By: Pharma Solutions Editors
As the pharmaceutical industry gradually adapts to the aftermath of nitrosamine contamination concerns, the focus has shifted toward finding effective, safe and simple strategies to mitigate the risk associated with these potential carcinogens. To address this important topic, dsm-firmenich recently led an eChalk Talk hosted by The American Association of Pharmaceutical Scientists (AAPS) entitled “Nitrite Scavengers – an elegant and simple solution to mitigate nitrosamines in drug products”. During the session, experts from dsm-firmenich – Dr. Anne-Cécile Bayne and Dr. Zdravka Misic – presented their findings on using nitrite scavengers as a solution for nitrosamine risk mitigation. This article highlights four key takeaways from the webinar and explains how nitrite scavengers, like alpha-tocopherol and ascorbic acid, can support safer drug production.
While the issue of nitrosamine contamination of food has been studied since the 1950s, nitrosamine presence in pharmaceutical products has been less well-examined, until recently. In 2018, a number of pharmaceutical drugs were found to contain unwanted nitrosamine impurities. This sparked concerns that nitrosamine contamination could be more common than first thought and has continued to drive interest in mitigating this risk. But why are nitrosamines so problematic?
Dr. Anne-Cécile Bayne, Global Science & Innovation Lead at dsm-firmenich, explains: “Nitrosamines are formed when a nitrosating agent reacts with a secondary or tertiary amine. This reaction can occur at any stage of drug production, and even during the storage of drug products. Because a number of nitrosamine compounds have carcinogenic potential, many drug developers have been affected by the incident.” The field is hard at work trying to better understand the risks to set appropriate guidelines for safer medicines.
“The identification of nitrosamines in drugs has posed a significant challenge for manufacturers across the pharmaceutical industry, who have had to act decisively to reassure the public and ensure the safety of their products. However, the challenge has been exacerbated even further by the many opportunities for nitrosamine formation at every stage of drug production. The risk is there depending on the ingredients used in the formulation for instance, to water being used, as well as packaging and storage choices made throughout the manufacturing and supply chain process. All of these factors can create conditions for the formation of nitrosamines.”
Dr. Zdravka Misic, Principal Scientist in Innovation at dsm-firmenich currently works on the development of various pharmaceutical formulations containing ascorbic acid and alpha-tocopherol to explore their impact on nitrosamine mitigation. She comments, “Nitrite scavengers, like ascorbic acid and alpha-tocopherol, offer a safe and simple solution for this issue. However, not all scavengers perform the same. Some are more active than others, some are better suited to certain formulations than others and not all are registered in the U.S. Food and Drug Administration’s (FDA) Inactive Ingredient Database.”
Both ascorbic acid and alpha-tocopherol are antioxidants that work by blocking nitrosation reactions at any stage of production and storage. Their addition to formulations has been mentioned by the FDA as a strategy worth exploring.
In the study performed by dsm-firmenich, placebo tablets containing ascorbic acid at a variety of concentrations (0.25, 0.50 and 1.00%) were produced. The tablets were then stored at 40°C and 75% relative humidity for seven days before being tested for nitrite levels. The presence of ascorbic acid clearly decreased the tablets’ nitrite content in all cases. Naturally, different pharmaceutical drugs have diverse formulation needs. However, the highlighted nitrite scavengers are easily processed, as Dr. Zdravka Misic explains: “Ascorbic acid is suitable for various delivery systems that range from solutions, syrups, gels to injections, tablets and capsules. Alpha-tocopherol is mostly used for creams, ointments and capsules. Both can be used in dry or wet processes, using wet granulation or direct compression methods; they also show low potential to modify drug absorption in the gastrointestinal tract, making them a valuable tool in the formulation development process.”
When asked to summarize the various benefits of these nitrite scavengers, Dr. Anne-Cécile Bayne said: “Ascorbic acid and alpha-tocopherol clearly have the potential to be part of successful strategies to mitigate nitrosamines and can be used in various drug products and manufacturing processes. What’s more? These nitrite scavengers have a low potential regulatory burden. This is due to the extensive existing safety data associated with these ingredients and their well-established use across the pharma, nutraceutical and food industries.”
As a purpose-driven innovation partner in the pharmaceutical industry, dsm-firmenich can assist drug developers in implementing a tried-and-tested mitigation strategy – ascorbic acid and alpha-tocopherol nitrite scavengers. We provide the technical guidance required for reformulating existing products or developing new pharmaceuticals. In addition to offering customers a range of high quality, pharma-grade ascorbic acid and alpha-tocopherol excipients, along with the expertise to formulate with them, our extensive experience with nitrite scavengers is backed by deep expertise in chemistry and toxicology.
dsm-firmenich’s guidance is also offered with sustainability front of mind. Dr. Anne-Cécile Bayne says: “For us, sustainability is intrinsically embedded in our purpose of bringing progress to life. We have ambitious sustainability targets and a strong vision to improve our overall carbon footprint, enable our customers to deliver solutions through sustainable innovations and advocate for system transformations. For example, our ascorbic acid generates 52% lower greenhouse gas emissions compared to average alternative vitamin C ingredients. However, no company can achieve net-zero on its own. To help our partners meet their sustainability goals, we have a roadmap in place, building on our Life Cycle Assessment expertise, which quantifies the environmental burden, resource consumption and human health impacts throughout the product’s life cycle – and that’s no different for our nitrosamine mitigation solutions.”
Want to learn more about the role of nitrite scavengers in nitrosamine risk mitigation? View the full eChalk Talk webinar on-demand here:
23 October 2023
4 min read