The regulation of nitrosamine impurities has been evolving rapidly due to concerns about their potential health risks, particularly their carcinogenicity. Regulatory authorities worldwide, including the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Therapeutic Goods Administration (TGA) in Australia, have introduced stringent guidelines to control and mitigate these impurities in pharmaceuticals. Below, we discuss the latest regulatory updates from these major health authorities.
The regulation of nitrosamine impurities in pharmaceuticals has undergone significant changes in recent years. Nitrosamines, a class of carcinogenic compounds, have been found in various medications, leading to recalls and regulatory scrutiny. As a result, global health authorities have implemented stricter guidelines to control and minimize nitrosamine contamination in active pharmaceutical ingredients (APIs) and finished drug products.
Regulatory bodies such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Therapeutic Goods Administration (TGA) in Australia have updated their guidance to ensure the pharmaceutical industry adheres to safe production practices. These updates impact drug manufacturers, requiring them to conduct thorough risk assessments, implement advanced testing methods, and adhere to new acceptable intake (AI) limits for nitrosamines.
In this blog, we explore the latest regulatory updates from major health authorities and their implications for the pharmaceutical industry.
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Set an appointmentU.S. Food and Drug Administration (FDA) Updates
September 2024: Revised Final Guidance on Nitrosamine Impurities :
In September 2024, the FDA issued a revised final guidance document titled “Control of Nitrosamine Impurities in Human Drugs.” This guidance provides pharmaceutical manufacturers with essential information on how to detect, assess, and mitigate nitrosamine impurities in their products.
Why Did the FDA Issue This Update?
The presence of nitrosamines in pharmaceuticals has raised significant public health concerns. Since 2018, multiple drug recalls—including medications for blood pressure, diabetes, and acid reflux—have been linked to unacceptable levels of nitrosamine impurities. The FDA’s revised guidance aims to prevent future contamination by establishing clear regulatory expectations.
Key Highlights of the FDA’s Guidance:
One of the most critical updates in the FDA’s guidance is the classification of nitrosamines into two categories:
- Small-molecule nitrosamine impurities: These are common nitrosamines such as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) that may form during drug manufacturing.
- Nitrosamine drug substance-related impurities (NDSRIs): These arise when the chemical structure of an active pharmaceutical ingredient (API) itself contributes to nitrosamine formation.
Example: If an API contains an amine group, it may interact with nitrite contaminants in manufacturing processes, leading to NDSRIs.
The FDA requires drug manufacturers to perform comprehensive risk assessments to determine the root causes of nitrosamine contamination. Common sources include:
- The use of nitrite-containing reagents in drug synthesis.
- Cross-contamination from shared manufacturing equipment.
- Impurities in raw materials or solvents.
- NDSRIs can be generated during the manufacturing process or during storage of a finished drug product over its shelf life. The known root causes of the presence of NDSRIs in drug products are (1) nitrosating impurities such as residual nitrite in excipients or other sources of nitrite impurities present in drug products (see section III.C.), which lead to nitrosation of the active ingredient to yield NDSRIs under certain conditions, and (2) NDSRIs carried over from APIs (see section III.B.2. and 3.). Generally, the presence of high levels of NDSRIs has been associated with drug products rather than APIs because NDSRI formation most often results from a reaction between the API or an API fragment and nitrite impurities present in the drug product
Example: In 2020, ranitidine-based drugs were recalled because they were found to degrade into NDMA over time, highlighting the need for stringent risk assessments.
The FDA has introduced enhanced analytical methods for detecting nitrosamines, including:
- High-Performance Liquid Chromatography (HPLC)
- Gas Chromatography-Mass Spectrometry (GC-MS)
- Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)
These methods enable manufacturers to detect nitrosamines at very low concentrations, ensuring product safety.
To reduce nitrosamine formation, manufacturers are advised to:
- Modify manufacturing processes to eliminate nitrosamine precursors.
- Use alternative solvents and reagents that do not contribute to contamination.
- Enhance cleaning procedures for shared production equipment.
European Medicines Agency (EMA) Updates
July 2024: New Guidelines for Marketing Authorization Holders:
Currently, the European Medicines Agency’s (EMA) human medicines committee (CHMP) is reviewing how the nitrosamine N-nitrosodimethylamine (NDMA) was found in some batches of ranitidine, a commonly used medicine for heartburn and stomach ulcers. Additionally, authorities are assessing recent test results that detected NDMA in certain EU batches of metformin, a widely used diabetes medication.
While further testing on metformin is underway, EMA advises patients to continue their treatment as prescribed, as the health risks of untreated diabetes far outweigh any potential concerns from trace amounts of nitrosamines. Given metformin’s critical role in diabetes management, EMA and national authorities are also working closely to prevent shortages and ensure continued availability for patients.
The EMA has been proactive in addressing nitrosamine contamination by updating its guidance for marketing authorization holders (MAHs) in July 2024. This update reinforces the need for ongoing evaluation of manufacturing processes to minimize nitrosamine risks.
Why Did the EMA Update Its Guidelines?
Following discoveries of nitrosamines in widely used drugs such as sartans, metformin, and rifampin, the EMA recognized gaps in risk assessment protocols. The updated guidance ensures that manufacturers:
- Conduct comprehensive risk evaluations.
- Continuously monitor for new potential sources of nitrosamine formation.
- Comply with stricter acceptable intake limits.
Since September 2019, an EU-wide initiative has been in place to provide pharmaceutical companies with clear guidance on managing nitrosamine impurities. This initiative includes:
✅ Comprehensive risk assessments by manufacturers
✅ Implementation of control and mitigation strategies
✅ Enhanced testing and regulatory oversight
At the same time, EU authorities are conducting a thorough review of the lessons learned from the presence of nitrosamines in sartan medicines (used to treat high blood pressure), an issue that first emerged in mid-2018. The findings from this lesson-learned exercise will help shape more robust measures to prevent and manage impurities in medicines going forward.
The new EMA guidelines apply to:
- All drugs containing chemically synthesized or biological active substances.
- Combination products that involve multiple active ingredients.
- Excipients that could act as sources of nitrosamine formation.
This broader scope ensures that nitrosamine risks are evaluated across all pharmaceutical formulations.
Pharmaceutical companies are now required to reassess their manufacturing processes regularly. If any risk of nitrosamine formation is identified, companies must:
- Implement corrective actions.
- Submit revised risk assessments to regulatory authorities.
- Update product labeling if necessary.
The EMA has introduced mandatory reporting requirements where manufacturers must:
- Regularly submit nitrosamine test results.
- Notify authorities of any detected nitrosamine impurities exceeding limits.
- Provide remediation plans for non-compliant products.
Therapeutic Goods Administration (TGA) of Australia Updates
February 2025: Setting Acceptable Intake Limits for Nitrosamines
The TGA in Australia has also reinforced its commitment to mitigating nitrosamine risks by setting Acceptable Intake (AI) limits for various nitrosamine compounds in February 2025.
Long-term exposure over a period of years to nitrosamines that exceed certain levels can increase the risk of developing cancer. Given this, the aim is to eliminate or minimise the levels of nitrosamines present in affected medicines, as their presence is generally considered unacceptable from both quality and safety perspectives. We have set acceptable intake (AI) limits for many nitrosamine impurities to ensure medicines remain both safe and of high quality. The limits are used to determine if regulatory actions are required for affected products.
Why Did the TGA Take This Step?
- The TGA observed a rise in cases of nitrosamine contamination in certain medications.
- To align with global regulatory standards, Australia needed well-defined AI limits for pharmaceuticals.
- There was a need to prevent unnecessary drug shortages due to recalls.
Key Updates from the TGA
The TGA has now established strict thresholds for nitrosamines, which vary based on:
- The type of nitrosamine compound.
- The route of administration (oral, injectable, etc.).
- The duration of treatment.
The TGA is actively working with:
- Pharmaceutical manufacturers to refine drug formulations.
- Regulatory scientists to improve detection techniques.
- International agencies to maintain global safety standards.
To ensure compliance, the TGA has recommended:
- More frequent testing of drug batches.
- Stronger oversight of raw material suppliers.
- Greater transparency in nitrosamine risk reporting.
- Sponsors must evaluate potential contamination risks.
- Prioritize medicines with long-term use and high doses.
- Conduct validated testing and implement preventative measures.
- If nitrosamine levels exceed AI limits, sponsors must notify TGA and propose risk mitigation strategies.
- Maintain records of investigations, CAPAs, and compliance within GMP frameworks.
- Variation requests must be submitted for process changes.
Conclusion: A Global Effort to Ensure Drug Safety
The FDA, EMA, and TGA are leading the charge in addressing nitrosamine contamination. Their updated regulatory frameworks are designed to ensure that medications remain safe, effective, and free from unacceptable levels of carcinogenic impurities.
Pharmaceutical manufacturers must stay informed, implement risk-based strategies, and comply with new testing and monitoring requirements to meet evolving regulatory expectations.
Key Takeaways
✅ Drug manufacturers must conduct thorough risk assessments.
✅ Improved testing methods are now required for nitrosamine detection.
✅ Global harmonization of safety standards is strengthening drug quality.
Stay updated on regulatory changes to ensure compliance and patient safety!
Relevant Guidelines:
- Quality Risk Management Guideline ICH Q9- external site- external site
- ICH M7(R1) Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk” (ICH M7 (R1))– external site
- US FDA Information about Nitrosamines Impurities in Medications- external site webpage including the FDA guidance for industry.
- Health Canada Nitrosamine impurities in medications: Overview- external site webpage.
- US Pharmacopoeia/National Formulary (USP/NF) Nitrosamine impurities- external site and Nitrosamine impurities general chapter- external site webpages.
- EDQM response nitrosamine contamination- external site and general chapter n-nitrosamines webpages.
- European Pharmacopoeia (Ph. Eur) general chapter n-nitrosamines- external site
Sagar Pawar
Sagar Pawar, a Quality Specialist at Zamann Pharma Support, brings over 11 years of experience in Quality domain for the pharmaceutical and medical technology industries. Specializing in qualification, validation, Computer System Validation (CSV), and Nitrosamine activities, Sagar is currently focused on enhancing the Zamann Service portfolio by developing and implementing robust strategies to address Nitrosamine-related challenges. Outside of work, Sagar enjoys trekking and cooking. Connect with Sagar on LinkedIn to discuss topics related to equipment qualification, GMP Compliance and Nitrosamine-related challenges.
