Parenteral pharmaceuticals must be “essentially free” from visible particulate matter (1). In the production of biopharmaceuticals with single-use systems (SUS), biocompatibility requires controlling interactions between drug substances/products and SUS surfaces to ensure drug product quality and patient safety with regard to extractables/leachables and particulate matter. Any particulate matter stuck to fluid-contacting surfaces of process components could wash off and contaminate process fluids. Depending on system configuration, a final drug product could be at risk for particulate matter from SUS. Risk assessments take into account potential particle sources (e.g., ingredients, SUS surfaces, final containers) and particle sinks (filtration and other purification steps) throughout an entire manufacturing process. Applications of SUS downstream of final filters presents the highest risk scenario, in which direct contact between drug substance/product and SUS components occurs. For example, applications of SUS in final fill and finish operations, aseptic vaccine production, or processing steps in the manufacture of cell and gene therapy products present the highest risks for potential particulate matter in final drug products as described in the guidelines for SUS particle risk assessment from the Bio-Process Systems Alliance (BPSA) (2).
“Clean-build” manufacturing of SUS components and assemblies in cleanrooms reduces particulate matter risks. Also, suppliers usually inspect SUS for particles during manufacturing, and end users typically inspect them before application as well. However, the turbidity of some SUS components makes visual inspection of their interior surfaces difficult. Given the size and complexity of many SUS assemblies, particles visible in final drug products (typically ≥100 µm) might not be seen in a visual inspection. A method is needed that extracts and measures particles present on SUS interior surfaces for a realistic assessment of particulate matter risk (2).
Historically, the most common particle measurement method applied to SUS is that described in chapter <788> of the US Pharmacopeia, so most SUS manufacturers claim that their SUS equipment meets USP <788> specifications (3). However, as detailed in a recent article, USP <788> is a standard for measurement of subvisible particles (10–100 µm) in final drug products, not for extraction and measurement of particles from SUS (4). Clearly missing is a standardized approach for liquid extraction of SUS surfaces and subsequent particle measurement. Currently, the ASTM International E55.04 committee on general biopharmaceutical standards is working toward developing a standard practice, but as of today no such standard exists.
To get an approximate sense of the degree of particle cleanliness currently available in polymer-based SUS bioprocess containers (“bags”), we measured visible particles (≥100 µm) in a small sampling of commercially available 20-L SUS bags. In a cleanroom, we partially filled the bags with purified water and agitated them, then filtered the resulting extracts onto filter membranes to collect particles. For measuring particles by “membrane microscopy,” we used an automated microscope to scan the filter membranes and image analysis methods to count and size the collected particles. We further analyzed a select number of membranes with infrared microscopy to identify chemically and thus classify the particles.
All SUS bags examined contained measurable amounts of visible particles, of which textile fibers and cellulose particles were most commonly found in six out of eight products. Because of our small sample size, no broad conclusions can be made regarding the level and type of visible particulate matter expected to be found in SUS bags. However, analysis of the types of particles we found indicates that implementation of SUS manufacturing process improvements probably would decrease the levels of visible particulate matter found inside SUS bags examined herein.
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1 USP <790> Visible Particulates in Injections. US Pharmacopeial Convention, Inc.: North Bethesda, MD, April 2015.
2 The 2014 Particulates Guide: Recommendations for Testing, Evaluation, and Control of Particulates from Single-Use Process Equipment. Bio-Process Systems Alliance (Society of Chemical Manufacturers and Affiliates): Arlington, VA, 2014; http://bpsalliance.org/technical-guides.
3 USP <788> Particulate Matter in Injections. US Pharmacopeial Convention, Inc.: North Bethesda, MD, July 2012.
4 Vogel JE, Wormuth K. Particulate Contamination in Single-Use Systems: Challenges of Detection, Measurement, and Continuous Improvement. BioProcess Int. 15(9) 2017: 16–20.
5 Johnson MW. Understanding Particles in Single-Use Bags. BioProcess Int. 12(4) 2014: supplement.
Corresponding author Klaus Wormuth is lead scientist, particles, at Sartorius Stedim Biotech GmbH in Göttingen, Germany; 49(0)551-3082610, email@example.com. Melanie Gauthier is a materials engineer; Mathieu Labedan is a business manager; Veronique Cantin and Manon Thaust are laboratory technicians; Fanny Gaston is a particles laboratory scientist; Nelly Montenay is manager of product development; and Magali Barbaroux is head of bag technologies, all at Sartorius Stedim Biotech in Aubagne, France.