Freeze-drying is commonly used to increase the shelf-life of pharmaceuticals and biopharmaceuticals. Freezing represents a crucial phase in the freeze-drying process, as it determines both cycle efficiency and product quality. For this reason, different strategies have been developed to allow for a better control of freezing, among them, the so-called vacuum-induced surface freezing (VISF), which makes it possible to trigger nucleation at the same time in all the vials being processed. We studied the effect of different vial types, characterized by the presence of hydrophilic (sulfate treatment) or hydrophobic (siliconization and TopLyo Si–O–C–H layer) inner coatings, on the application of VISF. We observed that hydrophobic coatings promoted boiling and blow-up phenomena, resulting in unacceptable aesthetic defects in the final product. In contrast, hydrophilic coatings increased the risk of fogging (i.e., the undesired creeping of the product upward along the inner vial surface). We also found that the addition of a surfactant (Tween 80) to the formulation suppressed boiling in hydrophobic-coated vials, but it enhanced the formation of bubbles. This undesired bubbling events induced by the surfactant could, however, be eliminated by a degassing step prior to the application of VISF. Overall, the combination of degasification and surfactant addition seems to be a promising strategy for the successful induction of nucleation by VISF in hydrophobic vials.

Parenteral products appear to be sensitive to process conditions in bioprocessing steps, such as interfacial stress and shear stress. The combination of these elements is widely believed and proven to influence product stability, but the defined roles of these players in the product damage process have not yet been identified. The present work addresses a current industrial problem, by focusing on the analysis of shear stress on protein-based therapeutics flowing in tubing by means of Computational Fluid Dynamics simulations. The purpose of this article is not to pinpoint the mechanism triggering the damage of the product, but it represents the first step towards wider experimental investigations and introduces a new strategy to quantify the average shear stress. The field of scale-down approaches, used to scale the commercial process down to the laboratory level, is also explored. Since quality control is critical in the pharmaceutical realm, it is essential that the scale-down approach preserves the same stress exposure as the commercial scale, which in the present work is considered to be that resulting from shear effects. Therefore, a new approach for scaling down the commercial process is proposed, which has been compared with traditional approaches and shown to provide greater representativeness between the two scales.

Fill-finish of parenteral formulations represents a crucial step in the pharmaceutical industry that necessitates careful monitoring of product stability down the line. Shear stress and interfacial stress are two elements that threaten product stability, the respective contributions of which are still up for debate. This article focuses on the analysis of shear stress in the sampling phase of the filling line. Specifically, Computational Fluid Dynamics (CFD) simulations were employed to determine the shear stress distribution experienced by a protein-based parenteral drug as it passes through sampling fittings of various shapes under laminar and turbulent regime conditions. Rather than seeking the specific mechanism triggering the destabilization of a product, an attempt was made to analyze the fluid dynamics within these fittings and offer further understanding of the resulting shear stress. In addition, information was collected on the product path within the fittings, which allowed the identification of equations suitable for describing the shear stress distribution. The proposed approaches made it possible to consider the actual flowrate subjected to a given shear stress at a given time. Finally, a comparison was drawn with respect to the fluid dynamics within classical straight tubing to outline differences. This study revealed that the shear stress experienced within the fittings was higher than that in the tubing. Moreover, significant differences were reported in the T-fitting case under turbulent conditions.

Protein-based parenteral drug products processed in a filling line can be exposed to shear stress of varying magnitude depending on the operation. These shear stresses and other factors, such as interfacial stress, have been the focus of many studies in recent years on the cause of product degradation. Estimating shear stress in individual operating units represents the first step towards a more in-depth study of the shear-induced product instability. In this frame, the present manuscript shows an innovative workflow to obtain a computational model of a peristaltic pump and evaluate the exposure of the product to shear stresses. This was accomplished through Computational Fluid Dynamics simulations combined with Lagrangian Particle Tracking techniques. In this way, the shear stress history of each individual product particle passing through the peristaltic pump was taken into account. The results provide insight into shear stress dynamics within a peristaltic pump and show potential for future applications.