From Polymorph Screening to Dissolution Testing - Solid Phase Analysis during Pharmaceutical Development and Manufacturing

Solid materials can exist in different physical structures without a change in chemical composition. This phenomenon, known as polymorphism, has several implications on pharmaceutical development and manufacturing. Various solid forms of a drug can possess different physical and chemical properties, which may affect processing characteristics and stability, as well as the performance of a drug in the human body. Therefore, knowledge and control of the solid forms is fundamental to maintain safety and high quality of pharmaceuticals. During manufacture, harsh conditions can give rise to unexpected solid phase transformations and therefore change the behavior of the drug. Traditionally, pharmaceutical production has relied on time-consuming off-line analysis of production batches and finished products. This has led to poor understanding of processes and drug products. Therefore, new powerful methods that enable real time monitoring of pharmaceuticals during manufacturing processes are greatly needed. The aim of this thesis was to apply spectroscopic techniques to solid phase analysis within different stages of drug development and manufacturing, and thus, provide a molecular level insight into the behavior of active pharmaceutical ingredients (APIs) during processing. Applications to polymorph screening and different unit operations were developed and studied. A new approach to dissolution testing, which involves simultaneous measurement of drug concentration in the dissolution medium and in-situ solid phase analysis of the dissolving sample, was introduced and studied. Solid phase analysis was successfully performed during different stages, enabling a molecular level insight into the occurring phenomena. Near-infrared (NIR) spectroscopy was utilized in screening of polymorphs and processing-induced transformations (PITs). Polymorph screening was also studied with NIR and Raman spectroscopy in tandem. Quantitative solid phase analysis during fluidized bed drying was performed with in-line NIR and Raman spectroscopy and partial least squares (PLS) regression, and different dehydration mechanisms were studied using in-situ spectroscopy and partial least squares discriminant analysis (PLS-DA). In-situ solid phase analysis with Raman spectroscopy during dissolution testing enabled analysis of dissolution as a whole, and provided a scientific explanation for changes in the dissolution rate. It was concluded that the methods applied and studied provide better process understanding and knowledge of the drug products, and therefore, a way to achieve better quality.

Lean Thinking in Software Development : Impacts of Kanban on Projects

The history of software development in a somewhat systematical way has been performed for half a century. Despite this time period, serious failures in software development projects still occur. The pertinent mission of software project management is to continuously achieve more and more successful projects. The application of agile software methods and more recently the integration of Lean practices contribute to this trend of continuous improvement in the software industry. One such area warranting proper empirical evidence is the operational efficiency of projects. In the field of software development, Kanban as a process management method has gained momentum recently, mostly due to its linkages to Lean thinking. However, only a few empirical studies investigate the impacts of Kanban on projects in that particular area. The aim of this doctoral thesis is to improve the understanding of how Kanban impacts on software projects. The research is carried out in the area of Lean thinking, which contains a variety of concepts including Kanban. This article-type thesis conducts a set of case studies expanded with the research strategy of quasi-controlled experiment. The data-gathering techniques of interviews, questionnaires, and different types of observations are used to study the case projects, and thereby to understand the impacts of Kanban on software development projects. The research papers of the thesis are refereed, international journal and conference publications. The results highlight new findings regarding the application of Kanban in the software context. The key findings of the thesis suggest that Kanban is applicable to software development. Despite its several benefits reported in this thesis, the empirical evidence implies that Kanban is not all-encompassing but requires additional practices to keep development projects performing appropriately. Implications for research are given, as well. In addition to these findings, the thesis contributes in the area of plan-driven software development by suggesting implications both for research and practitioners. As a conclusion, Kanban can benefit software development projects but additional practices would increase its potential for the projects.