Impact of post approval quantitative changes in excipient composition on nitrosamine formation: De-risking strategy.

Between 2018 and 2021, losartan was the most often recalled product (24% of total recalls) followed by metformin tablets (19% of total recalls) due to the presence of nitrosamine impurities. The objective of this work is to analyse the de-risking method in terms of reducing nitrosamine generation and establishing nitrite specifications in excipients. In light of these recalls, we simulated the influence of post-approval level 1 and level 2 changes in excipient compositions on nitrosamine formation in metformin SR (sustained release) and losartan film coated tablets. Furthermore, we investigated the de-risking approach in terms of reducing nitrosamine formation and establishing nitrite specifications in excipients. Level 1 changes in excipient composition resulted in no discernible increase in nitrosamine impurities for both metformin SR and losartan film coated tablets. On the other hand, level 2 changes resulted in more than 7% and 18% increase in nitrosamine levels in metformin SR and losartan film coated tablets, respectively. In fact, level 2 changes could cause nitrosamine impurities to exceed the AI (acceptable intake) limits. When low-nitrite level (LNL) excipients were employed, level 2 changes resulted in no significant increase in nitrosamine formation from their original values. Finally, specifications for nitrite in excipients were established. Selecting formulation excipients with LNLs is critical for risk mitigation as was demonstrated in this study. To continue enjoying the regulatory flexibility in terms of reducing post approval variation submissions, it is paramount to assess the impact of nitrite load of excipients on the total nitrosamine burden of the product during product development.