FDA Recent Updates to the Recommended Interim Acceptable Intake (AI) Limits for Certain Nitrosamine Impurities of Approved or Currently Marketed Products
Alameda, CA-The U.S. Food and Drug Administration (FDA) has reassessed the recommended Acceptable Intake (AI) limit for 8 out of 9 listed products in the CDER Nitrosamine Impurity Acceptable Intake Limits guidance (Table 1). The planned adjustment to the recommended interim (AI) limits are based on current market conditions such as public health risk, feasibility and complexity of implementing effective risk mitigation strategies and risk of drug shortages to name a few.
Table 1. Comparison of New versus Old FDA Recommended Interim AI Limits* for Certain Nitrosamine Impurities** for Approved or Currently Marketed Products
The updates suggest that despite the risk of exposure for these risk genotoxic impurities, the FDA’s maintains a similar expectation based on current market conditions and manufacturing capabilities. Of the drug products listed, Rifampin has received a lot of attention primarily due to its role in DDI studies as an optimal CYP3A4 inducer providing a favorable pharmacokinetic profile in clinic. The FDA maintained the recommended interim control limit of 1-methyl-4-nitrosopiperazine (MNP) at 5ppm for release of Rifampin.
In addition to the FDA’s recent reassessment of the interim AI limits update for MNP in Rifampin, the EMA also posted updated guidance for release of Rifampin noting an additional Carcinogenic Potency Categorization Approach (CPCA) category 3 NDSRI to its release criteria on June 1, 2026.
The EMA has identified N-nitroso-desmethyl-rifampicin as an NDSRI with an AI limit of 400 ng/day or 0.67ppm (Figure 2).
You may be wondering how this will affect the availability of Rifampin for clinical applications.
Key elements of the FDA’s and EMA’s recent announcements include:
- Higher expectations in cGMP release of rifampin, particularly with its involvement in healthy participants in clinical trials.
- Continued emphasis on patient safety while recognizing the importance of maintaining access to essential medicine.
- Expectations for sensitive analytical methods capable of reliably detecting and now quantifying N-nitroso-desmethyl-rifampicin at the revised AI limit for use in the EU.
These changes are designed to reduce unnecessary risk, especially in healthy volunteers participating in clinical trials and hold the industry to a higher standard.
Emery Pharma’s Role
Emery Pharma has supported Rifampin manufacturers and Clinical Research Organizations (CRO) with cGMP release testing solutions and will continue to do so even as AI limits change. Emery Pharma has been supporting release of rifampin for years, utilizing in-house validated test methods for MNP in rifampin at both 5ppm and 0.67ppm. With deep expertise in analytical method development, validation, impurity analysis, and regulatory-ready reporting, Emery Pharma is well positioned to support sponsors navigating the FDA’s and EMA’s updated guidance.
“As regulatory expectations evolve, the need for high-quality, defensible analytical data becomes even more critical,”
— Ron Najafi, Ph.D., Founder and CEO of Emery Pharma.
Looking Ahead
The FDA’s and EMA’s guidance updates demonstrate the agencies’ continued oversight and surveillance into evolving industry conditions. As the FDA and EMA guidance continue to evolve, early engagement, strong analytical foundations, and proactive regulatory planning will be essential for success.
Emery Pharma stands ready to support innovators at every stage—from early development through NDA submission and beyond.
For more information or to discuss your program, please contact Emery Pharma for a confidential consultation or see more about FDA’s recent updates here or the EMA’s recent AI updates here.
Media Contact:
Chris Purcell
Business Development Manager
Emery Pharma
Email: info@emerypharma.com
Website: emerypharma.com
