Nieto Alejandra, Roehl Holger, Brown Helen, Adler Michael, Chalus Pascal, Mahler Hanns-Christian
Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland;
Solid State Properties Analytics-Pharmaceutical Technical Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and.
PDA J Pharm Sci Technol. 2016 Jul-Aug;70(4):313-24. doi: 10.5731/pdajpst.2015.006080. Epub 2016 Mar 28.
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.
不同监管机构要求进行容器密封完整性（CCI）测试，以确保容器密封系统的密封性，防止可能的污染，例如微生物污染。微生物侵入CCI测试是通过在特定测试条件下将容器密封系统与微生物一起培养来进行的。物理CCI使用替代终点，如染料溶液渗入导致的染色或气体流动（氦气泄漏测试）。为了关联微生物CCI和物理CCI测试方法，并评估这些方法检测给定泄漏的能力，人们正在以各种不同方式在容器密封系统中引入人工泄漏。在我们的研究中，通过在玻璃瓶开口和橡胶塞之间插入铜丝来产生人工泄漏。然而，铜丝的插入会引入大小和形状未知的泄漏。通过非线性有限元模拟，根据线径和封盖力计算了橡胶塞和玻璃瓶之间的孔径大小。孔径大小与铜丝直径的关系是二次方的。利用获得的数据，我们能够计算泄漏大小并模拟泄漏形状。我们的结果表明，在评估临界泄漏大小时，应考虑人工泄漏的大小和形状，因为流速并不能独立地与孔的大小相关联。封盖力也会影响泄漏大小。对于所有线径，封盖力从30 N增加到70 N会导致孔径（泄漏大小）减少约50%。从30 N到50 N，减少约33%。
不同监管机构要求进行容器密封完整性（CCI）测试，以确保容器密封系统的密封性，防止污染，例如微生物污染。微生物侵入CCI测试是通过在特定测试条件下将容器密封系统与微生物一起培养来进行的。物理CCI使用替代终点，如染料溶液渗入导致的染色或气体流动。为了关联微生物侵入CCI和物理CCI测试方法，并评估这些方法检测给定泄漏的能力，人们正在以各种不同方式在容器密封系统中引入人工制造的缺陷（人工泄漏）。在我们的研究中，通过在玻璃瓶开口和橡胶塞之间插入铜丝来产生人工泄漏。到目前为止，铜丝的插入会引入大小和形状未知的泄漏。通过非线性有限元模拟，根据线径和封盖力计算了橡胶塞和玻璃瓶之间的有效孔径大小，并对泄漏形状进行了建模。我们的结果表明，在评估临界泄漏大小时，应考虑人工泄漏的大小和形状，因为流速并不能独立地与孔的大小相关联。
