Pharmacy Courses

Regulatory Focus on Nitrosamine Impurities

FDA initially were very keen on Elemental impurities and over the period switched to Nitrosamines in the products that are arising due to the process contributors. 

Recently FDA focus has shifted to the product related nitrosamines like - N-Nitroso Rasagiline etc. The limits for such impurities are very very low as compared to the general nitrosamines like NDMA NDEA etc. 

Recently EMA has published a guidance on 27th July for the product specific limits where many of the prone molecules limits have been recommended. If the molecule is prone to form Nitroso imp and the limit is not mentioned in any of the guidance, we need to follow 18 ng AI limit.

Moreover need to prove that it is below 18ng/day and need to take approval from the agency. Otherwise need to generate new AI limit and get approve.

However, as per USFDA default option limit is 26.5ng/day. But ANVISA, Heath canada, TGA are following EMA default option i.e. 18ng/day.

So, as of now 3 major root causes have been identified for the formation of genotoxic Nitroso imp- 

1. Due to Process components

2. Molecule containing tetrazole rings like Sartans

3. Molecue can form complex with Nitro group. 

Moreover, in addition to 3 root causes, Supplier excipient qualification, as still excipient having ppm level of nitrite impurities, which can lead to form Nitroso amine in stability.bMany more root causes mentioned in EMA Q&A guidance's.

Basically there are 3 minimum conditions required to form the nitrosamines.

1. Nitrite/ Nitrate 

2. Sec/Ter amines

3. Acidic environment

List of Nitrosamine Impurities

FDA has identified seven nitrosamine impurities that theoretically could be present in drug products: 

  • NDMA, N-nitrosodiethylamine (NDEA), 
  • N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), 
  • N-nitrosoisopropylethyl amine (NIPEA), 
  • N-nitrosodiisopropylamine (NDIPA), 
  • N-nitrosodibutylamine (NDBA), and 
  • N-nitrosomethylphenylamine (NMPA). 

Five of them (NDMA, NDEA, NMBA, NIPEA, and NMPA) have actually been detected in drug substances or drug products.

Resource Person: Dr. Dileep Bhosale (General Manager at Glenmark Pharmaceuticals)

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