Dynamics of Pressure Decay Leak Testing of Parenteral Products
Introduction
Validation methods for container closure integrity systems verify that specified defect sizes are detectable with a given method. Pressure decay container closure integrity testing may be used to inspect containers such as vials with liquid or lyophilized product content. Sealed containers exhibit a different, and decaying signal response when tested. It is important to consider container contents, defect size and the headspace of a container when selecting both a pressure decay system and the associated validation method.
Methods
Stainless steel orifice tubes were tested connected to a rigid test chamber. Tests were conducted on a blank chamber, and tubes with 20µm, 10µm, 5µm, and 3µm hole sizes were introduced in subsequent test cycles. Each stainless steel tube was tested with the end of the tube open to atmospheric conditions, and with the tube capped. When the tube was capped, the interior headspace of the tube was approximately 1ml. A capped tube reflects a closed container with limited headspace, a more realistic circumstance for pharmaceutical containers.
Rigid 20R Vials sealed with 12ml of added fluid were tested. Fifteen negative controls were compared with testing of a 20µm laser drilled vial. The expected outcome was that increasing fluid viscosity would decrease signal strength.
Figures
Shown are the simulated pressure curves for three different tests. The trend for both internal container headspace volume and orifice size are indicated. Following the red arrows upward shows an increasing level of signal strength, but a decreasing amount of time for signal response to be measured.
The decreasing time to measure the defect is a result of both
defect size and limited internal volume to support detection. A
container has limited headspace before the internal pressure of
the container reaches equilibrium with the test chamber
pressure. A larger defect will increase air flow into the
container, which increases the detectable change in pressure.
The larger defect size will cause the container to reach
equilibrium sooner. A smaller head space will further advance
the time at which the container headspace reaches equilibrium.
Once the container reaches equilibrium there is no further
flowrate to be detected. Both increasing the defect size, and
reducing the container volume, greatly inhibit the ability to
detect defects without taking specific measures to detect leaks
under those conditions.
Conclusions
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Headspace limitations significantly impact signal level during pressure decay testing.
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Containers with limited headspace, especially if liquid filled, will require specific attention to the validation method used for this type of container closure integrity test.
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Validating a pressure or vacuum decay type test solution should not rely solely on a flow from or into an unlimited volume.
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No correlation was able to be demonstrated between the viscosity of the fluid inside a container, and the measured
Discussion
Further research should be considered to provide additional guidance as it relates to container closure integrity testing using pressure decay. Capping vials creates an initial container overpressure, potentially saturating a defect with product. Observing the effects of defect saturation should be considered in future research. Further research should be conducted on the effects of defect geometry and to better understand the non-impact of viscosity on pressure decay performance. A greater range of fluid viscosities should be considered in future testing to better understand if there is any measurable phenomenon.
Research conducted by:
Guerney Hunt • Leo Chin • Oliver Stauffer • Heinz Wolf