Nitrosamine impurities for human drug products considering the risks which may arise from raw and packaging materials, manufacturing process of drug product, solvent and manufacturing equipment are showed below:



During nitrosamine risk assessment report preparation below information should be collected:

1. Composition (Raw materials and Packaging materials)

2. List of manufacturing and packaging equipment with material of construction which come in contact with drug product

3.  N-Nitrosamine free declaration from manufacturer/supplier


Root Causes for the Presence of Nitrosamine Impurities in APIs

  • Presence of secondary, tertiary, or quaternary amines and nitrite salts under acidic reaction conditions
  • Tertiary and quaternary amines used as reagents in the synthesis of APIs
  • Contamination of starting materials and raw materials
  • Presence of residual amines from recovered solvent or reagent
  • Lack of optimization of the manufacturing process for APIs


Presence of Nitrosamine Impurities in Excipients and Purified Water

Nitrite impurities are found in a range of commonly used excipients, which may lead to nitrosamine impurities forming in drug products during the drug product manufacturing process and shelf-life storage period. Some drug products may undergo degradation pathways that form nitrosamine impurities; this could potentially occur during drug product storage. The supplier qualification program should take into account to control the nitrosamine impurities level. Drug product manufacturers should also be aware that nitrite and nitrosamine impurities may be present in potable water.


Nitrosamine free Declaration

In supplier declaration it should be stated that there is no possibility for generation of N-Nitrosodimethylamine (NDMA) impurities or any other Nitrosamine impurities based on their knowledge of starting materials, production processes, equipment and packaging material.


As per FDA,

There are seven identified 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), Nnitrosodibutylamine (NDBA), and N-nitrosomethylphenylamine (NMPA) (Figure 2). Five of them (NDMA, NDEA, NMBA, NIPEA, and NMPA) have actually been detected in drug substances or drug products.


AI Limits for NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA in Drug Products


As per EMA,

Nitrosamines are chemical compounds classified as probable human carcinogens on the basis of animal studies.


Read also: Regulatory Focus on Nitrosamine Impurities