Does fogging impact container closure integrity for a lyophilized drug product?

The impact of fogging on container closure integrity (CCI) in lyophilized drug products in glass vials was investigated. Fogging occurs when the drug solution moves above the intended fill level on the side, shoulder, or neck of the vial and dries, resulting in lyophilized product above the fill level. Although fogging creates a cosmetic visual appearance defect, it has been hypothesized that fogging may impact CCI if the drug solution reaches the neck region of the vial. Worst-case fogging conditions were simulated to assess any impact on CCI. Different vial-stopper configurations (3R, 6R, and 20R vials) at various residual seal forces were prepared and then tested for CCI by dye ingress and helium gas leak testing. Results were subsequently confirmed by the presence of dried formulation buffer solution in the neck region of the vial. The results demonstrated that if adequate residual seal force is chosen for each vial-stopper configuration, CCI is not impacted by fogging in the neck region of the vial.