Can less than lifetime be applied for nitrosamines?

[@FernandaWaechter]

[description continued] The lifetime AI was very similar to what was already being used, but the AI for shorter exposures was actually way higher, showing that ICH M7 values include an additional margin of safety when compared to what is seen experimentally. This also shows that no saturation of DNA repair enzymes was seen, because short durations did indeed lead to lower cancer rates. So this study shows that the less than lifetime approach ensures a negligible risk of cancer and is protective of patient health when establishing limits for mutagenic impurities, including nitrosamines, if using ICH M7 principles. In fact, these studies performed with NDEA were one of the basis for the less than lifetime concept being included in ICH M7 in the first place. Nonetheless, the wider regulatory acceptance of this approach is still taking shape [EMA Q&A - temporary] , so even more investigations are underway in this area, to allow for the science to advance even more. Acknowledgements: Lhasa Limited, Joel Bercu, Maria Augusta Rodrigues References: Bercu JP, Masuda-Herrera M, Johnson G, et al. Use of less-than-lifetime (LTL) durational limits for nitrosamines: case study of N-nitrosodiethylamine (NDEA). Regul Toxicol Pharm. 2021;123: 104926. EMA/369136/2020, EMA Assessment Report, 25 June 2020 - www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf EMA/409815/2020 Rev. 14, EMA Questions & Answers, 21 December 2022 - www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-marketing-authorisation-holders/applicants-chmp-opinion-article-53-regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinal-products_en.pdf

[@yb7912]

Thanks for sharing it is very informative. TD50, CSF, BMDL values are almost calculated based on oral exposures. Is it possible to do route-to-route extrapolation as in the NOAEL? In other words, what do we do if the genotoxic-carcinogenic impurity is present in a parenteral drug formulation?

[@RAVAL39]

Your all videos on Nitrosamine concept are mind blowing

[@mattpopkim6535]

Another outstanding video- very informative and clear.

[@nileshbawane842]

Excellent Fernanda

[@bhushanborse917]

Good information, current topic in all pharmaceuticals industries, can you please elaborate more on control strategies. Thanks

[@nithinbommareddy39]

Your vedieos are so helpful. Keep going..

[@AA-bx8vk]

Thank you mam for the informative video. I have a question about NDSRI's recent guide from the USFDA "Recommended Acceptable Intake Limits for Nitrosamine Drug Substance Related Impurities (NDSRIs) Guidance for Industry" There is one NDSRI "N-nitroso-Desmethyl Erythromycin" with reported AI of 1500 ng/day. The drug substance is a Macrolide antibiotic, considering the exposure of Less than lifetime approach, what is the indicative control limit? Is it possible to explain? Thanks alot

[@FernandaWaechter]

Hi dear, to calculate the less than lifetime limit you need to know the duration of exposure to the drug. Usually antibiotics would be used for less than 1 month so the factor you would multiply the AI for - if using ICH M7 principles - is 80. In this case 1500 x 80 = 120,000 ng/day. However please note that as per the last EMA Q&A such a limit can only be considered after consultation with competent authorities as a temporary measure until further measures can be implemented to reduce the contaminant at or below 1500 ng/day.