Patient In-Use Stability Testing of FDA-Approved Metformin Combination Products for N-Nitrosamine Impurity

Metformin products in combination with glyburide, glipizide, pioglitazone, alogliptin, and linagliptin were repacked in pharmacy vials, stored at 30°C/75% RH for 3 months, and monitored for NDMA impurity. Initially, 18 products have NDMA level below ADI limit before exposure which decreased to 7 products meeting specification. In conclusion, in-use stability study provides quality and safety risk assessment of drug products where nitroso impurities are detected in the probable condition of use.


I just saw this online and came to post it and found you had beaten me to it @Yosukemino

We know that nitrosamines can increase in levels on stability, this has been shown by Merck and others in the past. I’m not sure what the “pharmacy vials” are that they have repackaged the product into are, and what level of protection they would provide from the stability conditions that have been utilised for this study, I can’t see the full study.

Interesting that only 18 out of 27 were under the 96 ng/day limit before they even started the additional stress study.


Here is the link to the previous paper that the author wrote. It may be helpful to understand this paper. This time, the author performed tests with combination products of metformin.

According to this paper, child-resistant, clear amber-colored polypropylene pharmacy vials that meet USP standards for light transmission and tightness are used for in-use stability tests. Though the author could not identify the major sources of NDMA increase in this study, he is considering differences in the products such as API, excipient, manufacturing method, process, and/or storage condition.

I do not know the MDDs of those combination products. The conclusion is from the value of a single tablet. For multiple doses, nitrosamine will increase double, triple, and so on. Therefore, I have to say nitrosamine contamination issues are still ongoing.


Please remember that this phenomenon is unique to NDMA. NDMA is the only volatile nitrosamine which is why the levels drop and, without checking, I would guess the more permeable the packaging, the better :grinning:

However even for NDEA the volatility is significantly lower and certainly for NDSRI’s there would be no equivalent effect

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This literature demonstrates the increase of NDMA in metformin combination tablets through stability testing. :grinning:

I know - but under accelerated conditions like open dish the NDMA will disappear–does this mean that you want the worst packaging so that the NDMA can evaporate :grinning:

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In fact, I find that the values reported are worrisome and cannot understand how could drug products with levels of NDMA 10-20x AI be commercialized. Were these purchased before the current Nitrosamine regulations, are the analytical results reliable? - there were instances when higher results were caused by interferences or in-situ Nitrosamine generation.

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