WCPS: Validating ICP-MS Using USP<232>/<233> for Elemental Impurity Analysis in Pharmaceutical Products

Importance of the topic

Pharmaceutical products must comply with strict elemental impurity limits to ensure patient safety. The new USP general chapters <232> and <233> establish Permitted Daily Exposure (PDE) values and validation protocols for 24 regulated elements. Accurate, sensitive, and reproducible analytical methods are essential for monitoring trace metals in drug substances and drug products, including those requiring organic solvent dissolution or speciation workflows.

Objectives and study overview

This study aimed to demonstrate the suitability of the Agilent 7700x ICP-MS platform for routine quantification of elemental impurities according to USP<232>/<233> guidelines. Key goals were to verify method detection limits, calibration linearity, long-term stability, spike recovery, and the ability to perform species‐specific measurements, particularly for inorganic arsenic.

Methodology and instrumentation

Sample preparation involved closed‐vessel microwave digestion (Milestone Ethos) using a mixed acid system (HNO₃, HCl, H₂O₂) optimized for pharmaceutical matrices. Final digests were diluted 250× prior to analysis. The Agilent 7700x ICP-MS was operated in helium collision cell mode to suppress polyatomic interferences. Method parameters included:

• RF power: 1550 W
• Carrier gas: 0.95 L/min; dilution gas: 0.15 L/min
• Sampling depth: 8 mm; spray chamber temperature: 2 °C
• Cell gas flow (He): 4 mL/min; KED voltage: 4 V

For speciation of As(III) and As(V), the ICP-MS was coupled to an Agilent 1260 LC system with a suitable anion‐exchange column. Calibration standards bracketing the PDE levels were prepared in matching acid matrices.

Instrumentation used

• Agilent 7700x ICP-MS with updated torch, firmware, and MassHunter software
• Milestone Ethos microwave digestion system
• Agilent 1260 HPLC for arsenic speciation

Main results and discussion

Detection limits for all 24 elements were well below the USP PDE-derived reporting limits (typically < 1 ng/mL for most analytes). Calibration curves exhibited excellent linearity (R² > 0.999) across the required concentration range. Drift tests showed signal changes of < 3% over an analytical batch, outperforming the 20% limit. Spike recovery experiments at 0.5× and 1.5× PDE levels yielded recoveries between 105–116% with RSDs < 4%. The helium collision mode effectively removed common interferences, and secondary isotopes provided unequivocal analyte confirmation. LC-ICP-MS separation of As(III) and As(V) was achieved in under 12 minutes, allowing accurate quantification of inorganic arsenic species.

Benefits and practical applications

• Compliance with USP<232>/<233> for routine quality control in pharmaceutical manufacturing
• High sensitivity and robustness for aqueous and organic solvent matrices
• Capability for full-mass screening and multi-element analysis in a single run
• Speciation workflows to address regulatory requirements for toxic element forms

Future trends and opportunities

Advances in collision/reaction cell chemistries and high-matrix introduction systems will further improve tolerance to diverse sample matrices. Integration of automated sample preparation and hyphenated techniques (GC-ICP-MS, HPLC-ICP-MS) will enable comprehensive impurity profiling. Emerging data-processing algorithms and artificial intelligence are expected to streamline method development and enhance anomaly detection.

Conclusion

The Agilent 7700x ICP-MS system, coupled with microwave digestion and optional LC speciation, meets and exceeds USP<232>/<233> requirements for elemental impurity analysis in pharmaceuticals. Its robust performance, low detection limits, inter-element interference removal, and flexible solvent compatibility make it an ideal tool for routine regulatory testing.

Reference

McCurdy E, Liba A, Hussain S. Validating ICP-MS Using USP<232>/<233> for Elemental Impurity Analysis in Pharmaceutical Products. Winter Conference on Plasma Spectrochemistry; 2012