Analysis of the shear stresses in a filling line of parenteral products

Drug manufacturing consists of a series of operations, generally referred to as formulation, filling, and finishing. Filling represents the most critical step, in which the drug product undergoes different processes, including mixing, pumping, filtration, and final filling into vials. As filling lines operate under faster and faster conditions, there is concern over stability of protein-based products, which may be sensitive to temperature changes, oxidation, light, ionic strength and shear stress. Among these, shear stress has gained interest over the past decades because of its frequent occurrence in filling lines. Exposure of protein-based parenteral drugs to such stresses is believed to promote unfolding and subsequent aggregation, which might alter the biological activity of the drug and raise the potential for side effects. Several studies conducted in recent years have tried to shed light on the actual impact of shear stress on drug products, but the presence of additional stresses (such as interfacial stress) has complicated the interpretation of the results. In this controversial landscape, it is therefore necessary to quantify shear stress in the operating units of the filling process as a first step for broader experimental investigations. Therefore, starting from some typical operating units, we developed a model for calculating the shear stress distribution using a shear history-based approach. In detail, we considered a representative number of particles within the domain and followed their trajectories, which allowed us to determine the average shear stress. Several operating units were analyzed and the resulting shear stress exposures were determined. The field of scale-down approaches, used to scale the commercial process down to the laboratory level, was also explored. They allow to perform product characterization experiments using smaller volumes of the drug products. A new approach for scaling down the commercial process was proposed, which was compared with traditional approaches and shown to provide greater representativeness between the two scales.