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

Importance of the Topic

Pharmaceuticals must comply with stringent guidelines to limit metallic impurities that pose health risks. The ICH Q3D guideline specifies daily exposure limits for 24 toxicologically relevant elements. Accurate and sensitive analysis of these trace elements in raw materials is essential to ensure product safety and regulatory compliance.

Objectives and Study Overview

This study demonstrates the determination of 24 elemental impurities in aspirin, salicylic acid and ibuprofen raw materials. The goal was to validate an analytical protocol using the Shimadzu ICPMS-2050 equipped with an organic solvent system, following ICH Q3D and pharmacopeial requirements (USP, EP).

Methodology and Instrumentation

Sample Preparation:

• Eluent: 500 mL ethanol with 5 mL HNO₃ and 2.5 mL HCl.
• Dissolution: 0.1 g raw material diluted to 10 mL (100× dilution).
• Calibration: Multielement standards at 0.5J, 1.0J and 1.5J (J = 30 % of PDE per 10 g dose).
• Internal standards: Be, Bi, Ga and Y at 0.2 mg/L using an online internal standard kit.

Used Instrumentation:

• ICP-MS: Shimadzu ICPMS-2050 with organic solvent torch.
• Sampling cone: Platinum; skimmer cone: Nickel.
• RF power: 1.60 kW; plasma gas flow: 20 L/min; auxiliary: 0.5 L/min; carrier: 0.55 L/min; mix gas: 0.35 L/min.
• Collision/reaction cell gases: He for most elements; H₂ mode optimized for Se and Cd interference removal.

Main Results and Discussion

Instrument detection limits ranged from 0.001 to 0.2 µg/L. Accuracy (recovery 94–111 %) and precision (RSD ≤3.8 %) met acceptance criteria across three spike levels (50 %, 100 %, 150 % of target). Hydrogen reaction mode effectively suppressed MoO interference on Cd, reducing false Cd signals from 1.42 to

Benefits and Practical Applications

The validated method enables simultaneous determination of 24 elemental impurities in ethanol-soluble raw materials with high sensitivity and robust interference control. It supports quality control laboratories in meeting ICH Q3D requirements and pharmacopeial specifications.

Future Trends and Potential Applications

Advances may include automated sample introduction for higher throughput, integration with speciation analysis and adaptation to emerging guidelines limiting additional trace elements. Implementation in continuous manufacturing and real-time monitoring could further enhance safety assurance.

Conclusion

The Shimadzu ICPMS-2050 organic solvent system provides a reliable, sensitive and compliant approach for quantifying 24 elemental impurities in pharmaceutical raw materials. Validation results confirm suitability for routine QC under ICH Q3D and pharmacopeial standards.

Reference

• ICH Q3D Guideline for Elemental Impurities (2015.09.30)
• ICH Q3D R2 Guideline Update (2023.01.20)
• USP <232> Elemental Impurities–Limits
• USP <233> Elemental Impurities–Procedures