Nitrosamines alerts: recall saga seems to be never ending

Since June 2018, pharmaceutical companies’ efforts to identify nitrosamine impurities have not stopped. Patient safety is a priority for the pharmaceutical industry, and the alert generated by the nitrosamines’ potential presence in certain types of drugs has prompted companies and specialised laboratories to continue investigating to identify and monitor these impurities potentially dangerous to human health.

New batch recall

In December 2021, the Health Sciences Authority (HSA) reported a recall of health products supplied in Singapore. Following the detection of the impurity N-nitroso salbutamol in therapeutic product Ventolin Tab 2mg manufactured by GlaxoSmithKline Pte Ltd, these batches are being recalled as a precautionary measure.
Our Pharma R&D Department dedicated to the nitrosamines identification, and further expanded in the last year to respond promptly to requests, continues its research to develop and validate robust, highly sensitive LC-MS/MS methods for the determination of these genotoxic impurities in APIs and pharmaceuticals.

Targeted methods for almost 20 API-derived nitrosamines (on demand /R&D level) – not exhaustive list

• 1-Nitroso-4-phenylpiperazine
• 4-(N-methyl-N-nitrosoamino)-1-(3-pyridil)-1-butanone (NNK)
• 4-(N-methyl-N-nitrosoamino)-1-(3-pyridil)-1-butanol (NNO)
• N-Nitroso Benazepril
• N-Nitroso Betahistin
• N-Nitroso Clonidine
• N-Nitroso-Diclofenac
• N-Nitroso Dorzolamide
• N-Nitroso Duloxetine 
• 4-Nitroso Hydrochlorothiazide (4-Nitroso HCT)
• 2-(4-nitrosopiperazin-1-yl)ethan-1-ol (Aripiprazole nitrosamine related impurity)
• N-Nitroso Naphazoline
• N-Nitroso Nevibolol
• N-Nitroso Phenylephrine
• N-Nitroso Pramipexole
• N-Nitroso Propanolol
• N-Nitroso Rasagiline
• N-Nitroso Tamsulosin
• N-Nitroso Zolmitriptan
• N-Nitroso desmethyl tripelennamine
• Methyl-N-Nitroso-Indoline (NMI, Indapamid Impurity A)

Multiresidual analysis (standard set)

1. N-Nitrosodimethylamine (NDMA)
2. N-Nitrosodiethylamine (NDEA)
3. N-Nitrosomethylethylamine (NMEA)
4. N-nitrosoethylisopropylamine (NEIPA)
5. N-methyl-4-aminobutyric acid (NMBA)
6. N-nitrosodiphenylamine (NDPHA)
7. N-nitrosodi-n-propylamine (NDPA)
8. N-nitroso-diisopropylamine (NDIPA)
9. N-nitroso-di-n-butylamine (NDBA)
10. N-nitrosomethylaniline (NMA)
11. N-nitroso-di-ethanolamine (NDELA)
12. N-nitroso-piperidine (NPIP)
13. N-nitroso-pyrrolidine (NPYR)
14. N-nitroso-morpholine (NMOR)