Is your pharmaceutical drug product at risk of nitrosamine formation?

• The presence of nitrosamines in drug products has become a big focus for the pharmaceutical industry following their identification in common pharmaceuticals prescribed for type 2 diabetes, high blood pressure and heartburn. To limit the risk of nitrosamine impurities in drugs, there is now an imminent legal obligation in several markets for manufacturers to present reformulation strategies and mitigation plans by Q3 2022.
• A potential mitigation strategy – and US Food and Drug Administration (FDA) recommended approach – for decreasing the risk of nitrosamine formation in existing and future pharmaceuticals is including antioxidants in formulations as nitrosamine blockers.
• Read on to learn more about the benefits of antioxidants, plus discover how DSM is supporting manufacturers in meeting new regulatory criteria for nitrosamines with its high-quality excipient portfolio and expert services. 

Nitrosamine formation concerns: the key facts

Nitrosamines are potent genotoxins and probable human carcinogens, which if taken regularly over a long period of time, could increase the risk of cancer. In June 2018, the US Food and Drug Administration (FDA) brought to attention the presence of N-nitrosodimethylamine (NDMA) in valsartan – a drug regularly used to treat high blood pressure – leading to its recall from the market. Since then, nitrosamine formation has been found to occur in other common drug products prescribed for the treatment of heartburn and type 2 diabetes.

The nitrosamine impurity issue is now at the top of global regulatory priorities for the pharmaceutical industry and has led to an imminent legal obligation for drug manufacturers to present their risk mitigation plans by Q3 2022 depending on the country. In September 2020, the FDA issued guidance for the industry to help ensure the safety of drug supplies in the USA. It recommended a three-step mitigation strategy that API and drug products manufacturers should follow to detect and prevent objectionable levels of nitrosamine impurities in pharmaceutical products. The European Medicines Agency (EMA) has also initiated similar risk assessment activities. To meet new regulations, formulators must act now to develop mitigation strategies to limit the formation of nitrosamines in their existing pharmaceutical products and future developments.

How does nitrosamine formation occur?

Nitrosamine impurities in drug products occur when nitrite and vulnerable amines are present. The prerequisites for nitrosamine formation are the presence of functional groups susceptible to nitrosamine formation, such as secondary amines, or the presence or in situ-formation of a nitrosating agent – like a nitrous acid – from nitrite.

In a first activation step, nitrite ions can easily transform into nitrosating agents such as N₂O₃ or NO+, especially under acidic conditions. In the second step, these nitrosating agents react with vulnerable amines, such as secondary or tertiary amines, and as a result nitrosamines are formed.

Drug products most at risk of nitrosamine formation are those that contain active pharmaceutical ingredients (APIs) whose structure comprises of secondary or tertiary amines, or tertiary ammonium salts. There is also a risk in drugs where the active is stabilized by buffers containing tertiary or quaternary amines, as well as in drug products where any excipient contains secondary or tertiary amines, or quaternary ammonium salts.

An FDA-recommended mitigation strategy: Ascorbic acid and alpha-tocopherol as nitrosamine formation blockers

In order to minimize the risk of nitrosamine formation in pharmaceutical products, the FDA has recently highlighted a mitigation strategy that details adding commonly used antioxidants, ascorbic acid or alpha-tocopherol, to drug formulations as excipients.¹ Among many nitrosamine inhibitors, most attention has focused on ascorbic acid, which reacts with a number of nitrosating agents. Moreover, as well as blocking nitrosamine formation, both ascorbic acid and alpha-tocopherol bring the added benefit of acting as stabilizers in the finished drug product formulation without safety concerns. Therefore, the two excipients offer formulators reliable and safe opportunities to redesign their pharmaceuticals – or develop new drugs – that minimize the risk of nitrosamine formation.

Develop risk-free formulations with a trusted partner

We understand that meeting new regulatory requirements concerning nitrosamine formation in drug products can come with unique and complex challenges. This takes more than ingredients; it takes a partner. As a purpose-led innovation partner in the pharmaceutical industry, DSM has solutions to address these pressing issues. We have the capability to help you prepare a plan incorporating our quality and sustainable supply of GMP-compliant ascorbic acid and alpha-tocopherol excipients.

In addition to our high-quality excipients – and the knowledge to formulate with them – we offer strong expertise in chemistry and toxicology. Over 70 years, our expert services have helped drug formulators worldwide overcome regulatory issues across the pharmaceutical market, positioning us as the partner of choice for addressing urgent challenges that may unfold. This makes us well prepared to support you in adhering to the new regulatory criteria for nitrosamine formation.