Accurate and Robust Measurement of Elemental Impurities in Pharmaceuticals by ICP-MS

Significance of the topic

Accurate determination of trace elemental impurities in pharmaceutical products is essential for patient safety and regulatory compliance. Metal contaminants can arise from raw materials, catalysts, processing equipment, packaging, or the environment; even trace amounts may present toxicological risk. Harmonized regulatory frameworks (ICH Q3D, USP, EMA, FDA) and the draft Indian Pharmacopeia (IP) General Chapter 5.10 require validated, sensitive analytical workflows capable of quantifying specified elements at permitted daily exposure (PDE)-derived limits.

Objectives and overview of the study

The study demonstrates an end-to-end workflow using the Agilent 7850 ICP-MS to meet IP General Chapter 5.10 requirements. Objectives included: measuring 24 elemental impurities in three over-the-counter oral tablet products, validating the method against IP 5.10 quantitative and limit procedure criteria, and showing robustness, linearity, sensitivity, specificity, accuracy, precision, and intermediate precision for routine QC testing.

Methodology

• Samples: Three commercial OTC tablets. Each tablet was homogenized; 0.100 ± 0.0005 g aliquots were predigested with 0.1 mL HCl and 6 mL HNO3, then microwave-digested and brought to 50 mL (overall dilution factor 500 considering the 10 g/day max dose).
• Calibration: Multi-level calibrations prepared at 0, 0.10, 0.25, 0.50, 0.75, 1.0, 1.50, and 2.25 J (J = PDE / (total dilution × max daily dose)), using NIST-traceable ICH/USP certified reference materials. Calibration spanned 0.10–2.25 J to cover the regulatory range.
• QC and validation design: Limit and quantitative procedures per IP 5.10 were performed: detectability (0.8 J vs 1.0 J), repeatability (six independent spiked preps at target levels), accuracy (spike-recoveries at 0.5–1.5 J), intermediate precision (duplicate-day analysis), and drift checks before/after batches.

Used instrumentation

• Agilent 7850 ICP-MS equipped with ORS4 octopole collision/reaction cell (He mode) and Agilent SPS 4 autosampler.
• Sample introduction: MicroMist glass concentric nebulizer, Peltier-cooled Scott-type double-pass quartz spray chamber (maintained at 2 °C), quartz torch (2.5 mm injector), nickel sampler and skimmer cones, 10-roller peristaltic pump.
• Software and presets: Agilent ICP-MS MassHunter with ICH/USP preset method and automated autotune/lens optimization; General Purpose plasma preset used.

Main results and discussion

• Sensitivity and detection limits: Instrument detection limits (IDLs) measured for all 24 elements were substantially below their corresponding J values after accounting for the 500× dilution factor (IDL × 500 << J for typical elements), ensuring quantitation at regulatory levels.
• Linearity and dynamic range: Seven-point linear calibration curves (0.10–2.25 J) gave correlation coefficients ≥ 0.999 for target analytes. The 7850’s dual-mode detector (pulse-counting and analog) provides a 10-order dynamic range enabling low-level and higher concentration measurement in a single run.
• Interference management and specificity: ORS4 with helium KED effectively reduced polyatomic interferences; monitoring secondary (qualifier) isotopes confirmed specificity. Agreement between primary and secondary isotopes and the use of He mode demonstrate reliable interference control consistent with IP 5.10 and ICH Q3D expectations.
• Accuracy and precision: Spike recoveries at 0.5, 1.0 and 1.5 J across three products were within 70–150% (most results clustered 95–105%). Repeatability RSDs for n=6 spiked preps were typically <5% (well under the 20% acceptance), and intermediate precision across two days (n=12 combined) showed %RSDs <7% (acceptance <25%).
• Stability and drift: Drift checks using QC standards at 0.5, 1.0 and 1.5 J measured before and after a 13-hour batch showed drift <8% (acceptance 20%), demonstrating long-run stability suitable for high-throughput QC workflows.
• Quantitation limit (QL): The method confirmed 0.5 J as the QL for target elements because accuracy at 0.5 J met acceptance criteria.

Benefits and practical applications of the method

• Regulatory compliance: The workflow meets draft IP 5.10 requirements and aligns with ICH Q3D, USP <233>/<1225>, enabling regulatory-ready elemental impurity testing for oral dosage forms.
• Operational efficiency: Pre-configured software methods, autotune, and General Purpose plasma settings reduce method development time and operator burden in routine QC environments.
• Robustness for complex matrices: High-temperature plasma and the ORS4 He mode improve matrix tolerance and ionization efficiency, reducing the need for excessive sample dilution and enabling analysis of APIs, excipients, and finished dosage forms with consistent performance.
• High throughput capability: Low drift and long-term signal stability support extended analytical runs and minimize re-analysis and instrument downtime.

Future trends and possibilities for use

• Expanded matrix coverage: Applying the validated workflow to additional dosage forms (liquids, semisolids, inhalables) with tailored digestion protocols and dilution strategies.
• Automation and data integrity: Increased integration of sample prep automation and LIMS connectivity to streamline large-scale QC studies and regulatory documentation.
• Advanced interference removal: Continued development of cell chemistries and data-processing algorithms to further lower interferences for challenging isotopes and matrices (e.g., ultra-trace mercury, halogen-associated polyatomics).
• Harmonized global adoption: As IP 5.10 is finalized, adoption alongside ICH Q3D and pharmacopeial chapters will drive standardized test panels, CRMs, and software templates across industry labs.

Conclusion

The Agilent 7850 ICP-MS, operated with ORS4 He mode and workflow-based MassHunter software, provides a sensitive, specific, and robust platform for quantifying 24 elemental impurities in oral tablets consistent with draft IP General Chapter 5.10. The method demonstrated excellent linearity, low detection limits relative to regulatory J-values, stable long-run performance, accurate spike recoveries, and low intra- and inter-day variability—supporting routine pharmaceutical quality control and regulatory compliance.

Reference

1. Pharmaffiliates. Understanding ICH Q3D Elemental Impurities: Class 1, 2 & 3, 2025.
2. U.S. Food and Drug Administration. Q3D(R2) Elemental Impurities – Guidance for Industry, 2022.
3. International Council for Harmonisation. Guideline for Elemental Impurities Q3D(R1), 2019.
4. European Medicines Agency. ICH Guideline Q3D(R2) on Elemental Impurities, 2022.
5. Assyro (blog). ICH Q3D: Guideline for Elemental Impurities in Pharmaceuticals, accessed June 2026.
6. Indian Pharmacopoeia Commission. Draft: 5.10 Elemental Impurities – Proposal for Inclusion in the Indian Pharmacopoeia, 2024.
7. Agilent Technologies. Octopole Collision/Reaction Cell and Helium mode, publication 5994-1172EN.
8. Agilent Technologies. Plasma Robustness and Matrix Tolerance, publication 5994-1173EN.