Sterile Filtration of NanoCrystal™ Drug Formulations

Abstract

A Nano Crystal™ dispersion of the iodinated x-ray contrast agent iodipamide was prepared by wet milling the drug substance in the presence of Pluronic® F127 stabilizer. The mean particle size of the formulation was 98 nm and all drug particles in the formulation were smaller than 220 nm as determined by dynamic light scattering. Approximately 1 liter of dispersion was filtered through a sterile 0.2-μm disposable capsule filter (Supor® 200 DCF™, 0.I m2 effective filtration area [EFA], Gelman Sciences) to condition the capsule. No drug concentration or size distribution changes were detected after the filtration process. The microbiological validation tests were performed using Pseudomonas diminuta organisms to challenge the capsule under simulated worst-case process conditions. The results showed that the Supor 200 DCF was able to retain 100% Pseudomonas diminuta organisms (≥107 organisms per cm2 of effective filtration area). Thus, this study demonstrated that terminal filtration is a feasible process to sterilize Nano Crystal™ drug dispersions that may be chemically or physically unstable at elevated temperatures and thus not amenable to terminal heat sterilization.