Module 3 - Strategic case studies in practice

Analytical technique

GC-MS/MS (DI)

High throughput RapidFire®-MS

GC-MS (HS)

LC-MS/MS

HPLC-UV

NDMA, NDEA

Analyte(s)

NDMA, NDEA

NDMA, NDEA

NDMA, NDEA

NDMA, NDEA

Sample amounts (DS and/ or DP)

250-500 mg DS or DP containing 250 mg of DS DE with MeOH or DCM; LLE with NaOH and DCM

50-500 mg DS or 50-250 mg DP; ‘one tablet’ Direct HS- analysis after dissolution in NMP or DMSO

50-100 mg DS or DP containing 50- 100 mg of DS

62-320 mg DS

DS (unknown)

DE with MeOH/, H2O (35:65 V/V)

Workup procedure

DE with MeOH

DE with MeOH

valsartan losartan

valsartan irbesartan losartan

valsartan irbesartan losartan

valsartan irbesartan losartan ranitidine

DS

irbesartan candesartan olmesartan 0.02-0.10 ppm 0.04-0.25 ppm 0.04-0.10 ppm 0.08 – 0.50 ppm

losartan

candesartan olmesartan

candesartan olmesartan

NDMA – LOD NDMA – LOQ NDEA – LOD NDEA – LOQ

0.002-0.01 ppm (DS) 0.005-0.05 ppm (DS) 0.002-0.01 ppm (DS) 0.007-0.03 ppm (DS)

0.005-0.04 ppm (DS)

0.010-0.15 ppm (DS)

10 ppm

0.08-0.5 ppm (DS)

0.1 ppm (DS)

25 ppm

0.006-0.02 ppm (DS)

0.02 ppm (DS)

25 ppm

0.05-0.08 ppm (DS)

0.02-0.15 ppm (DS)

50 ppm

Details

https://www.edqm.eu/en/ad-hoc-projects-omcl-network

2.3.7. Sensitivity of the analytical methods

To date, limits of detection (LOD) and limits of quantitation (LOQ) as low as 2 ppb and 5 ppb, respectively, could be reached for NDMA (NDEA: 2 ppb and 7 ppb, respectively) with respect to the amount of API. It should be noted that the LOQ is more relevant as it describes the threshold above that reliable quantitative results can be obtained. These results can be used to evaluate the need for routine control of any contaminant found. Nevertheless, both LOD and LOQ parameters correlate directly with the chosen and implemented workup procedure. The more API or finished product is extracted, purified, and concentrated, the higher is the possibility of reaching low LOD and LOQ values. Hence, a precise and detailed description of the individual laboratory processing of API and/or FP is necessary.

EMA/369136/2020

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