50 Pharmaceutical Technology
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Trends in Formulation 2022 eBook PharmTech.com
Qualit
y
a special cohort of their own. They are nonetheless a
cohort of concern as a class as they have AIs less than
the ICH M7 TTC of 1.5 µg/day in the majority of cases.
Also, in view of the fact that all the agencies of the
world have requested risk evaluation related to "nitro-
samines", the question remains if the "nitrosamides",
with completely different path of activation, should
be included in this evaluation. Because nitrosamides
are direct acting mutagens and appear to be positive
in the bacterial reverse mutagenicity assay (Ames
Assay) in the absence of metabolic activation, should
the outcome of an Ames assay be considered conclusive
evidence of N-nitrosamide mutagenicity or lack of it?
The jury is still out on all these subjects. However,
members of the pharmaceutical industry who have in-
cluded amides of primary amines/alkylcarbamates/
urea/guanidine in the same category with secondary
and tertiary amines in their risk evaluation, need to
keep in mind that the N-nitroso derivatives of the
former are different from nitrosamines, and therefore,
any surrogate AI approach used for N-nitrosamides,
for which no carcinogenicit y data ex ists, should
rely on data from other similar N-nitrosamides and
not N-nitrosamines.
References
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Reactive (Mutagenic) Impurities in Pharmaceuticals To
Limit Potential Carcinogenic Risk (ICH, 2018).
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Compound Chemistry and Biochemistry: Advances
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LA (propranolol hydrochloride) Capsules Due to a
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Opinion for the Ar t icle 5(3) of Regulat ion (EC) No
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human medicinal products, 23 Apr i l 2021 EM A/
409815/2020 Rev. 3,
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Request to evaluate the Risk of the Presence of N-Ni-
trosamine Impurities in Human Pharmaceutical,
Biologica l and Radiopharmaceutica l Products,"
Dec. 15, 2020 (Update 2).
13. C. L . Ga lt ress, e t a l., J. A m . C he m . S o c. 1 1 4 (4)
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175-181 (1983). ■
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