Effect of the freezing step on primary drying experiments and simulation of lyophilization processes

Lyophilization is a widely used preservation method for thermosensitive products. It consists of three process steps: freezing, primary and secondary drying. One of the major drawbacks is the long processing time. The main optimization effort was put into the primary drying phase since it is usually the longest phase. However, the freezing step is of immense importance for process efficiency and product quality. The lack of control during freezing comprises a challenge for process design and tech transfer. In this study, four different freezing steps (shelf-ramped freezing with and without holding step, precooled shelves and an ice fog method for controlled nucleation) are used and their impact on primary drying experiments and simulations is shown. Only the ice fog method is able to control the nucleation temperature leading to low dry layer resistances with low deviations. During the primary drying simulations, the control of the nucleation temperature drastically increases the precision and accuracy of the product temperature prediction. For optimal primary drying design and model predictive control, the nucleation temperature is strongly recommended to be controlled inside a Process Analytical Technology (PAT) concept to achieve reliable and reproducible process conditions

Emerging PAT for freeze-drying processes for advanced process control

Lyophilization is a widely used drying operation, but long processing times are a major drawback. Most lyophilization processes are conducted by a recipe that is not changed or optimized after implementation. With the regulatory demanded quality by design (QbD) approach, the process can be controlled inside an optimal range, ensuring safe process conditions. Process analytical technology (PAT) is crucial because it allows real-time monitoring and is part of a control strategy. In this work, emerging PAT (manometric temperature measurement (MTM), comparative pressure measurement, heat flux sensors, and ice ruler) are used for measurements during the freeze-drying process, and their potential for implementation inside a control strategy is outlined

Model-based product temperature and endpoint determination in primary drying of lyophilization processes

Lyophilization process design still relies mainly on empirical studies with high experimental loads. In the regulatory demanded Quality by Design approach, process modeling is a key aspect. It allows process design, optimization and process control to ensure a safe process and product quality. A modeling approach is outlined that is able to predict the primary drying endpoint and temperature profile of distinct vials. Model parameters are determined by a reproducible determination concept. Simulated results are validated with a fractional factorial Design of Experiments (DoE) in pilot scale. The model shows higher accuracy and precision than the experiments and similar parameter interactions for both the endpoint and temperature determination. This approach can now be used to explore the primary design space in lyophilization process design. This paper proposes a distinct method for endpoint determination and product temperature prediction by a modeling approach based on Velardi et al. combined with a distinct model parameter determination according to Wegiel et al. and Tang et al

Advanced Process Analytical Technology in combination with process modeling for endpoint and model parameter determination in lyophilization process design and optimization

Lyophilization is widely used in the preservation of thermolabile products. The main shortcoming is the long processing time. Lyophilization processes are mostly based on a recipe that is not changed, but, with the Quality by Design (QbD) approach and use of Process Analytical Technology (PAT), the process duration can be optimized for maximum productivity while ensuring product safety. In this work, an advanced PAT approach is used for the endpoint determination of primary drying. Manometric temperature measurement (MTM) and comparative pressure measurement are used to determine the endpoint of the batch while a modeling approach is outlined that is able to calculate the endpoint of every vial in the batch. This approach can be used for process development, control and optimization

Establishment of a research focus on resilient sustainable climate neutral agricultural production: resilient farming initiative

Efficient and sustainable agricultural production is a pivotal factor in meeting the nutritional needs of an expanding global population. However, it is imperative to optimize national, regional and local effectiveness to support government initiatives towards climate neutrality and resilience, while simultaneously ensuring economic viability for farmers. A significant reduction in the cost of goods must be accompanied by a decrease in their global warming potential contribution to maintain competitiveness in the world market. As such, it is necessary to adopt practices that enhance productivity while minimizing environmental impacts. This paper discusses potential solutions for the sustainable enlargement of botanical product portfolios towards essential oil products and natural extracts for value-added products, such as natural pharmaceuticals, cosmetics, agrochemicals and materials by direct waste valorization. Contributions from the fields of automation and digitalization provide the basic technology for the realization of the approaches presented. Agricultural photovoltaics can contribute to the goal of the reduction of the cost of goods and global warming potential, such as the already established utilization of biogas. The potential of the research initiative described is demonstrated by basic data on key characteristic numbers and costs from the literature. The economic potential for climate neutrality and the reduction of global warming potential contribution is seen in magnitudes of factors 5–10. A research initiative is recommended and exemplified for the industrialization of such integrated processing

Anodal transcranial direct current stimulation sustainably increases EEG alpha activity in patients with schizophrenia

Abstract Aims Transcranial direct current stimulation (tDCS) applied to the prefrontal cortex has been frequently used to elicit behavioral changes in patients with schizophrenia. However, the interaction between prefrontal tDCS and electrophysiological changes remains largely uncharted. The present study aimed to investigate cortical electrophysiological changes induced by tDCS in frontal areas by means of repeated electroencephalography (EEG) in patients with schizophrenia. Methods In total, 20 patients with schizophrenia received 13 minutes of anodal tDCS (1 mA) applied to the left dorsolateral prefrontal cortex (DLPFC). Repeated resting EEG was recorded before (once) and following (at five follow‐up time‐bins) tDCS to trace post‐tDCS effects. We used sLORETA for source reconstruction to preserve the localization of brain signals with a low variance and to analyze frequency changes. Results We observed significant changes after the stimulation in areas highly connected with the stimulated DLPFC areas. The alpha 1 (8.5‐10.0 Hz) activity showed a highly significant, long‐lasting, increase for up to 1 hour after the stimulation in the postcentral gyrus (Brodmann area 2, 3, and 40). Significant yet unstable changes were also seen in the alpha‐2 frequency band precentral at 10 minutes, in the beta‐1 frequency band occipital at 20 minutes, and in the beta‐3 frequency band temporal at 40 minutes. Conclusion We were able to show that anodal tDCS can induce stable EEG changes in patients with schizophrenia. The results underline the potential of tDCS to induce long‐lasting neurophysiological changes in patients with schizophrenia showing the possibility to induce brain excitability changes in this population

Mycoplasma bovis in Nordic European Countries: Emergence and Dominance of a New Clone

Mycoplasma (M.) bovis is an important pathogen of cattle implicated in a broad range of clinical manifestations that adversely impacts livestock production worldwide. In the absence of a safe, effective, commercial vaccine in Europe, reduced susceptibility to reported antimicrobials for this organism has contributed to difficulties in controlling infection. Despite global presence, some countries have only recently experienced outbreaks of this pathogen. In the present study, M. bovis isolates collected in Denmark between 1981 and 2016 were characterized to determine (i) genetic diversity and phylogenetic relationships using whole genome sequencing and various sequence-based typing methods and (ii) patterns of antimicrobial resistance compared to other European isolates. The M. bovis population in Denmark was found to be highly homogeneous genomically and with respect to the antimicrobial resistance profile. Previously dominated by an old genotype shared by many other countries (ST17 in the PubMLST legacy scheme), a new predominant type represented by ST94-adh1 has emerged. The same clone is also found in Sweden and Finland, where M. bovis introduction is more recent. Although retrieved from the Netherlands, it appears absent from France, two countries with a long history of M. bovis infection where the M. bovis population is more diverse