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  • FDA Guidance for Industry on the AI Limits for Nitrosamine Drug Substance-Related Impurities

    In Pharmaceutical Industry today’s main concern is the identification and presence of nitrosamines in drug products and drug substances. The manufacturers of active pharmaceutical ingredients (APIs) and drug products have the findings of nitrosamine impurities which may be likely human carcinogens and require the need for risk assessment strategy for potential nitrosamines and their presence.

    The US Food and Drug Administration (FDA) on 4th Aug 2023 released the final guidance document on the “Recommended Acceptable Intake Limits for Nitrosamine Drug substance-Related Impurities (NDSRIs guidance)”. This guidance recommends predicting the mutagenic and carcinogenic potential of nitrosamine drug substance-related impurities (NDSRIs) that might be present in drug products and recommends (AI) acceptable limits for NDSRIs to the manufacturers and applicants of drugs including prescription and over-the-counter (OTC) drug products.

    NDSRIs are the class of nitrosamine impurities that have been identified in many active pharmaceutical ingredients (APIs) and in drug products. These impurities share structural similarity to the API (having API fragment or API in the chemical structure) and hence unique to each API. Through nitrosation of APIs (or API fragments) NDSRIs form in the drug product which have secondary or tertiary amines when exposed to nitrosating agents like residual nitrites in excipients which are used to formulate drug products.

    This guidance suggests a risk-based safety assessment for NDSRIs to be used by the manufacturers and applicants to identify AI limits in their APIs and drug products in alliance with recommendations given in the guidance for industry control of Nitrosamine impurities in human drugs ( Feb 2021) Nitrosamine guidance.      

    The detection of nitrosamine impurities was found in some of the commonly prescribed medicines used for treating diabetes, antacids, and others. Nitrosamine impurities and their presence and investigation in some of the drug products have been carried out by the FDA since 2018 when the FDA was informed of the presence of an impurity as N-Nitrosodimethylamine (NDMA) in the angiotensin receptor blocker Valsartan.

    In drug products, the initial reports of nitrosamine impurities were of small molecules of nitrosamines such as NDMA, compounds that are formed by nitrosating reactions between amines (secondary, tertiary, or quaternary amines) and nitrous acid (nitrite salts under acidic conditions) that are generally due to synthesis of API conditions that introduce nitrite, nitrous acid, and amide solvents.

    FDA issued guidance to the industry in the year 2020, the Nitrosamine Guidance recommending that the manufacturers of drug products and API should take steps to detect and prevent unacceptable levels of nitrosamine impurities in drug products or to avoid their presence when feasible.

    The Nitrosamine guidance introduced a three-step process that manufacturers and applicants should take to mitigate nitrosamine impurities in their drug products.

    1. Conduct risk assessments for nitrosamine impurities in their APIs and drug products.
    2. Conduct confirmatory testing if risk is identified and
    3. A reported change is implemented to reduce or prevent the presence of nitrosamine impurities in drug products and APIs in approved and pending NDAs and ANDAs.

    FDA also recommends to the manufacturers and applicants whose drug products contain multiple nitrosamines: If more than one nitrosamine impurity (NDSRI(s) and /or small molecule nitrosamine(s) is identified and if the nitrosamine total level exceeds the recommended AI limit for most of the potent nitrosamine in the drug product based on the maximum daily dose the applicant or the manufacturer should contact the agency.

    Recommended AI limits for NDSRIs at risk of formation in certain APIs: FDA has identified a number of APIs that have secondary or tertiary amines and so are at risk for forming NDSRIs. Hypothetically under certain conditions related to the manufacturing and formulation process for the drug product, such as residual nitrites in excipients used to formulate the drug product, these APIs could form NDSRIs.

    FDA has applied the predicted carcinogenic potency categorization to these APIs. Furthermore correctly based on the scientific analysis of chemical structures they have concluded that when an API contains hypothetical nitrosated forms of secondary amine- and dimethyl tertiary amine- groups these recommended AI limits based on predicted carcinogenic potency should be applied to the NDSRIs to the extent they form in the these APIs.  

    Nitroso Impurities

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    FAQs:

    What is the FDA update for nitrosamine impurities?

    The US Food and Drug Administration (FDA) released the final guidance document on the “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)”.

    What are the steps to mitigate nitrosamine impurities in drug products?

    Nitrosamine guidance introduced a three-step process that manufacturers and applicants should take to mitigate nitrosamine impurities in their drug products. 1) Conduct risk assessments for nitrosamine impurities in their APIs and drug products, 2) Conduct confirmatory testing if risk is identified, 3) a report change is implemented to reduce or prevent the presence of nitrosamine impurities in drug products and APIs in approved and pending NDAs and ANDAs.

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