EMA addresses risk evaluation, mitigation for nitrosamines

Regulatory NewsRegulatory News | 06 August 2020 |  By 

An updated question-and-answer document from the European Medicines Agency (EMA) provides guidance on handling nitrosamine impurity testing for marketing authorization holders.
Marketing authorization holders (MAHs) are to perform a risk evaluation to ascertain whether chemically synthesized active pharmaceutical ingredients (APIs) are at risk for containing nitrosamines by 31 March 2021. Products containing biological APIs should undergo this first step in risk evaluation by 1 July 2021.
After completing a review launched in September 2019, EMA’s Committee for Medicinal Products for Human Use (CHMP) concluded that some biological medicines might also be at risk for containing nitrosamine impurities, so the current call for review has been extended to include biological medicinal products. Biologics particularly at risk include those containing chemically synthesized fragments, those where nitrosating reagents are added, and those packaged in nitrocellulose blister packs.
The initial evaluations are followed by a second step of confirmatory testing when risk is involved. Step 2 testing should be completed and reported to EMA by 26 September 2022 for chemical APIs and by 1 July 2023 for biological APIs.
The call for review’s third and final step requires MAHs to submit variations demonstrating implementation of effective risk-mitigating measures when nitrosamine presence is confirmed. Templates and detailed reporting guidelines and references are provided in the question-and-answer (Q&A) document.
Regulators worldwide have addressed the presence of nitrosamine impurities in medicines; the substance is present naturally in minute quantities, but long-term exposure to elevated levels may increase the risk of some cancers in humans. Nitrosamines, including N-nitrosodimethylamine (NDMA), may be formed as a by-product of API synthesis. To date, metformin, ranitidine, and some angiotensin receptor blockers are among the medicines which have been found to have elevated nitrosamine levels. (RELATED: More metformin recalled for NDMA; 6 firms now affected, Regulatory Focus 08 July 2020)
In addition to identifying which biologics might be at increased risk for nitrosamine impurities, the document also sets forth in detail the manufacturing, handling and packaging processes known to be identified with nitrosamine contamination in finished products. However, the list is not exhaustive, and “MAHs/Applicants and manufacturers should consider as part of the risk evaluation all potential sources of contamination or formation of nitrosamine,” says the Q&A.
The document also cautions that the minute amount of nitrosamine required to cross the impurity threshold means that great care must be taken with analytic methods. MAHs should conduct control experiments, giving consideration to using orthogonal analytical methods. The guidelines delineate specific requirements for analytic methods to be used in testing.
The Q&A also sets out the daily acceptable limit for various nitrosamines; none exceed 96 ng/day, and all limits apply only if a single nitrosamine is identified.
EMA has set forth a priority scheme for product testing using a risk-based approach: “MAHs may consider factors such as the maximum daily dose taken for the concerned medicinal product, duration of treatment, therapeutic indication and number of patients treated,” according to the Q&A document. Medicines that require higher daily dosing and those taken chronically may be placed at higher priority for evaluation and testing, notes the Q&A; the International Council on Harmonization’s Q9 guideline on quality risk management can guide the prioritization process.
Specific steps to be taken when nitrosamines are detected are addressed in the Q&A, including guidance about measures when the nitrosamine limit is and is not exceeded, including delineation of mitigation measures and required submissions.
The Q&A addresses the procedure for submitting variations for ongoing marketing authorizations as well as the approach when new marketing authorization applications are submitted.
Full recommendations from the “lessons learned” exercise are available on EMA’s website, which also links to the final findings of an Article 5(3) review of the nitrosamine impurities question.
EMA nitrosamines Q&A


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