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Are Nitrosamines a Concern for Biologic Manufacturers?

First described over a century ago, the class of organics known as N-nitrosamines are defined by the common structural feature, R2NNO. Since the mid-1950s when their carcinogenic nature was revealed,1 this functional class has continued to attract attention by researchers and, today, of the more than 300 nitrosamines identified, 90% are thought to be carcinogenic and/or genotoxi.2

The presence of nitrosamines in a range of foodstuffs and drinks as well as products such as tobacco is well documented. They are known to form during material preparation as well as in the digestive tract itself.3 The greatest risk for the presence or formation of N-nitrosamines comes from the confluence of three factors:

  • A nitrosating agent
  • (ii) A secondary or tertiary amine, and
  • (iii) Appropriate conditions (e.g., elevated temperatures, acidic conditions, liquid phase)4

Presence of Nitrosamines in Medicines

In mid-2018, regulators became aware of the presence of the nitrosamine N-nitrosodimethylamine (NDMA) in certain blood pressure medications.5 Further investigations led to the detection of several N-nitrosamine species in a range of pharmaceuticals including valsartan, antibiotics, antacids and antidiabetics. This resulted in the recall of these drug products and the temporary withdrawal of treatment for many patients globally.

In 2019, SGS adopted a center of excellence strategy for nitrosamine testing, utilizing expertise, sophisticated analytical instruments and method harmonization across its global network to support the pharmaceutical industry.

Beginning in late 2020, several additional products were removed from the market due to the detection of nitrosamine drug substance-related impurities (NDSRIs).6 These are essentially nitroso forms of the API which result from areaction between a nitrosating agent (e.g., nitrite) and a suitable amine/ amide-containing API under appropriate chemical conditions.7

It is estimated that about 20% of current small-molecule generic drugs have a reactive amine functional group which poses the potential for the formation of NDSRIs. As might be expected however, the genotoxicity of such derivatives can vary significantly depending on the molecular structure of the API.8

Method Development and Validation by SGS

SGS has already successfully applied its network of specialized laboratories to tackle the analytical challenges associated with a range of these somewhat unique impurities.

A coordinated regulatory strategy to address potential nitrosamine contamination in existing and new drug products has been established and includes an initial risk assessment followed by appropriate testing and mitigation of the manufacturing processes.9

While much attention was initially focused on traditional pharmaceutical products, in 2020 the EMA published an assessment report10 that directed all medicinal products, including biologics, into the scope of nitrosamine risk assessment. Other regulatory agencies such as Health Canada, Swiss Medic and ANVISA have now also emulated this guidance.