What Are Nitrosamine Impurities?

Nitrosamines are described in the International Conference for Harmonization (ICH) M7(R1) Guideline 5 as Class 1 impurities which are high-potency, mutagenic. They have been studied for many years due to their presence in foods, cosmetics, tobacco products, industrial solvents, and alcoholic beverages. National Toxicology Program in the 14th Report on Carcinogens published the detail of the toxicity associated with nitrosamines. Discovery of small-molecule nitrosamine impurities in marketed drugs, starting with N-nitrosodimethylamine (NDMA) in batches of Valsartan in 2018, has led to significant regulatory response, including drug recalls and regulatory guidance that requires the re-evaluation of all synthetic and formulation routes for the potential presence of nitrosamine impurities. Nitrosamines can form when a nitrosatable amine group and nitrosating agents, are combined under favourable conditions. Several of the API and intermediates with amine moiety are under scanner for this reason. Several drug recalls happened due to contamination with Nitrosamine Drug Substance Related Impurities (NDSRIs) eg, sartans, propranolol and other beta blockers, varenicline, orphenadrine etc. It was recently shown that up to 40% of common APIs and 30% of API impurities are potential nitrosamine precursors, as they contain vulnerable amine moieties.

Regulatory Concerns and Industry Impact

The U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other regulatory bodies have established strict limits on acceptable levels of nitrosamines in pharmaceutical products. Companies must now implement advanced analytical techniques to identify, quantify, and mitigate these impurities to comply with evolving regulations and ensure patient safety.

The Importance of Nitrosamine Testing in Pharma

Pharmaceutical manufacturers must proactively detect and control nitrosamine impurities to prevent drug recalls, regulatory non-compliance, and potential harm to patients. Comprehensive testing helps:

1. Ensure Drug Safety: Identifying and controlling nitrosamines reduces the risk of exposure to carcinogenic compounds.
2. Regulatory Compliance: Meeting stringent guidelines avoids penalties and maintains market authorization.
3. Maintain Product Integrity: Enhancing quality control safeguards the reputation of pharmaceutical brands and their products.

Challenges in Detecting Nitrosamines

1. Extremely Low Concentrations: Due to very high genotoxicity of the nitrosamines the regulatory agencies have set very low permissible limits for nitrosamines (typically in the parts-per-billion (ppb) range). Detecting such minute quantities requires highly sensitive and specialized analytical techniques.
2. Complex Drug Formulations: Pharmaceutical products contain multiple ingredients, including active pharmaceutical ingredients (APIs), excipients, and stabilizers. These components can interfere with the detection of nitrosamines, making it difficult to isolate and quantify them accurately.
3. Regulatory and Methodological Challenges: There is no universal method for nitrosamine detection across all drug formulations. Regulatory agencies recommend multiple techniques, such as LC-MS/MS (liquid chromatography-mass spectrometry) and GC-MS (gas chromatography-mass spectrometry), but these require optimization for each specific drug product.

To address these difficulties, pharmaceutical companies rely on validated reference standards and advanced analytical techniques.

Why Choose Axios Research Inc for Nitrosamine Standards?

As a leading provider of impurity reference standards, Axios Research Inc. offers a reliable source for high-purity nitrosamine reference materials. Each impurity standard is backed by a comprehensive certificate of analysis. These documents provide unambiguous identity and purity data, validated using advanced methods specific to the impurity to ensure accurate representation.

Nitrosamine impurities pose significant challenges in the pharmaceutical industry, necessitating stringent testing and regulatory compliance. Partnering with a trusted supplier like Axios Research Inc. ensures access to high-quality nitrosamine reference materials, helping pharmaceutical companies safeguard patient health and maintain regulatory compliance. As the industry continues to evolve, having a dependable impurity supplier is essential for success in the pharma market.