What are NDMA and NDEA and NMBA impurities?
contain NDMA, NDEA or NMBA impurities in the future whilst establishing suitable analytical methods to determine levels of these impurities and establish interim limits for nitrosamine impurities. NDMA and NDEA impurities NDMA is an impurity found in valsartan APIs and products and was the driver for a product recall by the FDA in July 2018.
What does NMBA mean for ARB?
The impurity is a known animal and potential human carcinogen. This is the first ARB recall resulting from the presence of NMBA, which is the third type of nitrosamine impurity detected in ARB medicines.
What is NMBA (N-nitrosodimethylamine)?
While NDMA (N-nitrosodimethylamine) and NDEA (N-nitrosodiethylamine) have been culprits in previous blood pressure medication recalls over the past year, this time the culprit is NMBA. Testing has found that NMBA levels in certain lots of losartan potassium blood pressure medications have exceeded the FDA’s interim acceptable intake limits.
What do we know about nitrosamine impurities in ARBs?
three nitrosamine impurities (NDMA, NDEA or NMBA) which have been found in some angiotensin II receptor blocker (ARB), such as valsartan, active pharmaceutical ingredients (APIs) and drug products. Robust analysis to determine if these are
What is nitrosamine impurity Nmba?
Impurity risk. Nitrosamine impurities found in some angiotensin II receptor blocker and histamine II receptor blocker medicines, have been the driver for recent product recalls. Laboratory studies have concluded that these impurities are classified as probable human carcinogens.
How many types of nitrosamine impurities are there?
FDA has identified seven nitrosamine impurities that theoretically could be present in drug products: NDMA, N-nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA), N-nitrosodiisopropylamine (NDIPA), N- nitrosodibutylamine (NDBA), and N- ...
What is NDMA and NDEA?
NDMA and NDEA are classified as probable human carcinogens and were believed to have been introduced into the finished products because of the manufacturing processes used to make the drug substance.
What are azido impurities?
What is the azide impurity? The impurity, known as azidomethyl-biphenyl-tetrazole (AZBT), is a compound that can form during the manufacture of the active ingredient in some sartan medicines. It is known to damage DNA, and as a result long-term exposure over years may increase an individual's risk of developing cancer.
What products contain nitrosamine?
Foods which have been shown to contain volatile nitrosamines include cured meats, primarily cooked bacon; beer; some cheeses; nonfat dry milk; and sometimes fish. It should be emphasized that not all samples analyzed contain detectable amounts of nitrosamines.
What is nitrosamine used for?
Nitrosamines are produced by the reaction of nitrites and secondary amines. Nitrites are used as food preservatives, e.g. cured meats. Secondary amines arise by the degradation of proteins (food). Nitrite and nitrosamine intake are associated with risk of gastric cancer and oesophageal cancer.
What drugs have NDMA in them?
To date, the FDA has found excessive amounts of NDMA in several lots of angiotensin receptor blockers (ie, valsartan, losartan, and irbesartan), metformin extended release products, and ranitidine tablet and syrup products.
What kind of drug is NDMA?
N-nitrosodimethylamine (NDMA) is a hepatotoxic agent and carcinogen contaminant in commonly used medications such as valsartan, losartan, irbesartan, and ranitidine.
What foods contain NDMA?
NDMA can also be found in many processed foods and beverages such as whiskey, beer, cured meats, bacon, and cheeses. Levels of NDMA in these foods are typically much higher than levels of NDMA found in treated drinking water. *One microgram per liter (µg/L) is the same as one part per billion (ppb).
Does losartan still contain NDMA?
We are currently aware of NDMA and NDEA in certain valsartan, irbesartan and losartan-containing products, and those products and some active pharmaceutical ingredients (API) used to manufacture them have been recalled from the U.S. market.
What are sartan drugs used for?
Valsartan, losartan, irbesartan and other “-sartan” drugs are a class of medicines known as angiotensin II receptor blocker (ARBs) used to treat high blood pressure and heart failure.
Which lots of losartan are recalled?
The affected lots of the voluntary recall by Legacy Pharmaceutical Packaging are the following: NDC 68645-494-54, losartan potassium tablets USP 50 mg, 30 count, Legacy Lot 180190, expires on 10/2020. NDC 68645-494-54, losartan potassium tablets USP 50 mg, 30 count, Legacy Lot 180191, expires on 10/2020.
Is NDMA a human carcinogen?
NDMA and NDEA belong to the so-called “cohort of concern”, which is a group of highly potent mutagenic carcinogens that have been classified by the WHO's International Agency for Research on Cancer as probably human carcinogens.
Can you use NDMA in EU?
Batches of product exceeding these limits for an individual impurity, or batches containing both NDMA and NDEA are not allowed in the EU. Revisions are being made to the European Pharmacopoeia to the drug substances monographs for the sartan series to include testing for nitrosamines.
Does the USFDA publish a list of ARB products?
The USFDA publishes a list of ARB products and their status with respect to nitrosamine content. 10 Like the EMA, the USFDA emphasised that the risks (such as stroke) of abruptly discontinuing these drugs far outweigh the low risk associated with continuing the medications with these impurities.
Background
- Medicine Regulatory Authorities first became aware of the presence of the nitrosamine impurity, Nnitrosodimethylamine (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. Further nitrosamine impurities were subs...
What Are Nitrosamines?
- 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.
Why Are They present?
- The formation of nitrosamines is generally only possible when secondary or tertiary amines react with nitrous acid. Nitrous acid itself is unstable but can be formed in situ from nitrites (NO2) under acid conditions. In the case of the sartan compounds, most contain a tetrazole ring and formation of this tetrazole ring employs the use of sodium nitrite. Coincidently the solvents employed eithe…
Toxicity
- NDMA and NDEA belong to the so-called “cohort of concern”, which is a group of highly potent mutagenic carcinogens that have been classified by the WHO's International Agency for Research on Cancer as probably human carcinogens. Despite the potency of these impurities, there is still a very low risk that nitrosamine impurities at the levels found could cause cancer in humans. Only …
Regulatory Action
- In the European Union (EU), following an Article 31 review of sartans at risk of containing nitrosamine impurities (those containing a tetrazole ring),9manufacturers were asked to review and make changes to their manufacturing processes to minimise nitrosamine impurities to the extent practically possible. A transition period of two years has been allowed to make these cha…
Test Methods
- The low levels at which the nitrosamine impurities occur creates challenges for testing. To assist in the testing of samples the USFDA has published several test methods that may be considered when determining nitrosamine content in the API or FPP. 1. https://www.USFDA.gov/media/124025/download 2. https://www.USFDA.gov/media/115965/do…
Recommendations
- For sartan, ranitidine and other products, where nitrosamines content has been positively identified, Regulatory Agencies should be taking steps to: 1. verify the levels of nitrosamine in the products on their markets, whether using national testing laboratories or self-declarations from the suppliers themselves. Appropriate test methods should be used. 2. request the MAHs of the…
References
- 1 - https://www.ema.europa.eu/documents/press-release/update-nitrosamine-impurities-ema-continues-work-preventimpurities- medicines_en.pdf
- 2 - https://www.ema.europa.eu/en/news/ema-review-ranitidine-medicines-following-detection-ndma
- 3 - https://www.USFDA.gov/news-events/press-announcements/statement-alerting-patients-a…
- 1 - https://www.ema.europa.eu/documents/press-release/update-nitrosamine-impurities-ema-continues-work-preventimpurities- medicines_en.pdf
- 2 - https://www.ema.europa.eu/en/news/ema-review-ranitidine-medicines-following-detection-ndma
- 3 - https://www.USFDA.gov/news-events/press-announcements/statement-alerting-patients-and-health-careprofessionals- ndma-found-samples-ranitidine
- 4 - https://www.ema.europa.eu/en/documents/referral/sartans-article-31-referral-chmp-assessment-report_en.pdf
