Analysis of Pharmaceutical Raw Materials Compliant with ICH Q3D Guideline Using ICP-MS with Collision Mode

Significance of the Topic

Elemental impurities in pharmaceutical products pose significant health risks and must be controlled to comply with international safety standards. The ICH Q3D guideline defines Permitted Daily Exposures (PDEs) for 24 toxicologically relevant elements. Reliable determination of trace metals in raw materials is essential for quality assurance, regulatory compliance, and patient safety.

Study Objectives and Overview

This study demonstrates the use of the Shimadzu ICPMS-2040 with an organic solvent system to quantify 24 elements specified in ICH Q3D in three pharmaceutical raw materials (aspirin, salicylic acid, and ibuprofen) prepared in ethanol. Key performance parameters—accuracy, precision, detection limits, and specificity—were evaluated against pharmacopeial requirements (USP, EP).

Methodology and Sample Preparation

Sample preparation steps:

1. Dissolve 0.1 g of each raw material in 10 mL eluent (500 mL ethanol with 5 mL HNO₃ and 2.5 mL HCl) to achieve a 100× dilution factor.
2. Prepare calibration standards at 0.5J, 1.0J, and 1.5J concentrations based on PDEs for each element.
3. Add internal standards (Be, Bi, Ga, Y at 0.2 mg/L) online during analysis.
4. Perform spike recoveries at 50 %, 100 %, and 150 % of target concentrations for accuracy and precision assessments.

Used Instrumentation

Instrumentation configuration:

• ICP-MS Model: Shimadzu ICPMS-2040 with organic solvent torch.
• Nebulizer: DC04; chamber cooled to –5 °C; platinum sampling cone; nickel skimmer cone.
• Gas flows: plasma 20 L/min, auxiliary 0.5 L/min, carrier 0.55 L/min, mix gas 0.35 L/min; He collision gas at 7 mL/min.
• RF power: 1.60 kW; sampling depth: 8 mm; peristaltic pump speed: 20 rpm.

Main Results and Discussion

Detection Limits and Calibration:

• Instrument detection limits ranged from 0.0007 µg/L (Tl) to 0.9 µg/L (Se).
• Linear calibration curves met criteria across the 0.5J–1.5J range.

Accuracy and Precision:

• Spike recoveries for all elements fell between 94 % and 111 %, exceeding the 70 %–150 % acceptance range.
• Repeatability (RSD) values were below 3.8 %, well under the 20 % threshold.
• Limits of quantitation were confirmed by accurate results at 50 % target concentrations.

Specificity and Interference Correction:

• MoO interference on Cd was effectively eliminated by combining He collision gas with interelement correction, delivering non-detectable false contributions.

Benefits and Practical Applications

This validated method enables simultaneous, high-sensitivity measurement of 24 elemental impurities in ethanol-based pharmaceutical samples. It simplifies sample preparation, accelerates routine QC testing, and supports adherence to ICH Q3D guidelines. The online internal standard addition reduces manual handling and improves analytical throughput.

Future Trends and Potential Applications

Emerging directions include automation of sample digestion, expansion to complex dosage forms, integration with hyphenated separation techniques for compound-specific impurity profiling, and real-time on-line monitoring in manufacturing processes. Advances in collision/reaction cell technology and data processing algorithms will further enhance interference removal and sensitivity.

Conclusion

The Shimadzu ICPMS-2040 organic solvent system demonstrates robust performance for quantitative analysis of ICH Q3D elements in pharmaceutical raw materials. Validation results confirm compliance with pharmacopeial accuracy, precision, specificity, and detection limit requirements, affirming its suitability for routine impurity testing.

References

1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Guideline for Elemental Impurities Q3D, 2015.
2. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Q3D(R2) Guideline for Elemental Impurities, 2023.
3. USP General Chapter <232> Elemental Impurities—Limits.
4. USP General Chapter <233> Elemental Impurities—Procedures.