Understanding Nitrosamine, Nitroso, and Azido Impurities Testing

Nitrosamine, Nitroso, and Azido impurities are classified as carcinogens because they may cause cancer. The excessive presence of these impurities can affect many organs including the lungs, brain, liver, kidney, bladder, stomach, oesophagus, and nasal sinus. Nitrosamines can be found in food, tobacco, cosmetics, toiletries, water, air and the human body. Of particular interest is the existence of nitrosamine impurities in drugs, APIs and other pharmaceutical products.

Nitrosamines can either occur naturally in the environment and body or as a result of product manufacturing processes. In recent years there has been a rise in interest in nitrosamines as various studies have provided evidence of their potentially harmful effects.

Top regulated nitrosamines

Over 300 types of nitrosamines have been identified to date. Our analytical portfolio includes, but is not limited to, the nitrosamines listed in the table below.

Please note, the Nitrosamines listed above could form from the degradation process of APIs and drug products and from manufacturing processes that use nitrosating agents. Furthermore, the set limits are only applicable if a finished product contains a single N-nitrosamine.

Nitrosamine Regulation

Nitrosamines were first detected in blood pressure medicines called sartans in 2018. While there is no existing universal regulation for nitrosamine, various regulatory authorities have mandated limits for the level of nitrosamines allowed in products. The European Union, Canada and USA have taken measures to restrict the presence of nitrosamines in pharma and other products.

The USFDA allows for a limit of 96 ng/day in certain angiotensin II receptor blocker (ARB) drug products. EMA (European Medicines Agency), on the other hand, allows for 30 ng/day in sartan drug products. For new Nitrosamies for which no toxicological information exist, the limit is fixed by the authorities at 18 ng/day. As such, regulators require product testing to reduce or eliminate the presence of nitrosamines, nitroso, and azido impurities. Furthermore, to prevent or limit the presence of nitrosamines, companies must implement appropriate controls and good manufacturing practices.

ICH: Guidelines for controls of impurities and contaminants

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) provides a guide for the study and control of nitrosamines. These guidelines are applicable to drugs and drug products produced by chemical synthesis.

Tools for routine analysis and analytical method validation include:

• ICHQ3D Elemental impurities
• ICHQ3A Impurities in new drug substances
• ICHQ3C Residual solvents
• ICHQ3B Impurities in new drug products

Nitrosamine, Nitroso and Azido Impurities Testing Methods

Nitrosamines can be detected at ppb level using liquid chromatography and/or gas chromatography coupled with a high-resolution mass spectrometer. Samples can be tested using either the targeted or untargeted analytical methods.

Targeted vs Untargeted Analysis

The COTECNA network includes of over 40 leading laboratories across the globe. We can assist you in determining the level of nitrosamines present in your products. Our laboratories are equipped with the latest mass spec instruments like Waters UPLC H-Class MS/MS (TQS Micro), Waters LC-MS/MS (XEVO TQ-XS), and Agilent GC MS/MS (Triple Quad).

In addition, our expert teams can tailor studies based on your needs and product requirements. We offer:

• Activities and excipients interaction studies.
• Analysis of excipients, APIs and PFs.

To learn more about our services or to request for a free quote, please contact us.