Ask the expert: how can ascorbic acid help mitigate nitrosamine risk in drug products?

Mitigating nitrosamine risks: the role of ascorbic acid in drug safety.

Summary

• Many nitrosamines are known carcinogens, exhibiting common genotoxic and tumorigenic activities.¹ Since 2018, there has been pressure by pharmaceutical regulators to assess, and reduce the risk of, nitrosamine formation in both in-development and on-market drug products.
• Nitrite scavengers – such as ascorbic acid and alpha-tocopherol – ultimately block nitrosation reactions by quenching the nitrite reactive species, making them useful as functional excipients for mitigating nitrosamine risk in drug formulations.
• In her presentation at Excipient World 2024, Dr. Anne-Cécile Bayne, Global Science and Innovation Lead Pharma at dsm-firmenich, outlined key considerations for nitrosamine mitigation using nitrite scavengers, with a focus on ascorbic acid.

Nitrosamines are abundant carcinogens found in a number of sources, including processed food and tobacco smoke. They have been studied for decades, with their first link to cancer being described back in the 1950s.² But concerns about nitrosamines in the pharmaceutical industry only really came to the fore in 2018, when they were found in some common drugs, including ranitidine, nizatidine and metformin, resulting in a number of recalls.¹ Since then, regulatory bodies – including the U.S. Food & Drug Administration (FDA) – have increased scrutiny of nitrosamines, requiring companies to evaluate, measure and mitigate them in their products. While the acceptable intake limits will no doubt change as the evidence for the safety and carcinogenicity of nitrosamines evolves, the need for a solution to control their presence will stay. During her presentation – ‘Ascorbic acid – A safe and effective excipient for nitrosamine mitigation in drug products’ – Dr. Bayne outlined the use of nitrite scavengers – such as the vitamins ascorbic acid and alpha-tocopherol - as functional excipients in drug formulations. But what are they, and how can they help? This article provides key insights from her talk.

1. How are nitrosamines formed in pharmaceutical products? 

Nitrosamines are formed by a chemical reaction between a nitrosating agent and a secondary or tertiary amine. The conditions for nitrosamine formation can be present at every stage of drug production, making it particularly challenging to control. The risk can be impacted by variables including the active pharmaceutical ingredient (API) chemical structure, formulation excipients, solvents, water, manufacturing process, and even packaging and storage decisions. There are many strategies that can be put in place to deal with the formation of nitrosamines, including strong qualification programs for new ingredients and ensuring the levels of nitrosating agents are kept low in formulations. One solution that has the potential to be helpful is the use of nitrite scavengers to reduce or stop nitrosamines from being formed.

2. What are nitrite scavengers and how can they reduce nitrosamine formation?

Nitrites are often present as impurities in drug products and can be converted into nitrosating agents like nitrous acid. Nitrite scavenging is therefore an effective way to inhibit the formation of nitrosamines. Nitrite scavengers work by quenching reactive nitrites and ultimately block the nitrosation reaction. There are many known nitrite scavengers, but not all are suitable for use in drug products. Only a few are listed on the FDA’s inactive ingredient database (IID)³, but even these have variable properties relating to their activity, the environment in which they can work, and their interactions with external compounds. So far, ascorbic acid and alpha-tocopherol have shown consistently good results, and both have been mentioned by the FDA as strategies worth exploring for nitrosamine mitigation.^4,5,6

3. What do we know about ascorbic acid as a functional excipient to reduce nitrosamine risk? 

Multiple studies have demonstrated that ascorbic acid and alpha-tocopherol are safe and effective nitrite scavengers; recent publications also show no impact on drug absorption at low levels.^5,7,8,9 Internal research at dsm-firmenich, outlined in the presentation, includes further studies on the efficacy of ascorbic acid in reducing nitrosamine formation. Firstly, we looked at the ability of ascorbic acid to decrease the amount of nitrite in a placebo tablet. We saw that it was able to reduce nitrite levels when used in a tablet produced by either direct compression or wet-granulation, with its effects increasing with higher concentrations – up to one percent. Next, we investigated ascorbic acid in a standard tablet formulation with a model API. We subjected a control and a formulation containing one percent ascorbic acid to two weeks of stress testing at high temperature and humidity and compared nitrosamine content after this time. The presence of ascorbic acid significantly reduced nitrosamine levels in the tablet. This effect was also repeated in two other drug models with different formulations and characteristics.

4. How will the regulatory agencies view the inclusion of ascorbic acid as a new ingredient for nitrosamine mitigation in drug formulations?  

Regulatory agencies, like the US Food and Drug Administration (FDA), are adding measures to facilitate the inclusion of nitrosamine mitigation agents, such as antioxidants like ascorbic acid and alpha-tocopherol, in drug formulations. According to the new guidance to the industry released by the FDA in September 2024¹⁰, when ascorbic acid is included in quantities up to 10 mg/dose (or maximum daily exposure, whichever is lower) in formulations containing Biopharmaceutics Classification System (BCS) I, II and III drugs, companies may demonstrate bioavailability (BA) / bioequivalence (BE) equivalency of reformulated products simply by providing comparative dissolution data in different pH conditions that confirm the lack of any adverse effect of said antioxidant on drug performance. This flexibility reflects cost and time saving opportunities, will significantly facilitate approval of reformulated products containing antioxidants like ascorbic acid, and ensure drug product supply is maintained with the population’s health and safety at heart.

5. What do formulators need to consider when using ascorbic acid?  

Using low levels of nitrite scavengers – even below one percent – in combination with low nitrite level APIs and excipients has been shown to significantly minimize nitrosamines. However, ascorbic acid is commercially available in a range of purities and grades, so it is important to evaluate how this will impact its efficacy when developing a formulation. In general, the smaller particle size of ultra-fine powders ensures the closest contact between the nitrite scavenger and nitrite source, leading to higher efficiency. It is also important to consider the manufacturing route, as wet-granulation poses a higher risk of nitrosamine formation compared to direct compression. Vitamin purity itself is also a major consideration during drug development, as it ultimately impacts the quality of the final formulation. As a purpose-driven innovation partner in the pharmaceutical industry, dsm-firmenich can provide not only the high-quality products, but also the technical guidance to successfully use nitrite scavengers within drug products, whether reformulating existing medicines or developing new pharmaceuticals.