Universally Applicable Methods for Comprehensive Risk Assessment of Elemental Impurities in Vitamin A and D Preparations

Background: Vitamin A and D deficiency in children is a common public health problem. In China, almost all children are administered vitamin A and D preparations daily and over the long term. Children are sensitive to elemental impurities, including heavy metals. However, there are no regulatory requirements or reports on the risk assessment of elemental impurities in marketed vitamin A and D preparations. Objective: The aim of this study was to propose an accurate and efficient method suitable for samples from different manufacturers to detect elemental impurities and conduct risk assessments according to the ICH Q3D guidelines. Methods: We developed a universally applicable digestion method for capsules and an ICP–MS method for quantitative analysis of 28 elemental impurities in vitamin A and D formulations. These methods were validated according to the USP 233 guidelines. Elemental impurities in 15 batches of vitamin A and D products from 10 manufacturers and their capsule shells were determined, and risk assessment was conducted according to the International Council for Harmonization Q3D guidelines. Results: All elemental impurities of toxicological concern met the Q3D requirements. However, the concentrations of various elements, including those of lead (not detected to 4.1 µg/g), arsenic (not detected to 7 µg/g), aluminum (not detected to 888 µg/g), and palladium (not detected to 36 µg/g), varied markedly. Moreover, the lead content in one batch from one manufacturer exceeded the control threshold. Conclusion: In this study, we successfully developed an effective digestion method for processing capsules containing samples from different sources and a sensitive ICP–MS method for quantitative determination of 28 elemental impurities in vitamin A and D preparations. ICP–MS should be implemented for the evaluation and control of elemental impurities in vitamin A and D preparations. This will ensure safe long-term vitamin A and D supplementation in children