@Naiffer,
Thanks for compiling the AI (as per FDA & EMA).
I just want to confirm the AI for NDMA impurity i.e. 96 or 26.5ng/day
Thanks again.
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hi experts,
Can any one explain how this 37 ng/day for n-nitroso varenicline is derived. SAR and read across from 1,2,3,6-Tetrahydro-1-nitrosopyridine which has TD50 value of 0.0601 mg/kg/day. if one compares molecular weights 112.13 and 240.26, which gives value of 28 ng/day. can some one explain.
Regards
Updated 05Apr22, thanks for the information!
Updated 05Apr22, thanks for the information!
Updated 05Apr22, thanks for the information!
@drprasadbakre I suggest watching the presentation from Dr. Nudelman (@conudel) from USP-Sindusfarma workshop where he explained the details and challenges of Varenicline.
The recording is here:
I want to make reference to a great post discussion lead by @SusanFelter and @conudel related to setting AIs for complex Nitrosamines by MW adjustments. As example:
Molar adjustment relative to NDEA (MW = 102 g/mol; AI = 26.5 ng/day
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N -nitroso-propranolol
Pfizer Canada ULC is recalling all lots of Inderal-LA (propranolol hydrochloride) extended release capsules, in 60 mg, 80 mg, 120 mg and 160 mg strengths, due to the presence of a nitrosamine impurity ( N -nitroso-propranolol) above the acceptable level.
However acceptable limit for N* -nitroso-propranolol not provided. Is there any reference for acceptable limit for N* -nitroso-propranolol
Thanks
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After inquiring to Health Canada about the information on limits for recent alerts for complex nitrosamines. This is the reply I received:
At this time, Health Canada has not yet established acceptable intake limits for these API-related nitrosamine impurities. Health Canada is currently co-operating with other regulators (including US FDA) in the Nitrosamine International Technical Working Group (NITWG) to establish acceptable intake limits for these API-related nitrosamine impurities.
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medications-guidance.pdf (1.5 MB)
@Naiffer_Host @sameer
As per recent “Guidance on nitrosamine impurities in medications” by Health Canada, MAHs and applicants may apply the class-specific threshold of toxicological concern (TTC) of 18 ng/day as a default limit for nitrosamine impurities not included in guidance. Refer attached guidance for more details.
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Thanks @ganeshmane for sharing.
Health Canada has adopted the same approach as EU. Looking forward to see when USFDA also allows the class specific limit of 18ng/day .
The table has been updated with published values from ANVISA’s Nitrosamine guideline (04May22)
n-nitroso-nortriptyline AI 26.5 ng/day defined by Health Canada.
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Update [5/5/2022] FDA is now confident in manufacturers’ ability to supply patients with varenicline containing the N-nitroso-varenicline impurity at or below the agency’s acceptable intake limit of 37 ng per day. Any newly manufactured varenicline for the U.S. market should have levels of the N-nitroso-varenicline impurity at or below that limit.
Alert here: FDA Updates and Press Announcements on Nitrosamine in Varenicline (Chantix) | FDA
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Some additional information as to why the change on Nitroso-Varenicline. Directly from FDA webpage (https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-analysis-varenicline-products)
For reference, consuming up to the acceptable intake limit, 37 nanograms, of N-nitroso-varenicline per day is considered reasonably safe for humans, based on lifetime exposure. N-nitroso-varenicline may increase the risk of cancer if people are exposed to it above the acceptable intake limit and over a long period of time, but a person taking a drug that contains N-nitroso-varenicline at-or-below the acceptable intake limit every day for 70 years is not expected to have an increased risk of cancer. Agency scientists evaluated the risk of exposure to N-nitroso-varenicline at interim acceptable intake levels up to 185 ng per day (92.5 ppm) and determined that it presents minimal additional cancer risk when compared to a lifetime of exposure to N-nitroso-varenicline at the 37 ng per day (18.5 ppm) level.
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Just see below option as well given by Health Canada in same guidance, Point-24, Page-16
“conduct a structure-activity relationship assessment with read-across to
justify a limit higher than 18 ng/day”
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Thank you for sharing the information, @Rafa. The limits list by Health Canada is useful because it includes the limit of NDSRI such as N -nitroso-methylphenidate, N -nitroso-duloxetine, N- nitroso-varenicline, N -nitroso-rasagiline and N nitroso-nortriptyline. And the limit of NDSRIs is considered to be calculated from those of nitrosamine with the same AI. This list is helpful to determine the limit of other nitrosamines!!
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Thank you for the information of Health Canada ! The limits of NNORT and NMPEA are surprisingly low compared to NDMA or other major nitrosamines. I’m interested in the reason.
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