A Dehydration-Diffusion Competition Framework Predicts Interfacial Film Risk in High-Concentration Biologics Fill-Finish.

High-concentration protein formulations are increasingly demanded for the development of subcutaneous injections owing to its clinical and commercial advantages. However, their high protein concentrations can lead to dried residues, causing failures in manufacturing operations such as piston pump seizing and filling needle clogging. Transient dehydration during fill-finish holds can generate interfacial viscoelastic films that resist redissolution and perturb delivery performance. Here, we establish an operational framework that links dehydration exposure to film mechanics and reversibility for high-concentration biologics. Using a bench-scale apparatus with controlled airflow, we observe orders-of-magnitude increases in interfacial storage modulus (G') with accumulated mass loss (m) and identify conditions where films fail to fully redissolve on minutes time scales. We define four portable readouts, maximum film strength (GM'), final film strength (GF'), imbibition time (tImb), and dissolving time (tDis)─to translate viscoelastic traces into process decision variables. Normalization by hydrodynamic volume fraction (ϕhyd) exposes two packing thresholds that organize mechanics and kinetics: a transition near random loose packing (RLP, ϕRLP ≈0.56), where percolation limits rearrangement and attenuates growth of GM', and a second near random close packing (RCP, ϕRCP ≈0.64), where bulk jamming undercuts further strengthening and slows film disintegration. Consistently, tImb steeply scales once mass loss approaches ∼30% (mapping toward RCP), while tDis reflects a protein diffusion-dominated recovery. A critical ∼52-55% mass-loss window marks a sharp rise in GF' and elastic persistence (G' > G″) after imbibition, indicating conditional irreversibility on process time scales. Together, these results yield an actionable "no-film/at-risk" map indexed to exposure dehydration flux, time, and formulation, providing quantitative limits for downtime and rewet strategies in fill-finish.