Expert view: 5 things you need to know about nitrosamines in drug formulation

By: DSM Pharma Solutions Editors

  • Nitrosamine risk mitigation is front of mind for many drug formulators following the discovery of N-nitrosodimethylamine (NDMA) in valsartan – a commonly used drug in the treatment of high blood pressure and heart failure.
  • To learn more about the situation, DSM interviewed Prof. Gerhard Eisenbrand – Senior Research Professor (Retired) Food Chemistry & Toxicology – and leading expert in the field, to discuss what we know about nitrosamines in the pharmaceutical industry and the steps formulators can take to minimize the risk of contamination in their drug products. 
  • Read on for the latest expert insights, plus discover how – as a purpose-led partner – DSM can support drug developers with their mitigation strategies.  

The presence of nitrosamine impurities 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. Now, mitigating nitrosamine contamination is at the top of global regulatory priorities for the pharmaceutical industry, with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) making it a legal obligation for drug manufacturers to present their reformulation and risk mitigation plans.

Below, we hear from Prof. Gerhard Eisenbrand – a retired Senior Research Professor Food Chemistry & Toxicology with extensive knowledge in the field of nitrosamines – on the implications of nitrosamine contamination for the pharmaceutical industry and how developers can address it quickly and safely

What do we know about N-nitroso compounds?

N-nitroso compounds (NOC) are chemical contaminants which first became known almost 40 years ago when they were found to be present in foods treated with sodium nitrite – like bacon, cheese, cured meats and fish. The most common NOCs are N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) nitrosamines. 

Evidence from laboratory studies, including animal studies, demonstrates that NOCs have the potential to cause cancer in multiple tissues in the body. In fact, more than 90% of 300+ NOCs are reported to be carcinogenic.[1] Some NOCs, like nitrosamines, require metabolic activation by CYP450 enzymes to become carcinogenic, whereas others, like N-nitroureas, are active without needing to be metabolized. As such, NOCs are one of the few chemicals classified by the ICH M7 as Cohort of Concern (CoC), which means they are considered highly potent mutagenic carcinogens and require strict control to minimize human exposure. The International Agency for Research on Cancer (IARC) also categorizes nitrosamines as ‘probably carcinogenic to humans’. 

How is the nitrosamine crisis affecting the pharmaceutical industry, and what can be done in the short term to mitigate it?

While there is a very low risk that nitrosamine impurities could cause cancer at the levels found in drug products, individuals may be at increased risk if exposed to nitrosamine impurities at above acceptable levels or over long periods of time. The identification of nitrosamine impurities in several commonly prescribed pharmaceuticals, including valsartan, antibiotics, antacids and antidiabetics therefore quickly led to the recall of these drugs products and the temporary withdrawal of treatment for many patients globally. 

Since then, multiple pharmaceutical authorities across the world – including the FDA and EMA – have taken action to harmonize strategies for addressing nitrosamine contamination in existing formulations and minimizing the risk of impurities in new drug developments. These strategies include steps like assessing the risk of nitrosamines, reporting the changes and then submitting mitigation plans, all to be completed by September 2022 in Europe for chemical medicines, July 2023 for biological medicines in Europe and October 2023 in the USA. With this in mind, developers are under pressure to formulate and share their plans with authorities to lower the risk of nitrosamine contamination in their formulation.

Can you explain how nitrosamines are formed in drug products? Are there any production (or formulation) steps in particular, that you think could cause critical issues related to NOC formation?

Nitrosamines, like NDMA, are formed when a secondary amine and nitrite, or other nitrosating agent, react. Consequently, nitrosamine formation may happen across the supply chain. There are a number of identified risk factors to bear in mind, including: 

  • The use of sodium nitrite (NaNO2), or other nitrosating agents during drug manufacture
  • The presence of reactive elements in the active pharmaceutical ingredient (API), intermediate or starting material
  • Using the synthetic route or specific manufacturing process conditions – especially those that are acidic
  • The presence of nitrosamine precursors in raw materials and excipients, or even packaging 
  • Any contact with nitrogen oxides (NOX) during the production and storage stages – a widely underestimated risk for nitrosamine development.

Looking at raw materials specifically, any API whose structure comprises secondary or tertiary amines, or tertiary ammonium salts, is at risk of nitrosamine formation – as are drugs where the active is stabilized by buffers containing tertiary or quaternary amines and drug products where any excipient contains secondary or tertiary amines, or quaternary ammonium salts. 

What can marketing authorization holders do to overcome nitrosamine contamination and prevent their drug products from being recalled?

The maximum acceptable intake of NDMA should not exceed 96 ng/day when taken over a lifetime – that is approximately 70 years. With this in mind, drug developers must imminently assess their pharmaceuticals for risk of nitrosamine contamination. If a risk is identified, confirmatory testing should be conducted, and if nitrosamines are detected at this stage an appropriate control strategy should be proposed and implemented.  

This could start with optimizing the processing of drug products, but even this might not prevent nitrosamine contamination. In such circumstances, drug developers may be required to reformulate existing pharmaceuticals to block nitrosamine formation. Adding specific antioxidants – like ascorbic acid or alpha-tocopherol – to formulations as nitrosamine formation inhibitors is recommended by the FDA as a potential mitigation strategy. By blocking the formation of toxic nitrosamine impurities, both excipients might contribute to keeping nitrosamine levels below the acceptable intake limits, making drugs safe for human use. Ascorbic acid and alpha-tocopherol therefore offer developers reliable and safe opportunities to redesign their pharmaceuticals, or innovate new drugs, without the risk of nitrosamine contamination.   

With this backdrop, how do you see the future of innovation in pharma from three dimensions: the science of treatment, the science of technology and the science of the expectant patient?

Global health authorities, the industry and patients themselves are already taking important steps to reduce the risk of nitrosamine exposure from current pharmaceuticals – as listed above. Going forward, I see more contamination limits being set and imposed, and potentially even the withdrawal of additional drug products from the market. However, this will be for rare cases only. There will also be more opportunities for innovation in the space as novel drug developments come to the fore – including new technology advancements and formulation strategies that support a risk-free future. For this to be successful, partnership across the industry is essential. 

How to develop risk-free formulations 

At DSM, we understand that meeting new regulatory requirements concerning nitrosamine formation in drug products can come with unique and complex challenges. As a purpose-led innovation partner in the pharmaceutical industry, DSM has solutions to address these pressing issues. This includes a portfolio of high-quality, GMP-compliant ascorbic acid and alpha-tocopherol excipients – and the knowledge to formulate with them.

Contact us to ensure, together, that your pharmaceutical products are fit for human use. Learn more about our quality ingredients and expert services here: 

Published on

16 May 2022

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References

  1. FDA. Nitrosamines as impurities in drugs; health risk assessment and mitigation workshop day 1. [PDF], accessed 1 April 2022.