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Information for Qualified persons (QP) of Marketing Authorisation Holders (MAHs) regarding N-Nitrosamine impurities in medicinal products

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Since 2018 there has been discussions of a problem related to the presence of N-Nitrosamine impurities in medicinal products containing chemically synthesized Active Pharmaceutical Ingredients (APIs). In this regard the EMA (European Medicines Agency), WHO (World Health Organization) and the FDA (U.S. Food and Drug Administration) have stated their opinions on mandatory measures that MAHs should take.

We would like to inform you about the services offered by Testing center GLOBALTEST in this connection, as well as to provide brief information about N-Nitrosamine impurities.

Brief information regarding N-Nitrosamine impurities in medicinal products

N-nitrosoamines refer to any molecule containing the nitroso functional group. These molecules are of concern because nitrosamine impurities are probable human carcinogens. Although they are also present in some foods and drinking water supplies, their presence in medicines is nonetheless considered unacceptable

Nitrosamine impurities can form during API processing under certain processing conditions and in the presence of some types of raw materials, starting materials, and intermediates. They may not be fully purged in subsequent steps of the API manufacturing process. The use of sodium nitrite (NaNO2), or other nitrites, in the presence of secondary or tertiary amines is a potential cause of nitrosamine formation.

Secondary amines can be present in reagents and solvents as impurities or degradants. They may also be part of reagents, solvents, APIs, their degradants, and precursor structures. F

All these cases lead to taking mandatory steps, including:

Mandatory steps, according to EMA’s document – ЕМА/189634/2019

Step 1 – Risk assessment
MAHs should perform risk evaluation of their medicinal products containing chemically synthesised API. MAHs together with API and finished product manufacturers are required to perform risk evaluations using quality risk management principles, as outlined in ICH Q9 guideline.

Step 2 confirmatory testing
in the event that a risk of presence of nitrosamines is identified as a result of the risk evaluation, confirmatory testing should be carried out using appropriately validated and sensitive methods in accordance with the prioritisation deriving from the risk evaluation conducted in step 1. Products identified as high priority should be tested as soon as possible. Confirmatory testing of all medicinal products identified to be at risk of presence of nitrosamines and submission of required changes in the manufacturing authorisations should be concluded at the latest within 3 years of the publication of this notification or at an earlier time if otherwise justified.

Services, offered by Testing Center Globaltest

Testing center GLOBALTEST offers development and validation of analytical methods and subsequent analyses for determination of N-Nitrosamine impurities in medicinal products. In order to be precise in this service, we would like you to present an information about the risk assessment performed and list of the identified N-Nitrosamine impurities subject of testing.

Based on the information obtained, we will prepare and send you a detailed Quotation for the development and validation of individual analytical method for the determination of the N-Nitrosamine impurities in the relevant product and their subsequent routine analyses.

The development and validation service includes:

  1. Development of analytical method;
  2. Validation of the developed method with the specific medicinal product provided by the client for the needs of the service;
  3. Presenting a finished Report for the validated method in English;
  4. Presenting a Test report (CoA) with results for the N-Nitrosamine impurities in the specific medicinal product provided by the client for the needs of the development and validation of the method;
  5. All services will be performed onside in the TC Globaltest labs;
  6. TAT – 50 days, starting from the assignment and delivery of all the reference materials and consumables for the service;

It is important to note that a single common method for determining N-Nitrosamine impurities for any medicinal product does not exist and cannot be developed and validated. An individual analytical method should be developed and validated for each individual medicinal product containing a chemically synthesized API.

The technical instruments, which TC Globaltest chose to use for these services, are GC/MS or LC/MS/MS. The judgment regarding their use may be yours, ours, or discussed. TC GLOBALTEST has experience in developing and validating analytical methods and performing routine analyzes for the identification of traces of N-nitrosamines such as N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEit), N-methyl-4-aminobutyric acid (NMBA) in various matrices. These N-nitrosamines are just an example of compounds that IC GLOBALTEST has worked with over the years. Incorporating other N-nitrosamines, different from the above mentioned is not difficult in the course of providing the service.

Performing routine subsequent analyses based on the developed method

TC GLOBALTEST offers a routine analyzes for the determination of N-Nitrosamine impurities in medicinal products based on the developed and validated method. The routine analyzes will be included in the general Quotation for the given medicinal product.

Contact information:


Phone: +359 700 20 661

Important links:

  1. European Medicines Agency’s information regarding N-nitrosamines – EMA/189634/2019 –
  2. World Health Organization’s article –
  3. ICH quideline Q9 for risk management – ICH Q9 guideline

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