FDA Issues Revised Guidance On Controlling Nitrosamine Impurities In Pharmaceuticals
By Vaibhav Patel, University of Minnesota
The U.S. FDA has been a global leader in ensuring drug safety and efficacy, often setting regulatory benchmarks that are followed worldwide. In September 2024, the FDA issued a revised version of its guidance titled Control of Nitrosamine Impurities in Human Drugs,1 which is an important directive for pharmaceutical manufacturers. This guidance, which represents the FDA's current thinking, provides a comprehensive framework to detect, prevent, and control nitrosamine impurities in active pharmaceutical ingredients (APIs) and drug products.
This article explores the significance of the FDA’s latest recommendations, explaining the nature of nitrosamine impurities, their root causes, and recommended strategies for mitigating their presence in pharmaceuticals. We also will discuss the implications of these recommendations for the global pharmaceutical industry and outline the best practices for ensuring compliance with the FDA guidelines.
Nitrosamine Impurities: Understanding The Risk
Nitrosamines are a class of chemical compounds that have the potential to cause significant harm to human health. These compounds can form during the pharmaceutical manufacturing process when amines (organic compounds derived from ammonia) interact with nitrosating agents such as nitrite salts under certain conditions, including acidic environments. The resulting nitrosamine compounds such as N-nitrosodimethylamine (NDMA) are known carcinogens. NDMA, for example, has been classified by the International Agency for Research on Cancer (IARC) as a probable human carcinogen based on evidence from animal studies.
Nitrosamines can form at various stages of drug manufacturing and may also be introduced into the product during storage or as a result of the contamination of raw materials. Since 2018, the unexpected discovery of nitrosamines in certain widely used drugs, such as angiotensin II receptor blockers (ARBs), has raised alarms across regulatory agencies. These impurities have led to recalls and even temporary drug shortages, highlighting the urgent need for effective risk-mitigation strategies.
The FDA's revised guidance aims to address these concerns by establishing clearer requirements and procedures for manufacturers to identify, assess, and control the presence of nitrosamine impurities in their products. While this guidance applies primarily to small molecule drugs, including both chemically synthesized APIs and drug products, it also encompasses biologics containing synthesized fragments and other at-risk products.
Root Causes Of Nitrosamine Impurities
One of the core objectives of FDA’s guidance is to identify the root causes of nitrosamine impurities, enabling manufacturers to adopt more effective control strategies. Several factors contribute to the formation of nitrosamines in pharmaceuticals, which vary depending on the materials and processes used during production. The following are some key root causes identified by the FDA.
Use of Amines in Synthesis
Nitrosamines are typically formed when secondary, tertiary, or quaternary amines react with nitrosating agents such as nitrite salts. This interaction often occurs under acidic conditions, rendering drug products and APIs with amine-containing reagents particularly vulnerable. The presence of amines in the reagents, solvents, or catalysts can trigger this reaction during production. For example, quenching reactions using nitrous acid to neutralize residual azide in certain chemical syntheses can create favorable conditions for nitrosamine formation.
Recovered Solvents, Reagents, and Catalysts
Another major source of nitrosamine contamination is the use of recovered solvents, reagents, and catalysts that have not been purified properly. During the recovery process, residual amines may remain in the solvents, which can react with nitrosating agents during the subsequent steps in the manufacturing process. Without proper monitoring and purification, these nitrosamines can be carried over into the final drug product, even when the drug product itself does not involve high-risk processes.
Vendor-Sourced Raw Materials
The quality and consistency of raw materials used in drug manufacturing play a significant role in controlling nitrosamine impurities. Vendor-sourced raw materials can contain trace amounts of nitrosamines or their precursors such as secondary or tertiary amines. In some cases, impurities can be introduced during the storage or transport of raw materials, particularly if solvents or chemicals are reused without adequate cleaning. Cross-contamination is another risk when raw materials are handled at facilities that also process nitrosamine-containing substances.
Inadequate Process Optimization and Control
The manufacturing process itself can contribute to nitrosamine formation if it is not properly optimized or controlled. Variability in reaction conditions, such as temperature, pH, and the sequence of reagent addition, can lead to the unintended formation of nitrosamines. Furthermore, poorly controlled purification steps may fail to remove these impurities effectively. For example, certain drying processes, such as fluid-bed drying at high temperatures, can promote nitrosamine formation in APIs containing nitrogen groups.
Excipients and Packaging Materials
In addition to the raw materials and the synthesis process, nitrosamine impurities also can originate from excipients used in drug formulations and packaging materials. Nitrites, common nitrosating agents, are often found in excipients such as preservatives, stabilizers, and fillers. These impurities can react with the amines present in the API, leading to nitrosamine formation during the shelf life of the drug product. Similarly, certain types of packaging materials can introduce nitrosamines into drug products via leaching or contamination.
The FDA’s Three-Step Mitigation Strategy
The FDA’s guidance outlines a three-step strategy for mitigating the risk of nitrosamine contamination in APIs and drug products. This structured approach helps manufacturers prioritize risk assessments, ensure thorough testing, and implement the necessary process changes. An overview of the recommended steps is provided below.
1. Conduct Risk Assessments
The first step in mitigating nitrosamine impurities is to conduct a thorough risk assessment. Manufacturers must assess their APIs and drug products to identify potential sources of nitrosamine formation, including raw materials, excipients, synthesis processes, and storage conditions. Risk assessment should prioritize high-risk products based on factors such as the maximum daily dose, duration of treatment, and patient population.
Risk assessments are essential not only for identifying the presence of nitrosamine precursors but also for evaluating the likelihood of nitrosamines forming under specific conditions. This requires collaboration between API and drug product manufacturers to ensure that all aspects of the production process are considered.
2. Perform Confirmatory Testing
Once a risk is identified, manufacturers must conduct confirmatory tests to verify the presence and concentration of nitrosamine impurities in their products. Testing should be carried out using validated and highly sensitive analytical methods capable of detecting trace amounts of nitrosamines. Chromatographic techniques, such as high-performance liquid chromatography (HPLC) coupled with mass spectrometry (MS), are often recommended for their specificity and sensitivity.
The FDA advises manufacturers to test multiple batches of products to ensure consistency and reliability. If nitrosamine impurities are detected, manufacturers must investigate the root cause and implement corrective actions to prevent their future occurrence.
3. Report and Implement Changes
If nitrosamine impurities are detected in APIs or drug products, manufacturers must take immediate action to mitigate the risk. This includes making changes to the manufacturing process, raw materials, or suppliers to reduce or eliminate nitrosamine formation. Any changes made to the approved drug application must be reported to the FDA in accordance with the relevant regulations, such as 21 CFR 314.70 for new drug applications (NDAs) and 21 CFR 601.12 for biologics.
Manufacturers are encouraged to work closely with the FDA during this process to ensure that all the necessary steps are taken to protect public health. In cases where nitrosamine levels exceed acceptable intake (AI) limits, product recalls may be required to remove the affected batches from the market.
Establishing Acceptable Intake Limits
A key component of the FDA guidance is the establishment of AI limits for nitrosamine impurities. These limits are designed to minimize the risk of cancer associated with long-term exposure to nitrosamines in pharmaceuticals. AI limits are typically set at levels that correspond to an additional cancer risk of one case per 100,000 people based on lifetime exposure (70 years).
For most nitrosamine impurities, the FDA has established specific AI limits based on toxicological data. However, for certain nitrosamines where data is lacking, manufacturers are advised to follow the recommended approach outlined in the International Council for Harmonisation (ICH) guidance M7(R2), which sets a general threshold of toxicological concern at 1.5 micrograms per day.
If a drug product contains multiple nitrosamines, manufacturers must ensure that the total level of nitrosamines does not exceed the AI limit for the most potent impurities. In some cases, a flexible approach may be necessary, particularly when AI limits for individual nitrosamines differ significantly.
Preventive And Control Measures
In addition to the three-step mitigation strategy, the FDA guidance outlines several preventive and control measures that manufacturers can implement to reduce the risk of nitrosamine contamination. These include:
Process Optimization
Manufacturers should optimize their API synthesis processes to avoid the conditions that may lead to nitrosamine formation. This includes selecting appropriate reagents and solvents, controlling reaction conditions, such as temperature and pH, and implementing effective purification steps to remove nitrosamine precursors. Where possible, nitrites should be replaced with alternative quenching agents to minimize the risk of nitrosamine formation during chemical reactions.
Supplier Qualification and Raw Material Control
Ensuring the quality and consistency of the raw materials is critical for controlling nitrosamine impurities. Manufacturers must implement robust supplier qualification programs to assess the risk of contamination in vendor-sourced materials. This may involve setting additional specifications for the raw materials, auditing suppliers, and conducting regular testing to monitor nitrosamines or their precursors.
Use of Recovered Materials
When using recovered solvents, reagents, or catalysts in the manufacturing process, manufacturers must ensure that these materials are adequately purified to remove residual nitrosamines. The FDA recommends using recovered materials only in the same step of the process from which they were collected, to prevent cross-contamination. If material recovery is outsourced to third-party contractors, manufacturers should audit these facilities to verify their cleaning procedures and to ensure compliance with good manufacturing practices.
Monitoring Excipients and Packaging
The excipients used in drug formulations must be carefully selected and monitored for nitrite impurities, which can react with APIs to form nitrosamines. Manufacturers should implement supplier qualification programs for excipients and conduct regular testing to ensure that nitrite levels remain within the acceptable limits. Packaging materials should also be evaluated for their potential to introduce nitrosamines into drug products through leaching or contamination.
Addressing Nitrosamine Drug Substance-Related Impurities
One of the significant additions to the FDA’s revised guidance is the focus on nitrosamine drug substance-related impurities (NDSRIs). These nitrosamines are formed when the API itself or a fragment of the API undergoes nitrosation during the manufacturing process or storage. NDSRIs are particularly challenging to control, because they are unique to each API and often lack comprehensive toxicological data.
The FDA recommends that manufacturers take special precautions to prevent NDSRI formation by screening excipients for nitrite impurities, incorporating antioxidants into formulations, and adjusting the pH of drug products to neutral or basic levels. These strategies can significantly reduce the risk of NDSRI formation and ensure that the drug product remains within the acceptable safety limits throughout its shelf life.
Conclusion: Ensuring Compliance And Protecting Public Health
The FDA’s revised guidance on nitrosamine impurities marks an important step forward in safeguarding the quality and safety of pharmaceuticals. As the global pharmaceutical industry continues to evolve, manufacturers must remain vigilant in their efforts to detect, prevent, and control nitrosamine impurities in their products.
By following the FDA’s three-step mitigation strategy — conducting risk assessments, performing confirmatory testing, and implementing process changes — manufacturers can effectively minimize the risk of nitrosamine contamination. Moreover, adopting preventive measures such as process optimization, supplier qualification, and careful selection of excipients and packaging materials will help ensure compliance with regulatory requirements and protect public health.
The road ahead requires ongoing collaboration between industry stakeholders and regulatory agencies. As new scientific insights emerge and manufacturing technologies advance, the FDA’s guidance will continue to evolve, helping the pharmaceutical industry to stay one step ahead in the fight against nitrosamine impurities.
Reference
- FDA. Guidance on Control of Nitrosamine Impurities in Human Drugs, September 2024 (Revision 2), https://www.fda.gov/media/141720/download
About The Author:
Vaibhav Patel is a quality assurance professional with over 13 years of experience in drug development. As the director of quality assurance and regulatory affairs at the University of Minnesota, he manages quality systems for clinical productions and ensures FDA compliance. His career covers various biopharmaceutical domains, including radiopharmaceuticals, nanomedicine, cell and gene therapy products, and monoclonal antibodies. Vaibhav's expertise includes developing phase-appropriate quality management systems, leading QA teams, and managing IND product releases as well managing CDMOs in the U.S., China, and India. Previously, he held roles at Elucida Oncology and Memorial Sloan-Kettering Cancer Center. Vaibhav is a certified Quality Auditor and holds a Regulatory Affairs Certification. He is an active member of the American Association of Pharmaceutical Scientists. He holds a master’s degree in pharmaceutical manufacturing from Stevens Institute of Technology and a Bachelor of Pharmacy from Rajiv Gandhi University of Health Sciences.