Nitrosamine Risk Assessment: Are You Prepared for the August 1, 2025 Deadline?
The FDA’s deadline is fast approaching. Let us help you stay compliant.
Whether you’re a formulation scientist, process chemist, analytical chemist, regulatory affairs specialist, or drug delivery expert, understanding nitrosamines—and how they form- is essential.
A quick note on why nitrosamines are such a regulatory concern:
They are extremely potent carcinogens, especially once metabolically activated by CYP enzymes. Volatile nitrosamines like NDMA and NDEA have acceptable daily intake limits up to 1,000 times lower than most genotoxic impurities, according to FDA and ICH M7 guidelines.
At Emery Pharma, we’ve built an extensive knowledge base on this topic, which you can explore on our website. You’re also welcome to reach out to us directly; our team is happy to help guide you through your specific questions and challenges.
With that context, we invite you to explore our FAQ and get up to speed on what you need to know and do, before the deadline.
- Why is the FDA requiring nitrosamine risk assessments?
Nitrosamines are a class of chemical compounds known for their carcinogenic potential, especially after metabolic activation. In the human body, particularly in the liver, enzymes such as cytochrome P450s (CYPs) hydroxylate nitrosamines, converting them into DNA-reactive species. These species can alkylate and methylate DNA bases, resulting in mutations, genomic instability, and cancer. Given their presence as process impurities or degradation products, controlling nitrosamines is essential for ensuring drug safety.
- What is the significance of the August 1, 2025 deadline?
The FDA mandates that all drug manufacturers complete nitrosamine risk assessments by this date. This includes:
- Prescription drugs
- Over-the-counter (OTC) drugs
- Investigational (clinical-stage) drugs
The assessment must include:
- Paper-based risk evaluation
- Confirmatory testing if a risk is identified
- Reporting results to the FDA
Failure to comply could result in regulatory actions, including refusal to file, clinical hold, or recall.
- What if a manufacturer is unable to meet the deadline?
The FDA acknowledges the complexity of identifying and quantifying nitrosamines, particularly nitrosamine drug substance-related impurities (NDSRIs). If a company is unable to meet the August 1 deadline, the FDA may consider granting an extension, but only if:
- A good-faith effort has been made to comply
- A status update and justification is submitted
The extension is not automatic and must be formally requested with appropriate documentation.
- What constitutes a “good-faith effort”?
A good-faith effort includes:
- Initiating risk assessments and analytical method development
- Contracting testing to qualified laboratories (such as Emery Pharma)
- Ordering or synthesizing relevant nitrosamine standards
- Preparing regulatory filings
- Ongoing communication with the FDA
Delays due to supply chain constraints or technical barriers must be documented with a clear plan of resolution.
- Which types of products and substances are included?
This requirement applies to:
- All chemically synthesized APIs
- Finished dosage forms
- Excipients and solvents
- Packaging materials (if leachable nitrosamines are suspected)
Particular focus should be placed on compounds with secondary or tertiary amine structures, which can form nitrosamines under certain manufacturing or storage conditions.
- What testing methods are recommended?
Analytical methods must be highly sensitive, typically with limits of detection in the parts-per-billion (ppb) range. Common techniques include:
- LC-MS/MS (triple quadrupole mass spectrometry)
- GC-MS
- High-resolution mass spectrometry (HRMS)
Method validation should follow ICH M7 and USP 1469 guidelines.
- What are the FDA’s expectations for controlling detected nitrosamines?
If nitrosamines are detected:
- <10% of Acceptable Intake (AI): Monitor and document.
- 10–100% of AI: Include control limits in release/stability specs.
- >100% of AI: Reformulate, change process, or implement alternate controls. Submit as a Prior Approval Supplement (PAS) or CBE-30 depending on impact.
- What are NDSRIs and why are they important?
Nitrosamine Drug Substance-Related Impurities (NDSRIs) are a subset of nitrosamines that are structurally related to the API itself. These are often harder to detect and require custom synthesis of reference standards and more sophisticated risk modeling. The FDA considers control of NDSRIs critical, as they may have API-specific carcinogenic potential.
- How should companies communicate with the FDA?
Use appropriate regulatory channels to:
- Submit risk assessment summaries and test results
- Request deadline extensions (especially for NDSRIs)
- Provide timely updates on testing progress
- Submit changes to DMFs or applications when applicable
- What are the consequences of non-compliance?
Failure to comply with the nitrosamine risk assessment requirement can result in:
- Warning letters
- Clinical holds
- Import alerts
- Recalls or market withdrawals
- Delays in ANDA/NDA reviews
Beyond regulatory risks, there is also a significant patient safety and liability concern.
The FDA has made it clear that nitrosamine control is not optional. If your team needs additional support, please don’t hesitate to reach out. Emery Pharma is at the forefront of nitrosamine testing and regulatory compliance — our team of experts is here to help guide you every step of the way.
