Stakeholders throughout the pharmaceutical value chain have had to deal with the recall of nitrosamine-containing medications, loss of revenue and, in some cases, reputational damage. Meanwhile, regulatory authorities have put stringent measures in motion to protect patients from potentially harmful medications, putting reformulation at the forefront of drug manufacturers’ minds, reports Anne-Cecile Bayne, Global Science and Innovation Lead, Pharma and Medical Nutrition at DSM
Following the discovery of harmful nitrosamine contaminants in commonly used drug products, including those used to treat high blood pressure, type II diabetes and heartburn, the pharmaceutical industry has had to act quickly.
Whilst reeling from the impact that nitrosamine contamination has had on the industry, drug manufacturers have been proactively searching for solutions to overcome the challenges that nitrosamine formation presents in drug development.
One key solution being explored — that may offer far-reaching benefits — is the use of certain antioxidants to protect drugs from nitrosamine contamination. Already used to reduce nitrosamine formation in the food industry for decades, could these antioxidants be the answer that the pharmaceutical industry is looking for?1
New nitrosamine regulations in the pharmaceutical space
Nitrosamines are organic compounds and their chemical structure, which includes nitrogen and oxygen, is volatile — meaning they can react with DNA, once activated, to potentially cause carcinogenic mutations.
There are more than 300 nitrosamines, the most common being N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), and it is estimated that more than 90% of them might be carcinogenic.2,3 Several studies have linked nitrosamines to the development of cancer in a wide range of different organs and species.4
Although the level of nitrosamines in pharmaceuticals is typically low, patients that take regular medication might have an increased risk of developing cancer.
Upon the discovery of unacceptable levels of NDMA in the commonly prescribed drug, valsartan, which is used to treat high blood pressure and heart failure, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) introduced new regulations that set out to mitigate nitrosamine contamination.5,6
Henceforth, pharmaceutical companies have a legal obligation to assess potential risks and implement strategies to mitigate them.
Stringent timeframes from regulatory agencies have increased the urgency to abide by the new regulations. In Europe, the EMA has advised manufacturers to complete confirmatory testing and submit variation applications by October 2023 for chemical medicines and July 2023 for biological products.
Moreover, in the US, there is also a requirement to submit pending new drug applications (NDAs) and abbreviated new drug applications (ANDAs) within the October 2023 timeframe. To comply, drug manufacturers need immediate solutions to help overcome any formulation challenges associated with nitrosamine formation.
The power of ascorbic acid and alpha-tocopherol antioxidants
Antioxidants are found naturally in the environment — such as in plants — and are named because of their ability to counteract oxidative stress (a process induced by free radicals).1 Free radicals have an unbalanced number of electrons, making them unstable and reactive, which can cause oxidative stress and subsequent cell damage and disease (such as cancer).1
Antioxidants can be classified as endogenous or exogeneous, meaning that they are naturally generated or externally supplied.1 Exogenous antioxidants can also be classified as nutrient-derived as they cannot be produced in the body and must be delivered through food or dietary supplements.1
Ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) are examples of nutrient-derived antioxidants. Given the important role of these vitamins in limiting oxidative stress, it is not surprising that their deficiency is linked to chronic disease.7,8
History of antioxidants in mitigating nitrosamine formation in food
Certain antioxidants have been used successfully to overcome nitrosamine formation in the food industry. Nitrosamines can be generated in food items, particularly during the process of drying and preservation.
In the 1980s, concerns grew about the risks associated with nitrosamine-contaminated foods and scientists estimated that individuals consumed approximately 1000 ng of volatile nitrosamines per day.9
To overcome the nitrosamine crisis at this time, manufacturers turned to antioxidants. A study demonstrated that when specific antioxidants, such as ascorbic acid and alpha-tocopherol, are added to foods at a ratio of more than two-fold compared with nitrite, nitrosamine formation is completely inhibited.9
It is therefore evident that antioxidants are beneficial when it comes to protecting us from harmful nitrosamines in food.
Utilising antioxidants to mitigate nitrosamine formation in drug products
In response to the identification of nitrosamine contaminants in drugs and following studies showing that long-term exposure to valsartan increased the risk of developing cancers, the pharmaceutical industry has looked to the success story of antioxidants in food.4
Subsequently, the use of specific antioxidants in drug development has been initiated to mitigate the risk of nitrosamine formation.
Nitrosamine contamination can occur at multiple stages throughout the pharmaceutical supply chain, which makes nitrosamine mitigation complex.
Optimising manufacturing processes to reduce the formation of contaminants is not always enough and it is therefore favourable to look at strategies to inhibit the formation of nitrosamines.
Antioxidants such as ascorbic acid and α-tocopherol are known blockers of nitrosamine formation.6 A recent study published by Nanda, et al., demonstrated that five different antioxidants, including ascorbic acid and alpha-tocopherol, when added to drug products, could inhibit nitrosamine formation by >80%.10
This promising study not only corroborates advice given by the FDA to explore the use of antioxidants, it also offers a safe solution for pharmaceutical companies to overcome the nitrosamine challenge.
The use of antioxidants in drug formulation also offers benefits beyond the mitigation of nitrosamine formation. In addition to their antioxidant properties, ascorbic acid and α-tocopherol act as stabilisers in the finished drug formulation product, which helps to protect the active pharmaceutical ingredient (API) from degradation.
These two antioxidants can also work together: ascorbic acid can regenerate α-tocopherol after it scavenges free radicals, further reducing oxidative stress in cells.11 With advanced scientific exploration and discovery, the industry can help solve the challenges of today and continue to support the health of patients worldwide.