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On August 6th the European Medicines Agency (EMA) issued a question-and-answer guide that provides further guidance to listing licensees (MAH) on dealing with nitrosamine impurities.
the guide highlights the potential risk of nitrosamine impurities in certain biological products, in addition to chemically synthesized APIs, and the current review requirements have been expanded to include biological products.
15-page question-and-answer guide on nitrosamine risk in biological products, the EMA requires MAH to conduct a risk assessment to determine whether chemically synthesized APIs are at risk of nitrosamines by March 31, 2021.
and for products containing bio-sourced APIs, the first step in the risk assessment should be completed by 1 July 2021.
the review, which was launched in September 2019, the EMA's Commission on Pharmaceuticals (CHMP) concluded that certain biological products may also be at risk of containing nitrosamine impurities, and therefore the current review requirements have been extended to include biological products.
biological products that are particularly at risk include biological products containing chemically synthesized fragments, biological products that add nitrite reagents, and biological products packaged in nitro cellulose bubbles.
, after the first step assessment, if the risk is identified, the second step, i.e. the confirmation test, is required.
second step of testing should be completed on time: for chemical APIs, they should be reported to the EMA by September 26, 2022, and for biological APIs, to the EMA by July 1, 2023.
third and final step in the review of the requirements: MAH is required to submit changes to demonstrate effective risk mitigation measures following confirmation of the presence of nitrosamines.
, detailed reporting guidance and reference materials are provided in the question-and-answer guide.
regulators around the world are concerned about the presence of the drug Central Asian nitroamine impurities.
the substance is present in nature in trace amounts, long-term exposure to elevated levels may increase the risk of certain cancers in humans.
nitrosamines, including N-nitrodamide (NDMA), can be formed as a by-product of API synthesis.
, metformin, renitinine and some angio-tension receptor blockers have been found to have high levels of nitrosamines.
other key elements of the paper, in addition to identifying which biological products may increase the risk of nitrosamine impurities, the document details the production, treatment and packaging processes known to be associated with nitroamine contamination in finished products in Central Asia.
, however, the list is not exhaustive, and the guidelines state: "MAHs/applicants and producers should include all potential sources of contamination or the formation of nitrosamines as part of their risk assessment."
the guidelines also warn that nitrosamines are often present in small amounts, which means extra care must be taken when analyzing methods.
mah should conduct control experiments and consider the use of orthpation analysis methods.
guide describes the specific requirements of the analysis method used for detection.
guidelines also list the daily acceptable limits for various nitrosamines;
EMA has developed a priority programme for product testing using a risk-based approach: "MAH may consider factors such as the maximum daily dose of the drug in question, the duration of treatment, treatment signs and the number of patients receiving treatment".
guidelines indicate that drugs that require higher doses and long-term use per day may be given higher evaluation and testing priorities.
ICH Q9 guide on quality risk management can guide the prioritization process.
guidelines describe the specific steps to be taken in the detection of nitrosamines, including measures to be taken when nitrosamines reach and do not exceed limits, including the development of mitigation measures and requirements for submission to regulatory authorities.
guide also addresses the ongoing process of submitting changes to a listing license and the methodology for submitting a new listing license application.
Ref.: (EMA) (2020-08-06) Nitrosamines EMEA-H-A5 (3)-1490 - Questions and answers for marketing Authorization 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.