Continuous manufacturing opens up new operation windows with improved product quality in contrast to documented lot deviations in batch or fed-batch operations. A more sophisticated process control strategy is needed to adjust operation parameters and keep product quality constant during long-term operations. In the present study, the applicability of a combination of spectroscopic methods was evaluated to enable Advanced Process Control (APC) in continuous manufacturing by Process Analytical Technology (PAT). In upstream processing (USP) and aqueous two-phase extraction (ATPE), Raman-, Fourier-transformed infrared (FTIR), fluorescence- and ultraviolet/visible- (UV/Vis) spectroscopy have been successfully applied for titer and purity prediction. Raman spectroscopy was the most versatile and robust method in USP, ATPE, and precipitation and is therefore recommended as primary PAT. In later process stages, the combination of UV/Vis and fluorescence spectroscopy was able to overcome difficulties in titer and purity prediction induced by overlapping side component spectra. Based on the developed spectroscopic predictions, dynamic control of unit operations was demonstrated in sophisticated simulation studies. A PAT development workflow for holistic process development was proposed.

In this study, the continuous Single-Pass Tangential Flow Filtration (SPTFF) concept is adapted for high protein concentrations. The work is based on the previously validated physico-chemical model for low concentrations and high viscosities. The model contains the Stagnant Film Model for concentration polarization, as well as the Boundary Layer Model for the mass transfer through the membrane. The pressure drop is calculated as a function of the Reynolds number. By performing preliminary experiments with a single ultrafiltration (UF) cassette, the model parameter are determined. The presented model is validated for a multi-step Single-Pass Tangential Flow Filtration. With subsequent simulation studies, an optimized process is found and confirmed by experiments. The outcome of this work shows the potential to optimize this multi-parameter dependent unit operation. This is reached by a model-based optimization allowing significant reduction of experimental efforts and applying the Quality by Design approach consistently. Furthermore, a comparison between the experimental setup and a commercial module is examined.

No abstract

No abstract

In this study, different unit operations for distillation, extraction, capturing and separation of essential oil components from essential oil plants are evaluated, on the example of limonene and carvone from caraway fruits. Hydrodistillation is the standard process for obtaining essential oils and leaves the distillation water (hydrolate) after phase separation of the essential oil and the distilled plant material (pomace) as waste streams. In this study, a process for the valorization of these waste streams, using different techniques, such as traps and pressurized hot water extraction, is developed, reaching high yields, with a plus of 35%, compared to established methods, and reducing the overall global warming potential of the whole process, as well as reducing the cost of goods by around 30%.