Nieto Alejandra, Roehl Holger, Brown Helen, Nikoloff Jonas, Adler Michael, Mahler Hanns-Christian
Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and
Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and.
PDA J Pharm Sci Technol. 2016 Mar-Apr;70(2):120-33. doi: 10.5731/pdajpst.2015.006098. Epub 2016 Jan 21.
Sometimes, drug product for parenteral administration is stored in a frozen state (e.g., -20 °C or -80 °C), particularly during early stages of development of some biotech molecules in order to provide sufficient stability. Shipment of frozen product could potentially be performed in the frozen state, yet possibly at different temperatures, for example, using dry ice (-80 °C). Container closure systems of drug products usually consist of a glass vial, rubber stopper, and an aluminum crimped cap. In the frozen state, the glass transition temperature (Tg) of commonly used rubber stoppers is between -55 and -65 °C. Below their Tg, rubber stoppers are known to lose their elastic properties and become brittle, and thus potentially fail to maintain container closure integrity in the frozen state. Leaks during frozen temperature storage and transportation are likely to be transient, yet, can possibly risk container closure integrity and lead to microbial contamination. After thawing, the rubber stopper is supposed to re-seal the container closure system. Given the transient nature of the possible impact on container closure integrity in the frozen state, typical container closure integrity testing methods (used at room temperature conditions) are unable to evaluate and thus confirm container closure integrity in the frozen state. Here we present the development of a novel method (thermal physical container closure integrity) for direct assessment of container closure integrity by a physical method (physical container closure integrity) at frozen conditions, using a modified He leakage test. In this study, different container closure systems were evaluated with regard to physical container closure integrity in the frozen state to assess the suitability of vial/stopper combinations and were compared to a gas headspace method. In summary, the thermal physical container closure integrity He leakage method was more sensitive in detecting physical container closure integrity impact than gas headspace and aided identification of an unsuitable container closure system.
Sometimes, drug product for parenteral administration is stored in a frozen state (e.g., -20 °C or -80 °C), particularly during early stages of development of some biotech molecules in order to provide sufficient stability. Container closure systems for drug products usually consist of a glass vial, rubber stopper, and an aluminum crimped cap. In the frozen state, the glass transition temperature (Tg) of commonly used rubber stoppers is between -55 and -65 °C. Leaks during frozen temperature storage and transportation are likely to be transient, yet they can possibly risk container closure integrity and lead to microbial contamination and sterility breach. After thawing, the rubber stopper is expected to re-seal the container closure system. Given the transient nature of the possible impact on container closure integrity in the frozen state, typical container closure integrity testing methods (used at room temperature conditions) are unable to evaluate and thus confirm container closure integrity in the frozen state. Here we present the development of a novel method (thermal container closure integrity) for direct measurement of container closure integrity by a physical method (physical container closure integrity) at frozen conditions, using a modified He leakage test. In this study, we found that the thermal container closure integrity He leakage method was more sensitive in detecting physical container closure integrity impact than gas headspace and aided identification of an unsuitable container closure system.
有时，用于肠胃外给药的药品以冷冻状态储存（例如，-20°C或-80°C），特别是在某些生物技术分子开发的早期阶段，以便提供足够的稳定性。冷冻产品的运输可能在冷冻状态下进行，但可能处于不同温度，例如，使用干冰（-80°C）。药品的容器密封系统通常由玻璃瓶、橡胶塞和铝压盖组成。在冷冻状态下，常用橡胶塞的玻璃化转变温度（Tg）在-55至-65°C之间。已知在其Tg以下，橡胶塞会失去弹性并变脆，因此可能无法在冷冻状态下保持容器密封完整性。在冷冻温度储存和运输过程中的泄漏可能是短暂的，但可能会危及容器密封完整性并导致微生物污染。解冻后，橡胶塞应重新密封容器密封系统。鉴于在冷冻状态下对容器密封完整性可能产生的影响具有短暂性，典型的容器密封完整性测试方法（在室温条件下使用）无法评估并因此确认冷冻状态下的容器密封完整性。在此，我们展示了一种新方法（热物理容器密封完整性）的开发，该方法通过物理方法（物理容器密封完整性）在冷冻条件下使用改进的氦气泄漏测试直接评估容器密封完整性。在本研究中，对不同的容器密封系统在冷冻状态下的物理容器密封完整性进行了评估，以评估小瓶/塞子组合的适用性，并与气顶法进行了比较。总之，热物理容器密封完整性氦气泄漏方法在检测物理容器密封完整性影响方面比气顶法更敏感，并有助于识别不合适的容器密封系统。
有时，用于肠胃外给药的药品以冷冻状态储存（例如，-20°C或-80°C），特别是在某些生物技术分子开发的早期阶段，以便提供足够的稳定性。药品的容器密封系统通常由玻璃瓶、橡胶塞和铝压盖组成。在冷冻状态下，常用橡胶塞的玻璃化转变温度（Tg）在-55至-65°C之间。在冷冻温度储存和运输过程中的泄漏可能是短暂的，但它们可能会危及容器密封完整性并导致微生物污染和无菌性破坏。解冻后，预计橡胶塞会重新密封容器密封系统。鉴于在冷冻状态下对容器密封完整性可能产生的影响具有短暂性，典型的容器密封完整性测试方法（在室温条件下使用）无法评估并因此确认冷冻状态下的容器密封完整性。在此，我们展示了一种新方法（热容器密封完整性）的开发，该方法通过物理方法（物理容器密封完整性）在冷冻条件下使用改进的氦气泄漏测试直接测量容器密封完整性。在本研究中，我们发现热容器密封完整性氦气泄漏方法在检测物理容器密封完整性影响方面比气顶法更敏感，并有助于识别不合适的容器密封系统。
