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Navigating the Next Phase of Nitrosamine Compliance for Pharmaceutical Producers

 

The Eye of the Storm

Significant in its scope and serious in its potential consequences, nitrosamine formation will be remembered by the pharmaceutical industry as one of the most concerning challenges of the early 2020s. The topic has shaped drug producers’ approach to research, development, testing and patient safety for almost half a decade at this point, and it still has not reached its crescendo. 

According to directives laid out by the U.S.  Food and Drug Administration (FDA) and European Medicines Agency (EMA), manufacturers around the globe were required to complete confirmatory testing for nitrosamine impurities and submit any plans for resultant changes to their products by October 1, 2023.(1)  With this deadline now passed, the industry is looking ahead to August 1, 2025. This is the final date by when, according to the FDA, drug marketing authorization holders (MAHs) must have actioned any formulation changes and confirmatory testing, proving their products fall within its nitrosamine acceptable intake (AI) limits established to protect patients.(2)  

At the halfway point between these two important dates in the nitrosamine story, formulators are firmly in the eye of the storm. The pharma industry has already battled through a whirlwind of regularly revised guidance, risk assessments, testing protocols and recalls, and while it may not all be smooth sailing ahead, the clouds are at last beginning to clear. 

At Roquette, it’s our mission to help drug manufacturers solve the toughest challenges in drug delivery, and nitrosamine mitigation is no exception. We’re here with a summary of pharma regulators’ responses so far and what it can tell us about the next chapter in nitrosamine compliance. 

Together, we can power through the eye of the storm to a bright, safe and healthy future for the pharma industry and the patients it serves every day.

(*) Please see references at the bottom of page

Clouds Gather

The origins of the nitrosamine challenge

N-nitroso compounds, or nitrosamines, are a group of chemical compounds classified as “probable human carcinogens” based on extensive animal tests, though their effects on human health are also well recognized. Six years ago, regular drug surveillance revealed the presence of N-nitrosodimethylamine (NMDA) in a class of blood pressure medications known as sartans, triggering a comprehensive, worldwide assessment of the presence of nitrosamine impurities in pharmaceutical products.

Regulators, such as the EMA, maintain the probability of exposure to carcinogenic effects through the presence of nitrosamines in drugs remains very low. Concerns persist, however, for patients with a chronic disease who may be at higher risk depending on their daily medication dose, the duration the medication must be taken and the baseline levels of nitrosamine contamination in the medicament.

Winds Pick Up

Plotting the timeline of regulatory concern surrounding nitrosamines in pharmaceutical products

  • September 19, 2019

    The European Medicines Agency (EMA) releases a pivotal announcement (EMA/189634/2019) laying out its intent “to evaluate the risk of the presence of nitrosamine impurities in human medicinal products containing chemically synthesized active pharmaceutical ingredients.”(3) 

  • August 3, 2020

    The EMA publishes updated guidance on the presence of nitrosamine impurities in human medicinal products (EMA/409815/2020 – latest revision July 19, 2024), containing an urgent directive for all MAHs of drugs sold within the EU to immediately conduct a comprehensive risk evaluation to ascertain any potential for nitrosamine formation.(4) 

  • August 4, 2023

    The FDA publishes its final guidance on the recommended acceptable intake (AI) limits for nitrosamine drug substance-related impurities (NDSRIs). These range from 26.5 ng/day to 1,500 ng/day depending on a wide variety of factors.(1)

  • September 2020

    The FDA publishes “Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry” (revised February 2021).(5) 

  • March 31, 2021

    A key deadline is reached with the FDA requiring drug producers to submit their initial risk assessments for any products susceptible to nitrosamine formation. 

  • October 1, 2023

    FDA and EMA deadlines require producers to complete confirmatory drug product testing and submit details of required changes – variation applications in the case of the EMA4 – to any affected drugs. The FDA, however, allows companies additional time to complete its full three-step mitigation strategy, based on increased awareness of NDSRIs since the publication of the initial guidance.(1)

  • August 1, 2025

    This is the FDA’s final extended deadline by which MAHs must have concluded testing to assure their products meet the organization’s recommended AI limits, as determined by their corresponding carcinogenic potency categories. This is the next significant milestone in the story of nitrosamine risk mitigation in pharma.

Forecast

What causes nitrosamine formation?

The FDA suggests several general root causes of the presence of nitrosamine impurities in APIs, including the following:

  • The presence of specific conditions known to influence the formation of nitrosamines, such as: (6)
    • Secondary, tertiary, or quaternary amines and nitrite salts, subjected to acidic conditions
    • The use of nitrous acid to quench residual azide
    • Nitrites, used in earlier reagent steps, that have been carried over into subsequent processes
    • Process factors like contact with contaminated water, packaging, etc.
  • Exposure to sources of amines in APIs, intermediates, or starting materials
  • Exposure to recovered solvents, catalysts, and reagents
  • The quenching process
  • Contamination via sources other than APIs, such as:
    • Excipients
    • Primary and secondary packaging materials
    • Nitrocellulose-based printing inks
Pressure drops

Overview of nitrosamine risk mitigation strategies 

Just as regulators’ position on the issue has evolved over the past five years, so too have strategies to prevent or mitigate the presence of nitrosamines in pharmaceutical processing. Typically, testing for these impurities is carried out on finished products, but we often advise our customers to begin their compliance process right from the start of the production line. 

Before the start of any processing activity, it is highly recommended that all raw materials – including APIs and excipients – are evaluated regarding the risk of nitrosamine impurities, nitrosating agents (such as nitrites), the environment in which the product is produced and how they are delivered to patients.(7)  This initial step can help save time and potential expense through the early identification of contaminated raw materials, as well as speed up the verification process of the final product. According to control options outlined in the EMA’s ICH M7(R1) guideline, the drug manufacturer must perform a risk assessment, which may confirm that nitrosamine levels detected in the API or other ingredients are below AI thresholds; therefore, impurities in the finished drug will not exceed acceptable limits.  

  • Pharmaceutical excipients constitute a significant proportion of the final drug product, comprising as much as 90% of the total volume in certain cases – so why are they overlooked in so many nitrosamine mitigation measures?(8,9)

While many testing strategies limit their focus to APIs, excipient testing should form an equally integral part of nitrosamine risk assessments. These ingredients play a crucial role in ensuring the optimal functionality of drug products, such as facilitating manufacturability, ensuring stability, promoting dose uniformity, and enabling effective delivery of the API. Given that they also account for the majority of overall product volume, excipients can contribute significantly to nitrite content and subsequent nitrosamine formation in a variety of drugs. 

To combat these risks, drug manufacturers can harness one, or a combination, of the following mitigation strategies:

  • Employ low nitrite excipients

It may seem obvious, but the careful selection of low nitrite excipients is one of the most effective ways to combat nitrosamine impurity formation while maintaining optimal therapeutic efficacy. This approach also offers the advantage of minimal additional costs or regulatory requirements, making it a simple, practical approach for nitrosamine control within the AI during the course of treatment. The main barrier to this otherwise elegant solution is that unlike for APIs, regulatory bodies have not mandated the testing of excipients for their nitrosamine risk, requiring only that the final drug meets acceptable intake levels. As a result, it can be difficult for manufacturers to find comprehensive or consistent nitrite assessments for many common excipient groups. 

 

Download our low nitrite technical data sheet

 

  • Design formulation conditions against the development of nitrosamine impurities

As with any form of contamination, certain production factors can greatly contribute to the formation of nitrosamine impurities. These include the use of large quantities of secondary amine APIs or other actives in their salt form, acidic formulation conditions, and the storage of products in high-humidity environments. With the support of an experienced formulation partner, drug manufacturers can set out tailored plans to optimize conditions within their production facilities to minimize the risk of nitrosamine formation.

Our nitrosamine story, so far

At Roquette, our specialists are dedicated to developing precise and highly sensitive testing methodologies to accurately quantify nitrite impurities in our APIs and excipients. Our proactive and constantly evolving approach to risk assessments has helped our solutions achieve among the lowest possible nitrosamine impurities on the market and ongoing compliance with the timelines set by international authorities.

We work with our partners to monitor nitrite levels across our extensive excipient portfolio, providing final product manufacturers with the up-to-date information they need to formulate risk mitigation strategies and ultimately safeguard patient health.

Our commitment to safety assurance doesn’t end with clear and accurate guidance though. We see it as our responsibility to help usher in a new, nitrite-conscious era in pharmaceutical manufacturing by ensuring producers never need to choose between optimal drug performance and nitrosamine risk.

This is our plan for building a complete range of quality-assured excipients and specialty APIs that give formulators the freedom to innovate without compromising patient safe

Active pharmaceutical ingredients

Following a comprehensive risk assessment (as defined by the EMA) of our entire API portfolio, we were able to confirm that the presence of nitrosamines in the Roquette API product range is considered as “negligible.” 

However, we weren’t content with the minimum requirement of assessing our API portfolio. As a true formulation partner, we knew a similarly comprehensive evaluation of our excipients range was also vital for ensuring producers’ peace of mind and patient safety. 

Excipients

Our experts have dedicated years of investigation to defining and designing appropriate testing protocols for the detection of nitrosating agents, such as nitrite in excipients, often in the absence of clear regulatory standards. 

Thanks to these efforts, we are now proud to offer among the industry’s largest collection of low nitrite excipients, unlocking safe, adaptable drug development without compromise. 

Beyond the Storm

Refocusing on patient experience

Regulatory shifts are nothing new in the world of pharma manufacturing, though the nitrosamine challenge has been exceptional – in scope and impact. With the majority of producers now well-versed on why and how NDSRIs form and exciting new nitrosamine formation-predicting software beginning to emerge, we can cautiously say the worst of the manufacturing-related disruption will soon be over. The focus moving forward then should be decidedly more human-centered. 

Securing patient safety and trust sits at the heart of everything we do at Roquette, but now we see an opportunity to take satisfaction one step further. Through offering a broad range of nitrosamine-assessed, below-LOD APIs and excipients, we aim to support risk-free drug development where patient-centricity – not nitrosamine mitigation strategy – takes center stage. As the storm clouds begin to clear and the industry prepares for what it hopes will be the final nitrosamine compliance milestone, we’re readying our partners for a future where nitrosamine mitigation is just another routine step in the production of safe, effective medications that meet users’ needs, preferences and even aspirations. 

See what our low nitrite excipients and APIs can do for your formulations. Explore the range and connect with our experts for tailored advice below.

 

Contact our experts

References

(1)  Covington, FDA Releases Final Guidance on Recommended Acceptable Intake Limits for Nitrosamines, August 2023, link to the study
(2)  U.S. Food & Drug Administration, Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) Guidance for Industry, Control of Nitrosamine Impurities in Human Drugs, Guidance for Industry, last updated 15 October 2024, link to the study 
(3) European Medicines Agency, Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products, July 2024, link to the study
(4) European Medicines Agency, Nitrosamine impurities, link to the study
(5) U.S Food & Drug Administration, Control of Nitrosamine Impurities in Human Drugs Guidance for Industry, link to the study
(6) Hemanth P.R. Vikram, Tegginamath Pramod Kumar, Gunjan Kumar, Narasimha M. Beeraka, Rajashree Deka, Sheik Mohammed Suhail, Sandeep Jat, Namitha Bannimath, Gayatiri Padmanabhan, Ravandur S. Chandan, Pramod Kumar, Bannimath Gurupadayya, Nitrosamines crisis in pharmaceuticals − Insights on toxicological implications, root causes and risk assessment: A systematic review, Journal of Pharmaceutical Analysis, Volume 14, Issue 5, 2024, 100919, ISSN 2095-1779, link to the study
(7) European Medicines Agency, EMA/409815/2020 Rev.21, Questions and answers for marketing authorization holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products, 19 July 2024, link to the study
(8) Abrantes C.G., Duarte D., Reis C.P. An Overview of Pharmaceutical Excipients: Safe or Not Safe. J. Pharm. Sci. 2016;105:2019–2026. doi: 10.1016/j.xphs.2016.03.019, link to the study
(9) - Haywood A., Glass B.D. Pharmaceutical excipients—Where do we begin? Aust. Prescr. 2011;34:112–114. doi: 10.18773/austprescr.2011.060, link to the study
       - van der Merwe, Jannes et al. “The Role of Functional Excipients in Solid Oral Dosage Forms to Overcome Poor Drug Dissolution and Bioavailability.” Pharmaceutics vol. 12,5 393. 25 Apr. 2020, doi:10.3390/pharmaceutics12050393, link to the study

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