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.

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.

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.

Para efetivamente tratar uma infecção, é necessário que o antibiótico possua atividade antimicrobiana adequada e seja capaz de inibir o crescimento do microrganismo patogênico. O doseamento microbiológico é uma metodologia indicada para a análise do antimicrobiano de forma simples, quando comparado com outras metodologias. A Food and Drug Administration (FDA) tem encorajado uma abordagem proativa para introduzir inovações e benefícios associados ao processo de produção farmacêutica. A Qualidade por Design Analítico (AQbD) ajuda no desenvolvimento de métodos analíticos robustos e de baixo custo, que são aplicáveis durante todo ciclo de vida do produto. Os métodos microbiológicos tradicionais, de forma geral, apresentam baixa reprodutibilidade e alta incerteza. Desta forma, justifica-se o desenvolvimento de métodos microbiológicos alternativos para a análise de antimicrobianos empregando-se os conceitos de Qualidade por Design Analítico, com a finalidade de melhorar a reprodutibilidade e reduzir a incerteza final. O objetivo deste trabalho foi aplicar o conceito de Qualidade por Design Analítico (AQbD) no desenvolvimento de método colorimétrico para análise de sulfato de neomicina. O sulfato de neomicina é um antimicrobiano aminoglicosídeo amplamente empregado no tratamento de infecções cutâneas ou mucosas, tais como queimaduras, úlceras, e dermatites infecciosas. Métodos cromatográficos como a cromatografia líquida de alta eficiência em fase reversa, de pareamento iônico ou cromatografia iônica com derivatização (pré ou pós-coluna) são utilizados para a análise de aminoglicosídeos, inclusive sulfato de neomicina. Contudo, de acordo com as farmacopeias, o método microbiológico é o método analítico de escolha para a análise de sulfato de neomicina e outros aminoglicosídeos. A análise colorimétrica é um método amplamente utilizado para a detecção e quantificação de diferentes substâncias, incluindo o crescimento microbiano em estudos de eficácia terapêutica. Neste trabalho, propomos o uso de resazurina como marcador colorimétrico. O indicador sofre uma reação de oxido-redução na qual altera a coloração em resposta à redução química resultante do crescimento celular. O uso de microplacas para a análise colorimétrica é uma alternativa ao método realizado em tubos de ensaio. Uma alternativa ao uso de espectrofotômetros para a análise colorimétrica é o uso de aparelhos smartphones, pois são equipados com CPUs rápidas, câmeras de alta resolução e sensores de imagem. O processamento da imagem captada pela câmera do dispositivo é utilizado como um analisador colorimétrico. Portanto, a aplicação dos conceitos de Qualidade por Design Analítico (AQbD) possibilitou o desenvolvimento racional de método microbiológico colorimétrico para análise de sulfato de neomicina. / To effectively treat an infection, the antibiotic must have adequate antimicrobial activity and be capable of inhibiting the growth of the pathogenic microorganism. The microbiological assay is an indicated methodology for the analysis of the antimicrobial in a simple way, when compared with other methodologies. The Food and Drug Administration (FDA) has encouraged a proactive approach to introducing innovations and benefits associated with the pharmaceutical production process. Analytical Design Quality (AQbD) assists in the development of robust, low cost analytical methods that are applicable throughout the product life cycle. Traditional microbiological methods, in general, have low reproducibility and high uncertainty. Thus, it is justified the development of alternative microbiological methods for the analysis of antimicrobials using the concepts of Quality by Analytical Design, in order to improve reproducibility and reduce final uncertainty. The objective of this work was to apply the concept of Quality by Analytical Design (AQbD) in the development of a colorimetric method for the analysis of neomycin sulfate. Neomycin Sulfate is an aminoglycoside antimicrobial widely used in the treatment of cutaneous or mucosal infections, such as burns, ulcers, and infectious dermatitis. Chromatographic methods such as reverse phase high performance liquid chromatography, ion-pairing or ion chromatography with derivatization (pre or post-column) are used for the analysis of aminoglycosides, including neomycin sulfate. However, according to pharmacopoeias, the microbiological method is the analytical method of choice for the analysis of neomycin sulphate and other aminoglycosides. Colorimetric analysis is a widely used method for the detection and quantification of different substances, including microbial growth in studies of therapeutic efficacy. In this work, we propose the use of resazurin as a colorimetric marker. The indicator undergoes an oxidation-reduction reaction in which it alters the coloration in response to the chemical reduction resulting from cell growth. The use of microplates for colorimetric analysis is an alternative to the method carried out in test tubes. An alternative to the use of spectrophotometers for colorimetric analysis is the use of smartphones because they are equipped with fast CPUs, high resolution cameras and image sensors. The image processing captured by the device\'s camera is used as a colorimetric analyzer. Therefore, the application of the concepts of Quality by Analytical Design (AQbD) allowed the rational development of a microbiological colorimetric method for analysis of neomycin sulfate.

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.

Human tissue banks are a potential source of cellular material for the emerging cellbased therapy industry; umbilical cord tissue (UCT) private banking is increasing in such facilities as a source of mesenchymal stem cells for future therapeutic use. However, early handling of UCT is relatively uncontrolled due to the clinical demands of the birth environment and subsequent transport logistics. It is therefore necessary to develop extraction methods that are robust to real world operating conditions,rather than idealised operation. This will be critical for all processes using primary tissue or cell sources. The research work undertaken in this PhD project was initiated by the collaboration with one of the leading private cord blood banks in the UK and later driven by the prospect of expanding the cell therapy and business potential of the bank. The investigation described in this thesis has focused on: - Developing an extraction method for human mesencymal stem cells (hMSCs) from UCT. - Understanding and minimizing the noticed variability in cell yield extracted from UCT by mapping the operating environment and assessing the risk factors before empirically determining their effect on the process. - Establishing the necessary process controls in the production of high quality hMSCs, through a series of wet experiments, targeted at narrowing down the sources of variability down to sub-process level. - Finding a novel method for assessing the cell content and viability of cords prior to processing. Therefore, helping the tissue processing facility to predict the risk of suboptimal cell yield from a given cord tissue section and processing method, given different operating ranges. - Determining the tissue storage requirements and isolation method with acceptable risk of adequate cell recovery. - Characterization of cells extracted from UCT via different extraction methods and comparison to primary cells extracted from other tissue sources. - Investigation of cryopreservation method for UCT. The result of this work provides a solid example of the type of data and analysis that will be required to inform a Quality-by-Design type approach for cell product development and manufacture. It will help tissue processing facilities and banks to predict the probability of cell yields from tissue sections given different operating ranges, and to aid and inform the experimental approach of others.

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.