Test Method Development For A Container Closure Integrity Test Using Headspace Gas Ingress

By Suzanne Kuiper, Ph.D., Lighthouse Instruments

To ensure patient safety, good container closure integrity (CCI) is of great importance for all sterile injectable products. Good CCI prevents ingress of contaminants, such as microorganisms and gases, that can negatively affect product sterility and/or efficacy. Not all defects that can cause a loss in CCI can be detected using visual inspection processes. A microscopic crack in the glass might be hidden underneath the aluminum crimp seal for example. Or a container has only temporarily lost closure and now appears to be sealed properly, even though an undesirable exchange between the sterile product and the non-sterile environment has occurred. CCI testing is therefore needed, to ensure that the closure of a product package has not been compromised.

Recent regulatory guidance has made clear that there is no ‘gold standard’ for CCI testing. Selection of an appropriate CCI test method should depend on the specific container closure system, the stage in the product life cycle, and the testing throughput required. Chapter <1207> of the United States Pharmacopeia (USP) describes various available CCI testing techniques, and provides guidance on method development and validation in various stages of the product life cycle. Headspace analysis (i.e., analysis of the region above the product) is described as a deterministic CCI test, which is such as blue dye ingress and microbial challenge testing [1],[2].

As a CCI test method, headspace analysis is based on detecting changes in the headspace gas composition that result from gas ingress through a leak. Non-destructive headspace analysis, using laser-based spectroscopy, can be used to directly quantify the gas concentration inside a sealed parenteral package. It can be applied to a range of product configurations, and formulations, and has historically been used for detecting leak defects in modified headspace product.