Container closure integrity (CCI) is a critical factor to ensure that product sterility is maintained over its entire shelf life. Assuring the CCI during container closure (C/C) system qualification, routine manufacturing and stability is important. FDA guidance also encourages industry to develop a CCI physical testing method in lieu of sterility testing in a stability program. A mass extraction system has been developed to check CCI for a variety of container closure systems such as vials, syringes, and cartridges. Various types of defects (e.g., glass micropipette, laser drill, wire) were created and used to demonstrate a detection limit. Leakage, detected as mass flow in this study, changes as a function of defect length and diameter. Therefore, the morphology of defects has been examined in detail with fluid theories. This study demonstrated that a mass extraction system was able to distinguish between intact samples and samples with 2 μm defects reliably when the defect was exposed to air, water, placebo, or drug product (3 mg/mL concentration) solution. Also, it has been verified that the method was robust, and capable of determining the acceptance limit using 3σ for syringes and 6σ for vials.
Lay abstract: Sterile products must maintain their sterility over their entire shelf life. Container closure systems such as those found in syringes and vials provide a seal between rubber and glass containers. This seal must be ensured to maintain product sterility. A mass extraction system has been developed to check container closure integrity for a variety of container closure systems such as vials, syringes, and cartridges. In order to demonstrate the method's capability, various types of defects (e.g., glass micropipette, laser drill, wire) were created in syringes and vials and were tested. This study demonstrated that a mass extraction system was able to distinguish between intact samples and samples with 2 μm defects reliably when the defect was exposed to air, water, placebo, or drug product (3 mg/mL concentration) solution. Also, it was verified that the method showed consistent results, and was able to determine the acceptance limit using 3σ for syringes and 6σ for vials.