Introduction: Metformin is a prescription drug used to control high blood sugar in patients with type 2 diabetes. The Regulatory agency announced that traces of Nitrosamine present in generic drug substances and drug product, further FDA and EMA investigation also led to the detection of these Nitrosamine impurities in low level of NDMA impurity in Metformin. Recent investigation: FDA has been investigating the presence of nitrosamines in drug products and in late 2019, become aware of NDMA in some Metformin products in other countries. The regulatory agency started testing to determine whether the Metformin in the U.S. supply was at risk, as part of the ongoing investigation into nitrosamine impurities across medication types. In February 2020, they had identified very low levels of NDMA in some samples, but at that time, no FDA-tested sample of Metformin exceeded the acceptable intake limit for NDMA. The FDA has maintained that it would continue with ongoing testing of Metformin and other medications, and if any levels of NDMA or other impurities were identified, swift action would be taken. Recently FDA became aware of reports of higher levels of NDMA in certain extended- release (ER) formulations of Metformin.

1. Nitrosamine impurities traces in Metformin
Introduction:
Metformin is a prescription drug used to control high blood sugar in patients with type 2
diabetes. The Regulatory agency announced that traces of Nitrosamine present in generic drug
substances and drug product, further FDA and EMA investigation also led to the detection of
these Nitrosamine impurities in low level of NDMA impurity in Metformin.
Recent investigation:
FDA has been investigating the presence of nitrosamines in drug products and in late 2019,
become aware of NDMA in some Metformin products in other countries. The regulatory agency
started testing to determine whether the Metformin in the U.S. supply was at risk, as part of the
ongoing investigation into nitrosamine impurities across medication types. In February 2020,
they had identified very low levels of NDMA in some samples, but at that time, no FDA-tested
sample of Metformin exceeded the acceptable intake limit for NDMA. The FDA has maintained
that it would continue with ongoing testing of Metformin and other medications, and if any
levels of NDMA or other impurities were identified, swift action would be taken. Recently FDA
became aware of reports of higher levels of NDMA in certain extended- release (ER)
formulations of Metformin.
In addition, EMA and national authorities are also assessing the impact of recent tests which
found NDMA in some EU batches of Metformin medicines, used for diabetes. Further results
from tests on Metformin in the EU are being awaited. In line with previous advice, patients
should continue taking their Metformin medicines as usual. The risk from not having adequate
diabetes treatment far outweighs possible risks from low levels of nitrosamines.
As Metformin is considered a critical medicine, EMA and national authorities are cooperating
closely to avoid possible shortages so patients can continue to get the treatments they need
Lab testing for the analysis of NDMA in metformin

2. FDA continues to investigate the presence of the N-Nitrosodimethylamine (NDMA) impurity in
Metformin approved for sale in the U.S. Metformin is a prescription drug used to control high
blood sugar in patients with type 2 diabetes. FDA testing has found NDMA in certain lots of
extended release (ER) Metformin and is recommending companies recall lots with levels of
NDMA above the acceptable intake limit of 96 nanograms per day. FDA is also collaborating
with international regulators to share testing results for Metformin. For reference, consuming up
to the acceptable daily intake limit, 0.096 micrograms (96 nanograms), of NDMA per day is
considered reasonably safe for human ingestion based on lifetime exposure. NDMA may
increase the risk of cancer if people are exposed to it above the acceptable level and over a long
period of time, but a person taking a drug that contains NDMA at-or-below the acceptable daily
intake limit every day for 70 years is not expected to have an increased risk of cancer
Conclusion
The FDA, EMA and other regulatory authorities are working closely with international drug
regulatory agencies and have been testing drug products for NDMA and are collaborating to
investigate the sources of these Nitrosamine impurities in Metformin, because of its extreme
toxicity regulatory authorities put forth the expectation of appropriate risk assessment and
control strategy.
References:
1. FDA alerts on nitrosamine impurity findings in metformin, available at
https://www.fda.gov/news-events/
2. European medicines agency , available at https://www.ema.europa.eu/en/news/update-
nitrosamines-eu-medicines
3. Laboratory analysis of metformin products, available at https://www.fda.gov/drugs