Vial Fogging: Practical Considerations For Vial Selection

By Gregory Sacha, Ph.D; and Kevin Bond, Ph.D.

Vial fogging is a common phenomenon observed in lyophilized biologic drug products, characterized by a haze of dried powder forming above the cake's surface inside the vial. This haze can appear as a dendritic pattern, branching, or a uniform fog, and while often deemed a cosmetic defect, severe fogging can occur in the neck of the vial, compromising container closure integrity and increasing the risk of sterility failure. Consequently, this can lead to the costly rejection of entire product batches, highlighting the importance of addressing vial fogging to minimize product loss.

The underlying causes of vial fogging are not well understood, but several factors can impact its severity. For instance, the hydrophobicity of the vial’s surface is a significant contributor, and certain formulation components, particularly surfactants, can also exacerbate the issue. Other potential mitigating strategies include proper depyrogenation of vials, optimizing processing conditions, and controlled nucleation, although not all of these can be implemented in a cGMP environment.

Visual observations indicate that fogging develops rapidly after filling, suggesting that prevention strategies should focus on minimizing fogging during the filling process rather than attempting to reduce it post-filling. Research conducted in Simtra BioPharma Solutions' R&D lab using a fluorescent dye demonstrated that formulations prone to fogging can flow up the vial's sides shortly after filling.

Certain vial types, like SCHOTT's TOPLYO, have been effective in eliminating fogging due to their hydrophobic inner coatings. However, these vials can lead to cake separation from the vial wall, which may not be aesthetically pleasing and tend to be more expensive. Vials with smooth, refinished inner surfaces, such as NIPRO's VIALEX, have shown to reduce fogging severity experimentally. Polymer-coated vials from SiO2 Materials Science also exhibit promise in mitigating fogging.

Additionally, reducing the fill volume can help decrease fogging severity by increasing the distance from the solution's surface to the vial neck, minimizing the likelihood of flow to the top. While this does not eliminate fogging entirely, it is a straightforward approach that does not require reformulation or switching vial types.

This document presents two case studies that explore critical factors contributing to vial fogging and inform vial selection decisions. The first study investigates three variables influencing fogging, while the second examines a marketed drug product's fogging mitigation strategies.