Validating the Agilent 7700x/7800 ICP-MS for the determination of elemental impurities in pharmaceutical ingredients according to draft USP general chapters <232>/<233>

Importance of the Subject

The United States Pharmacopeia chapters <232> and <233> establish stringent limits and procedures for elemental impurities in pharmaceutical substances. Compliance ensures patient safety by controlling toxic trace metals and supports regulatory approvals. Modern techniques such as ICP-MS provide the sensitivity and specificity needed for low-level multi-element quantification under complex matrices.

Objectives and Study Overview

This application study demonstrates the successful validation of an Agilent 7700x ICP-MS platform to quantify 16 regulated elemental impurities in gelatin capsule samples, following the May 2011 draft of USP<232>/<233>. Key aims include verifying detection limits, system suitability, spike recovery, precision, and ruggedness in accordance with draft USP requirements.

Methodology and Instrumentation

• Sample Preparation: Closed-vessel microwave digestion using Milestone Ethos system with HNO3, HCl, H2O2, and water according to USP<233> recommendations. Final solutions contained 2% HNO3 and 0.5% HCl for analyte stabilization.
• Instrument Configuration: Agilent 7700x ICP-MS equipped with Micromist nebulizer and helium collision cell (ORS3) mode. Operating parameters included RF power of 1550 W, plasma gas flows, lens settings, and He cell gas at 4 mL/min.
• Calibration and Standards: Multi-element external calibration curves covering sub-ppt to low ppb levels. Internal standards (Sc, Tb, Bi) were used for drift correction. Detection limits calculated at three times the blank standard deviation.
• Validation Procedures: System suitability checks with 2J standards, limit and quantitative procedures with spikes at 0.8J, 1J, 0.5J, and 1.5J levels. Assessment of repeatability (≤20% RSD) and ruggedness across days.

Main Results and Discussion

Detection limits for all 16 elements were in the low ng/L (ppt) range, well below USP component limits. System suitability tests over a seven-hour run showed drift below 7.5% and RSDs under 3%. Limit procedure validation confirmed accurate discrimination between 0.8J and 1J spikes, with recoveries within ±10% and RSDs <2%. Quantitative procedure spikes at 0.5J and 1.5J yielded recoveries between 86% and 116% with RSDs below 4%. Ruggedness tests across two days demonstrated inter-day differences under 10% and combined RSDs below 8%.

Benefits and Practical Applications

• Comprehensive multi-element analysis in a single run, reducing analytical time and cost.
• High sensitivity and specificity via He collision mode, effectively removing polyatomic interferences.
• Robust method capable of meeting and exceeding draft USP<232>/<233> performance criteria.
• Flexibility to add speciation by coupling with HPLC or GC for arsenic and mercury forms as required.

Future Trends and Potential Applications

Emerging general chapter <2232> for dietary supplements expands the need for trace metal analysis under similar guidelines. Advances in reaction/collision cell technologies and automated sample handling will further streamline elemental impurity workflows. Integration of speciation techniques and real-time monitoring could enhance process control and safety in pharmaceutical manufacturing.

Conclusion

The validated Agilent 7700x ICP-MS method using closed-vessel digestion and He mode detection meets all draft USP<232>/<233> requirements for sensitivity, accuracy, precision, and robustness. It provides a reliable and efficient solution for regulatory compliance in pharmaceutical quality control and can be readily adapted for related applications such as dietary supplements.

Reference

• USP General Chapter <232> Elemental Impurities—Limits.
• USP General Chapter <233> Elemental Impurities—Procedures.
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