Container Closure Integrity Testing—Practical Aspects and Approaches in the Pharmaceutical Industry

Abstract

The assurance of sterility of a parenteral drug product, prior to any human use, is a regulatory requirement. Hence, all strategies related to container closure integrity (CCI) must demonstrate absence of microbial contamination through leaks as part of the container closure system (CCS) qualification, during manufacturing, for quality control purposes and to ensure microbiological integrity (sterility) during storage and shipment up to the end of product shelf life. Current regulatory guidances, which differ between countries and regions, provide limited detail on how to assess CCI. The new revision of USP aims to provide extensive and detailed guidance for CCI assessments for sterile products. However, practical questions and considerations are yet to be addressed by the pharmaceutical industry. These may include: (1) choice of method, for example whether a deterministic CCI method (e.g., helium leak) is preferable over the probabilistic CCI method (e.g., microbial ingress), (2) the type of primary packaging (e.g., vial, syringe, device), (3) dosage form (e.g., liquid versus lyophilisate), (4) suitable acceptance criteria, (5) appropriate sample size, (6) the most appropriate way to introduce artificial leaks into the CCS, (7) ensuring suitable assurance of CCI during drug product manufacturing, and (8) evaluating CCI under intended shipment and storage conditions (e.g., in the frozen state).A group of European industry peers have met to discuss these and other related ques…