Understanding the clearance behaviour of elemental leachables during ultrafiltration/diafiltration from process streams

Abstract

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 road map 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) reduction or higher after 10 diavolumes. Clearance was linked to UF/DF process parameters, most notably pH, as well as to the physicochemical properties of the studied elements. Mathematical models based on Orthogonal Partial Least Squares (OPLS) regression were developed and validated using the sieving coefficient to characterize and predict the clearance behavior of elemental impurities during UF/DF. Results from this study lay a solid foundation for the understanding and prediction of UF/DF capacity to remove elemental leachables. PERL clearance modelling emerges as a valuable platform to support industry and regulatory bodies in developing sophisticated risk-based PERL testing strategies, ultimately ensuring patient safety. The data presented herein demonstrate the significant risk reduction that the UF/DF process provides for processing steps upstream in mAbs and other biologics processes.