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  • Control of Nitrosamine Impurities in Human Drugs

    The pharmaceutical industry is committed to producing safe and effective medicines. One aspect that has come under scrutiny is the presence of nitrosamine impurities in APIs and drug products. These impurities, considered potential human carcinogens, have led regulatory agencies to take a closer look. Let’s delve into the imperative task of Control of Nitrosamine Impurities in Human Drugs.

    Understanding the concern

    In the world of pharmaceuticals, ensuring patient safety is paramount. However, the presence of nitrosamine impurities in certain drugs has raised alarms due to their potential cancer-causing effects. This concern has prompted regulatory agencies to investigate the issue.

    Product recalls highlight the risk

    Some of the drugs including angiotensin II receptor blockers (ARBs), Ranitidine, Nizatidine, and Metformin have been recalled because of nitrosamine impurities which present a clear risk and presence of potential nitrosamines in any pharmaceutical products.

    FDA’s guidance

    The FDA’s guidance on “Control of Nitrosamine Impurities in Human Drugs” (Rev 1, Feb. 2021) offers a strategic approach. It encourages manufacturers to identify the root causes of nitrosamine formation in APIs and drug products. Manufacturers are advised to conduct risk assessments on marketed or approved products and take preventive actions to mitigate or prevent the formation of nitrosamines. This guidance is applicable for APIs synthesized chemically.

    Recent developments: Sitagliptin Case

    A recent case involving Sitagliptin highlights the ongoing nature of this challenge. The FDA detected nitrosamine impurities in certain samples of Sitagliptin, defined as Nitroso-STG-19 (also known as NTTP), a medicine used to control high blood pressure in patients with type 2 diabetes mellitus. This serves as a reminder that vigilance and ongoing quality efforts are essential to ensure the safety of pharmaceutical products.

    Understanding nitrosamine formation

    Nitrosamine formation occurs through reactions between nitrites and amines. Manufacturers must implement rigorous quality checks, evaluations, and investigations to mitigate potential risks and avoid product recalls.

    Nitrosamines contain nitro functional group (–NO) which forms when nitrates or nitrites in reaction with secondary or tertiary amines. Nitrites used as reagents in one step can carry over into successive steps, in spite of operation or purification it reacts with amines and produces nitrosamine impurities. Hence, whenever nitrites salts are present, the carryover into the next steps cannot be ruled out. In general risk of nitrosamine impurities formation in processes when there is the use of nitrites in the presence of secondary, tertiary, or quaternary amine.

    Crucial role of nitrosamine precursors

    Secondary, tertiary, or quaternary amine and nitrites also can be called nitrosamine precursors. The nitro group is related to mutagenicity and genotoxicity, which may be possible human carcinogens, based on the studies. As per the pre-clinical test study finding it is confirmed the evidence of their carcinogenicity. Due to this reason, nitrosamine content is not acceptable to regulatory agencies.

    Taking action to reach quality goals

    To curb nitrosamine impurities, manufacturers are advised to avoid reaction conditions that lead to their formation. The manufacturing process itself should be meticulously designed to facilitate the removal of these impurities in successive steps.

    Setting nitrosamine limits

    Nitrosamines or more correctly N-nitrosamines refer to any molecule containing the nitroso functional group. FDA recommends acceptable intake (AI) limits for nitrosamine impurities NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA as shown below in the table, and recommends that manufacturers use the mentioned limits in API and dug product when determining the limit for nitrosamines.

    NitrosamineAI Limit
    NDMA96.0 ng/day
    NDEA26.5 ng/day
    NDIPA26.5 ng/day
    NIPEA26.5 ng/day
    NMBA96.0 ng/day
    NMPA26.5 ng/day

    The term acceptable intake (AI) used in ICH M7 (R1) indicates the threshold of toxicological concern (TTC) considered for the impurity to be associated with negligible risk of carcinogenic or another toxic effect. Seven Nitrosamine impurities have been identified by FDA and may be present in drug products. Chemical structures of seven nitrosamine potential impurities in APIs and Drug products as represented below.

    Based on the above nitrosamine impurities, FDA has given acceptable interim limits for these impurities and also recommends the manufacturers to control the nitrosamine levels by reducing or removing the impurities if they are above the interim limit.

    Strategic Approaches for Nitrosamine Control

    Manufacturing Process Development

    Manufacturers of Active Pharmaceutical Ingredients (APIs) are advised to establish robust strategies for nitrosamine control. This involves meticulous development and design of the Route of Synthesis (ROS) and the implementation of plant processes. These actions align with recommendations set forth in key industry guidelines, including:

    • ICH M7 (R1): Guidance that addresses the assessment and control of DNA-reactive (mutagenic) impurities in pharmaceuticals.
    • ICH Q7: Guidelines on Good Manufacturing Practice for Active Pharmaceutical Ingredients, emphasizing quality systems and risk management.
    • ICH Q11: Guidance on Development and Manufacture of Drug Substances, underlining quality considerations during drug substance development.

    European Medicines Agency (EMA) Vigilance

    European Medicines Agency (EMA) continues to monitor the presence of nitrosamine impurities in medicines in cooperation with regulators from outside the European Union (EU) and to work with marketing authorization holders to find rapid solutions to address any adverse findings. EMA evaluated the risk of nitrosamine presence or formation during the manufacturing of human medicines and issued guidance to the marketing authorization holders (MAH) to avoid the presence of nitrosamine impurities.

    Recently European Medicines Agency (EMA) updated the guidance and recommendation for preventing the presence of nitrosamine and also in the context of applicants/MAHs of human medicinal products to work with active pharmaceutical ingredients (APIs) and finished products (FPs) manufacturers to control the presence of nitrosamine or below the limit.

    The EMA Framework

    On December 21, 2022, the European Medicines Agency published a comprehensive set of questions and answers. This publication addresses marketing authorization holders and applicants and delves into the CHMP opinion for Article 5(3) of Regulation (EC) no 726/2004 referral on nitrosamine impurities in human medicinal products. Key areas covered include regulatory actions taken upon identifying N-nitrosamines exceeding Acceptable Intake (AI), strategies to control nitrosamine presence until substance-specific AI is established, and methods to manage the presence of N-nitrosamines during Corrective and Preventive Action (CAPA) implementation.   

    Comprehensive Control Strategy

    In the pursuit of impeccable pharmaceutical quality, the manufacturing process must encompass a robust control strategy for N-nitrosamines. This involves multifaceted measures, both prospective and current, to mitigate the risk of generation or contamination with these impurities. Integral actions include potential modifications to the manufacturing process, enhancements in raw material quality, method development, meticulous specification setting, and comprehensive evaluations of equipment and premises. Moreover, a stringent environment monitoring and cleaning procedure further bolster the integrity of the pharmaceutical manufacturing process.


    How many nitrosamine impurities have been identified by FDA that may be theoretically present in drug products? 

    Nitrosamines or more correctly N-nitrosoamines refers to any molecule containing the nitroso functional group. Seven Nitrosamine impurities have been identified by FDA and may be present in drug products as N-nitrosodiethylamine (NDEA), NDMA, N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoisopropylethyl amine (NIPEA). N-nitrosomethylphenylamine (NMPA) and N-nitrosodibutylamine (NDBA). Actually, five of them have been detected in drug products and drug substances (NMPA, NIPEA, NMBA, NDEA, and NDMA).

    What are the measures to control the presence of nitrosamine?

    The manufacturing process should have a control strategy in regard to N-nitrosamines, further including the prospective and current measures to mitigate the risk of generation or contamination with nitrosamine ( like change in the manufacturing process, raw material quality change, development of methods, appropriate specifications and also to evaluate the equipment and premise like its environment monitoring and cleaning procedure).

    What are the FDA guidelines for Control Nitrosamine Impurities in Human Drugs?

    FDA guidance to “Control of Nitrosamine Impurities in Human Drugs” (Rev 1, Feb.2021) recommends that the nitrosamines are probable or possible human xdcarcinogens, so the manufacturers should consider the probable cause of nitrosamine formation and evaluate the risk of nitrosamine formation or contamination in their drug products and the agency may suggest that definite drug products become the priorities for risk assessment.