title: 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 <1207> 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 questions in order to provide their viewpoint and best practice on practical approaches to CCI. Their perspective is provided in this white paper. Through these discussions, it became clear that there is currently no gold standard for CCI test methods or for the generation of artificial leaks; therefore flexibility toward CCI approaches is required. Although there should be flexibility, any CCI approach must consider the intended use (e.g., CCS qualification, routine manufacturing, or quality control) and product design (e.g., primary packaging, liquid versus dried product).LAY 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 shelf life. Current regulatory guidances, which differ between countries and regions, provide limited detail on how to assess CCI. The new revision of USP <1207> 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.A group of European industry peers have met to discuss these and other related questions in order to provide their viewpoint and best practice on practical approaches to CCI. Their perspective is provided in this white paper. Through these discussions, it became clear that there is currently no gold standard for CCI test methods or for the generation of artificial leaks; therefore flexibility toward CCI approaches is required. Although there should be flexibility, any CCI approach must consider the intended use (e.g., CCS qualification, routine manufacturing, or quality control) and product design (e.g., primary packaging, liquid versus dried product).
authors: Late-Stage Pharmaceutical and Processing Development, Roche.
authors: Helen
authors: H
authors: Brown
authors: Drug Product Services, Lonza.
authors: Hanns-Christian
authors: HC
authors: Mahler
authors: Biologics Technical Development and Manufacturing, Novartis.
authors: James
authors: J
authors: Mellman
authors: Late-Stage Pharmaceutical and Processing Development, Roche.
authors: Alejandra
authors: A
authors: Nieto
authors: Pharmaceutical Sciences Operations, Sanofi.
authors: Daniel
authors: D
authors: Wagner
authors: Biological and Microbiological Services, Novartis.
authors: Matthias
authors: M
authors: Schaar
authors: Drug Product Services, Lonza.
authors: Roman
authors: R
authors: Mathaes
authors: Biologics Technical Development and Manufacturing, Novartis.
authors: Juergen
authors: J
authors: Kossinna
authors: Development Sciences, Abbvie.
authors: Franz
authors: F
authors: Schmitting
authors: Device Development, Roche; and.
authors: Sascha
authors: S
authors: Dreher
authors: Late-Stage Pharmaceutical and Processing Development, Roche.
authors: Holger
authors: H
authors: Roehl
authors: Device Development, Roche; and.
authors: Markus
authors: M
authors: Hemminger
authors: Drug Product and Device Methods, Janssen R&D kwuchne1@its.jnj.com.
authors: Klaus
authors: K
authors: Wuchner
mesh_terms: D004340:Drug Contamination / Q000517:prevention & control*; D004349:Drug Packaging / Q000295:instrumentation / Q000379:methods / Q000592:standards*; D004356:Drug Storage; D008422:Materials Testing; D008962:Models, Theoretical; D011786:Quality Control
keywords: Artificial leaks; Container closure integrity testing; Container closure system; Industry perspective; Methods for container closure integrity testing; Primary packaging; USP <1207>