Quitosana é um biopolímero encontrado principalmente na parede celular de crustáceos e é obtida pela desacetilação da quitina. Como biopolímero a quitosana é utilizada como excipiente para medicamentos e composição de alimentos. No entanto a quitosana devidamente purificada para uso farmacêutico ou alimentício tem custo financeiro elevado. Outro fator que contribui para o uso limitado é a falta de procedimento padronizado para desacetilação, o que resulta em materiais com diferentes graus de qualidade, dificultando suas aplicações e controle de qualidade de matéria prima e produto. Este trabalho tem como principal objetivo estabelecer procedimento reprodutível para a extração da quitina e da quitosana, por meio da aplicação dos conceitos de Quality by Design e planejamento de experimentos. A quitosana foi obtida pela desacetilação da quitina de crustáceos pelas etapas de desmineralização, desproteinização e despigmentação. O procedimento técnico para purificação da quitosana foi definido a partir de planejamento fatorial com ponto central para as etapas otimizadas, por meio da aplicação dos conceitos de Quality by Design e planejamento de experimentos. O projeto definiu um procedimento padronizado para purificação da quitosana que pode ser empregado em escala industrial, e financeiramente vantajoso para produção de medicamentos ou alimentos. / Chitosan is a biopolymer found mainly in the cell wall of crustaceans and is obtained by the deacetylation of chitin. As biopolymer chitosan is used as excipient for medicaments and food composition. However, chitosan duly purified for pharmaceutical or food use has a high financial cost. Another factor that contributes to the limited use is the lack of standardized procedure for deacetylation, which results in materials with different grades of quality, hindering their applications and quality control of raw material and product. This work has as main objective to establish a reproducible procedure for the extraction of chitin and chitosan, through the application of the concepts of Quality by Design and planning of experiments. Chitosan was obtained by the deacetylation of chitin from crustaceans through the demineralization, deproteinization and depigmentation stages. The technical procedure for purification of chitosan was defined from a factorial planning with a central point for the optimized steps, through the application of the concepts of Quality by Design and planning of experiments. The project defined a standard procedure for the purification of chitosan that can be used on industrial scale and financially advantageous for the production of medicines or foods.

Apixabana é um novo fármaco da classe dos anticoagulantes orais utilizado na prevenção e no tratamento de eventos de tromboembolismo venoso em pacientes submetidos à cirurgia de quadril e joelho, além de reduzir os riscos de acidente vascular cerebral e fibrilação arterial. Uma vez que impurezas e contaminantes podem estar presentes no produto farmacêutico final, as agências regulatórias preveem leis para monitorar essas substâncias. O conceito de Quality by Design (QbD), uma abordagem sistemática que inicia com objetivos pré-definidos e análise de risco, está sendo amplamente utilizado no âmbito farmacêutico para desenvolver formulações e metodologias analíticas. Sendo assim, este trabalho almejou desenvolver e validar um método indicativo de estabilidade simples, rápido e sensível utilizando cromatografia líquida de alta eficiência (CLAE) para determinação simultânea da apixabana e três impurezas sintéticas aplicando a abordagem QbD. O desenho experimental foi feito através do software MODDE® 11 (Umetrics, Suíça) e executado utilizando um cromatógrafo Shimadzu® LC-20A Prominence CLAE-DAD com detecção a 220 nm. O método cromatográfico foi estabelecido utilizando uma coluna Inertsil® CN-3 (150 × 4,6 mm, 5,0 μm) com temperatura do forno de 30°C e volume de injeção de 10 μL. A constituição da fase móvel foi metanol e água (50,2:49,8) com fluxo de 1,015 mL/min sem ajuste de pH. O método foi validado seguindo as guias do ICH e da ANVISA, sendo considerado específico, sensível, linear (r > 0,999), preciso (DPRs < 10% para as impurezas) e exato. Para especificidade, foi realizada busca de produtos de degradação submetendo os comprimidos de apixabana a condições de estresse (radiação UVC, temperatura, oxidação e hidrólise). As substâncias envolvidas no presente trabalho também foram caracterizadas quimicamente e avaliadas quanto ao seu perfil toxicológico in vitro através dos ensaios de MTT e vermelho neutro. A mistura da APX e suas impurezas demonstrou toxicidade aguda, porém este resultado não se manteve durante a exposição prolongada, sugerindo um mecanismo de compensação mitocondrial. Já a impureza 3 apresentou danos significativos em 96 horas de exposição, de modo que mais estudos devem efetuados para avaliar sua toxicidade. / Apixaban is a novel anticoagulant agent used to prevent and treat venous thromboembolic events in adults who have undergone total hip or knee replacement surgery and to lower the risk of stroke in patients with atrial fibrillation. As impurities and contaminants may be present in the pharmaceutical product, current regulatory guidelines recommend monitoring such substances. The concept of Quality by Design (QbD), a systematic approach that begins with predefined objectives and risk management, is being widely used in the pharmaceutical field to develop new formulations and analytical methods. Thus, the aim of this work was to develop and validate a simple, fast and sensitive stability indicating method by high-performance liquid chromatography (HPLC) for the simultaneous determination of apixaban and three synthesis impurities using QbD approach. Experiments were designed and assessed on MODDE® 11 (Umetrics, Sweden) software and carried out in a Shimadzu® LC-20A Prominence HPLC-DAD at 220 nm. The HPLC method was established using an Inertsil® CN-3column (150 × 4.6 mm, 5.0 μm) at the temperature of 30°C and injection volume of 10 μL. The mobile phase consisted of methanol and water (50.2:49.8) at a flow rate of 1.015 mL/min with no pH adjustment. Validation of the method was conducted according to ICH and ANVISA Guidelines, which was considered specific, sensitive, linear (r > 0,999), precise (RSD < 10% for impurities) and accurate. For specificity, a degradation study was performed by exposing apixaban tablets to stress conditions (UVC radiation, temperature, oxidation and hydrolysis). The related substances in the present study were also chemically characterized and toxicological profile was evaluated by in vitro tests MTT and neutral red. The mixture of APX and its impurities showed acute toxicity, but this result did not persist during prolonged exposure, suggesting a mitochondrial compensation mechanism. Yet, impurity 3 presented significant damages in 96 hours of exposure and further studies should be considered to evaluate its toxicity.

The U.S. Food and Drug Administration has accepted the guidelines put forth by the International Conference on Harmonization (ICH-Q8) that allow for operational flexibility within a validated design space. These Quality by Design initiatives have allowed drug manufacturers to incorporate more rigorous scientific controls into their production streams. <br>Fully automated control systems can incorporate information about a process back into the system to adjust process variables to consistently hit product quality targets (feedback control), or monitor variability in raw materials or intermediate products to adjust downstream manufacturing operations (feedforward control). These controls enable increased process understanding, continuous process and product improvement, assurance of product quality, and the possibility of real-time release. Control systems require significant planning and an initial investment, but the improved product quality and manufacturing efficiency provide ample incentive for the expense. <br>The fluid bed granulation and drying unit operation was an excellent case study for control systems implementation because it is a complex unit operation with dynamic powder movement, high energy input, solid-liquid-gas interactions, and difficulty with scale-up development. Traditionally, fluid bed control systems have either used first principle calculations to control the internal process environment or purely empirical methods that incorporate online process measurements with process models. This dissertation was predicated on the development of a novel hybrid control system that combines the two traditional approaches. <br>The hybrid controls reduced the number of input factors for the creation of efficient experimental designs, reduced the variability between batches, enabled control of the drying process for a sensitive active pharmaceutical ingredient, rendered preconditioned air systems unnecessary, and facilitated the collection of data for the development of process models and the rigorous calculation of design spaces. Significant variably in the inlet airstream was able to be mitigated using feedforward controls, while process analytical technology provided immediate feedback about the process for strict control of process inputs. Tolerance surfaces provided the ideal tool for determining design spaces that assured the reduction of manufacturing risk among all future batches, and the information gained using small scale experimentation was leveraged to provide efficient scale-up, making these control systems feasible for consistent use. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Pharmaceutics / PhD / Dissertation

Apixabana é um novo fármaco da classe dos anticoagulantes orais utilizado na prevenção e no tratamento de eventos de tromboembolismo venoso em pacientes submetidos à cirurgia de quadril e joelho, além de reduzir os riscos de acidente vascular cerebral e fibrilação arterial. Uma vez que impurezas e contaminantes podem estar presentes no produto farmacêutico final, as agências regulatórias preveem leis para monitorar essas substâncias. O conceito de Quality by Design (QbD), uma abordagem sistemática que inicia com objetivos pré-definidos e análise de risco, está sendo amplamente utilizado no âmbito farmacêutico para desenvolver formulações e metodologias analíticas. Sendo assim, este trabalho almejou desenvolver e validar um método indicativo de estabilidade simples, rápido e sensível utilizando cromatografia líquida de alta eficiência (CLAE) para determinação simultânea da apixabana e três impurezas sintéticas aplicando a abordagem QbD. O desenho experimental foi feito através do software MODDE® 11 (Umetrics, Suíça) e executado utilizando um cromatógrafo Shimadzu® LC-20A Prominence CLAE-DAD com detecção a 220 nm. O método cromatográfico foi estabelecido utilizando uma coluna Inertsil® CN-3 (150 × 4,6 mm, 5,0 μm) com temperatura do forno de 30°C e volume de injeção de 10 μL. A constituição da fase móvel foi metanol e água (50,2:49,8) com fluxo de 1,015 mL/min sem ajuste de pH. O método foi validado seguindo as guias do ICH e da ANVISA, sendo considerado específico, sensível, linear (r > 0,999), preciso (DPRs < 10% para as impurezas) e exato. Para especificidade, foi realizada busca de produtos de degradação submetendo os comprimidos de apixabana a condições de estresse (radiação UVC, temperatura, oxidação e hidrólise). As substâncias envolvidas no presente trabalho também foram caracterizadas quimicamente e avaliadas quanto ao seu perfil toxicológico in vitro através dos ensaios de MTT e vermelho neutro. A mistura da APX e suas impurezas demonstrou toxicidade aguda, porém este resultado não se manteve durante a exposição prolongada, sugerindo um mecanismo de compensação mitocondrial. Já a impureza 3 apresentou danos significativos em 96 horas de exposição, de modo que mais estudos devem efetuados para avaliar sua toxicidade. / Apixaban is a novel anticoagulant agent used to prevent and treat venous thromboembolic events in adults who have undergone total hip or knee replacement surgery and to lower the risk of stroke in patients with atrial fibrillation. As impurities and contaminants may be present in the pharmaceutical product, current regulatory guidelines recommend monitoring such substances. The concept of Quality by Design (QbD), a systematic approach that begins with predefined objectives and risk management, is being widely used in the pharmaceutical field to develop new formulations and analytical methods. Thus, the aim of this work was to develop and validate a simple, fast and sensitive stability indicating method by high-performance liquid chromatography (HPLC) for the simultaneous determination of apixaban and three synthesis impurities using QbD approach. Experiments were designed and assessed on MODDE® 11 (Umetrics, Sweden) software and carried out in a Shimadzu® LC-20A Prominence HPLC-DAD at 220 nm. The HPLC method was established using an Inertsil® CN-3column (150 × 4.6 mm, 5.0 μm) at the temperature of 30°C and injection volume of 10 μL. The mobile phase consisted of methanol and water (50.2:49.8) at a flow rate of 1.015 mL/min with no pH adjustment. Validation of the method was conducted according to ICH and ANVISA Guidelines, which was considered specific, sensitive, linear (r > 0,999), precise (RSD < 10% for impurities) and accurate. For specificity, a degradation study was performed by exposing apixaban tablets to stress conditions (UVC radiation, temperature, oxidation and hydrolysis). The related substances in the present study were also chemically characterized and toxicological profile was evaluated by in vitro tests MTT and neutral red. The mixture of APX and its impurities showed acute toxicity, but this result did not persist during prolonged exposure, suggesting a mitochondrial compensation mechanism. Yet, impurity 3 presented significant damages in 96 hours of exposure and further studies should be considered to evaluate its toxicity.

Apixabana é um novo fármaco da classe dos anticoagulantes orais utilizado na prevenção e no tratamento de eventos de tromboembolismo venoso em pacientes submetidos à cirurgia de quadril e joelho, além de reduzir os riscos de acidente vascular cerebral e fibrilação arterial. Uma vez que impurezas e contaminantes podem estar presentes no produto farmacêutico final, as agências regulatórias preveem leis para monitorar essas substâncias. O conceito de Quality by Design (QbD), uma abordagem sistemática que inicia com objetivos pré-definidos e análise de risco, está sendo amplamente utilizado no âmbito farmacêutico para desenvolver formulações e metodologias analíticas. Sendo assim, este trabalho almejou desenvolver e validar um método indicativo de estabilidade simples, rápido e sensível utilizando cromatografia líquida de alta eficiência (CLAE) para determinação simultânea da apixabana e três impurezas sintéticas aplicando a abordagem QbD. O desenho experimental foi feito através do software MODDE® 11 (Umetrics, Suíça) e executado utilizando um cromatógrafo Shimadzu® LC-20A Prominence CLAE-DAD com detecção a 220 nm. O método cromatográfico foi estabelecido utilizando uma coluna Inertsil® CN-3 (150 × 4,6 mm, 5,0 μm) com temperatura do forno de 30°C e volume de injeção de 10 μL. A constituição da fase móvel foi metanol e água (50,2:49,8) com fluxo de 1,015 mL/min sem ajuste de pH. O método foi validado seguindo as guias do ICH e da ANVISA, sendo considerado específico, sensível, linear (r > 0,999), preciso (DPRs < 10% para as impurezas) e exato. Para especificidade, foi realizada busca de produtos de degradação submetendo os comprimidos de apixabana a condições de estresse (radiação UVC, temperatura, oxidação e hidrólise). As substâncias envolvidas no presente trabalho também foram caracterizadas quimicamente e avaliadas quanto ao seu perfil toxicológico in vitro através dos ensaios de MTT e vermelho neutro. A mistura da APX e suas impurezas demonstrou toxicidade aguda, porém este resultado não se manteve durante a exposição prolongada, sugerindo um mecanismo de compensação mitocondrial. Já a impureza 3 apresentou danos significativos em 96 horas de exposição, de modo que mais estudos devem efetuados para avaliar sua toxicidade. / Apixaban is a novel anticoagulant agent used to prevent and treat venous thromboembolic events in adults who have undergone total hip or knee replacement surgery and to lower the risk of stroke in patients with atrial fibrillation. As impurities and contaminants may be present in the pharmaceutical product, current regulatory guidelines recommend monitoring such substances. The concept of Quality by Design (QbD), a systematic approach that begins with predefined objectives and risk management, is being widely used in the pharmaceutical field to develop new formulations and analytical methods. Thus, the aim of this work was to develop and validate a simple, fast and sensitive stability indicating method by high-performance liquid chromatography (HPLC) for the simultaneous determination of apixaban and three synthesis impurities using QbD approach. Experiments were designed and assessed on MODDE® 11 (Umetrics, Sweden) software and carried out in a Shimadzu® LC-20A Prominence HPLC-DAD at 220 nm. The HPLC method was established using an Inertsil® CN-3column (150 × 4.6 mm, 5.0 μm) at the temperature of 30°C and injection volume of 10 μL. The mobile phase consisted of methanol and water (50.2:49.8) at a flow rate of 1.015 mL/min with no pH adjustment. Validation of the method was conducted according to ICH and ANVISA Guidelines, which was considered specific, sensitive, linear (r > 0,999), precise (RSD < 10% for impurities) and accurate. For specificity, a degradation study was performed by exposing apixaban tablets to stress conditions (UVC radiation, temperature, oxidation and hydrolysis). The related substances in the present study were also chemically characterized and toxicological profile was evaluated by in vitro tests MTT and neutral red. The mixture of APX and its impurities showed acute toxicity, but this result did not persist during prolonged exposure, suggesting a mitochondrial compensation mechanism. Yet, impurity 3 presented significant damages in 96 hours of exposure and further studies should be considered to evaluate its toxicity.

This thesis investigates the use of micro-injection moulding (μIM), as a high-volume process, for producing three-dimensional, integrated microfluidic devices. It started with literature reviews that covered three topics: μIM of thermoplastic microfluidics, designing for three-dimensional (3-D) microfluidics and functional integration in μIM. Research gaps were identified: Designing 3-D microfluidics within the limitations of μIM, process optimisation and the integration of functional elements. A process chain was presented to fabricate a three-dimensional microfluidic device for medical application by μIM. The thesis also investigated the effect of processing conditions on the quality of the replicated component. The design-of-experiments (DOE) approach is used to highlight the significant processing conditions that affect the part mass taking into consideration the change in part geometry. The approach was also used to evaluate the variability within the process and its effect on the replicability of the process. Part flatness was also evaluated with respect to post-filling process parameters. The thesis investigated the possibility of integrating functional elements within μIM to produce microfluidic devices with hybrid structures. The literature reviews highlighted the importance of quality control in high-volume micromoulding and in-line functional integration in microfluidics. A taxonomy of process integration was also developed based on transformation functions. The experimental results showed that μIM can be used to fabricate microfluidic devices that have true three-dimensional structures by subsequent lamination. The DOE results showed a significant effect of individual process variables on the filling quality of the produced components and their flatness. The geometry of the replicated component was shown to have effect on influential parameters. Other variables, on the other hand, were shown to have a possible effect on process variability. Optimization statistical tools were used to improve multiple quality criteria. Thermoplastic elastomers (TPE) were processed with μIM to produce hybrid structures with functional elements.

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)

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.

A 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 de 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. / 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 tablets 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 very consuming of time, material, equipment 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.

Architecting e-business applications is a complex design activity. This is mainly due to the numerous architectural decisions to be made, including the selection of alternative technologies, software components, design strategies, patterns, standards, protocols, platforms, etc. Further complexities arise due to the fact that these alternatives often vary considerably in their support for different quality attributes. Moreover, there are often different groups of stakeholders involved, with each having their own quality goals and criteria. Furthermore, different architectural decisions often include interdependent alternatives, where the selection of one alternative for one particular decision impacts the selections to be made for alternatives from other different decisions. There have been several research efforts aiming at providing sufficient mechanisms and tools for facilitating the architectural evaluation and design process. These approaches, however, address architectural decisions in isolation, where they focus on evaluating a limited set of alternatives belonging to one architectural decision. This has been the primary motivation behind the development of the Architectural DEcision-Making Support (ADEMS) framework, which basically aims at supporting stakeholders and architects during the architectural decision-making process by helping them determining a suitable combination of architectural alternatives. ADEMS framework is an iterative process that leverages rigorous quantitative decision-making techniques available in the literature of Management Science, particularly Multiple Attribute Decision-Making (MADM) methods and Integer Programming (IP). Furthermore, due to the number of architectural decisions involved as well as the variety of available alternatives, the architecture design space is expected to be huge. For this purpose, a query language has been developed, known as the Architecture Query Language (AQL), to aid architects in exploring and analyzing the design space in further depth, and also in examining different ???what-if??? architectural scenarios. In addition, in order to support leveraging ADEMS framework, a support tool has been implemented for carrying out the sophisticated set of mathematical computations and comparisons of the large number of architectural combinations, which might otherwise be hard to conduct using manual techniques. The primary contribution of the tool is in its help to identify, evaluate, and rank all potential combinations of alternatives based on their satisfaction to quality preferences provided by the different stakeholders. Finally, to assess the feasibility of ADEMS, three different case studies have been conducted relating to the architectural evaluation of different e-business and enterprise applications. Results obtained for the three case studies were quite positive as they showed an acceptable accuracy level for the decisions recommended by ADEMS, and at a reasonable time and effort costs for the different system stakeholders.