Contains Nonbinding Recommendations
The discovery of nitrosamines in some types of drug products led FDA and other international
regulators to conduct a detailed analysis of these impurities in affected APIs and drug products.
8,9
Based on the Agency’s current understanding, this guidance discusses potential root causes of
nitrosamine formation and advises API and drug product manufacturers that they should (1)
conduct risk assessments of their approved or marketed products and products with pending
applications, and (2) take appropriate actions to reduce or prevent the presence of nitrosamines in
APIs and drug products.
Although nitrosamine impurities have been found in only some drug products, and batches of those
products have been recalled when there were unacceptable levels
10
of these impurities, nitrosamine
impurities might exist in other APIs and drug products due to use of vulnerable processes and
materials that may produce nitrosamine impurities. Therefore, the recommendations made in this
guidance apply to all chemically synthesized APIs. They also apply to drug products containing
chemically synthesized APIs and to drug products at risk due to other factors described in this
guidance (see sections II.B and C), and not just to the drug products that have been identified in
FDA announcements.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements are cited. The use of the
word should in Agency guidances means that something is suggested or recommended, but not
required.
II. BACKGROUND
FDA has been investigating the presence of nitrosamine impurities in certain drug products. Since
2018, several drug products including ARBs, ranitidine, nizatidine, and metformin have been
found to contain unacceptable levels of nitrosamines.
In June 2018, FDA was informed of the presence of an impurity identified as N-
nitrosodimethylamine (NDMA) in the ARB valsartan.
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Through investigation, the Agency
determined that numerous lots of valsartan and a few other ARB drug products from different
manufacturers contained unacceptable levels of nitrosamines. The drug product manufacturers
8
Other regulators with which FDA has been collaborating include the European Medicines Agency (EMA),
European Directorate for the Quality of Medicines and Healthcare (EDQM), Health Canada (HC), Therapeutic
Goods Adminis tration (TGA, Australia), Ministry of Health, Labour and Welfare/Pharmaceuticals and Medical
Devices Agency (PMDA/MHLW, Japan), Health Sciences Authority, Singapore (HSA, Singapore), and Swissmedic
(Switzerland).
9
FDA’s validated laboratory methods used in assaying nitrosamine impurities in various drugs as well as the
analytical results for various drugs and batches are available at
https://www.fda.gov/news-events/press-
announcements/fda-statement-fdas-ongoing-investigation-valsartan-impurities-and-recalls-and-update-fdas-current,
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-
ranitidine, and https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-
metformin.
10
See Table 1 in section III.A. of this guidance.
11
https://www.fda.gov/news-events/press-announcements/fda-statement-fdas-ongoing-investigation-valsartan-
impurities-and-recalls-and-update-fdas-current