In this white paper

We discuss the Helium leak and Dye ingress CCIT methods in relation to larger volume containers while reviewing potential strategies to address any issues.

We include technical considerations and case studies, as well as explaining how partnering with Lonza may help to overcome some of the challenges associated with CCIT of large volume containers.

Current challenges for CCIT of large volume containers

The assurance of sterility of a parenteral drug product, prior to any human use, is a regulatory requirement. Hence, all methodologies related to container closure integrity testing (CCIT) must demonstrate absence of microbial contamination through leaks and to ensure microbiological integrity (sterility).

CCIT methods for small drug product container closure systems feature methods to reliably detect artificial leaks <20 µm and have well established acceptance criteria. In contrast to CCIT of small drug product containers, CCIT of larger containers (e.g. drug substance/media fill bottles or flexible bags) is less defined and pose specific challenges, e.g. larger volume, larger container head space or a flexible nature of the container. Therefore, CCIT methods for drug substance containers typically show a method sensitivity to reliably detect artificial leaks of 100 µm in size.

The dye ingress method is the most commonly used CCIT method and industry standard. Dye ingress method parameters for small drug product containers are listed in the relevant pharmacopeia and standards (e.g. Ph. Eur. 3.2.9, USP<381>, ISO 8362-5). For larger drug substance containers, because of the challenges mentioned above, significantly more aggressive method parameters are required.

Another methodology commonly used as CCIT of small drug product containers is Helium Leak Mass Spectrometry. This methodology represents a highly sensitive deterministic test method particularly suitable for rigid containers (e.g. glass or polymer vials or Pre-filled Syringes) and specific test method adaptations (e.g. read out time) are required when testing flexible containers, mainly due to the diffusion phenomenon of the helium gas.

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