Analysis of Elemental Impurities in GLP-1 Receptor Agonist Oral Tablets by ICP-MS

Significance of the topic

The control of elemental impurities in pharmaceutical drug products is critical for patient safety and regulatory compliance. Oral solid dosage forms of peptide-based therapeutics such as GLP-1 receptor agonists introduce complex formulation elements (permeation enhancers, excipients, coatings) that can be sources of metallic contaminants. Accurate multi‑element quantification at regulatory limits (ICH Q3D(R2), USP <232>/<233>) is therefore essential for quality control, regulatory submissions, and lifecycle monitoring of novel oral biologic formulations.

Objectives and study overview

This application note describes the development and validation of an ICP‑MS method using an Agilent 7850 instrument to quantify the 24 ICH/USP‑regulated elemental impurities in a GLP‑1 receptor agonist oral tablet. The work demonstrates compliance with USP <232>/<233> and ICH Q3D(R2)/Q2(R2) across limit and quantitative procedures, evaluates system suitability and stability over an eight‑hour batch, and documents method performance metrics including detectability, precision (repeatability and intermediate precision), specificity, accuracy, linearity and range.

Methodology

- Sample format: indirect (digestion) following USP <233> because tablets are not directly soluble.
- Sample preparation: four tablets pulverized; 0.20 g aliquots digested in closed‑vessel microwave (MARS 6) with 6 mL HNO3 and 2 mL HCl (3:1) to decompose organics and stabilize Hg and PGEs. After cooling, digests diluted to 500 mL with 3% HNO3/1% HCl giving a total dilution factor of 2500. Two digestion blanks processed in parallel.
- Calibration and regulatory metric: J value concept used to convert oral PDE (µg/day) to target concentration in prepared sample (µg/L). Calibration levels and spike levels spanned 0.5–1.5 J; detectability checked at 0.8 J for limit procedures.
- QC strategy: a 1.5 J standard used for drift checks and run as QC every 15 samples across an eight‑hour run; system suitability defined as drift within ±20% per USP <233>.

Instrumentation used

- Agilent 7850 ICP‑MS with fourth‑generation Octopole Reaction System (ORS4) collision cell.
- ORS4 operated in helium (He) KED mode to suppress matrix‑derived polyatomic interferences (notably chloride‑based species such as ArCl+).
- Standard sample introduction: MicroMist glass concentric nebulizer, quartz spray chamber, quartz torch with 2.5 mm ID injector, nickel sampling and skimmer cones.
- Agilent SPS 4 autosampler for sample throughput.
- Agilent ICP‑MS MassHunter software: preset ICH/USP method, automated J‑value calculation, built‑in QC and system suitability reporting.
- Microwave digestion: MARS 6 (CEM) with specified ramp and hold program to 200 °C.

Main results and discussion

- Sensitivity and detection limits: Instrument detection limits (IDLs) were at the low ppt (ng/L) level for all elements; calculated J values were at least ~500× higher than IDLs, ensuring adequate margin for regulatory limits.
- System stability and drift: The 1.5 J drift check remained within 90–110% across the eight‑hour batch; QC RSDs (n=7) were generally <2.6% for all elements, demonstrating long‑term signal stability suitable for high‑throughput QC runs.
- Precision: Repeatability for six independent 1 J spiked preps was ≤2% RSD for all 24 elements (acceptance ≤20% RSD per USP <233>). Intermediate precision (n=12, different analysts/days) showed ≤3.2% RSD for all elements, confirming ruggedness across within‑lab variables.
- Detectability and limit procedures: 0.8 J spikes produced mean concentrations below the 1 J standard while 1 J spikes recovered within ±15% of the 1 J standard; this satisfied USP <233> detectability criteria.
- Accuracy and linearity: Spike recoveries at 0.5, 1.0 and 1.5 J were within 90–110% for all elements (USP acceptance 70–150%). Calibration curves for representative elements (As, Cd, Hg, Pb, Co, Ni, Pd, Os, Pt) demonstrated excellent linearity with R2 > 0.999; limits of quantitation and background equivalent concentrations were at ppt levels.
- Specificity: He KED mode with ORS4 effectively suppressed polyatomic interferences (e.g., ArCl+ on 75As); primary and qualifier isotope results agreed closely (typically ~99–101%), supporting unequivocal analyte identification per ICH Q2(R2)/USP <233> requirements.
- Speciation considerations: Although inorganic forms of As and Hg are the regulatory focus, only trace Li and Ni were detected in blanks and all other elements were below IDLs; therefore no As/Hg speciation was required in this study. The instrument workflow can be integrated with LC‑ICP‑MS if speciation becomes necessary.

Practical benefits and applications of the method

- Regulatory readiness: The validated method meets USP <232>/<233> and ICH Q3D(R2)/Q2(R2) requirements, enabling compliant routine release and stability testing of GLP‑1 oral tablets and similar peptide‑based oral solids.
- Throughput and robustness: Automated J‑value calculations, preset method templates, continuous QC monitoring, and proven eight‑hour stability support high‑throughput QC laboratories and method transfer across sites.
- Broad applicability: The generic He KED ORS4 approach allows simultaneous multi‑element analysis without extensive element‑specific optimization, simplifying implementation for matrices containing chloride and other challenging components.

Future trends and potential applications

- Integration of speciation workflows: Routine coupling of LC‑ICP‑MS for As and Hg speciation will become more common where organic forms are possible (e.g., marine‑derived ingredients).
- Greater automation and miniaturization: Advances in automated sample preparation and digestion (including miniaturized closed‑vessel systems) will reduce sample mass and reagent consumption while improving throughput and traceability.
- Wider adoption for complex biologics: The approach can be adapted to other peptide/protein oral formulations and complex combination products to accelerate regulatory submissions and reduce analytical development time.
- Enhanced data integrity and informatics: Tighter integration of instrument control software, LIMS and automated QC reporting will streamline lifecycle monitoring, trend analysis and cross‑site method transfer.

Conclusion

The Agilent 7850 ICP‑MS with ORS4 He KED demonstrated robust, sensitive and accurate quantification of all 24 ICH/USP elemental impurities in a GLP‑1 receptor agonist oral tablet matrix. The validated workflow satisfied detectability, precision, specificity and accuracy criteria defined by USP <233> and ICH Q2(R2), and the instrument/software features reduced manual effort for method setup and transfer. This application provides a regulation‑ready template for routine elemental impurity testing of peptide‑based oral solid dosage forms.

Reference

1. International Council for Harmonisation. ICH Q3D(R2): Guideline for Elemental Impurities. Step 4, April 2022.
2. United States Pharmacopeia. General Chapter <232> Elemental Impurities—Limits. USP–NF.
3. United States Pharmacopeia. Elemental Impurities—Procedures, General Chapter <233>. USP–NF.
4. International Council for Harmonisation. ICH Q2(R2): Validation of Analytical Procedures. Step 4, November 2023.
5. United States Pharmacopeia. Validation of Compendial Procedures, Chapter <1225>. USP–NF.
6. Agilent Technologies. Octopole Collision/Reaction Cell and Helium Mode, publication 5994‑1172EN.
7. Agilent Technologies. Meet The Growing Demand for Elemental Speciation, publication 5991‑4269EN.