Controlling Nitrosamine Impurities: Questions & Answers
The nitrosamines may occur in very small quantities in some drugs but they are a potential carcinogen. That’s why Nitrosamine impurities have been a source of concern in the pharmaceutical industry.
On 31 January 2022 The European Medicines Agency (EMA) announced a revised question and answer guidance explaining how marketing authorization holders (MAHs) should detect and control the risks of nitrosamines discovered in drug products and active pharmaceutical ingredients (APIs).
This guidance declares 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 options for manufacturers to calculate nitrosamine impurities:
In previous EMA revision stated that drugmakers can analyze the total daily intake of all identified N-nitrosamines and confirm these limits do not exceed the acceptance intake (AI) limits of the most potent nitrosamine. Another option is they can guarantee that the total risk level does not exceed one in 100,000 risks of cancer, per the International Council for Harmonisation’s M7(R1) guideline.
This latest revision adds new text stating that under the second option, drug manufacturing companies can either use a fixed or flexible approach for calculating acceptance intake (AI) limits.
3-Step Call for Review
This update was encouraged by EMA’s call for review to request that drug manufacturers review their manufacturing processes to identify, and if possible, diminish the risk of nitrosamine impurities and report the results back to authorities.
In step 2 confirmatory testing for chemically manufactured APIs and submit the results by 26 September 2022.
In the last 3rd step, MAHs will execute risk mitigation measures when a nitrosamine impurity is confirmed.
