Understanding Nitrosamine Impurities in Pharmaceuticals:
- Nitrosamines, particularly N-nitrosamines, are probable or possible human carcinogens.
- They can form during the synthesis of active pharmaceutical ingredients (APIs) or during the storage of finished drug products.
- FDA guidance emphasizes the need for risk assessment, mitigation strategies, and regulatory compliance to control nitrosamine levels.
Major Root Causes of Nitrosamine Formation in Drugs:
- Secondary, Tertiary, or Quaternary Amines: These amines can react with nitrosating agents, such as nitrites, to form nitrosamines.
- Vendor-Sourced Raw Materials: Contaminated raw materials, such as solvents (e.g., methylene chloride), have been found to contain nitrosamines.
- Recovered Solvents: Using recovered materials without proper controls can lead to cross-contamination.
- Process Control Issues: Inadequate optimization of pH, temperature, or reagent addition sequence can create favourable conditions for nitrosamine formation.
FDA’s Key Recommendations for Nitrosamine Mitigation:
- Acceptable Intake Limits (AI): FDA’s AI limits reflect permissible levels of nitrosamine exposure. For example, the acceptable intake for N-nitrosodimethylamine (NDMA) is 26.5 ng/day.
- Three-Step Strategy:
- Risk Assessments: Identify potential contamination points during API and drug product manufacturing.
- Confirmatory Testing: If a risk is identified, conduct sensitive tests for nitrosamine detection.
- Control Measures: Modify manufacturing processes to eliminate or reduce nitrosamine levels.
FDA’s Acceptable Intake Limits (AI)
- NDMA: 26.5 ng/day
- N-Nitrosodiethylamine (NDEA): 26.5 ng/day
- N-Nitroso-N-methyl-4-aminobutyric acid (NMBA): 26.5 ng/day
- When multiple nitrosamines are present, the total must not exceed the AI limit for the most potent nitrosamine.
Zenovel’s Risk Management & Mitigation Support:
- Risk Assessments: Our team conducts in-depth root cause analysis to identify points of nitrosamine contamination in manufacturing processes.
- Process Optimization: We help clients redesign their processes to prevent the formation of nitrosamines, including minimizing the use of secondary amines and controlling pH and temperature conditions.
- Vendor Audits & Quality Control: Zenovel implements supplier qualification programs to ensure raw materials meet stringent nitrosamine contamination controls.
Need Support in Nitrosamine Risk Mitigation? Let Zenovel Help You Achieve Compliance!
Contact Zenovel today for expert guidance and tailored solutions to meet the latest regulatory standards on nitrosamine impurities.
