Angewandte Naturwissenschaften (F11)
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Despite intensive research over the last three decades, it has not yet been possible to bring an effective vaccine against human immunodeficiency virus (HIV) and the resulting acquired immunodeficiency syndrome (AIDS) to market. Virus-like particles (VLP) are a promising approach for efficient and effective vaccination and could play an important role in the fight against HIV. For example, HEK293 (human embryo kidney) cells can be used to produce virus-like particles. In this context, given the quality-by-design (QbD) concept for manufacturing, a digital twin is of great importance for the production of HIV-Gag-formed VLPs. In this work, a dynamic metabolic model for the production of HIV-Gag VLPs was developed and validated. The model can represent the VLP production as well as the consumption or formation of all important substrates and metabolites. Thus, in combination with already described process analytical technology (PAT) methods, the final step towards the implementation of a digital twin for process development and design, as well as process automation, was completed.
Electroplating generates high volumes of rinse water that is contaminated with heavy metals. This study presents an approach for direct metal recovery and recycling from simulated rinse water, made up of an electroplating electrolyte used in industry, using reverse osmosis (RO). To simulate the real industrial application, the process was examined at various permeate fluxes, ranging from 3.75 to 30 L·m−2·h−1 and hydraulic pressures up to 80 bar. Although permeance decreased significantly with increasing water recovery, rejections of up to 93.8% for boric acid, >99.9% for chromium and 99.6% for sulfate were observed. The final RO retentate contained 8.40 g/L chromium and was directly used in Hull cell electroplating tests. It was possible to deposit cold-hued chromium layers under a wide range of relevant current densities, demonstrating the reusability of the concentrate of the rinsing water obtained by RO.
Abstract
(−)‐Menthol is one of the most popular aroma compounds worldwide. While in the past mostly extracted from mint plants, today (−)‐menthol synthesis from other raw materials is becoming more relevant. Common starting materials for menthol synthesis are m‐cresol, citral and myrcene, but also substrates like menthone, mono‐ and bicyclic terpenes and terpenoids have been used for this purpose in the past. As for many applications (−)‐menthol of high purity is required, asymmetric syntheses and enantiomeric resolution of obtained raw products are applied for menthol production. This review gives an overview on the most important synthetic menthol production processes of the companies Symrise, Takasago and BASF and relevant literature in the field of menthol synthesis with a focus on the last 20 years.
The development and adoption of digital twins (DT) for Quality-by-Design (QbD)-based processes with flexible operating points within a proven acceptable range (PAR) and automation through Advanced Process Control (APC) with Process Analytical Technology (PAT) instead of conventional process execution based on offline analytics and inflexible process set points is one of the great challenges in modern biotechnology. Virus-like particles (VLPs) are part of a line of innovative drug substances (DS). VLPs, especially those based on human immunodeficiency virus (HIV), HIV-1 Gag VLPs, have very high potential as a versatile vaccination platform, allowing for pseudotyping with heterologous envelope proteins, e.g., the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As enveloped VLPs, optimal process control with minimal hold times is essential. This study demonstrates, for the first time, the use of a digital twin for the overall production process of HIV-1 Gag VLPs from cultivation, clarification, and purification to lyophilization. The accuracy of the digital twins is in the range of 0.8 to 1.4% in depth filtration (DF) and 4.6 to 5.2% in ultrafiltration/diafiltration (UFDF). The uncertainty due to variability in the model parameter determination is less than 4.5% (DF) and less than 3.8% (UFDF). In the DF, a prediction of the final filter capacity was demonstrated from as low as 5.8% (9mbar) of the final transmembrane pressure (TMP). The scale-up based on DT in chromatography shows optimization potential in productivity up to a factor of 2. The schedule based on DT and PAT for APC has been compared to conventional process control, and hold-time and process duration reductions by a factor of 2 have been achieved. This work lays the foundation for the short-term validation of the DT and PAT for APC in an automated S7 process environment and the conversion from batch to continuous production.
Different mechanisms mediate the toxicity of RNA. Genomic retroviral mRNA hijacks infected host cell factors to enable virus replication. The viral genomic RNA of the human immunodeficiency virus (HIV) encompasses nine genes encoding in less than 10 kb all proteins needed for replication in susceptible host cells. To do so, the genomic RNA undergoes complex alternative splicing to facilitate the synthesis of the structural, accessory, and regulatory proteins. However, HIV strongly relies on the host cell machinery recruiting cellular factors to complete its replication cycle. Antiretroviral therapy (ART) targets different steps in the cycle, preventing disease progression to the acquired immunodeficiency syndrome (AIDS). The comprehension of the host immune system interaction with the virus has fostered the development of a variety of vaccine platforms. Despite encouraging provisional results in vaccine trials, no effective vaccine has been developed, yet. However, novel promising vaccine platforms are currently under investigation.
Despite great efforts to develop a vaccine against human immunodeficiency virus (HIV), which causes AIDS if untreated, no approved HIV vaccine is available to date. A promising class of vaccines are virus-like particles (VLPs), which were shown to be very effective for the prevention of other diseases. In this study, production of HI-VLPs using different 293F cell lines, followed by a three-step purification of HI-VLPs, was conducted. The quality-by-design-based process development was supported by process analytical technology (PAT). The HI-VLP concentration increased 12.5-fold while >80% purity was achieved. This article reports on the first general process development and optimization up to purification. Further research will focus on process development for polishing and formulation up to lyophilization. In addition, process analytical technology and process modeling for process automation and optimization by digital twins in the context of quality-by-design framework will be developed.
In this work, supported cellulose acetate (CA) mixed matrix membranes (MMMs) were prepared and studied concerning their gas separation behaviors. The dispersion of carbon nanotube fillers were studied as a factor of polymer and filler concentrations using the mixing methods of the rotor–stator system (RS) and the three-roll-mill system (TRM). Compared to the dispersion quality achieved by RS, samples prepared using the TRM seem to have slightly bigger, but fewer and more homogenously distributed, agglomerates. The green γ-butyrolactone (GBL) was chosen as a polyimide (PI) polymer-solvent, whereas diacetone alcohol (DAA) was used for preparing the CA solutions. The coating of the thin CA separation layer was applied using a spin coater. For coating on the PP carriers, a short parameter study was conducted regarding the plasma treatment to affect the wettability, the coating speed, and the volume of dispersion that was applied to the carrier. As predicted by the parameter study, the amount of dispersion that remained on the carriers decreased with an increasing rotational speed during the spin coating process. The dry separation layer thickness was varied between about 1.4 and 4.7 μm. Electrically conductive additives in a non-conductive matrix showed a steeply increasing electrical conductivity after passing the so-called percolation threshold. This was used to evaluate the agglomeration behavior in suspension and in the applied layer. Gas permeation tests were performed using a constant volume apparatus at feed pressures of 5, 10, and 15 bar. The highest calculated CO2/N2 selectivity (ideal), 21, was achieved for the CA membrane and corresponded to a CO2 permeability of 49.6 Barrer.
The oxidation of cumene and following cleavage of cumene hydroperoxide (CHP) with sulfuric acid (Hock rearrangement) is still, by far, the dominant synthetic route to produce phenol. In 2020, the global phenol market reached a value of 23.3 billion US$ with a projected compound annual growth rate of 3.4% for 2020–2025. From ecological and economical viewpoints, the key step of this process is the cleavage of CHP. One sought-after way to likewise reduce energy consumption and waste production of the process is to substitute sulfuric acid with heterogeneous catalysts. Different types of zeolites, silicon-based clays, heteropoly acids, and ion exchange resins have been investigated and tested in various studies. For every type of these solid acid catalysts, several materials were found that show high yield and selectivity to phenol. In this mini-review, first a brief introduction and overview on the Hock process is given. Next, the mechanism, kinetics, and safety aspects are summarized and discussed. Following, the different types of heterogeneous catalysts and their performance as catalyst in the Hock process are illustrated. Finally, the different approaches to substitute sulfuric acid in the synthetic route to produce phenol are briefly concluded and a short outlook is given.