Method to Predict Glass Vial Fogging in Lyophilized Drug Products

Abstract

a b s t r a c tGlass fogging is a phenomenon occurring in lyophilized drug products and can be described as a thin product layer deposited on the inner surface of the glass container, in the area not covered by the lyo cake itself. It is often considered a cosmetic defect; however, the loss of container closure integrity is a potential consequence of the fogging's expansion to the vial neck region, making this a potential critical defect. Thus, a method for predicting the extent of vial fogging before the actual freeze-drying is of particular interest for the pharmaceutical industry. For that reason, we evaluated a simple method ("simulated fogging") applicable to drug product formulations in a specific container closure system. Two different vial types with different surface hydrophilicity were tested using 3 model protein formulations, comparing the simulated fogging test and the degree of fogging after actual lyophilization. The simulated fogging method could predict fogging and showed a correlation to fogging in lyophilized drug product glass vials. We observed that all formulations showed fogging in the hydrophilic vials. By contrast, hydrophobic vials prevented fogging, however, interestingly with remaining defects of so-called droplet formation. Other than extent of fogging, no additional differences of lyophilized cake properties or other product quality attributes were observed between products using the different glass vial types tested.

Surface Treatment of Glass Vials for Lyophilization: Implications for Vacuum-Induced Surface Freezing

“…In line with this, we observed fogging in untreated vials and, to an even greater extent, in sulfate-treated vials (Figure 1B) where it is promoted by the low contact angles between the solution and container. The phenomenon was, in contrast, completely absent for the siliconized and TopLyo vials because of their hydrophobic surfaces and reduced wettability [39].…”

“…Fogging was also observed in our experiments. Fogging is defined as the spreading of the product and its deposition in spots or as a thin layer on the internal surface of the container above the cake [28,39]. Fogging is promoted by high surface wettability, as such being favored by hydrophilic coatings and surfactants [34,40].…”

Best Practices and Guidelines (2022) for Scale-Up and Tech Transfer in Freeze-Drying Based on Case Studies. Part 1: Challenges during Scale Up and Transfer

“…The difference in batch sizes should be noted as another source of uncertainty with respect to scale-up [13]. This may be important in dealing with challenges such as vial breakage and vial fogging [14,15]. Multiple factors affect both issues, and neither one is thoroughly understood.…”