Comparing Physical Container Closure Integrity Test Methods and Artificial Leak Methodologies.

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. While 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 product's shelf life. The new and revised United States Pharmacopeia (USP) General 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).LAY ABSTRACT: Sterility of drug products intended for parenteral administration is a critical quality attribute to ensure patient's safety and is thus a key requirement by health authorities. The absence of microbial contamination must be demonstrated by container closure integrity (CCI) of the container closure system (CCS). Currently, the revised United States Pharmacopeia (USP) General Chapter <1207> provides the most extensive guidance on how CCI should be assessed. Nevertheless, practical considerations on the choice of an appropriate CCIT method, artificial leaks or the choice of an acceptance criteria are lacking and must be addressed by the pharmaceutical manufacturer.This study provides 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).

Development of a nondestructive leak testing method utilizing the head space analyzer for ampoule products containing ethanol-based solutions.

The application of a head space analyzer for oxygen concentration was examined to develop a novel ampoule leak test method. Studies using ampoules filled with ethanol-based solution and with nitrogen in the headspace demonstrated that the head space analysis (HSA) method showed sufficient sensitivity in detecting an ampoule crack. The proposed method is the use of HSA in conjunction with the pretreatment of an overpressurising process known as bombing to facilitate the oxygen flow through the crack in the ampoule. The method was examined in comparative studies with a conventional dye ingress method, and the results showed that the HSA method exhibits sensitivity superior to the dye method. The results indicate that the HSA method in combination with the bombing treatment provides potential application as a leak test for the detection of container defects not only for ampoule products with ethanol-based solutions, but also for testing lyophilized products in vials with nitrogen in the head space. LAY ABSTRACT: The application of a head space analyzer for oxygen concentration was examined to develop a novel ampoule leak test method. The proposed method is the use of head space analysis (HSA) in conjunction with the pretreatment of an overpressurising process known as bombing to facilitate oxygen flow through the crack in the ampoule for use in routine production. The result of the comparative study with a conventional dye leak test method indicates that the HSA method in combination with the bombing treatment can be used as a leak test method, enabling detection of container defects.