Best Practices to Quantify and Identify Particulate Matter on the Interior Surfaces of Single-Use Systems.

The manufacturing of a wide range of biopharmaceuticals, from antibodies and vaccines to cell-based therapies, increasingly takes place in single-use processing equipment. Manufactured in clean rooms and sealed and sterilized, single-use systems (SUSs) are ready-to-use and easily scalable. Controls in the "clean-build" manufacturing of SUSs reduce the probability of occurrence of particulate matter in SUSs. However, the size, complexity, and limited transparency of SUSs clearly limit the detectability of particulate matter on the interior (fluid-contacting) surfaces of a SUS during a visual inspection, as demonstrated in a recent study. In applications downstream of final filters or in aseptic processing, particulate matter on the surfaces of a SUS could detach and contaminate the final drug product. A realistic assessment of this risk requires reliable test methods that quantify and identify particulate matter present on the interior surfaces of SUSs. Clearly problematic is the common certification of the cleanliness of a SUS via a force-fit adaptation of the pharmacopeial standard USP <788> entitled "Particulate Matter in Injections". USP <788> does not describe a procedure for extraction of particulate matter from the interior surfaces of SUSs. In addition, application of Method 1 Light Obscuration significantly limits the probability of detection for particles in the visible size range (≥ 100 µm). In this article, we describe best practices for extracting, counting, sizing, and chemically identifying particulate matter on the interior surfaces of SUSs. Highly effective procedures for the extraction of particulate matter result from application of the qualification methodology described in a recently published ASTM standard. Filtration of the liquid extract concentrates particulate matter onto the surface of a membrane filter, allowing rapid particle counting and sizing using automated membrane microscopy, along with detailed chemical identification using infrared microscopy and/or automated confocal Raman microscopy.

Single-Use System Integrity II: Characterization of Liquid Leakage Mechanisms.

This study investigated the liquid leakage mechanism through microchannels in a flexible single-use packaging system composed of multilayer plastic film. Based on this study, a relationship between the maximum allowable leakage limit (MALL) and the loss of package integrity can be established under different use-case conditions. The MALL is defined as the greatest leak size that does not pose any risk to the product. A specifically designed liquid leak test was used to determine the leakage time, i.e., the time it takes for a package to show leakage. As a result, this method was able to determine the leak size for which no liquid leakage is observed after 30 days. This leak size varied between 2 µm and 10 µm and can be considered the MALL for liquid egress under different use-case conditions. This article also compared the MALL results of this liquid leak test with those of the microbial ingress test, showing a direct correlation between both tests. As test samples, an ethylene vinyl acetate multilayer film (300 µm thick) and a polyethylene multilayer film (400 µm thick) were cut into 50 mm patches. Before the patches were assembled in a filter holder to form a leak-tight seal, artificial leaks in sizes of 2 -25 µm were laser drilled into the center of each patch. The test units were filled aseptically with culture media and mounted vertically on the test setup. Various pressures were applied to each test unit to simulate the constraints that single-use systems may be subject to under real-world conditions. To detect the exact leakage time, electric circuits with timers were attached below each film patch. Microscopic investigations, including light microscopy and computed tomography, were used to interpret and understand the physics and geometries of the microchannels to explain any deviation from the expected results.