Abstract
As described in USP <1207>, the container closure integrity (CCI) of a pharmaceutical package must be maintained throughout the product life-cycle to ensure sterility and stability. Current CCI test methods can be time-consuming, destructive, and lack the required sensitivity. This study presents a novel, fast, and non-destructive method for CCI testing that uses carbon dioxide as a tracer gas under effusive pressure conditions. Two types of defects were tested: laser-drilled defects located in the glass body (2, 5, and 10 μm nominal diameter) and tungsten wires inserted between the stopper and landing seal of the vial (41, 64, and 80 μm outer diameter). During each test session, vials were placed in a pressure vessel, isolated from ambient conditions, and pressure-cycled by first pulling a vacuum and then applying an overpressure of pure carbon dioxide gas. After being exposed to 20 psig (34.7 psia) of carbon dioxide for 30 minutes, the overpressure was released and vials were measured on an FMS-Carbon Dioxide Headspace Analyzer. This headspace gas analyzer utilizes a tunable diode laser absorption spectroscopy technique that employs frequency modulation to enhance measurement sensitivity. An increase of 1 torr or greater in the headspace carbon dioxide content after completion of the pressure cycling procedure was intended to serve as confirmation of leak detection. Using this method, all empty vials with either a 2 μm laser-drilled defect or 41 μm wire (effective defect size ~2 μm), or greater, at the stopper-seal interface were detected. Furthermore, vials filled with 1 mg/mL BSA in PBS were detected when containing a 5 μm laser-drilled defect below the liquid level or a 64 μm wire (effective defect size ~6.1 μm), or greater, at the stopper-seal interface (defect above the liquid level). This test can be used for a wide variety of vial types and headspace compositions.
- Container Closure Integrity
- Frequency modulation spectroscopy
- Headspace gas analysis
- Laser-drilled defects
- Microwires
- USP <1207>
- Received January 28, 2020.
- Accepted October 1, 2020.
- Copyright © 2020, Parenteral Drug Association
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