It is indeed very interesting the impact of milling/grinding based on NOx. It is something that for sure needs to be considered. There are complex and simple ways for doing it. The simple ways may not neccesarily reduce significantly the formation but are so easy that is worth trying (e.g., in the manufacturing instruction to put a note to please close the bag when you are not sampling).
Regarding the sample preparation, yes it does happen. It is normally recommended to perform a sample preparation assessment as part of the robustness.
Thank you for asking, @MarkS. When I talked with the excipient manufacturer, who provided MCC with nitrite of less than 0.1 ppm, he explained that the test samples would be carefully stored to remove as much air as possible and prevent air from entering them. I think it is the same. Grinding will increase nitrite in the samples. If there are serious concerns in the measurement, I guess an antioxidant might be added to the solvent.
Thank you for the additional information, @Diego_HM. I agree with you. It is noteworthy that grinding increased NOx gas in the API. Grinding in an agate mortar appears to be a model of pin mill grinding. NOx gas monitoring in the air may be mandatory in the milling/grinding processes.
it is interesting that JA recommends " If nitrosamines are detected, stability testing is required to ensure the shelf life, even if the acceptable limit is not exceeded".
If I am not mistaken this was a gap to EMA Q&A. Could you please confirm?
Thank you for asking, Eleni. The sentence “This includes testing not only of newly produced batches but also retained samples of batches still within expiry date” in “EMA Q&A Q8. How should confirmatory tests be conducted by MAHs and manufacturers?” means to take the stored samples in consideration for batch selection. Samples for stability tests may replace it. I think MAH should clarify the root cause of nitrosamine contamination and ensure the shelf life even in EMA.
Early considerationの文書は、科学的知見や情報等が必ずしも十分に集積されていない段階ではあるものの、新たな技術等のイノベーションの実用化と革新的な医薬品等の開発を促進するための参考情報として、その時点における考え方を示したものとなっているそうです。また、今後、新たに得られる知見や科学の進歩等により、変わり得るものでもあるそうです。
ここではニトロソアミンに関連するところのみを抜粋します。「第Ⅰ相～第Ⅱa相」と「第Ⅱb相～第Ⅲ相」で異なっており、前者ではcohort of concernの一つとして混入リスクがないことを説明していますが、後者では章立てして、原薬及び製剤の製造を通じてニトロソアミン不純物の混入リスクがないことを説明しています。
Hi Yosuke,
very very interesting input…well, isn’t extremely high levels of nitrite content the 524ppm? Even i have no idea about bentonite nature, i think that this is very weird.
Furthermore, it is a great surprise for me, the coating material to worsen so much the levels of nitrosamine impurity, as it is used in a relevant low concentration in the final product.
best regards
Christos
Thank you for your comments, Christos. 480 ppm of nitrite in bentnite looks very high. Bentonite is a type of clay that contains Ca2+ or Na+ internally and has a wide range of pH, from about 5 to 10. Bentonite is excavated from mountains.
0.6 mg of bentnite is used for one tablet. The changed bentonite will contain less than 46 ppm of nitrite.
The MDD of arotinol is 30 mg and the AI of N-nitroso arotinol is 1500 ng/day. If you need further information, do not hesitate to ask me.
Thank you for your advice. Yes, you are perfectly right. I did not know that bentonite adsorbs nitrogen ions like ammonium, nitrate, and nitrite ions well. And I thought it was for cosmetic use. It is interesting!
Natural Moroccan bentonite clay as an adsorbent for nutrient removal from synthetic leachate: Performance and evaluation
Is it really a surprise that coating is a potential source of nitrosamine formation?
Depending on the coating itself and the coating process used it could involve water, elevated temperature, hot gases, materials containing nitrites, etc.
As for the bentonite itself - does it release any absorbed nitrites again during the coating process? The data seems to suggest yes. But is it also able to absorb NOx gases during the coating/drying process?
I agree with you, Mark. In some cases, coatings are not free from nitrosamine contamination risks. Before 2018, if I had excipients with 500 ppm nitrite, I probably wouldn’t have paid much attention to them. But now it’s perfectly different. We have become sensitive…
