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Recent drug recalls in the United States from nitrosamine contamination prompt the need for more sensitive impurity testing methods and a re-evaluation of acceptable lower limit levels.
FDA is investigating several potentially carcinogenic substances found in small amounts in drugs used to treat elevated blood pressure and heartburn (1). Medicine regulatory authorities first became aware of the presence of nitrosamine impurities, including N-nitrosodimethylamine (NDMA), in 2018 after they were found in a number of blood pressure drugs. Traces were then also found in angiotensin II receptor blockers (ARBs), commonly known as “sartans” (2).
There is potential for nitrosamines to be present in active pharmaceutical ingredients (APIs) in drugs, depending on the API and the product manufacturing processes. If the drug contains a small-molecule API made by chemical synthesis, it is classed as “at risk”. FDA and manufacturers have worked to identify and recall medicines medications that may contain nitrosamines to identify those with levels above the World Health Organization’s (WHO) interim acceptable limits (2).
Recently, FDA requested that manufacturers withdraw all remaining prescription and over-the-counter (OTC) ranitidine (known commonly by the brand name Zantac) on the US market. However, the agency also emphasised that the risk (such as stroke) of abruptly discontinuing these drugs outweighs the low risk associated with continuing the medications despite their potential impurities and has reminded patients taking recalled ARBs to continue with their current medicine until their pharmacist or doctor provides a replacement (3). A list of ARBs and their status with respect to nitrosamine content has since been published (2). Any that did not meet the requirements were called in for testing – enforcing product recalls for many popular pharmaceutical brands.
Nitrosamines are formed by the interaction of secondary or tertiary amines with nitrite ions. A source of contamination in pharmaceutical manufacturing includes nitrosamine impurities occurring during API processing. However, the possibility of nitrosamine creation becomes broader than the presence of both nitrites and amines during synthesis of the API. Nitrites or amines can also be present in the raw materials themselves or form part of the reagents or solvents used during manufacturing.
For example, using sodium nitrite (NaNO2) in the presence of secondary or tertiary amines creates a potential source of nitrosamine. Amine solvents can degrade to secondary amines, which are known sources of nitrosamines. Dimethylamine in the common solvent dimethyl formamide (DMF) can cause nitrosamines to form. Tertiary amines include common bases, which allow nitrosamine formation.
Nitrosamines may also be present in APIs following the use of contaminated raw materials in manufacturing. Recycled solvents, reagents, and catalysts may pose a risk largely due to their quenching with nitrous acid on completion of the manufacturing process and, if the recycling is outsourced to a shared facility, this increases the risk of cross-contamination. One issue here is that the API manufacturer may not be aware of the risk of nitrosamines in the raw materials, particularly if nitrosamines cannot otherwise form during the manufacturing process, so they may not realize the need for testing.
Furthermore, there are currently no recognized standards relating to nitrosamine levels in the potable water used in pharmaceutical product manufacture. WHO guidelines suggest a limit of 100 parts per billion, but different countries may set their own interpretation.
The current most common methods for testing small-molecule pharmaceutical products are gas chromatography–mass spectrometry (GC–MS), liquid chromatography (LC)–MS/MS or high resolution (HR) LC–HRMS. Introducing a new step or having to outsource testing at different stages of production, however, can be expensive and may potentially incur delays in production. Testing using a thermal energy analyser (TEA) offers the pharmaceutical industry a new alternative.
The TEA detector can be used in-house to perform both rapid, routine prescreening of pharmaceutical samples for total nitrosamine content and more detailed, speciated analysis. Its selectivity and sensitivity for nitroso-containing compounds has led to it becoming the standard for nitrosamine analysis in many sectors including food safety and materials manufacturing, where it is used extensively.
The apparent total nitrosamine content (ATNC) method using TEA detection is a screening test that determines the total nitrosamine quantity in a sample, showing both volatile and non-volatile components. Any sample showing an ATNC below the specified level of concern cannot possibly contain any one compound above the total level and is therefore deemed safe. Any sample with an ATNC value higher than the level of concern can be further analyzed. This further analysis can be performed using the TEA interfaced to a GC, where volatile nitrosamines such as NDMA can be separated and quantified.
Other regions are also taking action on nitrosamines. For example, in Europe, the European Medicines Agency (EMA) has stipulated that all marketing authorization holders (MAHs) of pharmaceutical products must conduct a risk assessment to determine the potential nitrosamine content as well as putting in limits to ensure control of such impurities (4). In addition to the EMA, authorities in Canada, South Korea, and Switzerland have also issued similar instructions (4).
The WHO has outlined the processes to be taken by MAHs regarding nitrosamine impurities in pharmaceuticals-if the level of any nitrosamine impurity is below the interim acceptable limits, products are generally considered safe and may remain on the market. If levels of nitrosamines exceed the interim acceptable limits, these products should in general not be permitted on the market (2). This has led to some individual European national regulators taking precautionary measures to either recall or suspend distribution of all ranitidine products.
It is clear that MAHs must not only implement the risk assessment program but also demonstrate the results of their assessment as well as undertake process changes to ensure that, in future, a system is implemented to test that nitrosamine levels fall below the acceptable limits.
The recent detection of nitrosamines in widely prescribed pharmaceutical drugs has raised concerns about patient safety, prompting regulatory bodies to look into the issue and set acceptable limits. FDA recommends that drugs containing nitrosamine levels above these limits are to be recalled by the manufacturer as appropriate. While the pharmaceutical industry and health authorities are continuing to manage the risks, it is expected that regulations are likely to continue to evolve.
1. FDA, “Statement Alerting Patients and Health Care Professionals of NDMA Found in Samples of Ranitidine,” www.fda.gov (2019).
2. WHO, “Information Note: Update on Nitrosamine Impurities, World Health Organization,” www.who.int (2020).
3. FDA, “Statement on the Agency’s List of Known Nitrosamine-free Valsartan and ARB Class Medicines, as Part of Agency’s Ongoing Efforts to Resolve Ongoing Safety Issue,” www.fda.gov (2019).
4. EMA, “Information on Nitrosamines for Marketing Authorisation Holders,” www.ema.europa.eu, Sept. 19, 2019.
Andrew James*, firstname.lastname@example.org, is marketing director at Ellutia. James has worked at Ellutia for more than 20 years. During this time, he has been involved with many aspects of the business from product development to strategic planning and has developed extensive knowledge and experience in the chromatography industry. James has led the company’s marketing for the last eight years.
*To whom correspondence should be addressed.