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Understanding the clearance behaviour of elemental leachables during ultrafiltration/diafiltration from process
Noemí Dorival-García1, Anna Mulligan2, Ronan Hayes3
1Characterisation and Comparability Laboratory, The National Institute for Bioprocessing Research and Training (NIBRT), Foster Avenue, Mount Merrion, A94 X099, Co. Dublin, Ireland.
Journal of Pharmaceutical and Biomedical Analysis
|May 17, 2025
Summary
Trace elemental impurities from single-use technologies pose risks to biopharmaceuticals. Ultrafiltration/diafiltration (UF/DF) effectively removes these impurities, with clearance depending on process parameters and element properties.
Area of Science:
- Biopharmaceutical Manufacturing
- Analytical Chemistry
- Process Engineering
Background:
- Trace elemental impurities, known as process equipment related leachables (PERLs), are a concern in biopharmaceutical manufacturing using single-use technologies (SUTs).
- Existing regulatory guidelines (ICH Q3A) for PERLs do not adequately cover biologic drugs like monoclonal antibodies (mAbs).
- A standardized, risk-based testing strategy for PERLs in biologics is lacking, impacting product quality and patient safety.
Purpose of the Study:
- To investigate the clearance capacity of ultrafiltration and diafiltration (UF/DF) processes for elemental impurities.
- To inform extractable and leachable (E&L) evaluations by characterizing PERL behavior during UF/DF.
- To develop predictive models for elemental impurity removal during UF/DF.
Main Methods:
- Investigated the clearance of twenty-two spiked elements during UF/DF using concentrated protein samples.
- Developed and validated an inductively coupled plasma-mass spectrometry (ICP-MS) method per ICH Q2 (R1) guidelines.
- Employed Orthogonal Partial Least Squares (OPLS) regression and sieving coefficients to develop mathematical models for clearance prediction.
Main Results:
- Efficient clearance (>97%) of most elements (18 out of 22) was achieved after 10 diavolumes, representing a 2-log reduction or higher.
- Element clearance was influenced by UF/DF process parameters, particularly pH, and the physicochemical properties of the elements.
- Validated mathematical models successfully characterized and predicted elemental impurity clearance during UF/DF.
Conclusions:
- UF/DF processes demonstrate significant capacity for removing elemental leachables, providing substantial risk reduction for biologics manufacturing.
- PERL clearance modeling offers a valuable tool for developing robust, risk-based testing strategies, enhancing product safety and regulatory compliance.
- The findings support the use of UF/DF as a critical step in managing elemental impurities in monoclonal antibody and other biologic therapies.
Keywords:
Clearance efficiencyDownstream processingElemental impuritiesExtractables & LeachablesInductively coupled plasma mass spectrometryProcess-related impuritiesUltrafiltration/DiafiltrationMore Related Videos
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