Expert insights: Nitrosamine risk reduction with low nitrite excipients

Sep 02 2024

Regulatory agencies around the world, including the US Food and Drug Administration (FDA) and European Medicines Authority (EMA), aren’t taking any chances when it comes to N-nitrosamine (simply called nitrosamine) risk in drug products. To ensure patient safety, regulatory authorities require pharmaceutical companies to provide risk assessments and, if necessary, mitigation plans for their medicines. However, detecting nitrosamine impurities in pharmaceuticals – and then confidently controlling them – is no easy task, as impurity formation can happen at any stage of the development pipeline.

 

To help address this challenge, we interviewed Elizabeth Tocce, lead application scientist at IFF Pharma Solutions, for her insights on navigating the nitrosamine mitigation process, available strategies, and the benefits of working with a leading excipient manufacturer. Read on for valuable information.

 

  1. What do we know about the impact of nitrosamines in the pharmaceutical industry?

Nitrosamines are chemical compounds that can be found in food,[i] water,[ii]and drug products. Nitrosamine impurities in pharmaceuticals can occur when a nitrosating agent (like nitrite) and a vulnerable amine (like secondary and tertiary amines) react under favorable conditions.[iii],[iv]

 

This reaction can happen at multiple stages in the drug development pathway. From the manufacturing of active pharmaceutical ingredients (APIs) to the production and storage of formulated drug products, or even through the packaging materials used – highlighting the complexity of the challenge. With the International Agency for Research on Cancer (IARC) categorizing some nitrosamines as “probably carcinogenic to humans”,[v]addressing nitrosamine contamination risk is essential to ensure pharmaceutical products are safe for patient use.

 

  1. What steps are pharmaceutical companies taking to make drugs safer?

Regulatory authorities require manufacturers to submit risk mitigation plans for all their drug formulations – including marketed and new pharmaceutical products. This process involves companies evaluating, investigating and then identifying how they will control nitrosamine formation in pharmaceuticals.[vi],[vii],[viii]

 

As a first step, drug developers must carry out a risk assessment to detect potential nitrosamine impurities or risk of formation. If a risk is found, they must conduct analytical tests to identify and quantify nitrosamine presence. Should nitrosamines be present above levels indicated by regulatory agencies, drug developers must then swiftly put in place mitigation measures to reduce and control nitrosamine formation. As part of a holistic risk assessment, manufacturers should ask questions like, “At what stage in the development journey is risk of nitrosamine formation high?”; “Are the excipients or APIs I’m using contributing to the risk?” and “What influence is my manufacturing process having?”

 

Understanding the risk assessment and mitigation processes and answering key questions like the above form the foundation for implementing an appropriate mitigation strategy that is suitable for each product.

 

  1. What strategies are available for pharmaceutical companies?

There are many ways to approach a nitrosamine mitigation strategy, and each should be specifically designed for a drug product and its manufacturing process. Options include reducing reactive species like the vulnerable amine or nitrosating agent, modifying the manufacturing process to prevent reactions, changing the reaction environment (such as adjusting pH or mobile phase), and adding nitrite scavengers to neutralize the nitrosating agent.

 

One other effective tool is using low nitrite excipients.[ix],[x] Nitrites may be present in excipients, which can significantly influence the risk of nitrosamine formation if vulnerable amines are also present. Thus, although they cannot prevent nitrosamine formation entirely, low nitrite excipients can form part of a holistic strategy to remove this common route of nitrosamine presence without compromising on therapeutic efficacy of the final drug product. Moreover, low nitrite excipients carry minimal risk and regulatory requirements compared to full reformulation of a drug product. In response to the need for low nitrite solutions, we have introduced a portfolio of solutions to the market, including new Avicel® PH Low Nitrite grades.

 

 

  1. Can you tell us more about IFF Pharma Solutions’ low nitrite solutions?

Our Avicel® PH Low Nitrite (LN) Microcrystalline Cellulose (MCC) grades deliver the same performance and reliability as our other Avicel® brand products – just with the added benefit of being low nitrite. This makes them the perfect solution for formulators who need a low nitrite excipient, but don’t want to compromise on performance. Our analytical method to measure nitrite in MCC is sensitive enough to detect nitrites down to ppb levels.[xi] We have also refined our analytical methods to determine trace levels of nitrites in our widely used METHOCEL™ grades.11,[xii] Extensive testing of the METHOCEL™ product family, along with cutting-edge manufacturing facilities and years of production excellence, have provided us with a comprehensive understanding of nitrite levels in this portfolio.

 

In fact, our LN products are the first in the industry to measure and report nitrite levels for each batch. Providing data on nitrite levels through certificate of analysis (COA) and/or nitrosamine statements enhances security and quality control and helps to ensure ppb nitrite levels are below the acceptable limit, enabling formulators to make informed decisions for their nitrosamine strategies.

 

More details about our low nitrite solutions can be found in our brochure.

 

  1. What is your guidance for pharmaceutical companies looking to implement low nitrite excipients as part of their strategy?

Partnering with a leading excipient manufacturer that offers expertise and robust formulation and analytical capabilities can help drug developers to confidently and efficiently incorporate low nitrite excipients into their formulations as part of wider risk mitigation plans. My advice is to choose a partner that offers:

  • Support and guidance throughout the risk assessment and mitigation process
  • Has validated analytical methods to measure nitrites
  • Demonstrates a comprehensive understanding of nitrite content in excipients – and the wider drug development process
  • Formulation expertise to ensure continued product compatibility, functionality and seamless integration when switching to low nitrite excipients
  • Quality documentation to accelerate speed to market

 

If you’re interested in accessing additional resources related to adding low nitrite excipients to your drug formulation and discovering how we can best support you, fill out this inquiry form.

 

 

 

[i] Karwowska M, Kononiuk A. Nitrates/Nitrites in Food-Risk for Nitrosative Stress and Benefits. Antioxidants (Basel). 2020;9(3):241.

[ii] World Health Organization, "Nitrate and Nitrite in Drinking-water: Background document for development of WHO Guidelines for Drinking-water Quality WHO/FWC/WSH/16.52," WHO Press, Geneva, Switzerland, 2016.

[iii] T.Wainright, "The Chemistry of Nitrosamine Formation: Relevance to Malting and Brewing," Journal of the Institute of Brewing, 1986; 92(1): 49-64.

[iv] Bartsch H, Ohshima H, Pignatelli B. Inhibitors of endogenous nitrosation. Mechanisms and implications in human cancer prevention. Mutat Res.1988;202(2):307-324.

[v] World Health Organization, "Agents Classified by the IARC Monographs," 2022.

[vi] European Medicines Agency, "Nitrosamines EMEA-H-A5(3)-1490," 2021.

[vii] Health Canada, "Guidance on nitrosamine impurities in medications," 2022.

[viii] U.S. Food and Drug Administration, "Control of nitrosamine impurities in human drugs: Guidance for industry," 2021.

[ix] Boetzel R, Schlingemann J, Hickert S, ,et al, A Nitrite Excipient Database: A Useful Tool to Support N-Nitrosamine Risk Assessments for Drug Products. J Pharm Sci. 2023;112(6):1615-1624.

[x] Wu Y, Levons J, Narang AS, et al, Reactive impurities in excipients: profiling, identification and mitigation of drug-excipient incompatibility. AAPS PharmSciTech. 2011;12(4):1248-1263.

[xi]Zhu K, Kerry M, Serr B, Mintert M. Parts per billion of nitrite in microcrystalline cellulose by ion chromatography mass spectrometry with isotope labeled internal standard. J Pharm Biomed Anal. 2023;235:115648.

[xii]Zhu K, Kerry M, Serr B,et al, Highly sensitive two-dimensional ion chromatography mass spectrometry method for nitrite determination in hydroxypropyl methylcellulose. J Pharm Biomed Anal. 2024;248:116330