FDA: Updated Guidance for Nitrosamines

In September 2024, the U.S. FDA published Revision 2 of the document 'Control of Nitrosamine Impurities in Human Drugs' on its website. This 'Guidance for industry' replaces the previous version of 24 February 2021 and was published without a comment period, so that comments can still be submitted now.

The new version contains six chapters and three annexes, which are listed below:

I. INTRODUCTION
II. BACKGROUND
III. NITROSAMINE IMPURITIES AND ROOT CAUSES OF FORMATION
A. Nitrosamine Impurities 
1. Small-Molecule Nitrosamines 
2. NDSRIs
B. Root Causes of the Presence of Small-Molecule Nitrosamine Impurities in APIs 
1. General Conditions That Lead to Nitrosamine Formation 
2. Sources of Secondary, Tertiary, and Quaternary Amines That Can Form    Nitrosamines 
3. Vendor-Sourced Raw Materials Containing Nitrosamine Impurities 
4. Recovered Solvents, Reagents, and Catalysts as Sources of Nitrosamine Impurities
5. Quenching Process as a Source of Nitrosamine Impurities
6. Lack of Process Optimization and Control
C. Nitrosamine Impurities in Drug Products From Sources Other Than APIs
D. Root Causes of the Presence of NDSRIs in Drug Products
IV. RECOMMENDATIONS FOR CONTROL AND MITIGATION OF NITROSAMINES IN APIs AND DRUG PRODUCTS
A. Acceptable Intake Limits
B. Recommended Three-Step Mitigation Strategy
C. Recommendations for API Manufacturers 
1. Mitigating the Presence of Nitrosamine Impurities in APIs 
2. Control of Nitrosamine Impurities in APIs
D. Recommendations for Drug Product Manufacturers and Applicants 
1. Risk Assessment and Confirmatory Testing
2. Control of Nitrosamine Impurities in Drug Products 
a. Establishing reliability of API suppliers 
b. Establishing specifications in drug products 
3. Recommendations for Drug Product Manufacturers and Applicants on Reduction or Prevention of NDSRI Formation in Drug Products
V. IMPLEMENTATION OF RECOMMENDED AI LIMITS
A. Assessment of Test Results
B. Recommended Timeline for Implementing Risk Assessments, Confirmatory Testing, and Submission of Required Changes for  Nitrosamines  
1. Approved or Marketed Drug Products 
2. Drug Products in Development and Under FDA Review 
a. Presubmission stage 
b. After submission
C. Reporting Changes to Mitigate Nitrosamine Impurities 
1. Reporting Changes by API Manufacturers 
2. Reporting Changes for Drug Products Reformulated to Mitigate Nitrosamines
a. Stability data to support reformulated drug products 
b. Bioequivalence studies for reformulated products
VI. MAINTAINING THE DRUG SUPPLY
REFERENCES
APPENDIX A: TIMELINE OF FDA INVESTIGATIONS REGARDING NITROSAMINE IMPURITIES
APPENDIX B: FDA DETERMINATION OF RECOMMENDED ACCEPTABLE INTAKE LIMITS
APPENDIX C: EXAMPLE OF CONTROL AND SPECIFICATION FOR THE RECOMMENDED ACCEPTABLE INTAKE LIMIT FOR MULTIPLE NITROSAMINES IN ONE DRUG PRODUCT

Revision 2 of the document 'Control of Nitrosamine Impurities in Human Drugs' can be found on the FDA website.

In addition, the FDA provides current information and amendments in connection with the 'Guidance Document' on a separate website.