Nitrosamine Testing and Risk Assessment

Specialised Analytical services

Nitrosamines Analysis

International regulatory authorities have been investigating the presence of nitrosamine impurities in drug products since 2018. Several drug products including Valsartan, Losartan, Irbesartan, Ranitidine, Nizatidine, Varenicline, Rifampicin, Quinapril and Metformin were recalled from the market due to the presence of unacceptable levels of nitrosamine impurities. The term nitrosamine describes a class of compounds having a nitroso functional group bonded to an amine:

Regulatory guidance for industry has been published by the European Medicines Agency (EMA) in 2019 (Information on Nitrosamines for Marketing Authorization Holders, EMA/428592/2019) and the Food and Drug Administration (FDA) in 2021 (Control of Nitrosamine Impurities in Human Drugs, Revision 1). Recently, the Therapeutic Goods Administration (TGA) updated acceptable intake (AI) information for nitrosamines consistent with the EMA updates.

Therefore, pharmaceutical companies are required to assess the risk of nitrosamine contamination and develop appropriate control strategies to prevent or limit their presence in their drug product.

PharmSky offers nitrosamines assessments per regulatory requirements

Risk Assessment

A comprehensive risk evaluation to identify API and/or drug product nitrosamine risk. This includes assessment of API synthesis, excipients, reagents, solvents, water, drug product manufacturing and packaging materials for nitrosamines and nitrosamine precursors (nitrosating agents and secondary/tertiary amines). A risk assessment is required for existing commercial drug products and for any new drug applications.

Confirmatory Testing

If a risk is identified, the presence or absence of the nitrosamine must be determined. PharmSky provides confirmatory testing on drug products to verify the presence or absence of nitrosamines and their amount (if applicable). If any nitrosamine is found above acceptable levels, regulatory authorities should be notified as soon as possible.

Risk Mitigation

If the presence of a nitrosamine is confirmed, corrective actions should be implemented to prevent or reduce risks through submission of a variation. PharmSky provides support on regulatory strategy and required documentation to update the Marketing Authorisation, Dossier and Drug Master File (DMF) information.

Analytical Services

Why Choose PharmSky To Partner With?

PharmSky provides expertise in nitrosamine risk assessments and control strategies to minimize the risk of potential nitrosamines. Equipped with highly sensitive instruments, GC-MS/MS (Triple Quadrupole) and LC-QToF MS, and knowledge of pharmacopoeia guidelines (USP <1469> and EP 2.5.42), we can develop targeted methods to test for nitrosamine contaminants and nitrosamine drug substance related impurities at trace amounts.

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Frequently Asked Questions

The term nitrosamine describes a class of compounds having a nitroso functional group bonded to an amine:

Nitrosamines are formed by reaction of amines (secondary, tertiary or quaternary amines) with a nitrosating agent (e.g. nitrites or nitrates) under acidic conditions.

NDSRIs are a class of nitrosamines similar in structure to the API (having the API or an API fragment in the chemical structure) and are generally unique to each API.

 

We follow FDA guidance published in September 2024: Control of Nitrosamine Impurities in Human Drugs Guidance for Industry.

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