RESUMEN
Intravenous lipid emulsions are biocompatible formulations used as clinical nutrition products and lipid-based delivery systems for sparingly soluble drugs. However, the particle-size distribution is associated with risks of embolism. Accordingly, the mean particle diameter (MPD) and particle-distribution tailing (characterized as the pFAT5 value) are critical quality attributes that ensure patient safety. Compliance with the limits stated in the United States Pharmacopoeia is ensured by high-pressure homogenization, the final step of the manufacturing process. The US Food and Drug Administration's Quality-by-Design approach requires a control strategy based on deep process understanding to ensure that products have a consistent and predefined quality. Here we investigated the process parameters of a jet-valve high-pressure homogenizer, specifically their effect on the MPD, pFAT5 value and droplet count (determined by microscopy) during the production of a Lipofundin MCT/LCT 20% formulation. We provide deep insight into droplet breakup and coalescence behavior when varying the process pressure, emulsion temperature and number of homogenization cycles. We found that high shear forces are not required to reduce the pFAT5 value of the particle distribution. Finally, we derived a control strategy for a rapid and cost-efficient two-cycle process that ensures patient safety over a large control space.
RESUMEN
Up to now biomass has been measured online by impedance analysis only at low cell densities in yeast fermentations. As industrial fermentation processes focus, for example, on producing high target concentrations of biocatalysts or pharmaceutical proteins, it is important to investigate cell growth under high cell-density conditions. Therefore, for the first time, biomass has been measured online using impedance analysis in a 50L high-pressure stirred tank reactor. As model organism the yeast Arxula adeninivorans was cultivated in two chemically defined mineral media at a constant growth rate in fed-batch mode. To ensure aerobic culture conditions over the entire fermentation time, the fermentations were conducted at an elevated headspace overpressure of up to 9.5bar. The highest oxygen transfer rate value of 0.56molL(-1)h(-1) ever reported for yeast fermentations was measured in these investigations. Unlike previous findings, in this study a linear correlation was found between capacitance and biomass up to concentrations of 174gL(-1) dry cell weight.