EMA offers more clarity on controlling multiple nitrosamines

The European Medicines Agency (EMA) last week issued a revised question and answer guidance describing how marketing authorization holders (MAHs) should identify and control the risks of nitrosamines identified in drug products and active pharmaceutical ingredients (APIs).
 
The guidance contains minor revisions from a previous revision from October 2021. The revised guidance includes a new nitrosamine that should be tested: N-nitrosodipropylamine (NDPA) with a daily permissible threshold not to exceed 26.5 parts per million (ppm), and offers more clarity on how to assess the risk of multiple nitrosamines in a drug substance. 
 
Nitrosamine impurities have been a source of concern to regulators worldwide 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.
 
The guidance states that marketing authorization holders and applicants of all human medicinal products “should ensure that the presence of nitrosamines is controlled and kept as low as possible, irrespective of marketing status or the type of product (e.g. generics and over the counter (OTC) products).”
 
Two testing options for multiple impurities
 
EMA gives manufactures two options for calculating nitrosamine impurities when more than one is detected. Manufacturers can either calculate the total daily intake of all identified N-nitrosamines and ensure these limits do not exceed the acceptance intake (AI) limits of the most potent nitrosamine, or they can ensure that the total risk level does not exceed a one in 100,000 risk of cancer, per the International Council for Harmonisation’s M7(R1) guideline.
 
The revision adds new text stating that under the second option, manufacturers can either use a fixed or flexible approach for calculating AI limits.
 
Under the fixed approach, fixed AI limits can be set for individual nitrosamines, while “no limit for total N-nitrosamines is needed.” Under the flexible approach, each nitrosamine “should be specified at its AI limit in ppm/ppb [parts per million/parts per billion] and an additional limit for total nitrosamines is required.”
 
The update also adds a decision tree outlining options for controlling products with multiple nitrosamines.
 
Three-step review
 
The update was prompted by EMA’s call for review to request that manufacturers review their manufacturing processes to identify, and if possible, mitigate the risk of nitrosamine impurities and report outcomes back to authorities.
 
The call for review consists of three steps: the first step is for MAHs to perform a risk evaluation to identify APIs or finished products at risk of nitrosamines. The next step calls for confirmatory testing when a risk is involved and to report results back to authorities. The third step is for MAHs to implement risk mitigation measures when a nitrosamine impurity is confirmed.
 
Under Step 2, confirmatory testing for chemically synthesized APIs and submitting any changes must be completed by 26 September 2022. For products containing biological APIs, confirmatory testing and submitting changes must be done by 1 July 2023.
 
Under the first step, MAHs had to conduct evaluate whether chemically synthesized APIs are at risk for containing nitrosamines by 31 March 2021. For products containing biological APIs, these evaluations should have been conducted by 1 July 2021.
 
EMA said that nitrosamines can come from many sources, including using sodium nitrite or other nitrating agents in the presence of secondary or tertiary amines in the manufacturing process; using sodium nitrite in combination with reagents, solvents and catalysts; using contaminated raw materials in the API manufacturing process; or using contaminated recovered or recycled materials such as solvents, reagents and catalysts.
 
EMA Q&A on nitrosamine testing