Vaccination is a strong and effective way to prevent spreading of infectious diseases and promotes global health. In the future, the importance of vaccines is expected only to increase, driven by factors such as increased international traveling, higher healthcare expenditures, and a growing population. To meet the growing demands, it is necessary to shorten process development timelines for the production of new vaccines without compromising on safety, efficacy, consistency, and stability of the product. Therefore, it is necessary to advance process development approaches of vaccines to respond quickly and in event of an emerging infectious disease. The work in this thesis employed mathematical modeling and simulation techniques to accelerate this process development. The developed methods are particularly valuable for early phase process development, aiming to enhance process knowledge and minimize the consumption of valuable resources and material. While the project has a focus on vaccine production processes, the modeling tools and methods developed are also applicable to other (bio)pharmaceutical processes. In Chapter 2, we discussed the present and future process development approaches in (bio)pharmaceutical purification with an emphasis on vaccines. The primary needs are to establish standardized processes and to improve understanding of both production processes and host cell impurities. Modeling, when combined with high throughput experimentation, can play a crucial role in achieving these goals...@en

The growing group of health-conscious consumers drives the development and sales in the market of low- or non-alcoholic beverages. In particular, sales in alcohol-free beer (AFB) has drastically gained in recent years, giving the incentive to further advance alcohol-free products. This thesis comprises the development of a new technology to produce an alcohol-free beer with an improved flavour, that is, an AFB with a significantly lower concentration in Strecker aldehydes. Despite the fact that Strecker aldehydes are present at trace concentrations of a few micrograms per litre, these compounds are majorly associated with the characteristic wort offflavour in alcohol-free beer. In the first stage, the origin of wort flavours is elucidated, and furthermore, the impact of the changed production process in comparison to regular beer and its resulting changes in the product is discussed. The most significant pathways of origin are the Maillard reactions and Strecker degradation, however, many other formation pathways have been suggested. While alcohol-free beers produced through regular fermentation and subsequent dealcoholisation are generally low in wort off-flavour, biologically produced AFBs exhibit a rather strong wortiness. This is because yeast’s activity during the fermentation is restricted to prevent alcohol formation, having the side effect that other compounds such as aldehydes are not converted to neutral or characteristic beer flavours. As it is impossible to prevent the formation of wort flavour, selective removal is required to produce an alcohol-free beer with improved flavour profile (balance). Subsequently, technologies applied to remove aldehydes from aqueous streams are investigated. Mechanisms that can be exploited for such removal are various – from separation based on size or volatility (distillation, pervaporation or membrane filtration) through sorption or conversion – past research has nearly studied all removal techniques available for aldehydes. However, most of the available techniques are not selective enough for a complex matrix such as beer, or not suitable for the application in the food industry. Nonetheless, adsorption is identified as the most promising technique to facilitate selective aldehyde removal. As a benchmark system, a dealcoholisation plant (spinning cone column) is studied with special focus on wort flavour removal. While volatile aldehydes such as 3-methylbutanal can relatively easily be reduced, methional, having a high boiling point, is not sufficiently separated from the end-product. Furthermore, due to the impact of heat, and ergo, the continuous formation and evaporation of these flavours, a plateau in their concentration is observed, where no further removal seems possible. This theory is proven by spiking a reactive sugar into the base and forming the mass balance over the system. Hence, in order to achieve a high reduction on high boiling wort flavours, another technology, such as adsorption, is required. To test, whether a suitable adsorbent can be identified, a wide screening experiment covering three adsorbent types (amine-functionalized polymers, hydrophobic resins and zeolites) and a total of 21 materials is performed. ZSM-5 type zeolites prove to have a superior selectivity as well as a relatively high capacity compared to other adsorbents. The choice of the right pore size and hydrophobicity is crucial for the separation success. Adsorption of the compounds of interest is non-competitive within the design space and robust against small changes in the beer matrix. The process is transferred to pilot scale, where it is shown that the zeolite effectively reduces wort off-flavour while maintaining the original character of the beverage. The reduced wort flavour concentration is also maintained over a period of 4 months ageing. Interestingly, the formation rates of aldehydes related to ageing are similar for the treated and reference product, with the exception of trans-2-nonenal, which is manifold lower in the treated AFB. A trained sensory panel confirms the difference in taste for both, the fresh and the aged product. In order to upscale this process to industrial scale, also the dynamics of the adsorption process on granular, binderless ZSM-5 zeolite is studied. The homogenous surface diffusion model is employed to regress the intraparticle diffusivity. The so obtained parameters indicate strong intraparticle mass transfer limitations as well as an inverse correlation of the effective diffusion coefficient to the molecules’ hydrophobicity. To avoid this process bottleneck, material improvements such as smaller crystal size and smaller granules are recommended. Finally, all obtained parameters are translated into a unit operation design. With a simple packed-bed operation of crushed particles, the production costs can be as much as 40 % lower than thermal dealcoholisation unit. Nonetheless, several assumptions still need to be verified, such as the material regenerability as well as other non- process-related factors such as material stability and food safety. Concluding, the newly developed technology for selective wort flavour removal in AFB in combination with restricted fermentation represents a great alternative to conventionally produced AFB. @en