Dissertations / Theses on the topic 'Process analytical technologies (PAT)'

Many areas of science now generate huge volumes of data that present visualization, modeling, and interpretation challenges. Methods for effectively representing the original data in a reduced coordinate space are therefore receiving much attention. The purpose of this research is to test the hypothesis that molecular computing of vectors for transformation matrices enables spectra to be represented in any arbitrary coordinate system. New coordinate systems are selected to reduce the dimensionality of the spectral hyperspace and simplify the mechanical/electrical/computational construction of a spectrometer. A novel integrated sensing and processing system, termed Molecular Factor Computing (MFC) based near infrared (NIR) spectrometer, is proposed in this dissertation. In an MFC -based NIR spectrometer, spectral features are encoded by the transmission spectrum of MFC filters which effectively compute the calibration function or the discriminant functions by weighing the signals received from a broad wavelength band. Compared with the conventional spectrometers, the novel NIR analyzer proposed in this work is orders of magnitude faster and more rugged than traditional spectroscopy instruments without sacrificing the accuracy that makes it an ideal analytical tool for process analysis. Two different MFC filter-generating algorithms are developed and tested for searching a near-infrared spectral library to select molecular filters for MFC-based spectroscopy. One using genetic algorithms coupled with predictive modeling methods to select MFC filters from a spectral library for quantitative prediction is firstly described. The second filter-generating algorithm designed to select MFC filters for qualitative classification purpose is then presented. The concept of molecular factor computing (MFC)-based predictive spectroscopy is demonstrated with quantitative analysis of ethanol-in-water mixtures in a MFC-based prototype instrument.

In this thesis novel configurations and operating strategies in the mixed suspension mixed product removal (MSMPR) crystalliser are investigated, aided by integrated process analytical technologies (PAT) and crystallisation informatics system (CryPRINS) tools. The MSMPR is an idealised crystalliser model that assumes: steady-state operation; well mixed suspension with no product classification, such that all volume elements contain a mixture of particles (small and large) and crystal size distribution (CSD) that is independent of location in the crystalliser and is identical of the product withdrawn; and uniform supersaturation thought, leading to constant nucleation and growth rates. Single-stage MSMPR designs with continuous recycle/recirculation and modified heat exchanger were investigated and found to minimise fouling, encrustation and transfer line blockages. In particular, a modified MSMPR with baffled heat exchanger was found to significantly reduce the temperature between incoming feed hot feed solution and the cooled crystalliser, leading to a significant reduction in fouling, encrustation and blockages. In addition, the concept of the periodic mixed suspension mixed product removal (PMSMPR) crystallisation process is demonstrated for the first time viz single- and multi-stage cascaded operations. This method of operation involves the periodic transfer of slurry (addition and withdrawal) at high flow rates from either a single stirred vessel or between a number of stirred vessels arranged in series. The PMSMPR is therefore characterised by periodic withdrawals of product slurry. Similar to the MSMPR, the product withdrawn from a PMSMPR has exactly the same composition as the vessel at the time of removal. The rapid withdrawal of slurry at high flow rates in PMSMPR operation leads to the prevention of particle sedimentation and blockage of transfer lines. The transfer of slurry (to/from) the PMSMPR is followed by a holding (or pause) period when no addition or withdrawal of slurry takes place. The holding period extends the mean residence time of the PMSMPR relative to a typical MSMPR, thereby increasing the yield and productivity of crystallisation as more time is allowed for consumption of available supersaturation viz crystal growth and nucleation. A state of controlled operation (SCO) in the periodic flow process, defined as a state of the system that maintains itself despite regular, but controlled disruptions was characterised using the PAT tools and CryPRINS within an intelligent decision support (IDS) framework. The crystallisation of paracetamol (PCM) from isopropyl alcohol (IPA) using different configurations of a single-stage continuous MSMPR crystalliser that incorporated continuous recycle and recirculation loop, and a novel design with baffled heat exchanger was investigated. Crystallisations of PCM-IPA carried out in the MSMPR without heat exchanger suffered from severe fouling, encrustation and blockage problems due to the high level of supersaturation (S = 1.39) in the crystalliser, which was required for the initial burst of nucleation to generate enough particles for later growth, as well as the large temperature difference between the incoming feed (45 oC) and the crystalliser (10 oC). Using the modified MSMPR design with baffled heat exchanger, the challenges of fouling, encrustation and blockage were significantly reduced due to the rapid lowering of the feed stream temperature prior to entering the crystalliser. In addition, the closed loop system led to conservation of material, which is a great benefit since large amounts of materials would otherwise be required if the MSMPR was operated with continuous product removal. This design is great for research purposes, in particular, to investigate process design and optimisation. Continuous crystallisation of PCM in the presence of hydroxyl propyl methyl cellulose (HPMC) additive was investigated in the modified MSMPR design with heat exchanger. HPMC was found to improve the crystallisation performance, leading to complete avoidance of fouling, encrustation and blockages at a concentration of 0.05 wt%. However, the yield of crystallisation was significantly reduced (28.0 %) compared to a control experiment (98.8 %, biased due to fouling/encrustation) performed without additive addition. Regardless, the productivity of crystallisation was more than four times that achieved in batch linear cooling (LC) (0.62 0.86 g/L-min) and batch automated dynamic nucleation control (ADNC) (0.24 0.25 g/L-min) runs. Aspects of the periodic flow crystallisation of single- and multi-component (co-crystals) molecular systems have also been examined to demonstrate the concept of state of controlled operation . The single component systems studied were PCM and glycine (GLY), each representative of compounds with slow and fast growth kinetics, respectively. The co-crystal systems investigated were urea-barbituric acid (UBA) and p Toluenesulfonamide-Triphenylphosphine oxide (p-TSA-TPPO). UBA is a polymorphic co-crystal system with three known forms (I, II and III). Form I UBA was successfully isolated in a three-stage periodic flow PMSMPR crystalliser. This study demonstrates the capability of periodic flow crystallisation for isolation of a desired polymorph from a mixture. p-TSA-TPPO exists in two known stoichiometric co-crystal forms, 1:1 and 3:2 mole ratio p-TSA-TPPO, respectively. The two crystalline forms exhibit solution mediated transformation, which proves to be a difficulty for separation. For this study, the implementation of temperature cycles in batch and flow control in semi-batch and periodic PMSMPR crystallisers were investigated to isolate pure 1:1 and 3:2 p-TSA-TPPO, respectively. Different regions of the ternary diagram of p-TSA, TPPO and acetonitrile (MeCN) were investigated. The desired co-crystal form was isolated all crystallisation platforms investigated. However, greater consistency was observed in the semi-batch and PMSMPR operations respectively. Periodic flow crystallisation in PMSMPR is a promising alternative to conventional continuous MSMPR operation, affording greater degrees of freedom operation, slightly narrower RTD profiles, consistent product crystal quality (size, shape and distribution), longer mean residence times, higher yield and productivity and significant reduction in fouling, encrustation and transfer line blockages over prolonged operating periods. Furthermore, the PMSMPR is a versatile platform that can be used to investigate a range of different molecular systems. Relative to batch operation, the PMSMPR can operate close to equilibrium, however, this is dependent on the system kinetics. In addition, retrofitting of batch crystallisers to operate as PMSMPRS fairly simple and require only subtle changes to the existing design space. The integrated array of PAT sensors consisted of attenuated total reflectance ultra violet/visible spectroscopy (ATR-UV/vis), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), focused beam reflectance measurement (FBRM), particle vision microscopy (PVM) and Raman spectroscopy. The results from the studies reported here illustrate very well the use of PAT and information system tools together to determine when the continuous and periodic MSMPR operations reaches a steady-state or state of controlled operation (i.e. periodic steady-state). These tools provided a better understanding of the variables and operating procedures that influence the two types of operations.

This work presents a comprehensive study on the application of PAT tools to study, monitor and control polymorphism during batch cooling crystallization processes. For the first time, the same techniques were used to control and adjust polymorphic purity of the solid phase but also to investigate the relation between chemical equilibrium in solution and polymorphic outcome of cooling crystallization. Crystallization is an important unit operation used as separation and purification technique. It is widely employed in the pharmaceutical, chemical, agrochemical, food and cosmetics industries but also in the electronic, metallurgic and material industries. More than 90% of the APIs on the market are produced by crystallization, therefore, monitoring and control this process is fundamental to ensure the quality of the final product. The implementation of process analytical technology (PAT) tools during the development stage of APIs has largely helped in better understanding and optimizing both batch and, more recently, continuous crystallization. Polymorphism is the capacity of a compound to crystallize in more than one different crystalline structure, which can have different properties such as density, melting point, bioavailability and solubility. The choice of solvent, pH, kinetic conditions and presence of impurities has very strong effect on the polymorphic outcome of a cooling crystallization in solution. Understanding this phenomenon as well as being able to monitor and control it during industrial crystallization is one the biggest challenges for pharmaceutical industries.

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

Software sensors are a potent tool to improve biotechnological real time process monitoring and control. In the current project, algorithms for six partly novel, software sensors were established and tested in a microbial reactor system. Eight batch and two fed-batch runs were carried out with a recombinant Escherichia coli to investigate the suitability of the different software sensor models in diverse cultivation stages. Special respect was given to effects on the sensors after recombinant protein expression was initiated by addition of an inducer molecule. It was an objective to figure out influences of excessive recombinant protein expression on the software sensor signals.

Two of the developed algorithms calculated the biomass on-line and estimated furthermore, the specific growth rate by integration of the biomass changes with the time. The principle of the first was the application of a near infrared probe to obtain on-line readings of the optical density. The other algorithm was founded on the titration of ammonia as only available nitrogen source. The other two sensors analyzed for the specific consumption of glucose and the specific production of acetate and are predicted on an in-line HPLC system.

The results showed that all software sensors worked as expected and are rather powerful to estimate important state parameters in real time. In some stages, restrictions may occur due to different limitation affects in the models or the physiology of the culture. However, the results were very convincing and suggested the development of further and more advanced software sensor models in the future.

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
A espectroscopia de infravermelho próximo (NIRS) é uma técnica de análise bastante conhecida e utilizada em diversas indústrias, tais como a alimentar, química, petroquímica, agroquímica. É também usada na indústria farmacêutica desde há alguns anos (EMEA, 2003). A Farmacopeia Americana - United States Pharmacopeia (USP) considera a NIRS um ramo da espectroscopia vibracional, partilhando aplicações e princípios com muitas medições espectroscópicas. As suas aplicações utilizam espectros medidos em comprimento de onda. A interacção entre a radiação NIR e a matéria pode fornecer informação qualitativa e quantitativa avaliada a partir da composição química e física de amostras. A técnica é rápida, simples, não destrutiva e analisa múltiplos componentes em praticamente qualquer matriz, com níveis de exactidão e precisão comparáveis aos métodos de referência primários. Não é necessária qualquer preparação ou manipulação da amostra, nem utilização de reagentes (Foss, 2002). Na indústria farmacêutica, o método de análise NIRS vem sendo aplicado há mais de 20 anos, estando inicialmente focalizado na análise de matérias-primas, mais recentemente tem sido também aplicado na análise de formulações sólidas e liquidas para controlo de qualidade do produto final, bem como para monitorização de operações de produção. As amostras de material recebido são inspeccionadas por este método, e a identidade e qualidade do mesmo é confirmada, a partir de algoritmos de padrões conhecidos. O método fornece informação quase em tempo real para controlo de processos de produção, como sejam identificação de matériasprimas, sistemas de recuperação de solventes ou secagem da mistura, por intermédio de técnicas de regressão estatística (Reich, 2005). Para que um processo de análise se possa implementar em processos industriais é necessário assegurar a sua robustez, pelo que um método NIRS deve ser desenvolvido tendo em conta requisitos considerados na produção e controlo, como características ópticas da amostra, sensibilidade e selectividade para o analito (Foss,2002). Os principais objectivos deste trabalho monográfico consistem:  Estudo da técnica em análise, espectroscopia de infravermelho próximo;  As suas aplicações nas diversas fases do processo de produção;  Caracterizar o potencial da tecnologia em estudo, na análise dos diversos processos de controlo e produção farmacêutica. A elaboração deste trabalho de revisão bibliográfica foi efectuada através duma pesquisa sobre a temática, em publicações científicas, livros da especialidade e monografias. Os artigos consultados foram pesquisados, na sua maioria, em motores de busca disponibilizados pela Universidade Fernando Pessoa. As palavraschave utilizadas na realização da pesquisa foram as seguintes: “Espectroscopia de Infravermelho Próximo”, “Indústria Farmacêutica ”, “Aplicações NIRS”, “Tecnologias de Análise de Processos PAT”, “Monitorização de Processos”. Near infrared spectroscopy (NIRS) is an analyses technique very well known and used in many industries, like the chemical, petrochemical, biochemical and food industry. It is also being used in pharmaceutical industries in the recent years (EMEA, 2003). The United States Pharmacopeia (USP) considers NIRS as a branch of vibrational spectroscopy, sharing applications and principles with many spectroscopic measurements. Its applications use spectra measured in wavelength. The interactions between NIR radiation and matter may provide qualitative and quantitative information evaluated from the chemical and physical composition of the samples. This technique is fast, simple, non destructive and also analyzes multiple components in virtually any matrix, providing levels of precision and accuracy comparable with the primary reference methods. It’s not necessary any preparation or manipulation of the sample, and the reagent application is also discarded (Foss, 2002). In the pharmaceutical industry, NIRS method has been used for more than twenty years, initially focused in the analysis of raw materials, and more recently applied also to solid and liquid drug analysis, in the purpose of final quality control, and as well in the production line processes monitoring. Samples of incoming materials are inspected with this method, and the process of identity and quality of those products is assured, being compared with tables from confirmed acceptable samples. The process produces information almost in real time, using regression analysis, in the processes monitoring applications, as in raw material identification, solvent recovery systems or drying processes (Reich, 2005). For the application of the processes in industrial environment it is necessary to assure its strength, for that the NIRS must be developed bearing in mind the requirements considered in the production and control, as in the optical features of the sample, sensibility and selectiveness of the analyte (Foss, 2002). The main objectives of this monograph consist of:  Study of the analysis technique, near infrared spectroscopy;  Its applications in various stages of production;  To characterize the potential of the technology under study, the analysis of the various control processes and pharmaceutical production. The development of this literature review was conducted through a survey on the topic in scientific publications, specialty books and monographs. The selected papers were searched, mostly in search engines provided by the University. The keywords used in the research were as follows: "Near Infrared Spectroscopy", "Pharmaceutical Industry", "NIR Application", "Process Analytical Technology PAT", "Process 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.

In the production of paper, the quality of the pulp is an important factor both for the productivity and for the final quality. Reliable real-time measurements of pulp quality are therefore needed. One way is to use acoustic or vibration sensors that give information-rich signals and place the sensors at suitable locations in a pulp production line. However, these sensors are not selective for the pulp properties of interest. Therefore, advanced signal processing and multivariate calibration are essential tools. The current work has been focused on the development of calibration routes for extraction of information from acoustic sensors and on signal processing algorithms for enhancing the information-selectivity for a specific pulp property or class of properties. Multivariate analysis methods like Principal Components Analysis (PCA), Partial Least Squares (PLS) and Orthogonal Signal Correction (OSC) have been used for visualization and calibration. Signal processing methods like Fast Fourier Transform (FFT), Fast Wavelet Transform (FWT) and Continuous Wavelet Transform (CWT) have been used in the development of novel signal processing algorithms for extraction of information from vibrationacoustic sensors. It is shown that use of OSC combined with PLS for prediction of Canadian Standard Freeness (CSF) using FFT-spectra produced from vibration data on a Thermo Mechanical Pulping (TMP) process gives lower prediction errors and a more parsimonious model than PLS alone. The combination of FFT and PLS was also used for monitoring of beating of kraft pulp and for screen monitoring. When using regular FFT-spectra on process acoustic data the obtained information tend to overlap. To circumvent this two new signal processing methods were developed: Wavelet Transform Multi Resolution Spectra (WT-MRS) and Continuous Wavelet Transform Fibre Length Extraction (CWT-FLE). Applying WT-MRS gave PLS-models that were more parsimonious with lower prediction error for CSF than using regular FFT-Spectra. For a Medium Consistency (MC) pulp stream WT-MRS gave predictions errors comparable to the reference methods for CSF and Brightness. The CWT-FLE method was validated against a commercial fibre length analyzer and good agreement was obtained. The CWT-FLE-curves could therefore be used instead of other fibre distribution curves for process control. Further, the CWT-FLE curves were used for PLS modelling of tensile strength and optical parameters with good results. In addition to the mentioned results a comprehensive overview of technologies used with acoustic sensors and related applications has been performed.
Vid framställning av pappersprodukter är kvaliteten på massan en viktig faktor för produktiviteten och kvalitén på slutresultatet. Det är därför viktigt att ha tillgång till tillförlitliga mätningar av massakvalitet i realtid. En möjlighet är att använda akustik- eller vibrationssensorer i lämpliga positioner vid enhetsoperationer i massaprocessen. Selektiviteten hos dessa mätningar är emellertid relativt låg i synnerhet om mätningarna är passiva. Därför krävs avancerad signalbehandling och multivariat kalibrering. Det nu presenterade arbetet har varit fokuserat på kalibreringsmetoder för extraktion av information ur akustiska mätningar samt på algoritmer för signalbehandling som kan ge förbättrad informationsselektivitet. Multivariata metoder som Principal Component Analysis (PCA), Partial Least Squares (PLS) and Orthogonal Signal Correction (OSC) har använts för visualisering och kalibrering. Signalbehandlingsmetoderna Fast Fourier Transform (FFT), Fast Wavelet Transform (FWT) och Continuous Wavelet Transform (CWT) har använts i utvecklingen av nydanande metoder för signalbehandling anpassade till att extrahera information ur signaler från vibrations/akustiska sensorer. En kombination av OSC och PLS applicerade på FFT-spektra från raffineringen i en Termo Mechnaical Pulping (TMP) process ger lägre prediktionsfel för Canadian Standard Freeness (CSF) än enbart PLS. Kombinationen av FFT och PLS har vidare använts för monitorering av malning av sulfatmassa och monitorering av silning. Ordinära FFT-spektra av t.ex. vibrationssignaler är delvis överlappande. För att komma runt detta har två signalbehandlingsmetoder utvecklats, Wavelet Transform Multi Resolution Spectra (WT-MRS) baserat på kombinationen av FWT och FFT samt Continuous Wavelet Transform Fibre Length Extraction (CWT-FLE) baserat på CWT. Tillämpning av WT-MRS gav enklare PLS-modeller med lägre prediktionsfel för CSF jämfört med att använda normala FFT-spektra. I en annan tillämpning på en massaström med relativt hög koncentration (Medium Consistency, MC) kunde prediktioner för CSF samt ljushet erhållas med prediktionsfel jämförbart med referensmetodernas fel. Metoden CWT-FLE validerades mot en kommersiell fiberlängdsmätare med god överensstämmelse. CWT-FLE-kurvorna skulle därför kunna användas i stället för andra fiberdistributionskurvor för processtyrning. Vidare användes CWT-FLE kurvor för PLS modellering av dragstyrka samt optiska egenskaper med goda resultat. Utöver de nämnda resultaten har en omfattande litteratursammanställning gjorts över området och relaterade applikationer.
QC 20100629

В современном мире рынок фотографических услуг развивается семимильными шагами. Фотосалоны и фотостудии особенно актуальны среди начинающих бизнесменов. Чтобы повысить продажи, многие компании все чаще предлагают возможность записать клиента онлайн с помощью CRM. CRM-система актуальна по разным причинам: развитие бизнес-процессов, роли интернета и использование мобильных устройств в бизнесе, развитие и удешевление технологий обработки данных и ИТ-инфраструктуры. И, конечно же, большую роль сыграл тот факт, что технические возможности CRM-систем достигли совершенства. Они позволяют отследить путь покупателя с момента первого контакта с ним для перепродажи. Она создает технологию продаж, связывая рекламу, аналитические инструменты и саму систему продаж в единую систему. Результаты выпускной квалификационной работы будут использованы в фотостудии при внедрении CRM-системы AppEvent.
In the modern world, the photographic services market is developing by leaps and bounds. Photo salons and photo studios are especially relevant among novice businessmen. To boost sales, many companies are increasingly offering the option to sign up a customer online using CRM. The CRM system is relevant for various reasons: the development of business processes, the role of the Internet and the use of mobile devices in business, the development and reduction of the cost of data processing technologies and IT infrastructure. And, of course, the fact that the technical capabilities of CRM systems have reached perfection played an important role. They allow you to track the path of the buyer from the moment of the first contact with him for resale. It creates sales technology by linking advertising, analytical tools and the sales system itself into a single system. The results of the final qualifying work will be used in the photo studio when implementing the AppEvent CRM system.

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.

Дисертаційна робота присвячена розробленню та обґрунтуванню методології ефективного використання земельних ресурсів для розвитку сонячної енергетики на основі даних дистанційного зондування Землі та ГІС-технологій. За допомогою застосування даної методології були знайдені найбільш придатні місця для розташування наземних промислових сонячних фотоелектричних електростанцій на території Заставнівського району Чернівецької області. У розділі 1 «Аналіз використання земельних ресурсів України в альтернативній енергетиці» розглянуто та проаналізовано сучасний стан використання земельних ресурсів, динаміку розвитку альтернативних джерел енергії в паливно-енергетичному комплексі держави та правовий режим земель альтернативної енергетики. Встановлено, що на території України є біля 10 % земель, які можуть бути потенційно придатними для розташування на них об’єктів альтернативної енергетики, а саме наземних сонячних фотоелектричних електростанцій. Визначено, що державне стимулювання виробництва електричної енергії з альтернативних джерел енергії у вигляді «зеленого» тарифу, надбавки за дотримання рівня використання обладнання українського виробництва та аукціонної ціни, позитивно впливає на розвиток альтернативних джерел енергії, що особливо чітко відображається на динаміці розвитку сонячної енергетики протягом 2016 – 2018 років. Встановлено, що в Україні сприятливі кліматичні умови для розвитку сонячної енергетики - річна сума глобальної сонячної радіації у країні (1 070 - 1 750 кВт год на один кв. метр і вище) більша, ніж у Німеччині – світового лідера у галузі сонячної енергетики. У розділі 2 «Розроблення методології ефективного використання земельних ресурсів для розвитку сонячної енергетики» розроблено методологію для знаходження та аналізу земельних ресурсів для подальшого їх використання для потреб паливно-енергетичного комплексу держави, а саме для об’єктів сонячної енергетики - наземних промислових сонячних електростанцій потужністю від 500 кВт і вище, які виробляють електроенергію за допомогою фотоелектричних панелей. Створено технологію вибору земельних ділянок для оптимального розташування наземних сонячних електростанцій. Запропоновано застосування програмного забезпечення FOSS, даних дистанційного зондування Землі та джерел даних, які є у вільному доступі, що дозволить на безоплатній основі всім зацікавленим інвесторам, підприємцям, органам виконавчої влади використати дану методологію та створити власну карту-схему придатності земель для СЕС. Вдосконалено та обґрунтовано методику вибору критеріїв та вимог щодо розміщення наземних фотоелектричних сонячних електростанцій. Запропоновано застосування методу множинного коефіцієнта рангової кореляції для визначення узгодженості експертних суджень щодо оцінки критеріїв вибору, та методу аналізу ієрархій для присвоєння ваги кожному критерію оцінки, і, таким чином, визначення їх відносної важливості у остаточному рішенні. У розділі 3 «Експериментальні дослідження (на прикладі Заставнівського району Чернівецької області)» виконано апробацію теоретичних досліджень щодо вибору земельних ділянок для сонячної енергетики на території «пілотного» Заставнівського району Чернівецької області. Визначено критерії оцінки та виключення, що враховуються для оптимального розміщення наземної сонячної електростанції саме для даної території. Встановлено узгодженість експертних суджень, та кожному з критеріїв оцінки визначено надійну вагу у прийнятті остаточного рішення. Виконано процедуру впорядкованого зваженого усереднення для отримання початкової карти-схеми придатності земель для наземних СЕС, та процедуру контрольованої класифікації супутникового зображення для створення маски непридатних земель для розташування СЕС. Створено результуючу карту-схему придатності земель з визначеними оптимальними місцями розташування сонячних електростанцій, що відображає 58 земельних ділянок загальною площею 7,56 кв.км (755,74 га), які придатні для розташування наземних фотоелектричних сонячних електростанцій. Визначено ефективність трансформації земельних ділянок у землі сонячної енергетики та річну продуктивність наземних сонячних електростанцій розташованих на обраних земельних ділянках. This dissertation is devoted to the development and the substantiation of a methodology for the efficient use of land resources for the purpose of developing the solar industry on the basis of Remote Sensing data and GIS-technologies. With the help of this methodology, the most suitable places for the location of ground-mounted industrial solar photovoltaic power plants were found on the territory of Zastavna district in the Chernivtsi region. In section 1 "Analysis of the use of Ukraine's land resources in the renewable energy industry", the current state of the use of land resources, the dynamics of renewable energy sources development in the fuel and energy complex of Ukraine and the legal regime of land of renewable energy industry are reviewed and analyzed. It is established that on the territory of Ukraine there is about 10% of land that may be potentially suitable for placing solar photovoltaic power plants. It is determined that state incentives for the production of electric energy from renewable energy sources in the form of a “green” tariff, an allowance for compliance with the level of use of Ukrainian production equipment and auction prices have a positive effect on the development of renewable energy sources, which is particularly reflected in the dynamics of solar energy development in years 2016 - 2018. It is established that in Ukraine there are favorable meteorological conditions for the development of solar energy - the annual amount of global solar radiation in the country (1 070 - 1 750 kWh per square meter and above) is higher than in Germany - the world`s leader in the field of solar energy. In section 2 "Development of a methodology for the efficient use of land resources for the purpose of developing the solar industry" a methodology for finding and analyzing land resources for their further use for the needs of the country's fuel and energy complex, namely for solar energy facilities - ground-mounted industrial solar photovoltaic power plants with a capacity of 500 kW and higher is developed. A technology of selection of the land plots for optimal location of ground-mounted solar power plants is created. It is proposed to apply FOSS (Free and Open Source Software), Remote Sensing data and data sources which are freely available, in order to allow all interested investors, entrepreneurs, authorities to follow this technology and create their own Land Suitability Map for solar power plants for free. The method for selecting the criteria and requirements for the optimal site selection of ground-mounted solar photovoltaic power plants has been improved and substantiated. Application of the method of multiple coefficient of rank correlation for determination of the consistency of expert judgments with respect to the selection of evaluation criteria, and the method of Analytical Hierarchy Process for assigning the weights to each evaluation criteria to determine their relative importance in the final decision, are proposed. In section 3 “Experimental studies (on the example of Zastavna district in the Chernivtsi region)” an approbation of theoretical studies on selection of land plots for solar industry on the territory of the "pilot" Zastavna district in the Chernivtsi region was performed. The evaluation and exclusion criteria, which are taken into account for the optimal site selection for solar power plants, are determined for this territory. The consistency of expert judgments is established, and the reliable weight for each evaluation criteria is determined. The procedure of Ordered Weighted Averaging is performed to obtain an initial Land Suitability Map for ground-mounted solar power plants, and a procedure of supervised satellite image classification was applied to create a mask of unsuitable lands for solar power plants. The final Land Suitability Map with optimal locations for solar power plants is created. It represents 58 land plots with a total area of 7.56 sq.km (755.74 hectares), which are suitable for the placement of ground-mounted solar photovoltaic power plants. The efficiency of transformation of land plots into the category of lands of the solar energy industry and the annual performance of solar power plants located on selected land plots are determined.

Yes
Real time measurement of melt rheology has been investigated as a Process Analytical Technology (PAT) to monitor hot melt extrusion of an Active Pharmaceutical Ingredient (API) in a polymer matrix. A developmental API was melt mixed with a commercial copolymer using a heated twin screw extruder at different API loadings and set temperatures. The extruder was equipped with an instrumented rheological slit die which incorporated three pressure transducers flush mounted to the die surface. Pressure drop measurements within the die at a range of extrusion throughputs were used to calculate rheological parameters such as shear viscosity and exit pressure, related to shear and elastic melt flow properties respectively. Results showed that the melt exhibited shear thinning behavior whereby viscosity decreased with increasing flow rate. Increase in drug loading and set extrusion temperature resulted in a reduction in melt viscosity. Shear viscosity and exit pressure measurements were found to be sensitive to API loading. These findings suggest that this technique could be used as a simple tool to measure material attributes in-line, to build better overall process understanding for hot melt extrusion.

Dissertação de Mestrado Integrado em Engenharia Química apresentada à Faculdade de Ciências e Tecnologia
A segurança dos pacientes e a eficácia dos medicamentos são as principais preocupações da indústria farmacêutica, para a qual a garantia da qualidade do produto é essencial.Convencionalmente, o processamento na indústria farmacêutica é realizado em regime descontínuo, sendo a qualidade dos lotes garantida através de testes laboratoriais a amostras recolhidas, por forma a monitorizar os atributos críticos de qualidade (CQAs) do produto.Contudo, ao longo dos anos, surgiram várias tecnologias que permitem maior conhecimento do produto e do processo de fabrico, possibilitando um melhor desenvolvimento, fabrico e garantia de qualidade através do controlo e da análise de dados do processo.Estas tecnologias, tecnologias analíticas de processo (PAT), utilizam instrumentação e modelação matemática para monitorizar continuamente os CQAs de um produto, permitindo a passagem de testar a qualidade do produto acabado com métodos analíticos off-line para assegurar a qualidade do produto através da monitorização contínua e em tempo real dos seus atributos.Os sensores on-line PAT fornecem a informação necessária para inferir as principais variáveis de controlo de qualidade do sistema, embora corrompida por ruídos, biases, e imprecisões de equipamento.A qualidade desta informação pode ser melhorada através da aplicação de um algoritmo de estimativa óptima, combinando as medições disponíveis com o conhecimento prévio do sistema e dos equipamentos de medição.Neste projecto, a espectroscopia de infravermelhos (IR) é utilizada para monitorizar a concentração do reagente limitante de uma reacção em tempo real.Um modelo PLS é calibrado a partir dos dados IR recolhidos para prever a concentração do reagente, e um modelo cinético para descrever o comportamento do sistema com base nos primeiros princípios é desenvolvido.Esta informação é combinada aplicando o algoritmo do filtro de Kalman estendido híbrido (HEKF).Este trabalho evidencia os resultados favoráveis da aplicação de algoritmos da família do filtro de Kalman para combinar informação resultante dos sensores e informação mecanística, que permitem obter previsões mais precisas do que as obtidas quando a mesma informação é utilizada individualmente.A aplicação do algoritmo HEKF produz uma melhoria de precisão de 50.3 % em relação ao modelo PLS, e uma melhoria de precisão de 80.0 % em relação ao modelo cinético.Esta aplicação permite também identificar o tempo final da reacção 15 minutos antes da sua ocorrência.
Patient safety and drug efficacy are the major concerns in the pharmaceutical industry, for which product quality assurance is essential.Conventionally, pharmaceutical manufacturing consists in batch processing with off-line laboratory testing conducted on collected samples to monitor the product's critical quality attributes (CQAs).However, throughout the years, several technologies with the potential to increase insight into the product and the manufacturing process have emerged, allowing for improved pharmaceutical development, manufacturing, and quality assurance through process control and analysis of process data.These technologies, process analytical technologies (PAT), employ instrumentation and mathematical modelling to continuously monitor the CQAs of a pharmaceutical product, allowing the shift from testing the quality of the finished drug product with off-line analytical methods to assuring the product’s quality by continuous, real-time monitoring of its attributes.PAT on-line sensors provide the information needed to infer key quality control variables of the system, albeit corrupted by noise, biases, and device inaccuracies.The quality of this information can be improved through application of an optimal estimation algorithm, by combining the available measurement data with prior knowledge of the system and of the measuring devices.In this project, infrared (IR) spectroscopy is used to monitor the concentration of the limiting reagent of a reaction in real-time.A PLS model is calibrated from the collected IR data to predict the concentration of the reagent and a kinetic model is developed to describe the behaviour of the system based on first principles. This information is combined applying the hybrid extended Kalman filter (HEKF) algorithm.This work evinces the favourable outcomes of applying Kalman-filter-like algorithms to combine sensor and mechanistic information, which yield predictions that are more accurate than those obtained by the same information, if individually used.The application of the HEKF algorithm yields an accuracy improvement of 50.3 % with respects to the PLS model, and an accuracy improvement of 80.0 % with respects to the kinetic model.This application also makes possible to identify the reaction's end time 15 minutes before the occurrence.

Yes
Three-dimensional printing (3DP) has the potential to cause a paradigm shift in the manufacture of pharmaceuticals, enabling personalised medicines to be produced on-demand. To facilitate integration into healthcare, non-destructive characterisation techniques are required to ensure final product quality. Here, the use of process analytical technologies (PAT), including near infrared spectroscopy (NIR) and Raman confocal microscopy, were evaluated on paracetamol-loaded 3D printed cylindrical tablets composed of an acrylic polymer (Eudragit L100-55). Using a portable NIR spectrometer, a calibration model was developed, which predicted successfully drug concentration across the range of 4–40% w/w. The model demonstrated excellent linearity (R2 = 0.996) and accuracy (RMSEP = 0.63%) and results were confirmed with conventional HPLC analysis. The model maintained high accuracy for tablets of a different geometry (torus shapes), a different formulation type (oral films) and when the polymer was changed from acrylic to cellulosic (hypromellose, HPMC). Raman confocal microscopy showed a homogenous drug distribution, with paracetamol predominantly present in the amorphous form as a solid dispersion. Overall, this article is the first to report the use of a rapid ‘point-and-shoot’ approach as a non-destructive quality control method, supporting the integration of 3DP for medicine production into clinical practice.
Open Access funded by Engineering and Physical Sciences Research Council United Kingdom (EPSRC), UK for their financial support (EP/L01646X).

Tese de mestrado, Engenharia Farmacêutica, Universidade de Lisboa, Faculdade de Farmácia, 2016
Process Analytical Technology (PAT) is defined by the FDA in the PAT initiative issued in 2004 as ”a system for designing, analyzing, and controlling manufacturing through timelymeasurements (i.e.,during processing) of critical quality and performance attributes of raw and inprocess materials and processes, with the goal of ensuring the final product quality”. Since then, the pharmaceutical companies have been adopting gradually this technology in their manufacturing lines. PAT tools are indeed well recognized as a critical tool for achieving better process and product control leading to the possibility of real time release testing. This thesis evaluated the technical and economic feasibility of implementation of PAT systems into a Portuguese pharmaceutical company manufacturing line of solid forms. To accomplish this task, two products were used as models. These products were selected since they cover most unit operations of the solid forms installed manufacturing line. The work was divided in two parts. The first part is concerned with the identification of critical quality attributes (CQAs) and critical process parameters (CPPs) of the two model products in order for the proposition of opportunities of implementation of PAT strategies. These opportunities are described in detail and evaluated according to a series of criteria. Nine opportunities were identified, mainly involving NIR and RAMAN spectroscopy as suitable technology. The implementation of the identified opportunities, is expected to permit the possibility of real time release for the two products. The second part focuses on the economical feasibility of the identified PAT implementation. The economic analysis indicated that the implementation of all opportunities will reduce manufacturing / quality control time and costs substantially. The expectation of return-of-investmentis achieved in a time frame between 5 to 8 years respectively considering optimistic and pessimist scenarios.

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2016
Pharmaceutical manufacturing has been changing over the last years, especially, due to significant advances in science and engineering. The lack of flexibility, quality consistency, robustness of manufacturing, the need to respond faster to market shortage and the necessity of better process control demanded the establishment of new technologies, such as Process Analytical Technology (PAT), Quality by Design (QbD) and, more recently, Continuous Pharmaceutical Manufacturing (CPM). Through these approaches became possible to design manufacturing processes using principles of engineering, material science and quality control to ensure acceptable and reproducible product quality and performance throughout a product's shelf life. Fundamentally, they allow an understanding of the product and manufacturing process, starting with product development and basically building quality in, not testing it. This review focuses on these three approaches, but specially on the continuous manufacturing process, that is starting to be incorporated and developed in some breakthrough pharmaceuticals. Companies, especially the ones with new biopharmaceuticals, have begun utilizing continuous manufacturing as an alternative to batch manufacturing in various parts of the production process. Continuous manufacturing allows that materials are sent directly and continuously to the next step for further processing, after reliably produce an intermediate material or product with acceptable characteristics, guaranteeing their consistent quality. Unfortunately, in Portugal, the development of these techniques still needs to be encouraged. This could happen because companies have the perception that the existing regulatory system is rigid and unfavorable to the introduction of innovative systems. On the contrary, regulatory entities support de introduction of these technologies, providing guidelines with models for an effective quality management system for the pharmaceutical and biotech industry.
A indústria farmacêutica tem vindo a sofrer mudanças nos últimos anos, especialmente, devido aos avanços na ciência e na engenharia. A falta de flexibilidade, consistência na qualidade dos produtos, robustez do processo de produção e a necessidade de responder, com brevidade, à falta de medicamentos e de ter um melhor controlo do processo exigiu o estabelecimento de novas tecnologias como o Process Analytical Technology (PAT), o Quality by Design (QbD) e, mais recentemente, a produção contínua. Através destas estratégias torna-se possível desenhar o processo de produção usando fundamentos de engenharia, ciência dos materiais e de controlo de qualidade, assegurando uma qualidade do produto aceitável e reprodutível e também a sua performace durante o ciclo de vida do medicamento. Fundamentalmente, estas permitem um conhecimento sobre o produto e o processo de produção, começando no desenvolvimento do produto e, desta forma, construindo qualidade e não apenas testando-a. Esta monografia tem como foco estas três abordagens, mas especialmente o processo de produção contínua que está a começar a ser incorporado e desenvolvido em alguns medicamentos de ponta. As indústrias, especialmente aquelas a produzir novos biossimilares já começaram a utilizar a produção contínua, como uma alternativa aos processos com lotes, em várias secções do processo de produção. A produção contínua permite que os materiais sejam enviados, directa e continuamente, para o próximo passo, depois de produzirem materiais intermédios ou o produto final com fiabilidade e características aceitáveis, garantindo uma qualidade consistente. Infelizmente, em Portugal, o desenvolvimento destas técnicas ainda precisa de ser encorajado. Isto poderá acontecer, já que as indústrias têm a percepção que o sistema regulatório é rígido e não vê de forma favorável a introdução de sistemas inovadores. Contrariamente, as entidades regulatórias incentivam a introdução das mesmas, providenciando guidelines com modelos para um sistema de controlo de qualidade efectivo para a indústria farmacêutica e biotecnológica.

Waste resulting from healthcare activities is hazardous due to its potential risk of infection to healthcare workers, waste workers and the public. Many tools and approaches have been applied in waste management in developed countries, but are not suitable for application in developing countries due to their complexity and extensive data and resource requirements. WasteOpt was therefore developed and applied as an appropriate decision-making tool in the developing country context. WasteOpt comprises of the Analytical Hierarchy Process (AHP), costing and Life cycle management (LCM). The purpose of this study was to identify environmentally sound technologies (ESTs) that minimise the risk of infection by healthcare waste (HCW) in rural clinics. Rural clinics were selected because apart from financial constraints, they are challenged by the lack of procedure, infrastructure and technologies to develop reasonable waste management plans that can be implemented within a practicable time frame. WasteOpt was applied to aid in identifying ESTs in relation to the infection risks and costs of the technologies. Experts in waste management in Lesotho were involved in a workshop for the ranking of technologies. The overall weighting values of the rankings were converted to risk factors for individual options and for alternatives (combination of options). Risk factors were classified as low, medium and high risk. The technologies within a single class were differentiated by analysing the cost of acquiring and running the technology to qualify as ESTs. The ESTs identified for Lesotho are Engineered containers, Refrigerated engineered facility, engineered wheeled transport, detailed procedures, multi chamber incinerator, engineered pit and landfill. Ten (10) clinics in Lesotho were also assessed as case studies using the WHO RAT. The RAT was first modified to include questions on financial management at the clinics. The calculated risk factors were applied to the case studies to assess the risk under which healthcare workers operate in those clinics. The additive minimum risk for the overall life cycle of waste was 4.0 (excluding central treatment and disposal). The clinic workers were found to be at a risk of between 1.1 x 10-4 and 7.8 x 10-5, which proves that rural clinics in Lesotho are still using inappropriate technologies. In terms of financing for waste management, public clinics were found to have little decision-making powers over funds and had less accountability measures. CHAL clinics which are managed by churches in Lesotho had more control of funds and exhibit more accountability. All clinics had no targets for saving funds from waste management activities. WasteOpt can be applied as a decision-making tool for HCW in Lesotho since it overcomes the barriers that inhibit environmentally sound management of HCW in developing countries. In conclusion: WasteOpt can be applied as a decision-making tool for different types of waste by replacing HCW options with respective ones and designing a relevant questionnaire for qualitative data capture. WasteOpt can then be applied in a developing country to aid sustainable waste management decision-making. Informed decision-making helps resource poor managers to select cost-effective but low-risk options, which will be sustainable in the future.
Dissertation (MSc (Environmental Technology))--University of Pretoria, 2007.
Chemical Engineering
unrestricted

Митикасов А. М. Цифровізація виробничих і організаційних процесів в Концерні «Міські теплові мережі» : кваліфікаційна робота магістра спеціальноісті 051 «Економіка» / наук. керівник В. В. Глущевський. Запоріжжя : ЗНУ, 2020. 111 с.
UA : Проведено аналіз теоретичних і практичних підходів до вирішення завдань адаптивного ціноутворення, складання ефективних планів закупівель товарно-матеріальних цінностей, системної структуризації техніко-економічних та управлінських бізнес-процесів. Обґрунтовано концептуальну ідею проведення комплексного аналізу перебігу бізнес-процесів, на базі запровадження спеціалізованих інформаційно-аналітичних систем, що реалізують комплекс техніко-економічних задач різного рівня складності. Здійснено формалізація структурно-функціональних, логічних, інформаційних описів об`єктів, процесів, організаційних процедур для здійснення постановок прикладних техніко-економічних та управлінських задач. Обґрунтовано рекомендації щодо вдосконалення системи управління з урахуванням перспектив створення та запровадження спеціалізованих інформаційно-аналітичних систем економічного аналізу для цифровізації його виробничих і організаційних бізнес-процесів.
EN : The analysis of theoretical and practical approaches to solving the problems of adaptive pricing for heat carriers, drawing up effective plans for the procurement of inventory, systemic structuring of technical, economic and managerial business processes associated with the marketing activities of the Concern "City Heating Networks". The conceptual idea of conducting a comprehensive analysis of the course of business processes, which are associated with marketing pricing for the services of the Concern "City Heating Networks", on the basis of the introduction of specialized information and analytical systems that implement a complex of technical and economic tasks of different levels of complexity has been substantiated. The formalization of structural and functional, logical, informational descriptions of objects, processes, organizational procedures for the implementation of the statement of applied technical, economic and managerial tasks has been carried out. Recommendations for improving the management system of the Concern «City Heating Networks» are substantiated, taking into account the prospects for the creation and implementation of specialized information and analytical systems of economic analysis for the digitalization of its production and organizational business processes.