Nitrosamines are formed through specific chemical reactions during drug manufacturing or storage. These impurities have become a major focus for regulatory bodies due to their potential health risks. Here’s how they are generated:
1. Reaction Between Nitrites and Amines:
- Key Players: Nitrites (NO₂⁻) and secondary/tertiary amines.
- Reaction: Nitrites react with amines, especially under acidic or high-temperature conditions, forming nitrosamines.
- Example: Sodium nitrite used in APIs or excipients can react with residual amines in the formulation.
2. Use of Nitrosating Agents in Manufacturing:
- Nitrosating agents like nitrous acid (HNO₂) or nitrates can directly form nitrosamines when amines are present.
- Common sources include contaminated solvents, reagents, or raw materials.
3. API Degradation:
- Certain Active Pharmaceutical Ingredients (APIs) degrade over time to release amines, which can then react with nitrites to form nitrosamines.
- Example: Degradation of sartans (like Valsartan) under improper storage conditions.
4. Contaminated Water or Reagents:
- Water or reagents used during synthesis might already contain nitrites, introducing nitrosamine risks.
- Even trace contamination can result in nitrosamine formation.
5. Cross-Contamination in Equipment:
- Shared manufacturing facilities or improper cleaning can lead to cross-contamination of nitrites or nitrosating agents, increasing risk.
6. Packaging Interactions:
- Packaging materials containing nitrocellulose or nitrates can leach nitrites into the drug product, especially under humid or warm conditions.
Preventing Nitrosamine Formation:
- Use nitrite-free reagents and solvents.
- Optimize storage conditions to minimize degradation.
- Regular equipment cleaning to avoid cross-contamination.
- Conduct thorough risk assessments during development.
Read also:
- Highlights of Recent FDA Guidance on Nitrosamine Drug Substance
- Best Practices to control N-Nitrosamine Impurities
Resource Person: Dev Soni