Introduction The Regulatory agency announced that Nitrosamine impurities N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) are said to be present in generic drug substances and drug product, especially in angiotensin II receptor blockers (ARBs) and belongs to a family of analogue compounds referred to as the sartans. Further FDA and EMA investigation also led to the detection of these Nitrosamine impurities in Pioglitazone and low level of NDMA impurity found in Metformin. Food Drug Administration (FDA) The U.S. Food and Drug Administration is investigating several potentially cancer-causing substances, called nitrosamines, recently found in some drugs, including those used to treat elevated blood pressure, heartburn, acid reflux, and diabetes. Some of these drugs from certain manufacturers – including angiotensin II receptor blockers (ARBs), Ranitidine, Nizatidine, and Metformin – have been recalled because of nitrosamine impurities. Most recently, the FDA announced that its testing showed levels of the nitrosamine N-Nitrosodimethylamine (NDMA) in some samples of the extended release (ER) formulation of the diabetes medicine Metformin that exceed the agency’s acceptable intake limit.

1. Nitrosamine Impurity: A Regulatory Perspective
Introduction
The Regulatory agency announced that Nitrosamine impurities N-nitrosodimethylamine
(NDMA) and N-nitrosodiethylamine (NDEA) are said to be present in generic drug substances
and drug product, especially in angiotensin II receptor blockers (ARBs) and belongs to a
family of analogue compounds referred to as the sartans. Further FDA and EMA investigation
also led to the detection of these Nitrosamine impurities in Pioglitazone and low level of NDMA
impurity found in Metformin.
Food Drug Administration (FDA)
The U.S. Food and Drug Administration is investigating several potentially cancer-causing
substances, called nitrosamines, recently found in some drugs, including those used to treat
elevated blood pressure, heartburn, acid reflux, and diabetes. Some of these drugs from certain
manufacturers – including angiotensin II receptor blockers (ARBs), Ranitidine, Nizatidine,
and Metformin – have been recalled because of nitrosamine impurities. Most recently, the FDA
announced that its testing showed levels of the nitrosamine N-Nitrosodimethylamine (NDMA) in
some samples of the extended release (ER) formulation of the diabetes medicine Metformin that
exceed the agency’s acceptable intake limit. The agency is also asking all manufacturers of ER
versions of Metformin to evaluate their risk of excessive NDMA and to test at-risk products
before each batch is released onto the U.S. market. If testing shows NDMA above the acceptable
intake limit, the manufacturer should inform the agency and should not release the batch to the
U.S. market. The FDA continues to work with manufacturers to investigate the source of
nitrosamines in drug products and whether they are at a level that may constitute risks to human
health. Some nitrosamines may increase the risk of cancer if people are exposed to them above

2. acceptable levels and over long periods of time. People taking drugs that contain NDMA at or
below the acceptable intake limits every day for 70 years are not expected to have an increased
risk of cancer. FDA has also published validated methods to detect and quantify NDMA and
NDEA impurities in all ARB drug substances and some drug products.
European Medicines Agency (EMA)
The European medicines regulatory has issued recommendations on impurities in medicines
following the conclusion of an exercise to draw on lessons learnt from the presence of
nitrosamines in a class of blood pressure medicines known as sartans. The guidance aim to
explain the responsibilities of companies involved in the manufacture of medicines and to amend
guidance on controlling impurities and good manufacturing practice and also cover the
management of impurities once detected, communication with patients and healthcare
professionals, and international cooperation. Regulators in the EU first became aware that they
were present in some sartan medicines in mid-2018 and this led to immediate regulatory action,
including the recall of medicines and measures to stop the use of active substances from certain
manufacturers. A review by EU in April 2019, established the sources of nitrosamines and set
out new manufacturing requirements for sartans. Although the exercise focused on nitrosamines
in sartans, the recommendations will help reduce the risk of impurities being present in other
medicines and ensure that regulators are better prepared to manage cases of unexpected
impurities in the future. In September 2019, EMA launched an Article 5(3) procedure to provide
additional guidance to companies that make and market medicines in the EU and the procedure
which will provide the key scientific opinion on the presence of nitrosamine impurities in human
medicines containing chemically synthesized active substances. Reviewing practices on the basis
of experience is one of the ways the authorities in the EU ensure that medicines in the EU are of
the highest quality. EU authorities will continue working closely with the European Directorate
for the Quality of Medicines & HealthCare and international partners and will take necessary
measures to protect and reassure patients.
Other Regulatory Agency
Therapeutic Goods Administration (TGA) of Australia advised in a public notice that it has
introduced requirements for sponsors of 'sartan' blood pressure medicines to take measures
to avoid the presence of N-nitrosamine impurities in medicines and implement rigorous
testing of their medicines to identify the presence of any N-nitrosamine impurities. The TGA
will provide a two year transition period (2019-2021) to allow sponsors to review and if
make necessary changes to their manufacturing processes and to implement adequate testing
methods. During the transition period sponsors must inform the TGA if they identify the
presence of N-nitrosamine compounds in their medicines. Changes to manufacturing
processes and/or controls if needed should be lodged as a 'category 3' request under section 9D
(3) of the Therapeutic Goods Act 1989 (the Act). The TGA Laboratories has adapted a publically
available US-FDA test method. Health Canada continues to work closely with international
regulatory partners including the FDA and the EMA to share information and coordinate efforts
on inspections, risk assessments and public communications. Health Canada has provided a
method that has been developed to detect and quantify the Nitrosamine impurities NDMA and
NDEA in angiotensin II receptor blockers (ARBs).
Conclusion:

3. Regulatory authorities such as FDA, EMA, TGA and Health Canada published several notices to
guide the manufacturer to control and limit Nitrosamine impurities to acceptable levels. The
authorities have also issued guides for marketing authorities to assess the Nitrosamine impurities
in human medicinal products. Nitrosamine impurity formation can be avoided by selecting
proper reagent, catalyst and solvents in the manufacturing of drug substances.
References:
 U. S. Food and Drug Administration update (Feb 6, 2020), what to know and do about
possible nitrosamines in your-medication, https://www.fda.gov/consumers/consumer-updates
 Tabrez Shaikh et al., (2020) Nitrosamine Impuirtes in Drug Substance and Drug
Products. Journal of Advances in Pharmacy Practices (2582-4465), 2(I), 48-57 .
 Heads of Medicines agencies, https://www.hma.eu/whatsnew.html
 Therapeutic Goods administration (TGA), n-nitroso compounds in sartans blood pressure
medicines, available at https://www.tga.gov.au