulatórios têm exigido da indústria farmacêutica sua adesão na melhoria contínua relativa ao desempenho de seus processos e, por consequência, na qualidade do produto. O objetivo do presente trabalho foi o desenvolvimento e validação de método analítico empregando espectroscopia no infravermelho próximo, assim como a avaliação do processo de fabricação de comprimidos de Captopril 25 mg, empregando abordagem racional-científica. Com referência à avaliação do processo, foram adotadas as seguintes ferramentas: análise de modos e efeitos de falhas (FMEA); gráficos de controle; índices de capacidade e análise de variância (ANOVA). A espectroscopia por infravermelho próximo (NIR) foi selecionada por apresentar maior rapidez na obtenção dos resultados, maior simplicidade na preparação das amostras, multiplicidade das análises a partir de uma única leitura e por apresentar característica não invasiva. Os resultados comprovaram a adequação dessa tecnologia na avaliação quantitativa do Captopril nas etapas de mistura de pós e de compressão. Os desvios padrão relativos na determinação da uniformidade de Captopril na mistura de pós e nos comprimidos empregando método no NIR foram, respectivamente 3,15 e 0,18%. No que se refere à avaliação da estabilidade e da capacidade do processo, as ferramentas adotadas permitiram a compreensão das fontes de variabilidade, assim como a determinação de seu grau, nas diferentes etapas do processo. Os índices de capacidade (CpK) relativos à uniformidade de Captopril (% p/v) na mistura de pós, ao peso médio do comprimido, à uniformidade de conteúdo e à % (p/v) dissolvida de Captopril, no ensaio de dissolução, foram 0,70, 1,94, 1,80 e 2,19, respectivamente. / The Good Manufacturing Practices (GMP) for Medicinal Products point out that the pharmaceutical industry must direct efforts to understand the variation of the processes, including the sources, the level of variation and the variation impact on the process in characteristics of the product. The manufacturing process has shown meaningful changes, especially in the introduction of new analytical technologies that allow the process control in real time. The approach based on risk analyses and on the new Pharmaceutical Quality System is a central key for the GMP for the XXI century. The Regulatory Agencies have demanded the pharmaceutical industry to adhere the continuous improvement related to the performance of its processes and, consequently, the product quality. Thus, the present paper aimed the development and validation of the analytical method employing NIR spectroscopy as the assessment of manufacturing process of Captopril 25 mg tablets, using rational scientific approach. Regarding the process assessment, the following tools were adopted: analysis of failure modes and effects analysis (FMEA), control charts, capability indexes, as well as analysis of variance (ANOVA). The near-infrared spectroscopy was selected due to its greater speed in getting the results, simplicity in sample preparation, and multiplicity of analysis from a single reading and provide non-invasive feature. The results confirmed the suitability of this technology in quantitative assessment of Captopril on the steps of mixing powders and compression. The relative standard deviations for the determination of Captopril uniformity in the post mixtures and in the tablets employing NIR were 3,15 e 0,18%, respectively. In reference to the stability assessment and process capacity, the tools adopted permitted the understanding of the sources of variability, as well as the determination of their level in different phases of the process. The capacity indexes relating to Captopril uniformity (% p/v) in the powder mixture, the average weight of the tablet, the content uniformity and the % (p/v) dissolved Captopril, in the dissolution assay were 0,70, 1,94, 1,80 and 2,19, respectively.

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.

As Boas Práticas de Fabricação de Medicamentos (BPFM) enfatizam que a indústria farmacêutica deve dirigir seus esforços no sentido de compreender a variação do processo, incluindo as fontes, o grau de variação e o impacto dessa variação nas características de qualidade do produto. O processo de fabricação de medicamentos tem apresentado significativas mudanças, em especial no que se refere à introdução de tecnologias analíticas que permitem o controle do processo em tempo real. A abordagem baseada na análise de risco e no novo Sistema de Qualidade Farmacêutica constitui ponto central das BPFM para o século XXI. Os órgãos regulatórios têm exigido da indústria farmacêutica sua adesão na melhoria contínua relativa ao desempenho de seus processos e, por consequência, na qualidade do produto. O objetivo do presente trabalho foi o desenvolvimento e validação de método analítico empregando espectroscopia no infravermelho próximo, assim como a avaliação do processo de fabricação de comprimidos de Captopril 25 mg, empregando abordagem racional-científica. Com referência à avaliação do processo, foram adotadas as seguintes ferramentas: análise de modos e efeitos de falhas (FMEA); gráficos de controle; índices de capacidade e análise de variância (ANOVA). A espectroscopia por infravermelho próximo (NIR) foi selecionada por apresentar maior rapidez na obtenção dos resultados, maior simplicidade na preparação das amostras, multiplicidade das análises a partir de uma única leitura e por apresentar característica não invasiva. Os resultados comprovaram a adequação dessa tecnologia na avaliação quantitativa do Captopril nas etapas de mistura de pós e de compressão. Os desvios padrão relativos na determinação da uniformidade de Captopril na mistura de pós e nos comprimidos empregando método no NIR foram, respectivamente 3,15 e 0,18%. No que se refere à avaliação da estabilidade e da capacidade do processo, as ferramentas adotadas permitiram a compreensão das fontes de variabilidade, assim como a determinação de seu grau, nas diferentes etapas do processo. Os índices de capacidade (CpK) relativos à uniformidade de Captopril (% p/v) na mistura de pós, ao peso médio do comprimido, à uniformidade de conteúdo e à % (p/v) dissolvida de Captopril, no ensaio de dissolução, foram 0,70, 1,94, 1,80 e 2,19, respectivamente. / The Good Manufacturing Practices (GMP) for Medicinal Products point out that the pharmaceutical industry must direct efforts to understand the variation of the processes, including the sources, the level of variation and the variation impact on the process in characteristics of the product. The manufacturing process has shown meaningful changes, especially in the introduction of new analytical technologies that allow the process control in real time. The approach based on risk analyses and on the new Pharmaceutical Quality System is a central key for the GMP for the XXI century. The Regulatory Agencies have demanded the pharmaceutical industry to adhere the continuous improvement related to the performance of its processes and, consequently, the product quality. Thus, the present paper aimed the development and validation of the analytical method employing NIR spectroscopy as the assessment of manufacturing process of Captopril 25 mg tablets, using rational scientific approach. Regarding the process assessment, the following tools were adopted: analysis of failure modes and effects analysis (FMEA), control charts, capability indexes, as well as analysis of variance (ANOVA). The near-infrared spectroscopy was selected due to its greater speed in getting the results, simplicity in sample preparation, and multiplicity of analysis from a single reading and provide non-invasive feature. The results confirmed the suitability of this technology in quantitative assessment of Captopril on the steps of mixing powders and compression. The relative standard deviations for the determination of Captopril uniformity in the post mixtures and in the tablets employing NIR were 3,15 e 0,18%, respectively. In reference to the stability assessment and process capacity, the tools adopted permitted the understanding of the sources of variability, as well as the determination of their level in different phases of the process. The capacity indexes relating to Captopril uniformity (% p/v) in the powder mixture, the average weight of the tablet, the content uniformity and the % (p/v) dissolved Captopril, in the dissolution assay were 0,70, 1,94, 1,80 and 2,19, respectively.

The overall objective of this work has been to adopt new developments and techniques in the area of measurement, modelling and control of fermentation processes. Flow cytometry and software sensors are techniques which were considered ready for application and the focus was set on developing tools for research aiming at understanding the relationship between measured variables and process quality parameters. In this study fed-batch cultivations have been performed with two different strains of Escherichia coli (E.coli) K12 W3110 with and without a gene for the recombinant protein promegapoietin. Inclusion body formation was followed during the process with flow cytometric detection by labelling the inclusion bodies with first an antibody against the protein promegapoietin and then a second fluorescent anti-antibody. The approach to label inclusion bodies directly in disintegrated and diluted cell slurry could be adopted as a method to follow protein production during the process, although the labelling procedure with incubation times and washings was somewhat time-consuming (1.5 h). The labelling of inclusion bodies inside the cells to follow protein production was feasible to perform, although an unexplained decrease in the relative fluorescence intensity occurred late in process. However, it is difficult to translate this qualitative measurement into a quantitative one, since a quantitative protein analysis should give data proportional to the volume, while the labelling of the spheric inclusion bodies gives a signal corresponding to the area of the body, and calibration is not possible. The methods were shown to be useful for monitoring inclusion body formation, but it seems difficult to get quantitative information from the analysis. Population heterogeneity analysis was performed, by using flow cytometry, on a cell population, which lost 80-90% viability according to viable count analysis. It was possible to show that the apparent cell death was due to cells incapable of dividing on agar plates after induction. These cells continued to produce the induced recombinant protein. It was shown that almost all cells in the population (≈97%) contained PMP, and furthermore total protein analysis of the medium indicated that only about 1% of the population had lysed. This confirms that the "non-viable" cells according to viable count by cfu analysis produced product. The software sensors XNH3 and µNH3, which utilises base titration data to estimate biomass and specific growth rate was shown to correlate well with the off-line analyses during cultivation of E. coli W3110 using minimal medium. In rich medium the µNH3 sensor was shown to give a signal that may be used as a fingerprint of the process, at least from the time of induction. The software sensor KLaC* was shown to respond to foaming in culture that probably was caused by increased air bubble dispersion. The RO/S coefficient, which describes the oxygen to substrate consumption, was shown to give a distinct response to stress caused by lowered pH and addition of the inducing agent IPTG. The software sensor for biomass was applied to a highly automated 6-unit multi-bioreactor system intended for fast process development. In this way also specific rates of substrate and oxygen consumption became available without manual sampling. / QC 20100819

Made available in DSpace on 2015-08-19T13:52:53Z (GMT). No. of bitstreams: 2 4.pdf: 437106 bytes, checksum: d927c757f12edab980517854aaef9262 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2012 / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos/Farmanguinhos. Rio de Janeiro, RJ, Brasil. / Esta dissertação avalia o impacto da aplicação do princípio de Quality by Design(QbD) apresentado no Guia ICH Q8(R2) Desenvolvimento Farmacêutico sobre a qualidade do processo de desenvolvimento e de produção de novos medicamentos de Farmanguinhos.O objetivo do desenvolvimento farmacêutico é projetar um produto de qualidade cujo processo de fabricação permita, de forma consistente, alcançar o desempenho pretendido com reprodutibilidade e confiabilidade. As informações e os conhecimentos adquiridos a partir de estudos de desenvolvimento farmacêutico e da experiência de fabricação podem servir de base para o gerenciamento de riscos de qualidade, bem como fornecem uma compreensão científica para subsidiar a definição do espaço do projeto, das especificações e dos controles de fabricação. As recomendações do Guia ICH Q8(R2) permitem sistematizar o conhecimento adquirido a partir da aplicação de métodos científicos e do gerenciamento de risco ao desenvolvimento de um produto e seu processo de fabricação. A compreensão dos fatores associados ao desempenho do produto, que deve ser demonstrada pela empresa a fim de embasar e viabilizar a flexibilização dos critérios regulatórios, pode ser adquirida pela aplicação da Tecnologia Analítica de Processo (PAT). O guia da Food and Drug Administration(FDA) referente à PAT destina-se a apoiar a inovação e a eficiência no desenvolvimento, fabricação e garantia de qualidade de produtos farmacêuticos. Sua estrutura é baseada na compreensão do processo para facilitar a inovação e as decisões regulatórias da indústria e da autoridade sanitária. A indústria farmacêutica brasileira vem se esforçando para estabelecer sistemas de qualidade robustos, baseados em conhecimentos científicos e nos princípios da análise e gerenciamento de riscos. Para Farmanguinhos , a implantação do Guia ICH Q8(R2) poderá trazer diversos benefícios, incluindo a melhoria na eficiência do processo de desenvolvimento e um significativo ganho de qualidade, com minimização dos riscos. Além disso, proporcionará uma estratégia para aumentar o conhecimento e a compreensão de seus produtos e processos de fabricação, e introduzirá práticas e conceitos oriundos da normatização global mais recente, facilitando a consolidação do Instituto como centro de referência em pesquisa, desenvolviment o tecnológico e produção de fármacos e medicamentos. Pela avaliação feita, apesar do processo de desenvolvimento farmacêutico de Farmanguinhos se encontrar num nível de maturidade inicial, há um esforço da equipe técnica multidisciplinar em buscar a aderência de suas atividades e da estrutura de documentação às diretrizes do Guia ICH Q8(R2). É apresentada uma proposta de procedimento para utilização dos princípios do QbD e da PAT no Instituto, a qual, se introduzida, em alguma extensão, na rotina de trabalho da Unidade, trará um ganho tecnológico e de qualidade, bem como um incremento na celeridade de possíveis alterações pós-registro que se façam necessárias no futuro. / This work evaluates the impact of the app lication of the principle of Quality by Design (QbD) presented in the ICH Guideline Q8(R2) "Pharmaceutical Development" on the quality of the development process and prod uction of new drugs of Farmanguinhos. The goal of pharmaceutical development is designing a quality product whose manufacturing process to consistently achieve the desired performance with reproducibility and reliability. The information and knowledge gained from studies of pharmaceutical development and manufacturing experience can serve as a basis for the risk management of quality, as well as provide a scientific understanding to subsidize the design space definition, specifications and manufacturing controls. The recommendations of the ICH Guideline Q8(R2) enable to systematize the knowledge acquired from the application of scientific methods and risk management to the development of a product and its manufacturing process. Understanding of the factors associated with the performance of the product, which must be demonstrated by the company in order to support and enable flexible regulatory criteria, can be acquired by application of Pr ocess Analytical Technology (PAT). The Food and Drug Administration (FDA) guideline for th e PAT is intended to support innovation and efficiency in the development, manufacturi ng and quality assurance of pharmaceuticals. Its structure is based on the understanding of the process in order to facilitate innovation and industry regulatory decisions and health authority. The Brazilian pharmaceutical industry has been trying hard to establish robust quality systems, based on scientific knowledge and the pr inciples of risk analysis and management. For Farmanguinhos, implementation of ICH Q8(R2) can bring several benefits, including improving the efficiency of the development process and a significant gain in quality, with minimization of risks. In addition, it will provide a strategy to increase the knowledge and understanding of their products and manufacturing processes, and introduce practices and concepts from the latest global standardization, facilitating the consolidation of the Institute as the center of reference in research, technological development and production of drugs and medicines. An evaluation was made, and it was possible conclude there is a multidisciplinary technical team effort in seeking the grip of its activities and structure documentation guide ICH Guidelines Q8(R2), despite the pharmaceutical development process of Farmanguinhos is in initial maturity level. A procedural proposal for use of QbD and PAT principles at the Institute is presented. If it is introduced, in some extent, in the routine work of the Unit, it will bring a technological and quality gain, as well as an increase in the speed of possible post-registration changes that may be required in the future.

京都大学 / 新制・課程博士 / 博士(情報学) / 甲第24041号 / 情博第797号 / 新制||情||135(附属図書館) / 京都大学大学院情報学研究科システム科学専攻 / (主査)教授 加納 学, 教授 下平 英寿, 教授 石井 信 / 学位規則第4条第1項該当 / Doctor of Informatics / Kyoto University / DFAM

Les entreprises pharmaceutiques ont progressivement adopté le concept de Process Analytical Technology (PAT) afin de contrôler et d'assurer en temps réel la qualité des produits pharmaceutiques au cours de leur production. Le PAT et un composant central du concept plus général de Quality-by-Design (QbD) promu par les agence régulatrices et visant à construire la qualité des produits via une approche scientifique et la gestion des risques.Une méthode basée sur la spectroscopie proche infrarouge (PIR) a été développée comme un outil du PAT pour contrôler en ligne la cristallisation d'un principe actif pharmaceutique. Au cours du procédé les teneurs en principe actif et en solvant résiduel doivent être déterminées avec précision afin d'atteindre un point d'ensemencement prédéfini. Une méthodologie basée sur les principes du QbD a guidé le développement et la validation de la méthode tout en assurant l'adéquation avec son utilisation prévue. Des modèles basés sur les moindres carrés partiels ont été construits à l'aide d'outils chimiométriques afin de quantifier les 2 analytes d'intérêt. La méthode a été totalement validée conformément aux requis officiels en utilisant les profils d'exactitude. Un suivi du procédé en temps réel a permis de prouver que la méthode correspond à son usage prévu.L'implémentation de cette méthode comme à l'échelle industrielle au lancement de ce nouveau procédé permettra le contrôle automatique de l'étape de cristallisation dans le but d'assurer un niveau de qualité prédéfini de l'API. D'autres avantages sont attendus incluant la réduction du temps du procédé, la suppression d'un échantillonnage difficile et d'analyses hors ligne fastidieuses. / Pharmaceutical companies are progressively adopting and introducing the Process Analytical Technology (PAT) concept to control and ensure in real-time product quality in development and manufacturing. PAT is a key component of the Quality-by-Design (QbD) framework promoted by the regulatory authorities, aiming the building of product quality based on both a strong scientific background and a quality risk management approach.An analytical method based on near infrared (NIR) spectroscopy was developed as a PAT tool to control on-line an API (active pharmaceutical ingredient) crystallization. During this process the API and residual solvent contents need to be precisely determined to reach a predefined seeding point. An original methodology based on the QbD principles was applied to conduct the development and validation of the NIR method and to ensure that it is fitted for its intended use. Partial least squares (PLS) models were developed and optimized through chemometrics tools in order to quantify the 2 analytes of interest. The method was fully validated according to the official requirements using the accuracy profile approach. Besides, a real-time process monitoring was added to the validation phase to prove and document that the method is fitted for purpose.Implementation of this method as an in-process control at industrial plant from the launch of this new pharmaceutical process will enable automatic control of the crystallization step in order to ensure a predefined quality level of the API. Other valuable benefits are expected such as reduction of the process time, and suppression of a difficult sampling and tedious off-line analyzes.

Résumé : À partir de 2002, grâce à l’introduction du concept de la Qualité par la Conception (en anglais Quality by Design : QbD) par l’agence américaine des produits alimentaires et médicamenteux, l’industrie pharmaceutique a intensifié les efforts et les investissements pour permettre une libération en temps réel des lots commerciaux. Le QbD propose que la qualité soit construite dès la conception initiale du médicament plutôt que d'être évaluée à la fin de sa fabrication. Ainsi, avec l’initiative QbD, les tests de contrôle de la qualité des médicaments, réalisés après la fabrication des comprimés, peuvent être éliminés si les paramètres qui les influencent sont contrôlés. En effet, ces tests de contrôle qualité dits traditionnels requièrent en général plusieurs heures pour leurs préparations et leurs réalisations. Tel est le cas du test de dissolution. Ce test est très consommateur de ressources matérielles et humaines. La réalisation de stratégies de contrôle pour les tests de dissolution basée sur une approche QbD pourrait être bénéfique pour l'industrie pharmaceutique. À travers ce travail, nous avons pu : • proposer différentes stratégies novatrices de contrôle du test de dissolution de comprimés pharmaceutiques sur la base des principes du QbD, • apporter un nouvel éclairage sur la compréhension des phénomènes impliqués dans la dissolution de comprimés pharmaceutiques. Les résultats de ce projet de recherche ont permis 1) la mise en évidence des paramètres critiques influençant le test de dissolution, 2) l’élaboration et l’évaluation de modèles statistiques pour les combinaisons de variation de paramètres selon un plan d’expérience préalablement conçu, 3) la corrélation du test de dissolution à des paramètres critiques de procédés de fabrication et d’attributs de matériaux grâce aux technologies d’analyse de procédés. // Abstract : With the introduction in 2002 of the concept of Quality by Design (QbD) by the Food and Drug Administration, the pharmaceutical industry intensified efforts and investments to reach real time release of commercial batches, reducing time between manufacturing and availability to the patient. QbD proposes that quality should be built in the initial design of a product rather than being assessed at the end of the tablet manufacturing. Thus, with the QbD initiative, quality control tests of tablets like dissolution testing performed after manufacturing could be removed if the parameters impacting them are controlled. Indeed, quality control tests such as traditional dissolution tests generally require several hours for their preparation and their realizations. Dissolution tests are time consuming, require large amounts of material and human resources. The elimination of these tests through a QbD approach could be beneficial for the pharmaceutical industry. Thanks to this work, it was possible to :  propose different innovative strategies to control the dissolution test of pharmaceutical tablets based on the principles of Quality by Design,  have a better understanding of this quality control test. The main results relies on 1) the identification of critical parameters influencing the dissolution test, 2) the development and evaluation of statistical models for the combination of variation of parameters according to an experimental design, 3) the correlation of dissolution test to critical manufacturing process parameters and attributes of materials through process analysis technology.