Nitrosamine Impurities – Information Guide

This article contains information about Nitrosamine impurities, its different types and mitigation plan to avoid presence of these impurities for pharmaceutical Drug substances and Drug products.

What is mean by Nitrosamine Impurities for pharmaceutical Drug substances and Drug Products ?

Nitrosamine impurities can form when amines react with nitrites, which can be present as impurities in some Drug Substances, Excipients and Drug Products.

It can be named as N-nitrosamines, i.e. any molecule containing the nitroso functional group. These molecules are of concern because nitrosamine impurities are probable human carcinogens.

It can potentially form during the manufacturing or storage of certain pharmaceuticals, particularly those that contain amines.

Formation of nitrosamines is possible in the presence of secondary, tertiary, or quaternary amines and nitrite salts under acidic reaction conditions. Under these conditions, nitrite salts may form nitrous acid, which can react with an amine to form a nitrosamine. in short processes that use nitrites in the presence of secondary, tertiary, or quaternary amines are at risk of generating nitrosamine impurities

Despite purification stages available in manufacturing process, Nitrites used as reagents in one step can carry over into subsequent steps and reacts with amines to generate nitrosamine impurities. So whenever nitrile salts are present in process, carryover of it may not be ruled out.

Nitrites are common nitrosating impurities that have been reported at PPM level in many excipients too.

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.

Nitrite and nitrosamine impurities may be present in potable water in addition to that  some drug product may undergo degradation that form Nitrosamine Impurities this could potentially occur during drug product storage.

What are the mitigating plans to avoid presence of Nitrosamine Impurities in APIs and Drug Products.

Below are some mitigation plans can be done during processing of APIs Manufacturing

• More precautions should be taken while using  when route of synthesis involves the use of amide solvents.
• API manufacturers should optimize manufacturing process for APIs during route of synthesis development to minimize or prevent the formation of these impurities
• Feasibility to be checked for usages of  bases other than secondary, tertiary, or quaternary amines (when possible) if during synthesis conditions nitrosamines may form.
• Developing a manufacturing process that enables the removal of nitrosamine impurities during subsequent processing steps.
• Whenever possible reaction conditions should avoid that may produce nitrosamines. when not possible, that  process should adequately controlled and make sure that process is enough capable for consistently reducing nitrosamine impurities through appropriate robust studies.
• API manufacturers  should check feasibility for removal of quenching steps when there is a risk of nitrosamine formation from the main reaction mixture to reduce the risk of nitrosamine formation.
• Potable water used in API manufacture may contain low levels of nitrite and even nitrosamines from environmental contamination.
  Therefore to avoid unacceptable levels of these impurities in API, API manufacturers should analyze nitrite and nitrosamine levels in water and use water that has been purified and removed unacceptable impurities.

Below are the some mitigation plans can be done before Drug product manufacturing.

Conducting a risk assessment: The pharmaceutical manufacturer should assess the risk of nitrosamine impurities forming during the manufacturing process of the drug products .

Reviewing Raw materials: The manufacturer should review the quality of the raw materials used in the manufacturing process, including their nitrite levels, and ensure that they are of good quality.

Implementing process changes: If a risk assessment shows that these impurities could form during the manufacturing process, the manufacturer should consider process changes to reduce or eliminate the risk during manufacturing of drug product.

What are the different types of Nitrosamine Impurities?

Plz find the Different types of N-Nitrosamine Impurities found in  Drug Substances, Dug Products and Excipients.

Reference : 1. FDA guide on Control of Nitrosamine Impurities in Human Drugs https://www.fda.gov/media/141720/download

2. EMA – https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf

For More Detailed Information you can click on Below link :

FDA : https://www.fda.gov/media/141720/download

EMA : https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf