REGULATORY AFFAIRS – NITROSAMINES: WHICH STEPS SHOULD BE TAKEN?

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In June 2018, N-nitrosodimethylamine (NDMA) and similar compounds known as nitrosamines, classified as probable human carcinogen based on animal studies, were unexpectedly found in several blood pressure medicines known as sartans leading to some recalls and resulting in new manufacturing requirements and stricter limits for nitrosamines for these medicinal products.
Traces of NDMA have also been found in the active substance pioglitazone hydrochloride; however, considering that the levels of this impurity were within the temporary limits set after the review of sartans, no action was taken about the products on the market.

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In September 2019, EMA started an EU-wide review of ranitidine medicines after tests showed that some of these products too contained the impurity NMDA.
Considering the above-mentioned events, as a precaution, the Committee for Medicinal Products for Human Use (CHMP) asked to all Marketing Authorization Holders (MAHs) to review the medicinal products containing chemically synthesized active substances for the presence of nitrosamines.
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MAHs have the responsibility to review all the authorized medicinal products which contain chemically synthesized active substances, included generic and OTC medicinal products within 19 March 2020 (6 months from 19 September 2019, date of release of EMA notification “Information on nitrosamines for marketing authorization holders “).
The MAHs must:
  • Perform a risk assessment together with the active substance/s and finished product manufacturers using quality risk management principles according to ICH Q9 guideline (FMEA and FMCEA approaches). The sequence in which medicinal products are to be evaluated and prioritized should consider factors such as the maximum daily dose taken, duration of treatment, therapeutic indication and number of patients treated.
  • Notify the competent authorities when the risk assessment is concluded and provide them with the relevant outcome; risk evaluation documents do not need to be submitted but should be made available upon request.
  • When the risk assessment identifies the chance of nitrosamine presence, medicinal products must be tested in order to confirm the presence of nitrosamines using suitable validated test methods. If tests confirm the presence of nitrosamines, the competent authorities must be informed as soon as possible, irrespective of the amount detected, and the applicable variations (e.g. changes to the manufacturing process or to the specifications) should be submitted.
Testing and variations submission must be concluded within 19 September 2022 (3 years from 19 September  2019, date of release of EMA notification “Information on nitrosamines for marketing authorization holders “)

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