Sterile pharmaceuticals require they be developed and manufactured using suitable container closure systems to maintain sterility until product opening. Characterizing container closure integrity (CCI) in relation to rubber stopper displacement was controversially discussed during the Annex 1 revision process. An automated inspection system can reject units with displaced rubber stoppers, and the related acceptance criteria for such in-process testing can be established by adequate studies. In this manuscript, we describe a novel helium leak CCI testing method to study the relation of rubber stopper displacement and CCI. Ten different commonly used vial-rubber stopper combinations were characterized, which led to robust test results. Pronounced differences between the different vial-rubber stopper combinations were observed, clearly showing that the combination of different stoppers, vials, and caps led to significant differences in allowable stopper displacement for routine manufacture.
Keywords: CCI; Container closure integrity; Container closure system; Primary packaging; Rubber stopper displacement.
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