Quantitation of NDMA and NDEA in Metformin and 5 Sartan APIs as per the EDQM method Procedure B

Importance of the Topic

Analytical detection of genotoxic nitrosamines such as NDMA and NDEA has become critical after regulatory findings in valsartan and metformin products. Ensuring safe levels of these impurities supports patient safety and regulatory compliance.

Objectives and Study Overview

The study adapted the EDQM Procedure B GC-MS method to quantify NDMA and NDEA in metformin and five sartan APIs. It evaluated method sensitivity improvements, calibration strategies and applicability beyond sartans.

Used Instrumentation

• Gas Chromatograph–Mass Spectrometer GCMS-QP2020 NX
• AOC-30i autosampler
• SH-I-624Sil MS capillary column (30 m × 0.25 mm, 1.4 µm df)
• Helium carrier gas

Methodology

• Followed EDQM Procedure B with two sample preparation protocols: one for valsartan, losartan, olmesartan and metformin; a second for candesartan and irbesartan
• Performed three-point calibration (15, 30, 60 ppb) for both sample preps rather than single-point by EDQM
• Internal standard: N-nitrosoethylmethylamine (NEMA)
• Extraction used alkaline aqueous solution and dichloromethane partitioning or direct DCM extraction depending on API
• GC parameters: splitless injection, column flow 1.0 mL/min, temperature gradient from 40 °C to 280 °C
• MS detection in SIM mode monitoring ions m/z 74, 88, 102

Main Results and Discussion

• Calibration curves demonstrated excellent linearity (R2 = 0.999) for both NDMA and NDEA
• Relative retention times matched expected values (NDMA 0.9; NDEA 1.1)
• Signal-to-noise ratios for spiked APIs at 15 ppb exceeded regulatory threshold (≥ 10)
• Repeatability (%RSD) for reference solutions was < 2.1% across all levels
• Recovery study at 15 ppb yielded 95–122% across six APIs
• Limit of quantitation: Shimadzu method achieved 15 ppb for both analytes versus 30 ppb by EDQM
• Quantitation in actual samples found NDMA in valsartan at 17.6 ppb; all other measurements were below LOQ

Benefits and Practical Applications

• Enhanced sensitivity with LOQ halved compared to standard EDQM method
• Demonstrated method transferability to metformin beyond original sartan scope
• Robust performance metrics support routine QA/QC implementation in pharmaceutical analysis

Future Trends and Opportunities

• Extension of nitrosamine screening to additional APIs and dosage forms
• Automation of sample preparation to increase throughput
• Integration with high-resolution MS for confirmatory analysis and broader impurity profiling
• Development of multi-analyte methods covering emerging nitrosamine contaminants

Conclusion

The application of EDQM Procedure B on a Shimadzu GCMS-QP2020 NX system with AOC-30i enabled reliable quantitation of NDMA and NDEA in metformin and five sartan APIs. The modified calibration approach and lowered LOQ enhance method sensitivity and broaden applicability, ensuring pharmaceutical safety and compliance.