Establishment and Validation of an ICP-MS Method for Simultaneous Measurement of 24 Elemental Impurities in Ubenimex APIs According to USP/ICH guidelines

Abstract

Background: To control the potential presence of heavy metals in pharmaceuticals, the United States Pharmacopeia (USP) and International Conference on Harmonization (ICH) have put forth new requirements and guidelines. USP <232> and ICH Q3D specify 24 elemental impurities and their concentration limits in consideration of the permitted daily exposure (PDE) of different drug categories (oral, parenteral and inhalation). while USP <233> describes more information about sample preparation and method validation procedure. Objective: To establish and verify an ICP-MS method for the determination of 24 elemental impurities (Cd, Pb, As, Hg, Co, V, Ni, Tl, Au, Pd, Ir, Os, Ph, Ru, Se, Ag, Pt, Li, Sb, Ba, Mo, Cu, Sn, Cr) in ubenimex APIs according to USP/ICH guidelines. Method: Samples were analyzed by ICP-MS after direct dissolution in diluted acid solution. All elements were detected in He/HEHe mode (except for Li, which was in No gas mode). Results: The spiked recoveries were within 80-120% except Hg (79.4% at 0.5J level in HEHe mode) and Cd (121.9% at 0.5J level in HE mode). The RSD of repeatability (N = 6) for all elements were < 7.0% and intermediate precision (N = 12) were < 9.0%. The correlation coefficients of linear (R) for 24 elements were all > 0.998. The limits of detection (LOD) were < 1 ng/mL except that Ni was 1.23 ng/mL in HEHe mode. The contents of 24 elements in 3 batches of samples were significantly lower than the actual target limit of ICH, while the highest content of Pd did not exceed 10 μg/g. Conclusion: The established method was proved to be simple, sensitive and accurate. It successfully applied to the elemental impurity determination in 3 batches of ubenimex APIs from different manufactories. This method also provided technical guidance for determination of multiple elements in pharmaceutical products.