A New Control Strategy for High-Pressure Homogenization to Improve the Safety of Injectable Lipid Emulsions.

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.