PT - JOURNAL ARTICLE AU - Peláez, Sarah S AU - Mahler, Hanns-Christian AU - Herdlitschka, Christoph AU - Wertli, Anton AU - Kahl, Matthias AU - Koulov, Atanas AU - Matter, Anja AU - Singh, Satish K AU - Widmer, Martina AU - Germershaus, Oliver AU - Mathaes, Roman TI - Comparing Physical Container Closure Integrity Test Methods and Artificial Leak Methodologies AID - 10.5731/pdajpst.2018.009332 DP - 2019 Jan 01 TA - PDA Journal of Pharmaceutical Science and Technology PG - pdajpst.2018.009332 4099 - http://journal.pda.org/content/early/2019/01/15/pdajpst.2018.009332.short 4100 - http://journal.pda.org/content/early/2019/01/15/pdajpst.2018.009332.full AB - The sterility of drug products intended for parenteral administration is a critical quality attribute (CQA) because it serves to ensure patient safety, and is thus a key requirement by health authorities. Whilst sterility testing is a probabilistic test, the assurance of sterility is a holistic concept including adequate design of manufacturing facilities, process performance, and product design. Container closure integrity testing (CCIT) is necessary to confirm the integrity of a container closure system (CCS), until the end of a products’s shelf life. The new and revised United States Pharmacopeia (USP) informational chapter <1207> is a comprehensive guidance on CCI. Nevertheless, practical considerations including the choice of CCIT methods, the acceptance criteria, or the positive control samples (artificial leaks) must be addressed by the pharmaceutical manufacturer. This study is the first to provide a systematic comparison of four commonly used physical CCIT (pCCIT) methods [Helium (He) leak, vacuum decay, laser-based headspace analysis (HSA), and dye ingress] and four commonly used modes of creating artificial leaks (laser-drilled micro holes, copper wire introduced leaks, and two types of capillary leaks). The results from these experiments provide comprehensive data to allow a direct comparison of the capabilities of the individual methods. The results confirmed that the He leak detection method, which is considered the “gold-standard” for pCCIT regarding method sensitivity, indeed demonstrates the highest detection sensitivity (lowest detection limit). In comparison to the dye ingress method, HSA and vacuum decay, also demonstrated better detection sensitivity in our study. Capillary leaks with orifice diameter (capillary leak with flow according to an ideal orifice) and micro holes yielded similar leak rates, whereas capillaries with nominal diameters yielded significantly lower leak rates. In conclusion, method sensitivity cannot be compared by means of a leak diameter, but requires the consideration of multiple impacting factors (e.g. path length, uniformity).