Nitrosamines New EMA Guidelines

Nitrosamines are classified as probable human carcinogens (substances that could cause cancer) on the basis of animal studies. In 2018, nitrosamines were found in a number of blood pressure medicines known as ‘sartans’, leading to a recall of several products.

Then, a nitrosamine impurity has been detected in a few batches of PDF icon pioglitazone from one company and in PDF icon batches of ranitidine. An EU-wide review of ranitidine has been initiated.


Information on nitrosamines for marketing holders


Marketing authorisation holders and APIs’ manufacturers are responsible for ensuring that their products are manufactured in accordance with relevant regulations. Consequently, they are responsible for ensuring that the quality of each batch of their product is fully satisfactory.

On September 19th, 2019, European Medicines Agency (EMA) published a new requirement that Marketing Authorization Holders (MAHs) for human medicines containing chemically synthesized active substances must review their medicines for the possible presence of nitrosamines impurities:

Information on nitrosamines for marketing authorization holders (EMA/189634/2019). Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products EMA/351053/2019 rev 1: “Temporary interin limits for NMBA, DIPNA and EIPNA impurities in sartan blood pressure medicines” and updates “Nitrosamine impurities in human medicinal products

Other authorities started an equivalent approach, e.g. Health Canada , TGA (Australia), Swissmedic, and recently FDA has also request to control nitrosamine impurities in human drugs .


What are nitrosamines?


Nitrosamines are chemical compounds classified as probable human carcinogens on the basis of animal studies. According to these studies, a long-term nitrosamines exposition could lead to a higher risk of cancer. They are formed by the reaction of secondary amines, amides, or it’s derivate with nitrites or nitrosantes agents. Nitrosamines are classified by ICH M7 Guidelines as Class 1 impurities, and they must been controlled.


How LEBSA act?

In order to be in compliance with this new requirement, and to assure people’s health and client’s compliance, as soon as we knew these guidelines our Regulatory Affairs team started to work with the risk evaluation of all our products, according to ICH Q9 guidelines. This assessment has considered all the items detailed in EMA guidelines:


  1. We considered all possible sources of nitrosamines formation (nitrosable and nitrosante agents, impurities, water used, cleaning procedure, recovered materials, degradation, contamination packaging, etc.) for all our marketed and developed APIs.
  2. We evaluated the risk as Low Risk, Medium Risk and High Risk. If needed, a Confirmatory test (with its validation) was done.
  3. On February 2020 the evaluation was finished and all our clients were notified about the conclusions (then the deadline has been moved to March 2021).


Fortunately, our APIs are free of Nitrosamines and we commit to maintain this assessment updated.

We have adjusted SOPs and we have added nitrosamine item into suppliers’ evaluation. Periodically, we review and follow up guidelines and internal documents. If a change supposes a risk in nitrosamine formation, we commit to evaluate the change and notify clients with the new results.

For future lunches, this evaluation is planned to be done during the Impurities evaluation and it will be added in this section as EMA requests.


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