Container Closure Integrity Test Using Frequency Modulation Spectroscopy Headspace Analysis with Carbon Dioxide as a Tracer Gas.

Abstract

As described in USP <1207>, the container closure integrity (CCI) of a pharmaceutical package must be maintained throughout the product lifecycle 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 nondestructive 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 the 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 min, the overpressure was released and the 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 in the headspace carbon dioxide content after completion of the pressure cycling procedure was intended to serve as confirmation of leak detection. 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 by this method. Furthermore, vials filled with 1 mg/mL bovine serum albumin in phosphate-buffered saline 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) were detected. This test can be used for a wide variety of vial types and headspace compositions.