While being a generally high-volume package configuration used for decades, the application of deterministic container closure integrity test methods for IV Bags has increased in recent years. A combination of increased adoption of current industry best practices, changing regulation, and a proliferation of small-batch cell and gene therapies stored, processed, or transported in these packages has in turn yielded increased inquiries regarding deterministic test method validation. However, IV Bag package systems have numerous challenges when it comes to the application of CCI tests due to factors such as:
- The use of polymeric materials of construction makes them conducive to expansion, permeation of gases, and outgassing under vacuum
- Their typical large volume and flexible profile present key obstacles to fitting them for instrument change parts and creating positive controls
- Many IV Bag systems have a variety of ports and tubing connections which prove limiting when it comes to testing for leaks and creating suitable change parts
Some examples of limiting factors specific to the current USP 1207 deterministic methods include:
High Voltage Leak Detection: The primary limiting factor in the application of HVLD appears to be size of the package and availability of lab-scale solutions to accommodate such samples. Theoretically, as liquid filled packages, they would be candidates for HVLD testing. However, the physical limitations, and questions about the impact of the plastic material, often rules out HVLD from a feasibility perspective.
Headspace Analysis: The large volume of IV bags are not conducive to placement into modern laser-based headspace analyzers, which are typically made to accommodate vials and other parenteral configurations. For this reason alone, it is typically not considered even from a feasibility standpoint.
Helium Leak Detection: With helium leak testing, a package is filled with helium gas and subjected to vacuum, where escaping helium is quantified. Due to the molecularly porous nature of flexible polymeric materials, and the small, light nature of helium, permeation through the materials makes helium leak testing difficult. This is exacerbated by large surface areas of large IV bag systems.
Vacuum Decay: As with other pressure-based analyses, application of vacuum decay to large flexible systems like IV bags is limited by sample size and materials of construction. In vacuum decay, a sample is subjected to vacuum, and the pressure rise inside of the vacuum chamber over time is measured. In a non-leaking sample, a certain amount of pressure rise (vacuum decay) will occur. It is expected that over that same period of time, a leaking package would yield a greater pressure rise in comparison. However, the molecularly porous surface area and outgassing of gas trapped in and on package materials can “mask” smaller defects.
With years of experience developing and validating USP 1207 CCI Testing methods, the CS Analytical team spent over two years developing alternative test methods for IV Bags that eliminate and overcome the challenges that the traditional USP 1207 methods present. The CS Analytical approach meets the deterministic intent of USP 1207 and provides effective options for clients to consider when working to qualify their IV Bag package systems with a method that uses positive controls and validates to specific micron level leak rates.