In-Depth Analysis of “Dusting” Defects in Lyophilized Biological Drug Products

Lyophilization is a vital technique utilized in the stabilization of active pharmaceutical ingredients in biological drug products. During the manufacturing of lyophilized biopharmaceutics containing trehalose, a sporadic “dusting” defect has been observed on the vial stopper.To investigate this defect and explore its underlying mechanism, six batches of lyophilization were conducted to simulate the manufacturing conditions. Bovine serum albumin (BSA) was employed as a model drug, formulated in a histidine buffer system with either trehalose or sucrose as lyoprotectants and polysorbate 80 (PS80) as a surfactant. Additionally, two placebo formulations, containing histidine buffer, PS80, and either trehalose or sucrose were served as controls. The lyophilization cycle was systematically optimized by adjusting annealing temperature, drying phase pressure, and gas backfilling procedures, after which the dusting severity was assessed.Mechanistic insights were gained through measurements of collapse temperature (Tc), residual moisture content, and microstructural analysis via scanning electron microscopy (SEM). Under identical lyophilization conditions, trehalose-based formulations exhibited more pronounced dusting compared to sucrose-based formulations. Adjustments in process parameters, such as lowering the annealing temperature and increasing drying pressure, effectively mitigated the dusting phenomenon. These strategies aimed at promoting controlled microcollapse and enhancing sublimation resistance, thereby minimizing the generation of powder fragments during lyophilization and reducing their entrainment by water vapor and subsequent attachment to the rubber stopper.Moreover, controlling the backfill gas flow further minimized powder dispersion during manufacturing. Overall, these findings provide valuable guidance for optimizing lyophilization processes to enhance both the quality and the aesthetic appearance of lyophilized biopharmaceuticals.