Medication recalls in the United States
Recently, the FDA asked manufacturers to withdraw all prescription and over-the-counter ranitidine (commonly known as the brand name Zantac) from the US market. However, the agency also pointed out that the risk (like a stroke) of suddenly stopping these drugs outweighs the low risk associated with continuing the drugs despite their potential impurities and reminded patients taking ARAs to recall continue with their current medication until their pharmacist or doctor provides a replacement (3). A list of ARAs and their status in relation to nitrosamine content has since been published (2). Anyone who did not meet the requirements was called in for testing, resulting in product recalls for many popular pharmaceutical brands.
How are nitrosamines formed?
Nitrosamines are formed by the interaction of secondary or tertiary amines with nitrite ions. One source of contamination in pharmaceutical manufacturing includes nitrosamine impurities occurring during processing of API. However, the possibility of creation of nitrosamines becomes wider than the presence of both nitrites and amines during API synthesis. Nitrites or amines can also be present in the raw materials themselves or form part of the reagents or solvents used during manufacture.
For example, using sodium nitrite (NaNO2) in the presence of secondary or tertiary amines creates a potential source of nitrosamine. Amino solvents can degrade into secondary amines, which are known sources of nitrosamines. Dimethylamine in the common solvent dimethylformamide (DMF) can cause the formation of nitrosamines. Tertiary amines include common bases, which allow the formation of nitrosamines.
Nitrosamines can also be present in APIs as a result of the use of contaminated raw materials in manufacturing. Recycled solvents, reagents and catalysts can present a risk largely due to their quenching with nitrous acid at the end of the manufacturing process and, if the recycling is subcontracted to a shared facility, this increases the risk. of cross contamination. One problem here is that the API manufacturer may not be aware of the risk of nitrosamines in raw materials, especially if nitrosamines cannot be formed otherwise during the manufacturing process, so they may not. realize the need for testing.
In addition, there are currently no recognized standards for nitrosamine levels in drinking water used in the manufacture of pharmaceuticals. WHO guidelines suggest a limit of 100 parts per billion, but different countries may define their own interpretation.
The most common current methods for testing small molecule pharmaceuticals are gas chromatography-mass spectrometry (GC-MS), liquid chromatography (LC) -MS / MS, or high resolution LC-HRMS (HR) . Introducing a new step or having to outsource testing at different stages of production can, however, be costly and lead to production delays. Testing using a thermal energy analyzer (TEA) offers the pharmaceutical industry a new alternative.
Pre-screening with thermal energy analysis
The TEA detector can be used internally to perform both rapid and routine preselection of pharmaceutical samples for total nitrosamine content and more detailed and specific analysis. Its selectivity and sensitivity for nitroso-containing compounds has led it to become the standard for nitrosamine analysis in many industries, including food safety and materials manufacturing, where it is widely used.
The Apparent Total Nitrosamine Content (TNAC) method using TEA detection is a screening test that determines the total amount of nitrosamines in a sample, showing both volatile and non-volatile components. Any sample showing an ATNC below the specified level of concern cannot contain any compounds above the total level and is therefore considered safe. Any sample with an ATNC value above the level of concern may be analyzed further. This additional analysis can be performed using TEA interfaced to GC, where volatile nitrosamines such as NDMA can be separated and quantified.
The future of nitrosamine testing
Other regions are also taking action on nitrosamines. For example, in Europe, the European Medicines Agency (EMA) has stipulated that all marketing authorization holders (MAs) for pharmaceutical products must perform a risk assessment to determine the potential nitrosamine content as well as set limits to ensure the control of these impurities (4). In addition to the EMA, authorities in Canada, South Korea and Switzerland have also issued similar instructions (4).
WHO has described the processes to be followed by MAHs regarding nitrosamine impurities in pharmaceutical products – if the level of nitrosamine impurity is below the provisional acceptable limits, the products are generally considered safe and may stay in the market. If nitrosamine levels exceed provisional acceptable limits, these products should generally not be permitted on the market (2). This has led some European national regulators to take precautionary measures to recall or suspend the distribution of all ranitidine products.
Clearly, MAHs must not only implement the risk assessment program, but also demonstrate the results of their assessment and undertake process changes to ensure that in the future, a system is implemented to test that nitrosamine levels fall below acceptable limits.
The recent detection of nitrosamines in widely prescribed pharmaceutical drugs has raised concerns about patient safety, prompting regulators to look into the matter and set acceptable limits. The FDA recommends that drugs containing nitrosamine levels above these limits be recalled by the manufacturer, if applicable. As the pharmaceutical industry and health authorities continue to manage risk, regulations are expected to continue to evolve.
1. FDA, “Statement alerting patients and healthcare professionals to the presence of NDMA in ranitidine samples, ” 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 Drugs, as Part of the Agency’s Continuing Efforts to Address the Ongoing Safety Issue, ” www.fda.gov (2019).
4. EMA, “Information on nitrosamines for marketing authorization holders, ” www.ema.europa.eu, September 19, 2019.
About the Author
Andre James*, [email protected], is Marketing Director at Ellutia. James has worked at Ellutia for over 20 years. During this time, he has been involved in 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 past eight years.
*To whom correspondence should be addressed.