According to the CMDh practical guidance for Marketing Authorization Holders (MAHs) of nationally authorized products, the evaluation of nitrosamine impurity or cross-contamination in a marketed product is a critical criterion. Nitrosamines are proven to be carcinogenic and can affect the overall output of the formulated product.

Considering the severity, the Co-ordination group for Mutual recognition and Decentralised procedures – human (CMDh) issued the following first three (03) steps a manufacturer must follow to mitigate the amount of impurity in the final drug product.

Step 1: Risk Evaluation

As per the guidelines stated by the United States Food and Drug Administration (USFDA) to mitigate nitrosamine impurity, MAHs were obliged to submit the conclusions of the risk evaluations of all their product categories for chemically synthesized Active Pharmaceutical Ingredients (APIs) and biological APIs by the end of 2021. If the required documents aren’t already submitted, the MAHs must ensure the applications are submitted to the CMDh within the newly specified timelines.

The template released by the CMDh includes two (02) case scenarios:

  1. If no risk is identified, MAHs must just submit step 1 only after reaching a conclusion about the products.
  2. If Risk is identified in the product, the MAHs should go ahead and submit the step 1 response template and continue with step 2 confirmatory testing of the finished product.

The manufacturer must use the given templates to raise concerns to the national competent authority as soon as the individual risk assessment is finalized. The MAHs can submit one (01) application with different groups for similar product outcomes.

Step 2: Confirmatory Testing

The MAH needs to carry out further confirmatory tests post informing the Health Authority (HA) about the presence of nitrosamine. A MAH can use the template for step 2, which is ‘Nitrosamine detected above the acceptable intake,’ reporting if the present levels of nitrosamine:

  1. Surpasses the acceptable intake limit
  2. Exceeds the lifetime excess cancer risk of 1:100,000
  3. Is a newly identified nitrosamine that is not covered in the Committee for Medicinal Products for Human Use’s (CHMP’s) article 5 (3) opinion, irrespective of the amount detected

If the detected impurity doesn’t include the enlisted scenarios, step 2, the ‘Nitrosamine detected template,’ must be used.

Update: The deadline for the completion of the confirmatory testing is September 26, 2022.

Step 3: Update the HAs

Post the confirmatory testing, the manufacturers must submit the amended manufacturing process protocols to the HA. The revised protocol must include procedures that help bypass the nitrosamine impurity.

Update: The CHMP and CMDh have extended the previously stated deadline for submitting documents with variations in applications for chemical medicines from September 26, 2022, to October 01, 2023, in July 2022

Nitrosamine impurities are critical to biologically or chemically synthesized drug products. To safeguard the patient population from such possible impurities or cross-contamination, HAs state stringent quality protocols. At Freyr, our team of experts is well-versed with the template format and final draft review stated by the CMDh. Submit your confirmatory testing results within the stated timelines and in the correct format. Contact us for compliance best practices.


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