EMA updates Q&A on nitrosamine assessment and testing

Regulatory NewsRegulatory News | 07 July 2021 |  By 

The European Medicines Agency (EMA) has published an updated “question and answer” guidance describing how manufacturers should assess the risk of nitrosamine impurities in drug products and how to test products for these impurities.
It contains minor revisions from a previous version published last year. (RELATED: EMA addresses risk evaluation, mitigation for nitrosamines, Regulatory Focus, 6 August 2020).

EMA wants marketing authorization holders (MAHs) and manufacturers to evaluate whether their products are at risk of N-nitrosamine formation, test at-risk products for the impurities, and report on these outcomes. For products containing chemically synthesized active pharmaceutical ingredients (APIs), risk evaluations should have been reported by 31 March 2021; for products containing biological APIs, these evaluations should have been conducted by 1 July 2021.
The call for review consists of three steps: Step 1 is for MAHs to perform a risk evaluation to identify if APIs or finished products could be at risk for the presence of nitrosamines. If a risk is identified, MAHs must proceed to Step 2 and conduct confirmatory testing either to confirm or refute the presence of nitrosamines and report the outcome as soon as possible. The third step is for the MAHs to implement risk mitigation measures if the presence if nitrosamines is confirmed.
The most recent update adds a new section addressing line extensions and variations applications. "No risk evaluation is generally necessary when submitting line extension or variation applications,” according to the updated section. “The risk evaluation is only required to be submitted for products in scope of the call for review.” That is, risk assessments should be performed for all products for which a potential risk has been identified, irrespective of the marketing status of the product.
In some “exceptional cases,” however, a potential risk that comes to light during the assessment could still warrant investigation for the presence of nitrosamines.
The guideline also updates the previous version by adding a new nitrosamine that should be tested: N-nitrosomorpholine (NMOR) with a daily permissible threshold not to exceed 127 parts per million (ppm).
Nitrosamine impurities have been a hot button topic since they were detected in valsartan medicines in 2018 and subsequently recalled by EU authorities. Though nitrosamines occur naturally in very small quantities, they are a potential carcinogen. (RELATED: EU recalls some valsartan medicines over impurity, Regulatory Focus 6 July 2018)
By September 2019, N-nitrosodimethylamine (NDMA) and a related nitrosamine had been discovered in two additional angiotensin receptor blockers in addition to valsartan.  EMA then called on MAHs to review their chemically synthesized APIs to identify and mitigate the risk of the presence of nitrosamine impurities and report the outcome back to authorities. This review was later extended to biologics.
In late 2019, these recalls were extended to another drug class when certain lots of the antacid ranitidine were found to contain NDMA. Beginning in 2020, several US  companies voluntary recalled extended-release metformin drugs because of elevated levels of NDMA (RELATED: FDA names five companies recalling NDMA-contaminated metformin, Regulatory Focus 12 June 2020).
EMA’s updated Q&A guideline on nitrosamine testing


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Tags: EMA, Nitrosamines

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