Help me gather the Acceptable Limits information as a resource for all the community…
Last Updated: 14-Dec-22
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Dear Naiffer,
Thanks for compiling the ready limits for EMA and FDA. I have few things to add as listed below:
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N-nitrosovarenicline limits are also provided by the FDA as 37ng/day. Furthermore, FDA also allows interim limits (185ng/day) for manufacturer whose product is already approved to lessen the impact to patients from a drug shortage. (please refer enclosed doc).
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Unlike EMA, default limit for substance with unknown carcinogenic data is not traceable from the FDA nitrosamine guidance. I could see the default limit of 26.5ng/day for total impurities only with a daily dose less than 880mg/day i.e 0.03ppm. Could you please help me locate?
Text is reproduced below.
A recommended limit for total nitrosamines of 0.03 ppm is not more than 26.5 ng/day and is considered acceptable. For drug products with an MDD above 880 mg/day, the limit for total nitrosamines should be adjusted so as not to exceed the recommended limit of 26.5 ng/day. If nitrosamines without published AI limits are found in drug products, manufacturers should use the approach outlined in ICH M7(R1) to determine the risk associated with the nitrosamine and contact the Agency about the acceptability of any proposed limit.
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Same is the case with NDBA impurity (not traceable in FDA nitrosamine guidance).
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Limit for N-nitroso orphenadrine is 26.5ng/day as per FDA. Please refer below text from FDA:
Thanks,
Sumit K Jain
FDA Updates and Press Announcements on Nitrosamine in Varenicline (Chantix) _ FDA.pdf (136.4 KB)
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Hi, @Naiffer_Host
It’s a good idea. And I want to add some comments.
The limit of NDMA in both FDA and EMA is 96.0 ng/ day. NIPEA and EIPNA are the same compounds. And I think the limit of MeNP in FDA is considered 96.0 ng/ day when calculated from 0.16ppm and 600mg, the daily intake of rifampin.
I post my presentation slide. It’s almost the same as yours.
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@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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