Nitrosamine Risk Assessment - APIs

Preliminary Evaluation (Q1)

Q1. Is Sodium Nitrate or any other Nitrosating agents involved in the Route of Synthesis (ROS) for the API?
Q2. Is Sodium Nitrate or any other Nitrosating agents involved in the ROS for the Key Starting Material (KSM)?
Q3. Are Secondary or Tertiary Amines used in API ROS?
Q4. Are Secondary or Tertiary Amines used in API KSM ROS?
Q5. Are amide-based solvents (e.g., DMF, NMP) used in the API’s ROS?
Q6. Are amide-based solvents (e.g., DMF, NMP) used in the KSM’s ROS?
Q7. Are azides (e.g., NaN3) used in the API’s ROS?
Q8. Are azides (e.g., NaN3) used in the KSM’s ROS?
Q9. Are recovered solvents used during the API manufacturing process?
Q10. Are recovered solvents used during the KSM manufacturing process?
Q11. Is there a possibility that solvents used in the process contain triethylamine or other secondary/tertiary amines alongside nitrites?
Q12. Are third-party facilities involved in recovering solvents used for the API?
Q13. Are third-party facilities involved in recovering solvents used for the KSM?
Q14. Are nitrosating agents used in any other product/process at the API site?
Q15. Are nitrosating agents used in any other product/process at the KSM site?
Q16. Are secondary/tertiary amines used in any other process at the API site?
Q17. Are secondary/tertiary amines used in any other process at the KSM site?
Q18. Are amide-based solvents (e.g., N,N-DMF, NMP) used in any other process at the API site?
Q19. Are amide-based solvents (e.g., N,N-DMF, NMP) used in any other process at the KSM site?
Q20. Is water used in the manufacturing process?
Q21. Are there other risks of nitrosamine presence in API process?
Q22. Risk of NDSRI: Does the API has secondary/tertiary amine functional group and nitrites are involved in manufacturing process?
Q23. Risk of NDSRI: Can degradation of starting materials, intermediates or API produce secondary/tertiary amine functional groups with nitrites present in the manufacturing process?
Q24. Risk of NDSRI: Is formation of any NDSRI listed as per USFDA Guidance: Control of Nitrosamines in Human Drugs or EMA / CMDh: Appendix 1 for Nitrosamines possible in API/KSM process?