La presente tesis doctoral surge ante la necesidad creciente por parte de la mayoría de empresas, y en especial (pero no únicamente) aquellas dentro de los sectores farmacéu-tico, químico, alimentación y bioprocesos, de aumentar la flexibilidad en su rango ope-rativo para reducir los costes de fabricación, manteniendo o mejorando la calidad del producto final obtenido. Para ello, esta tesis se centra en la aplicación de los conceptos del Quality by Design para la aplicación y extensión de distintas metodologías ya exis-tentes y el desarrollo de nuevos algoritmos que permitan la implementación de herra-mientas adecuadas para el diseño de experimentos, el análisis multivariante de datos y la optimización de procesos en el ámbito del diseño de mezclas, pero sin limitarse ex-clusivamente a este tipo de problemas. Parte I - Prefacio, donde se presenta un resumen del trabajo de investigación realiza-do y los objetivos principales que pretende abordar y su justificación, así como una introducción a los conceptos más importantes relativos a los temas tratados en partes posteriores de la tesis, tales como el diseño de experimentos o diversas herramientas estadísticas de análisis multivariado. Parte II - Optimización en el diseño de mezclas, donde se lleva a cabo una recapitu-lación de las diversas herramientas existentes para el diseño de experimentos y análisis de datos por medios tradicionales relativos al diseño de mezclas, así como de algunas herramientas basadas en variables latentes, tales como la Regresión en Mínimos Cua-drados Parciales (PLS). En esta parte de la tesis también se propone una extensión del PLS basada en kernels para el análisis de datos de diseños de mezclas, y se hace una comparativa de las distintas metodologías presentadas. Finalmente, se incluye una breve presentación del programa MiDAs, desarrollado con la finalidad de ofrecer a sus usuarios la posibilidad de comparar de forma sencilla diversas metodologías para el diseño de experimentos y análisis de datos para problemas de mezclas. Parte III - Espacio de diseño y optimización a través del espacio latente, donde se aborda el problema fundamental dentro de la filosofía del Quality by Design asociado a la definición del llamado 'espacio de diseño', que comprendería todo el conjunto de posibles combinaciones de condiciones de proceso, materias primas, etc. que garanti-zan la obtención de un producto con la calidad deseada. En esta parte también se trata el problema de la definición del problema de optimización como herramienta para la mejora de la calidad, pero también para la exploración y flexibilización de los procesos productivos, con el objeto de definir un procedimiento eficiente y robusto de optimiza-ción que se adapte a los diversos problemas que exigen recurrir a dicha optimización. Parte IV - Epílogo, donde se presentan las conclusiones finales, la consecución de objetivos y posibles líneas futuras de investigación. En esta parte se incluyen además los anexos. / Aquesta tesi doctoral sorgeix davant la necessitat creixent per part de la majoria d'em-preses, i especialment (però no únicament) d'aquelles dins dels sectors farmacèutic, químic, alimentari i de bioprocessos, d'augmentar la flexibilitat en el seu rang operatiu per tal de reduir els costos de fabricació, mantenint o millorant la qualitat del producte final obtingut. La tesi se centra en l'aplicació dels conceptes del Quality by Design per a l'aplicació i extensió de diferents metodologies ja existents i el desenvolupament de nous algorismes que permeten la implementació d'eines adequades per al disseny d'ex-periments, l'anàlisi multivariada de dades i l'optimització de processos en l'àmbit del disseny de mescles, però sense limitar-se exclusivament a aquest tipus de problemes. Part I- Prefaci, en què es presenta un resum del treball de recerca realitzat i els objec-tius principals que pretén abordar i la seua justificació, així com una introducció als conceptes més importants relatius als temes tractats en parts posteriors de la tesi, com ara el disseny d'experiments o diverses eines estadístiques d'anàlisi multivariada. Part II - Optimització en el disseny de mescles, on es duu a terme una recapitulació de les diverses eines existents per al disseny d'experiments i anàlisi de dades per mit-jans tradicionals relatius al disseny de mescles, així com d'algunes eines basades en variables latents, tals com la Regressió en Mínims Quadrats Parcials (PLS). En aquesta part de la tesi també es proposa una extensió del PLS basada en kernels per a l'anàlisi de dades de dissenys de mescles, i es fa una comparativa de les diferents metodologies presentades. Finalment, s'inclou una breu presentació del programari MiDAs, que ofe-reix la possibilitat als usuaris de comparar de forma senzilla diverses metodologies per al disseny d'experiments i l'anàlisi de dades per a problemes de mescles. Part III- Espai de disseny i optimització a través de l'espai latent, on s'aborda el problema fonamental dins de la filosofia del Quality by Design associat a la definició de l'anomenat 'espai de disseny', que comprendria tot el conjunt de possibles combina-cions de condicions de procés, matèries primeres, etc. que garanteixen l'obtenció d'un producte amb la qualitat desitjada. En aquesta part també es tracta el problema de la definició del problema d'optimització com a eina per a la millora de la qualitat, però també per a l'exploració i flexibilització dels processos productius, amb l'objecte de definir un procediment eficient i robust d'optimització que s'adapti als diversos pro-blemes que exigeixen recórrer a aquesta optimització. Part IV- Epíleg, on es presenten les conclusions finals i la consecució d'objectius i es plantegen possibles línies futures de recerca arran dels resultats de la tesi. En aquesta part s'inclouen a més els annexos. / The present Ph.D. thesis is motivated by the growing need in most companies, and specially (but not solely) those in the pharmaceutical, chemical, food and bioprocess fields, to increase the flexibility in their operating conditions in order to reduce production costs while maintaining or even improving the quality of their products. To this end, this thesis focuses on the application of the concepts of the Quality by Design for the exploitation and development of already existing methodologies, and the development of new algorithms aimed at the proper implementation of tools for the design of experiments, multivariate data analysis and process optimization, specially (but not only) in the context of mixture design. Part I - Preface, where a summary of the research work done, the main goals it aimed at and their justification, are presented. Some of the most relevant concepts related to the developed work in subsequent chapters are also introduced, such as those regarding design of experiments or latent variable-based multivariate data analysis techniques. Part II - Mixture design optimization, in which a review of existing mixture design tools for the design of experiments and data analysis via traditional approaches, as well as some latent variable-based techniques, such as Partial Least Squares (PLS), is provided. A kernel-based extension of PLS for mixture design data analysis is also proposed, and the different available methods are compared to each other. Finally, a brief presentation of the software MiDAs is done. MiDAs has been developed in order to provide users with a tool to easily approach mixture design problems for the construction of Designs of Experiments and data analysis with different methods and compare them. Part III - Design Space and optimization through the latent space, where one of the fundamental issues within the Quality by Design philosophy, the definition of the so-called 'design space' (i.e. the subspace comprised by all possible combinations of process operating conditions, raw materials, etc. that guarantee obtaining a product meeting a required quality standard), is addressed. The problem of properly defining the optimization problem is also tackled, not only as a tool for quality improvement but also when it is to be used for exploration of process flexibilisation purposes, in order to establish an efficient and robust optimization method in accordance with the nature of the different problems that may require such optimization to be resorted to. Part IV - Epilogue, where final conclusions are drawn, future perspectives suggested, and annexes are included. / Palací López, DG. (2018). Quality by Design through multivariate latent structures [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/115489 / TESIS

Der Einfluss des Raumcharakters auf die menschliche Tätigkeit ist einer der Grundsätze der „Umwelt-Mensch-Beziehung“ – und findet sich in allen Maßstabsebenen. Zur Beschreibung des Raumcharakters auf Siedlungsmaßstabsebene wird dieser Grundsatz beispielsweise mit den Thesen kognitive Karte (E. Tolman), visuelle Wahrnehmung (J. Gibson), Raumverständlichkeit (K. Lynch) und territoriale Ansprüche (H. Hertzberger) diskutiert. Es wird bisher dargelegt, dass sich das sozialpsychologische Verhalten gewissermaßen auf den Raumcharakter auf Siedlungsmaßstabsebene bezieht. Räume sind also mit ihrer sozialpsychologischen Raumqualität entsprechend zu charakterisieren. Jedoch ist nach heutigem Stand der Siedlungsraumcharakter hinsichtlich der sozialpsychologischen Raumqualität schwierig quantitativ zu bewerten, sodass es mithilfe der empirischen bzw. subjektiven Methode nötig ist, die oben genannten Thesen praktisch zu prüfen. Da diese Arbeit die Position des Apriorismus bzw. der Naturwissenschaft bezieht, wird mithilfe des Werkzeugs Space Syntax versucht, eine apriorische bzw. relativ objektive Methode zur Prüfung dieser Thesen zu entwickeln, um den Siedlungsraumcharakter in die sozialpsychologische Raumqualität umzuwandeln. Durch diese Methode können städtebauliche Maßnahmen zur Lösung der sozialen bzw. sozialpsychologischen Probleme in vorhandenen Siedlungen oder zur Vermeidung dieser Probleme bei Siedlungsneubau vorgeschlagen werden. In dieser Arbeit wird die Methode durch eine Grundtypenanalyse von Siedlungsmorphologien hinsichtlich der jeweiligen sozialpsychologischen Raumqualität musterhaft aufgebaut. Die Stadt Raunheim im Ballungsraum Frankfurt/Rhein-Main, als eine Siedlung in einer wachsenden Metropolregion, wird als Beobachtungsobjekt empirisch untersucht; das Migrationsverhalten dient als sozialpsychologischer Indikator zum Beweisen der Methode.

Additives, incorporated in film coating formulations, and their process parameters are generally selected using a trial-and-error approach. However, coating problems and defects, especially those associated with aqueous coating systems, indicate the necessity of embracing a quality-by-design approach to identify the optimum coating parameters. In this study, the feasibility of using thermal and rheological measurements to help evaluate and design novel coating formulations has been investigated. Hydroxypropyl methylcellulose acetate succinate (HPMCAS), an enteric coating polymer, was used as the film forming polymer. Differential Scanning Calorimetry (DSC), Dynamic Mechanical Analysis (DMA), and Parallel Plate Shear Rheometery (PPSR) were used to evaluate the effect of different plasticisers on the performance of HPMCAS. The results illustrate that, for identical formulations, the DSC and DMA methods yielded up to 40% differences in glass transition temperature (Tg) values. Moreover, Tg measured using loss modulus signals were always 20-30 oC less than those measured using tan delta results in DMA testing. Absolute and relative Tg values can significantly vary depending on the geometry of the samples, clamp size, temperature ramping rate and the frequency of the oscillations. Complex viscosity data for different formulations demonstrated a variable shear thinning behaviour and a Tg independent ranking. It is, therefore, insufficient to rely purely on Tg values to determine the relative performance of additives. In addition, complex viscosity results, obtained using both the DMA and PPSR techniques at similar temperatures, are shown to be comparable. The results from both techniques were therefore used to produce continuous master curves for the HPMCAS formulations. Additionally, step strain tests showed that HPMCAS chains do not fully III disentangle after 105 seconds as predicted by the Maxwell model. Finally, in situ aqueous-based coating experiments proved that mixtures of triethyl acetyl citrate and acetylated monoglyceride (TEAC/AMG), even without cooling of the suspension, do not cause blocking of the spray nozzle whereas triethyl citrate (TEC) based formulae did. TEAC (alone or in a combination with AMG) exhibits superior wettability to HPMCAS than TEC/AMG formulations and can be used to enhance the efficiency and film quality of the dry coating process.

<p>To apply Industry 4.0 technologies and accelerate the modernization of continuous pharmaceutical manufacturing, digital twin (DT) and advanced process control (APC) strategies are indispensable. The DT serves as a virtual representation that mirrors the behavior of the physical process system, enabling real-time monitoring and predictive capabilities. Consequently, this facilitates the feasibility of real-time release testing (RTRT) and enhances drug product development and manufacturing efficiency by reducing the need for extensive sampling and testing. Moreover, APC strategies are required to address variations in raw material properties and process uncertainties while ensuring that desired critical quality attributes (CQAs) of in-process materials and final products are maintained. When deviations from quality targets are detected, APC must provide optimal real-time corrective actions, offering better control performance than the traditional open loop-control method. The progress in DT and APC is beneficial in shifting from the paradigm of Quality-by-Test (QbT) to that of Quality-by-Design (QbD) and Quality-by-Control (QbC), which emphasize the importance of process knowledge and real-time information to ensure product quality.</p> <p><br></p> <p>This study focuses on four key elements and their applications in a continuous dry granulation tableting process, including feeding, blending, roll compaction, ribbon milling and tableting unit operations. Firstly, the necessity of a digital infrastructure for data collection and integration is emphasized. An ISA-95-based hierarchical automation framework is implemented for continuous pharmaceutical manufacturing, with each level serving specific purposes related to production, sensing, process control, manufacturing operations, and business planning. Secondly, investigation of process analytical technology (PAT) tools for real-time measurements is highlighted as a prerequisite for effective real-time process management. For instance, the measurement of mass flow rate, a critical process parameter (CPP) in continuous manufacturing, was previously limited to loss-in-weight (LIW) feeders. To overcome this limitation, a novel capacitance-based mass flow sensor, the ECVT sensor, has been integrated into the continuous direct compaction process to capture real-time powder flow rates downstream of the LIW feeders. Additionally, the use of near-infrared (NIR)-based sensor for real-time measurement of ribbon solid fraction in dry granulation processes is explored. Proper spectra selection and pre-processing techniques are employed to transform the spectra into useful real-time information. Thirdly, the development of quantitative models that establish a link between CPPs and CQAs is addressed, enabling effective product design and process control. Mechanistic models and hybrid models are employed to describe the continuous direct compaction (DC) and dry granulation (DG) processes. Finally, applying APC strategies becomes feasible with the aid of real-time measurements and model predictions. Real-time optimization techniques are used to combine measurements and model predictions to infer unmeasured states or mitigate the impact of measurement noise. In this work, the moving horizon estimation-based nonlinear model predictive control (MHE-NMPC) framework is utilized. It leverages the capabilities of MHE for parameter updates and state estimation to enable adaptive models using data from the past time window. Simultaneously, NMPC ensures satisfactory setpoint tracking and disturbance rejection by minimizing the error between the model predictions and setpoint in the future time window. The MHE-NMPC framework has been implemented in the tableting process and demonstrated satisfactory control performance even when plant model mismatch exists. In addition, the application of MHE enables the sensor fusion framework, where at-line measurements and online measurements can be integrated if the past time window length is sufficient. The sensor fusion framework proves to be beneficial in extending the at-line measurement application from just validation to real-time decision-making.</p>