Read this article in:
  • English
  • Português
  • Español
  • Risk Assessment for Nitrosamine Impurities

    In today’s pharmaceutical industry, the focus on identifying and assessing nitrosamines in drug products and active pharmaceutical ingredients (APIs) has intensified due to the potential carcinogenic nature of these impurities. Nitrosamines are of great concern as they can be genotoxic, mutagenic, and possibly carcinogenic. Detecting nitrosamine impurities in commonly prescribed medicines used for various treatments raises alarms about potential sources and manufacturing processes that may lead to their presence.

    The Importance of Nitrosamine Risk Assessment

    Nitrosamine risk assessment is critical for pharmaceutical manufacturers to comply with regulatory requirements and ensure the safety of patients. The FDA has been actively investigating nitrosamine impurities since 2018, focusing on drugs such as angiotensin II receptor blockers (ARBs) like ranitidine, nizatidine, and metformin. In response to the increasing concern, the FDA has released guidance for the industry on nitrosamine formation and its root causes in APIs and drug products, emphasizing the need for risk assessment and preventive action.

    Nitrosamine impurities were first found in some of the commonly prescribed medicines used for the treatment of diabetes, antacids, and others.

    FDA Guidance and Recommendations

    The FDA’s “Control of Nitrosamine Impurities in Human Drugs” (Rev 1, Feb.2021) guidance identifies nitrosamines as probable or possible human carcinogens. Accordingly, manufacturers should evaluate the risk of nitrosamine formation or contamination in their drug products, with particular attention to definite drug products prioritized for risk assessment.

    Steps to Mitigate Nitrosamine Impurities

    Drug product and API manufacturers take the following steps to mitigate nitrosamine impurities in their products:

    • Assess the risk of nitrosamine impurities: This includes assessing all marketed products, APIs, and products that are under-approved or pending applications. The risk assessment should be conducted in a timely manner, based on the prioritization of the drugs.
    • Conduct confirmatory testing for the presence of any nitrosamine impurities. This testing should be done using validated methods.
    • Report changes implemented to reduce or prevent nitrosamine impurities in drug products and APIs. This includes submitting a DMF (Drug Master File) and amendments to 21 CFR 314.420(c).

    Recommendations to API manufacturers

    1. Evaluate the manufacturing process and carry out a risk assessment to identify the potential for nitrosamine impurities. If the risk is identified, confirmatory testing should be done for the batches using appropriate validated methods.
    2. Take suitable actions to reduce the risk of nitrosamine contamination for APIs where there is potential for nitrosamine impurities. This may include changes to the manufacturing process, the use of different raw materials, or the addition of nitrosamine scavengers.
    3. If nitrosamines are present, detect and investigate the root cause. This may involve working with a qualified laboratory to identify the specific nitrosamine impurity and its source.
    4. Implement necessary changes to the manufacturing process to prevent or reduce nitrosamine impurities. This may involve changes to the temperature, pH, or other process parameters.

    Recommendations to Drug manufacturers

    1. Perform a risk assessment for the potential of nitrosamine impurities in drug products. This assessment should include collaboration with the API manufacturer to identify the risk of nitrosamine impurities in the API raw materials or other process conditions.
    2. Evaluate any pathway (including degradation) that may initiate nitrosamine formation during storage or drug product manufacture.
    3. If the risk assessment finds that there is no potential for nitrosamine impurities, no further action is required.
    4. If a risk of nitrosamine is identified, batches should be tested using appropriate validated methods.
    5. If nitrosamine impurities are detected, the manufacturer should investigate the root cause and implement changes to reduce or mitigate nitrosamine impurities in the manufacturing process.
    6. If an API DMF holder makes process changes in the ROS based on the confirmatory testing, they must submit amendments to the DMF and inform each manufacturer of the drug product that referenced the DMF (including approved and pending applications) in accordance with 21 CFR 314.420(c).
    7. If the drug product needs changes to prevent nitrosamine formation, the application holder should submit a supplement to notify the FDA of any such changes to conditions established in the approved applications beyond variations already provided for in their applications as per 21 CFR.


    How to evaluate nitrosamine risk assessment? 

    The risk assessment must include the evaluation of any pathway (including degradation) that may initiate nitrosamine during storage or drug product manufacture. If the risk assessment finds out that there are no potential nitrosamine impurities then no need for any further action if a risk of nitrosamine is identified in the drug product then testing of batches to be done with proper validation methods and if there is the detection of nitrosamine impurity than manufacturer should explore the root cause and apply changes to reduce or mitigate nitrosamine impurities in the manufacturing process.

    What is the main focus of pharmaceuticals on nitrosamine impurities?

    In the Pharmaceutical Industry main focus are the identification and presence of nitrosamines in drug products and the manufacturers of APIs and Drug products have the findings of nitrosamine impurities which may be likely human carcinogens in the drugs and requires the need risk assessment strategy in pharmaceutical products for potential nitrosamines presence.

    What are the measures to control the presence of nitrosamine?

    The manufacturing process should have a control strategy in regard to N-nitrosamines and include 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).


    Contact us for Nitrosamine Assessment Services