title: Artificial Leaks in Container Closure Integrity Testing: Nonlinear Finite Element Simulation of Aperture Size Originated by a Copper Wire Sandwiched between the Stopper and the Glass Vial.
abstract: Container closure integrity (CCI) testing is required by different regulatory authorities in order to provide assurance of tightness of the container closure system against possible contamination, for example, by microorganisms. Microbial ingress CCI testing is performed by incubation of the container closure system with microorganisms under specified testing conditions. Physical CCI uses surrogate endpoints, such as coloration by dye solution ingress or gas flow (helium leakage testing). In order to correlate microbial CCI and physical CCI test methods and to evaluate the methods' capability to detect a given leak, artificial leaks are being introduced into the container closure system in a variety of different ways. In our study, artificial leaks were generated using inserted copper wires between the glass vial opening and rubber stopper. However, the insertion of copper wires introduces leaks of unknown size and shape. With nonlinear finite element simulations, the aperture size between the rubber stopper and the glass vial was calculated, depending on wire diameter and capping force. The dependency of the aperture size on the copper wire diameter was quadratic. With the data obtained, we were able to calculate the leak size and model leak shape. Our results suggest that the size as well as the shape of the artificial leaks should be taken into account when evaluating critical leak sizes, as flow rate does not, independently, correlate to hole size. Capping force also affected leak size. An increase in the capping force from 30 to 70 N resulted in a reduction of the aperture (leak size) by approximately 50% for all wire diameters. From 30 to 50 N, the reduction was approximately 33%.
  Container closure integrity (CCI) testing is required by different regulatory authorities in order to provide assurance of tightness of the container closure system against contamination, for example, by microorganisms. Microbial ingress CCI testing is performed by incubation of the container closure system with microorganisms under specified testing conditions. Physical CCI uses surrogate endpoints, such as coloration by dye solution ingress or gas flow. In order to correlate microbial ingress CCI and physical CCI test methods and to evaluate the methods' capability to detect a given leak, artificially created defects (artificial leaks) are being introduced into the container closure system in a variety of different ways. In our study, artificial leaks were generated using inserted copper wires between the glass vial opening and rubber stopper. Up to date, the insertion of copper wires introduced leaks of unknown size and shape. With nonlinear finite element simulations, the effective aperture size between the rubber stopper and the glass vial was calculated, depending on wire diameter and capping force, and the leak shape was modelled. Our results suggest that the size as well as the shape of the artificial leaks should be taken into account when evaluating critical leak sizes, as flow rate does not, independently, correlate to the hole size.
authors.affiliation: Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland; alejandra.nieto-pena@roche.com.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Nieto
authors.affiliation: Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland;
authors.forename: Holger
authors.initials: H
authors.lastname: Roehl
authors.affiliation: Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland;
authors.forename: Helen
authors.initials: H
authors.lastname: Brown
authors.affiliation: Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland;
authors.forename: Michael
authors.initials: M
authors.lastname: Adler
authors.affiliation: Solid State Properties Analytics-Pharmaceutical Technical Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and.
authors.forename: Pascal
authors.initials: P
authors.lastname: Chalus
authors.affiliation: Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland; Lonza AG, Drug Product Services, Basel, Switzerland.
authors.forename: Hanns-Christian
authors.initials: HC
authors.lastname: Mahler
mesh_terms: D003300:Copper / Q000592:standards; D004340:Drug Contamination / Q000517:prevention & control; D004349:Drug Packaging / Q000295:instrumentation / Q000379:methods* / Q000592:standards; D020342:Finite Element Analysis; D005898:Glass / Q000592:standards; D006801:Humans; D017711:Nonlinear Dynamics; D012408:Rubber / Q000592:standards; D013678:Technology, Pharmaceutical / Q000295:instrumentation / Q000379:methods / Q000592:standards
chemical_list: D003300:Copper; D012408:Rubber
keywords: Artificial leaks; Capping; Container closure integrity; Finite element simulations; Helium leak test; Microbiological quality; Sterility