Effects of surface treatment and pre-freezing behavior on vial fogging in lyophilization

Abstract Vial fogging, characterized by residue deposition on the inner vial wall above the lyophilized cake, presents cosmetic and regulatory concerns for injectable drug products. This study investigates how vial surface treatment influences fogging severity and early-stage liquid behavior prior to freezing. Six types of 10R vials differing in surface treatment, geometry, and manufacturing origin were evaluated using a model formulation containing a fluorescent tracer to visualize liquid redistribution. Pre-freeze-drying (pre-FD) creeping behavior was analyzed for representative treated and untreated vial types to examine early-stage liquid migration associated with interfacial instabilities and Marangoni-driven flow. The temporal evolution of the thin film was also evaluated to demonstrate how the film state at freezing influences the resulting fogging morphology. Following lyophilization, fogging severity was classified using a height-based framework supported by UV fluorescence imaging. A strong correlation was observed between pre-FD creeping and post-FD fogging severity across different solution temperatures during filling. Surface-treated vials consistently exhibited reduced creeping and lower fogging severity compared to untreated vials. Additional experiments employing controlled ice nucleation (RD-CIN) through rapid depressurization resulted in complete suppression of fogging for most treated vial types, whereas most untreated vials continued to exhibit severe fogging.