ICH Q3D Elemental Impurities Analysis of Drug Substances by EDX

Significance of the Topic

This study addresses the critical need to monitor elemental impurities in pharmaceuticals in accordance with ICH Q3D guidelines, which set strict limits on daily exposure to 24 toxic elements. While inductively coupled plasma techniques remain standard, energy dispersive X-ray fluorescence (EDX) offers a non-destructive, reagent-free alternative when properly validated.

Objectives and Study Overview

The primary aim was to evaluate an EDX-7000 instrument, equipped with a pharmaceuticals impurities analysis package, for quantifying 12 ICH Q3D elements in drug substances. Two representatives—benazepril hydrochloride and captopril—were selected to demonstrate method performance under regulated conditions.

Methodology and Instrumentation

Permitted daily exposures were converted to concentration limits using option 2b for a reference intake of 300 mg per day. Control thresholds were set at 30% of the maximum permitted concentration and spike levels at half that value. Calibration curves were established with two certified aqueous standard mixtures. Test powders were spiked, homogenized, and measured in polypropylene film–lined containers.

• EDX setup: EDX-7000, Rh target X-ray tube, silicon drift detector, filters for element groups, 50 kV excitation, auto current, 1800 s integration per filter.
• Verification: Microwave digestion and ICP-MS analysis (ICPMS-2030) with 5000× dilution for Class 1/2A elements and 25000× for Class 2B.

Main Results and Discussion

Validation followed USP <735> criteria covering accuracy, precision, specificity, quantitation limit, linearity, and robustness. Key outcomes included:

• Recoveries between 92% and 108% for all elements.
• Precision with relative standard deviations below 6%.
• Limits of quantitation well below control thresholds.
• Correlation coefficients above 0.994, indicating excellent linearity.
• Robustness across sample mass variations within ±12%.
• Strong agreement between EDX and ICP-MS results, even for sulfur-rich matrices.

Benefits and Practical Applications

EDX enables rapid, cost-effective screening of elemental impurities without extensive sample preparation or consumption of reagents. The validated approach is adaptable to diverse drug substances and formulations, supporting quality control and regulatory compliance in pharmaceutical development and manufacturing.

Future Trends and Opportunities

Potential advances include:

1. Automated, high-throughput sample handling integrated with EDX analysis.
2. Expansion of detectable elements and lowering of detection limits.
3. Real-time impurity monitoring in continuous manufacturing environments.
4. Hybrid analytical platforms combining EDX with mass spectrometric data.

Conclusion

The EDX-7000 method package fulfills ICH Q3D requirements for 12 critical elements in drug substances, offering a reliable and efficient alternative to ICP-AES and ICP-MS for controlling elemental impurities.

References

• ICH Harmonised Guideline Q3D Guideline for Elemental Impurities, Final version 22 March 2019.
• United States Pharmacopeia USP <233> Elemental Impurities – Procedures.
• United States Pharmacopeia USP <735> X-Ray Fluorescence Spectrometry, May 2015.