FDA: Aktualisierter Leitfaden für Nitrosamine

Im September 2024 hat die U.S. FDA auf Ihrer Webseite die Revision 2 des Dokumentes "Control of Nitrosamine Impurities in Human Drugs" veröffentlicht. Diese "Guidance for industry" ersetzt die Vorgängerversion vom 24. Februar 2021, und wurde ohne Kommentierungsphase publiziert, so dass Kommentare auch jetzt noch eingereicht werden können.

Die neue Version enthält sechs Kapitel und drei Anhänge, die im Folgenden aufgeführt sind:

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

Die  Revision 2 des Dokumentes "Control of Nitrosamine Impurities in Human Drugs" finden Sie auf der Webseite der FDA.

Zusätzlich stellt die FDA auf einer separaten Webseite aktuelle Informationen und Anpassungen im Zusammenhang mit dem "Guidance Document" zur Verfügung.