The scope of this paper focuses on CCIT of viral vector gene therapy drug product (DP). Cell therapies are out of scope. The strategy proposed here for CCIT is applicable to all advanced therapy medicinal product (ATMP) drug products that are manufactured in small lot sizes, typically <500 vials.
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This paper provides some considerations and guidance on defining a justifiable sample size for CCIT when required for parenteral biopharmaceutical finished products. This is a particularly important consideration when using destructive test method. It also summarizes a practical and risk-based strategy, both representing scientifically justified approaches. These approaches prevent unnecessary sampling and testing while retaining high product quality. Where the integrity of each individual container is assured by a suitably qualified process, additional CCI sampling and testing would not normally be required.
Container closure (CCI): Dye ingress methods for container-closure integrity testing: An industry position paper
The release of the expanded USP<1207> in 2016 cast doubt over the validity of so-called probabilistic analytical methods, including one the biopharmaceutical industry’s most universal tests – the dye ingress method for container closure integrity
With the dye ingress method ubiquitously used without issue for decades, this paper highlights the continued value and applicability of this and other probabilistic analytical tests. In addition, this paper also describes how any method, whether probabilistic or deterministic, stands or falls on the quality of its development and validation, and not necessarily on the properties of the test itself.
The most important factor is to apply a test method is not how it is labelled, but lies in its development, qualification and whether it meets the need for which it is designed.
Container closure integrity (CCI): Container closure integrity control versus integrity testing during routine manufacturing
In 2014 uncertainty around regulation for container closure and integrity testing (CCIT) fed a perceptible shift in mindset across the industry, causing some concern amongst many subject matter experts in biological manufacturers. Their concern was that gaps in guidance was enabling skewed expectations such that they would promote 100% CCIT for the release of drug product batches. This paper addresses this concern by re-stating the principles of CCI, qualification, process control and in-process testing to establish the framework within all effective container closure integrity programs. It concludes that performing 100% CCIT does not provide certainty that a process is well controlled and introduces an additional step that is not always necessary or suitable for the high processing speeds in the industry.