Latest Guidances regarding Nitrosamine Impurities

Are you aware of the latest news on Nitrosamines in Europe and US? Do you know the details and deadlines? HORN Pharmaceutical Consulting is glad to help you find out more.

1.Situation in EU

A review of all marketed products is needed with respect to their risk of nitrosamines. This is requested from the Marketing Authorisation Holder (MAH) and concerns drug products containing drug substances produced by chemical synthesis and biologics. 
The process consists of 3 steps:
  • Step 1: Risk evaluation
    • Deadlines:
      • chemical medicines: 31. March 2021 (consider extension of deadline)
      • biological medicines: 1 July 2021 

  • Step 2: Confirmatory testing (if a risk is identified in step 1)
  • Step 3: Submission of the variation/Update of the MAA (e.g. changes in the manufacturing process)
    • Deadlines:
      • chemical medicines: 26. Sept. 2022
      • biological medicines: 1 July 2023

In order to standardize the process, templates are available for reporting the outcome of steps 1 and step 2. If you have identified a risk and move into confirmatory testing, you need to have sufficiently sensitive methods which are validated. An update of your risk assessment is needed, if you identify new risks. 

For biologics, special consideration should be given on the following risk factors: biologics containing chemically synthesized fragments, using processes with nitrosating agents or being packed in certain packaging materials containing nitrocellulose. 

The previous letter ‘Information on nitrosamines for marketing authorisation holders’ (EMA/189634/2019, published on 19 September 2019) was replaced by the CHMP Article 5(3) opinion and the latest Question and Answer document. For further details see:

2. Situation in US

FDA published on 1 September 2020 a Guidance on Control of Nitrosamine Impurities in Human Drugs for immediate implementation. 

API-manufacturers (DMF-holders) should check their manufacturing process and identify risks for potential nitrosamine contamination. If a risk is identified, testing is needed. If testing detects nitrosamine impurities, then root cause analysis is needed and changes should be implemented to prevent these impurities. 

Drug product manufacturers also need to follow this approach. The deadlines are as 
  • Step 1: Risk assessment (by 1. March 2021)
  • Step 2: Confirmatory testing
  • Step 3: Submission of changes (by 1. Sept. 2023)

For new submissions the same process is applied, but can be filed as amendments, if the corresponding information is not readily available at the time of submission.

Both, EU and US have this 3-step approach and the same deadline for step 1, but different deadlines for step 3. Please do not underestimate the work-load involved in getting the risk assessments done. If a risk is present you need to move into step 2 and obtain results with sufficiently validated methods. 

Consider that not only the API, but also excipients and packaging material may lead to nitrosamine impurities in the drug product. Consider risk factors already during development of your drug substance and your drug product. Think about potential new risks, if you introduce changes.

Please feel free to contact us at, if you need support on these activities.
We know the details and guide you through the process.



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