Mass extraction container closure integrity physical testing method development for parenteral container closure systems

摘要

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.