Understanding the clearance behaviour of elemental 2025 Journal of Pharmaceu

The introduction of trace elemental impurities through the use of single use technologies (SUTs) during biopharmaceutical manufacturing is a key concern as the presence of process equipment related leachables (PERLs), such as process-related elemental impurities, has potential harmful implications on product quality and patient safety. ICH Q3A provides a regulatory roadmap for PERLs but excludes biologic drugs like monoclonal antibody (mAb) therapies. Consequently, the industry lacks a synchronized, risk-based testing strategy for PERLs based on the likelihood of their presence in the final drug product. Ultrafiltration and diafiltration (UF/DF) operations have been demonstrated to clear leachables from the drug product during downstream purification. Hence, it is attractive to characterize PERL behavior during UF/DF to inform subsequent extractable and leachable (E&L) evaluation of the formulated biologic. The reduction capacity of twenty-two elements spiked into concentrated protein samples during UF/DF processes was investigated using an inductively coupled plasma-mass spectrometry (ICP-MS) method, which was developed and validated according to ICH Q2 (R1) guidelines. Most elements (18) were efficiently cleared (> 97%), representing a 100-fold (2-log) increase in clearance efficiency, while some elements required further investigation to understand their behavior during the process.