Analysis of elemental impurities in pharmaceutical products in accordance with USP General Chapters <232> and <233>

Importance of the Topic

Analysis of elemental impurities in pharmaceutical products is crucial to ensure patient safety and meet stringent regulatory standards. Trace levels of metals such as lead, arsenic, cadmium, and mercury can affect drug stability, efficacy, and shelf-life. The implementation of USP General Chapters <232> and <233> together with ICH Q3-D guidelines mandates robust methods for detection and quantification of 24 elements across all stages of drug manufacturing.

Objectives and Study Overview

This application note describes the development and evaluation of a single-quadrupole ICP-MS method using a Thermo Scientific iCAP RQ instrument. The goal was to determine 24 elemental impurities in both finished pharmaceutical products and individual components, demonstrating compliance with USP <232>/<233> requirements and the risk-based approach outlined in ICH Q3-D.

Methodology

Sample Preparation:

• Accurately weigh 0.10 g of active pharmaceutical ingredient (API) and dissolve in 20 mL of 1% v/v HNO₃ (total 200× dilution).
• Calculate limit concentrations from permitted daily exposures (PDEs) assuming a 10 g daily dose.
• Spike all solutions (blanks, standards, samples) with an internal standard mixture containing Be, Sc, Y, Tb, and Bi.
• Prepare six calibration standards gravimetrically over 0.05 J to 2 J, where J is the limit concentration for each element.

System Suitability and Validation:

• Verify instrument performance with automated checks for sensitivity (⁷Li, ⁵⁹Co, ¹¹⁵In, ²³⁸U) and oxide/doubly charged ratios (¹⁴⁰Ce¹⁶O⁺/¹⁴⁰Ce⁺, ¹³⁷Ba²⁺/¹³⁷Ba⁺).
• Assess linearity (R > 0.998 for all elements) and instrument detection limits (IDLs) to ensure sensitivity below 0.1 J.
• Perform drift test on 1.5 J standard before and after batch (drift < 5% for all elements).
• Evaluate accuracy via triplicate spikes at 0.1 J, 1 J, and 2 J; recoveries ranged 90–110% (acceptance 70–150%).

Instrumentation Used

• Thermo Scientific iCAP RQ ICP-MS with Kinetic Energy Discrimination (KED) mode using pure He cell gas (4.5 mL/min).
• Teledyne CETAC ASX-560 autosampler for unattended operation.
• Glass concentric nebulizer (400 µL/min), cyclonic quartz spray chamber, quartz torch and 2.5 mm injector.
• Ni-tipped sample and skimmer cones; RF power 1,550 W; coolant gas 14 L/min; auxiliary gas 0.8 L/min; nebulizer flow 1.16 L/min; three replicates of 10 sweeps each with 0.05 s dwell time.
• Thermo Scientific Qtegra ISDS Software for instrument control, data processing, 21 CFR Part 11–compliant audit trails, and automated reporting.

Main Results and Discussion

Linearity across 0.05 J–2 J showed correlation coefficients above 0.998 for all 24 elements. IDLs were well below target values (0.0003–0.78 µg/kg). Three API batches yielded all analytes below method quantification limits (MQL), demonstrating purity. Drift checks confirmed stable performance (< 5% variation). Accuracy tests at low (0.1 J), medium (1 J), and high (2 J) levels delivered recoveries within the 90–110% range, illustrating precision and reliability for trace to higher concentrations.

Benefits and Practical Applications

• Single-mode KED approach eliminates the need for multiple methods or hydride generators.
• High sensitivity and wide dynamic range support current and future regulatory limits.
• Automated system suitability and audit-ready data management streamline compliance with USP and FDA 21 CFR Part 11 requirements.
• Suitable for routine quality control of APIs, excipients, intermediates, and finished dosage forms.

Future Trends and Applications

Advances in ICP-MS technology and software are expected to further reduce detection limits and improve throughput. Adoption of collision/reaction cell chemistries, high-resolution mass analyzers, and advanced data analytics will enhance selectivity and enable real-time process monitoring for continuous manufacturing. Integration with laboratory information management systems (LIMS) will facilitate fully automated workflows from sample receipt to regulatory reporting.

Conclusion

The validated single-quadrupole ICP-MS method on the iCAP RQ platform delivers accurate, precise, and interference-free quantification of 24 elemental impurities in pharmaceutical materials. Combined with the Qtegra ISDS Software’s comprehensive control and reporting features, this workflow meets USP <232>/<233> and ICH Q3-D requirements and supports efficient, compliant quality control operations.

References

• USP General Chapter <232>
• USP General Chapter <233>
• ICH Guideline Q3-D (R1)
• USP General Chapter <730> Plasma Spectrochemistry