Czermak Peter, Catapano Gerardo
University of Applied Sciences Giessen-Friedberg, Department of Biotechnology, Wiesenstr. 14, 35390 Giessen, Germany.
PDA J Pharm Sci Technol. 2003 Jul-Aug;57(4):277-86.
In the pharmaceutical industry, the integrity of sterile filters is critical to ensure sterility of filtered products. Filter integrity is frequently tested by measuring gas diffusion across water-contacting hydrophobic or hydrophilic membranes with the same automated test devices. Constant device accuracy over the whole range of possible operating conditions is an especially important requirement, as set by the GMP regulations for product critical devices. In this paper, we investigate the accuracy of gas diffusion rate and water intrusion rate estimates provided by a batch-operated and a refilling, continuous-flow commercial automated test device used both for diffusive flow tests and water intrusion tests. Tests were performed on custom-designed model filter systems and full-scale filters over a broad range of gas diffusive flow rates and upstream gas volumes. Neither tested device provided accurate measurements of gas diffusion rate when a small gas diffusion flow was measured out of a very large upstream volume. The batch-operated device provided measurements of gas diffusion rates (either gas diffusion or water intrusion rate) with an accuracy that strongly depends on the gas diffusion rate and on the gas volume upstream from the membrane. Gas diffusion rate measurements were particularly biased in diffusive flow tests of filters with less than 500 mL gas upstream volume. Gas diffusion rates were underestimated by as much as -14.5% in diffusive flow tests and -25% in water intrusion tests. The refilling, continuous flow device generally provided consistent and accurate gas diffusion rate and water intrusion rate measurements within less than 5% of the reference value, practically independent of the gas diffusion flow rate and upstream volume value. A serious bias was only noted in diffusion flow tests at very high upstream volumes and low gas diffusion rate. The results reported in this paper show the importance of qualifying the automated test devices used to assess sterile filter integrity.
在制药行业，无菌过滤器的完整性对于确保过滤产品的无菌性至关重要。过滤器完整性通常通过使用相同的自动化测试设备测量气体透过与水接触的疏水或亲水膜的扩散来进行测试。根据产品关键设备的GMP法规要求，在整个可能的操作条件范围内保持设备精度恒定尤为重要。在本文中，我们研究了两种商用自动化测试设备（一种是分批操作的，另一种是可再填充的连续流设备）在进行扩散流测试和水侵入测试时所提供的气体扩散速率和水侵入速率估计值的准确性。测试在定制设计的模型过滤系统和全尺寸过滤器上进行，涵盖了广泛的气体扩散流速和上游气体体积范围。当从小的气体扩散流量中测量出非常大的上游体积时，两种测试设备都无法准确测量气体扩散速率。分批操作的设备所提供的气体扩散速率（无论是气体扩散速率还是水侵入速率）测量准确性强烈依赖于气体扩散速率和膜上游的气体体积。在膜上游气体体积小于500 mL的过滤器扩散流测试中，气体扩散速率测量存在特别大的偏差。在扩散流测试中，气体扩散速率被低估多达-14.5%，在水侵入测试中被低估多达-25%。可再填充的连续流设备通常能提供一致且准确的气体扩散速率和水侵入速率测量值，偏差在参考值的5%以内，实际上与气体扩散流速和上游体积值无关。仅在非常高的上游体积和低气体扩散速率的扩散流测试中发现了严重偏差。本文所报告的结果表明了对用于评估无菌过滤器完整性的自动化测试设备进行鉴定的重要性。
