Alembic Recalls Anti-depressant Medicine for NDSRI Nitroso Desmethyldoxepin

The API synthetic manufacturing process for Doxepin typically involves building the tricyclic core (dibenzoxepinone ring system) from a phthalide intermediate. This is followed by the introduction of the dimethylamino propyl side chain typically by a Grignard reaction with reagents like 3-(N,N-dimethylamino)propyl chloride. The API synthetic route do not involve use of nitrites or other nitrosating agents and thus risk of NDSRI formation during API synthesis is generally low. However nitrites from common excipients like microcrystalline cellulose, magnesium stearate etc. can lead to formation of the NDSRI impurities in Doxepin hydrochloride by interaction with the dimethylamine functional group on the API.

Key Takeaways:

Companies should perform a comprehensive risk assessment of potential for formation of Nitrosamines and NDSRI impurities in the drug product and take mitigation measures. This should include:

• API structure assessment: Identify all potential nitrosamine-forming functional groups (secondary, tertiary, and quaternary amines, amides, etc.).
• Excipient Risk assessment: Evaluate excipients for the presence of nitrites and other nitrosating agents, especially when used with APIs containing vulnerable functional groups.
• Process Assessment: Evaluate process conditions (e.g., pH, temperature, moisture) which can facilitate nitrosamines formation
• Forced degradation studies: Assess formation of the NDSRIs in the drug product in stressed conditions / accelerated stability conditions
• Confirmatory testing / stability monitoring: Track formation of NDSRI impurities in drug products with APIs having vulnerable functional groups
• Nitrite scavangers in the formuation: Consider nitrite scavengers like ascorbic acid, BHA (Butylated Hydroxy Toluene) in the formulation to reduce impact of nitrite impurities.  
• Reformulation / Change of of excipients / source of excipients: Evaluate and implement changes to excipient suppliers, excipients in the drug formulation to reduce the risk from nitrite and other nitrosating impurities