In Dec 2021, 23 lots of Metformin HCl ER Tabs, USP 750 mg were recalled due to OOS for NDMA Impurity (at 17 month long term stability) by Viona Pharmaceuticals Inc, these tabs were mfd by Cadila Healthcare Ltd, Ahmedabad, India.
https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/viona-pharmaceuticals-inc-issues-voluntary-nationwide-recall-metformin-hcl-extended-release-tablets-0
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@DAB Thank you for sharing the information. As OOS was observed in the stability test samples, both nitrosating agents and DMA may be contained in the tablets or the packages, HDPE bottles, and react during storage. The tablets consist of API, Hypromellose, IPA, Povidone, MCC, and Glyceryl behenate according to SDS. And API is a tertiary amine and manufactured from DMA. I guess nitrite contamination in excipient may be one of the root causes if artifacts did not interfere with NDMA assay. What do you think about it?
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Hi @Yosukemino
I do agree with your suggestion of a potential nitrite contamination in the excipients. More so, being a ER formulation, there is a possibility of use of novel excipients so perhaps that will also require consideration on case basis.
Since it’s an OOS issue , so am sure the mfr might have done a complete Phase 1 and Phase 2 Investigation to evaluate an assignable cause and then taken a decision to Recall the impacted lot and another 23 lots were recalled even though they were within valid shelf life. Now this is something that requires attention that the nonimpacted batches have also been recalled.
What’s interesting to note is that this OOS was observed in one lot at 17 month long term, does this imply that all the lots at accelerated stability had no issues?
The excipient compatibility data can throw some light on this issue.
There’s also a possibility that perhaps the API lot that went into this lot had potential issues on retest/stability.
Any potential contamination issues specific to this lot or issues due to container closure system with the formulation can also be evaluated.
And last but not the least the Analytical method related specificity aspects also require attention.
These are my Inputs on the basis of the available published info.
Hopefully we will get to know more on this from the Agency or mfr.
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Hi, @DAB.
Thank you for sharing your thoughts. I understood it. And I agree with you, we hope for further information. Other threads @sameer posted may be helpful to understand this issue. For some Metformin ER tablets, NDMA formation in long-term and accelerated stability conditions were not observed.
As @ASrinivasan pointed out, the difference of nitrite/nitrate amounts from batch to batch in excipients may play a key role, I guess.
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For information through EFPIA industry shared a paper that defined industry’s position in terms of understanding of the risk of NDMA formation within Metformin based products. Dialogue in relation to this continues…
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