Simple sensitive ICP-MS method development and validation for quantitative evaluation and risk assessment of elemental impurities in anticoagulant drug product: study aligned with ICH Q3D guideline

Abstract

Background

Elemental impurities in pharmaceutical products present significant risks to patient safety due to their potential toxicity. These impurities may arise from various sources, including raw materials used in the process, manufacturing operations, processing equipment, and packaging materials. In this study, a simple, sensitive, and reliable analytical method using Inductively Coupled Plasma–Mass Spectrometry (ICP-MS) was developed and validated for the quantification of elemental impurities in anticoagulant drug products, specifically Apixaban, Edoxaban, and Rivaroxaban. The developed ICP-MS method enables accurate and precise determination of elemental impurities, ensuring effective monitoring and control of potentially toxic elements in these pharmaceutical formulations to support product quality and patient safety. The method targeted the determination of 24 elemental impurities classified according to the ICH Q3D Guideline for Elemental Impurities, including Class-1 elements (As, Pb, Hg, and Cd), Class-2A elements (Ni, V, and Co), Class-2B elements (Pd, Ir, Os, Tl, Ru, Pt, Au, Se, Ag, and Rh), and Class-3 elements (Cu, Mo, Li, Sn, Sb, Cr, and Ba). The analytical procedure was developed using ICP-MS, and the optimised method was validated in accordance with USP General Chapter <233> and <730>, confirming its suitability for accurate and reliable multi-element analysis.

Results

The analytical procedure was validated by assessing specificity, accuracy, sensitivity, selectivity, precision, linearity, range, and LOD–LOQ precision in accordance with ICH Q3D Guideline for Elemental Impurities and relevant pharmacopeial requirements. All 24 elements showed excellent linearity with correlation coefficients greater than 0.99. Accuracy was demonstrated across the range from LOQ (30%) to 200% of the target level, and recovery was within acceptable limits, i.e. 70%–150%, and the %RSD for precision was within acceptable limits, i.e. below 20%. The validated method proved linear, accurate, and sensitive for quantifying elemental impurities in anticoagulant drug products containing Apixaban, Edoxaban, and Rivaroxaban.

Conclusion

The study demonstrates that the validated ICP-MS method is simple, highly sensitive, and accurate for the determination of elemental impurities in anticoagulant drug products. All detected elements were below the permissible daily exposure limits defined by the ICH Q3D Guideline for Elemental Impurities, confirming compliance with safety requirements. These findings support the suitability of ICP-MS as a reliable technique for routine quality control of pharmaceutical formulations.