Background
Medicine Regulatory Authorities first became aware of the presence of the nitrosamine impurity, N nitrosodimethylamine (NDMA), in products containing valsartan in July 2018. Valsartan is an Angiotensin II Receptor Blocker (ARB) and belongs to a family of analogue compounds commonly referred to as the sartans.
Nitrosamines, or more correctly N-nitrosoamines, refer to any molecule containing the nitroso functional group. These molecules are of concern because nitrosamine impurities are probable human carcinogens. Although they are also present in some foods and drinking water supplies, their presence in medicines is nonetheless considered unacceptable.
Further nitrosamine impurities were subsequently detected in other medicines belonging to the sartan family, including: N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitroso-ethylisopropylamine (NEIPA) and N -nitroso-N-methyl-4-aminobutyric acid (NMBA).
More recently, nitrosamine impurities have been reported in several other products.
Nitrosamines are not expected to be formed during the manufacture of the vast majority of APIs outside the class of sartans with a tetrazole ring. However, it is now known that these impurities can form during production under certain conditions and when certain solvents, reagents and other raw materials are used. In addition, impurities can be carried over during the manufacturing process when using already-contaminated equipment or reagents. Therefore, despite the low risk of nitrosamines being present, all FPP applicants and APIMF holders are being requested to conduct a risk assessment to determine the likelihood of the presence of nitrosamines, and if necessary take measures to mitigate the risk of nitrosamine formation or presence during manufacture.
Action
WHO Prequalification Unit – Medicines will be contacting FPP applicants and APIMF holders to request that a risk evaluation is undertaken. A risk evaluation should be undertaken for any Prequalified API or FPP, accepted APIMF, or any FPP or APIMF currently under evaluation by 31 December 2020.
Applications to prequalify an FPP, API or submissions of APIMFs made prior to 31 December 2020 do not require the availability of risk assessment at the time of submission. However, such an evaluation must have been undertaken within 6 months of the acceptance for assessment of the application.
For applications made after 31 December 2020, it is expected that a risk assessment for the presence of nitrosamines will have been conducted prior to submission.
Once the risk assessments have been completed the outcome of the evaluation should be reported to WHO Prequalification Unit – Medicines, using designated templates. The risk assessments themselves do not need to be submitted.
Risk assessments may be requested by WHO Prequalification Unit – Medicines for targeted APIs known to be at risk of nitrosamine content and should be made available if requested by WHO Prequalification Inspection Team.
APIMF holders are reminded that they should provide the appropriate information relating to the risk evaluation they have performed for their APIMFs or prequalified APIs to their FPP customers, even if no risk has been identified, such that FPP applicants using the APIMF procedure or a Prequalified API can use this information to fulfil their responsibilities in a timely manner.
The European Medicines Agency (EMA) and US Food and Drug Administration (USFDA) websites contain further information regarding the nitrosamine issue. WHO has also published an information note on this issue at the following web address:
https://www.who.int/medicines/publications/drugalerts/InformationNote_Nitrosamine-impurities/en/
For further information, please contact Dr Matthias Stahl (stahlm@who.int).