N-Nitrosamine risk assessment of pharmaceuticals
has moved from an initial focus on the potential presence of known
small-molecule N-nitrosamines such as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine
(NDEA) in active substances toward the potential for generation of
more complex nitrosamine drug substance-related impurities (NDSRIs)
in drug products. While N-nitrosation of simple secondary
amines is well-understood, more complex amines can undergo alternative
reaction pathways that can be more challenging to predict. A number
of such complex amines are known not to undergo N-nitrosation but are either unreactive or react by alternative pathways
such as C-nitrosation or nitration to generate non-N-nitrosamine products. This article proposes a standard
set of three orthogonal nitrosation forced degradation type reaction
conditions that can be used to investigate the potential for generation
of novel N-nitrosamines by nitrosation of complex
amines. These complementary reaction conditions are considered to
provide a thorough evaluation of the potential for N-nitrosamine formation from complex amines with respect to risk factors
within pharmaceutical manufacturing. If, after investigation of nitrosation
under the proposed conditions, formation and isolation of an N-nitrosamine is not possible, the resultant understanding
of chemical reactivity and stability can be used to justify that the N-nitrosamine in question would not be expected to be generated
from the complex amine in the drug substance or product. If an N-nitrosamine is formed under these reaction conditions,
the information gained can be used as part of the risk assessment
and also provides a starting point for the development of a process
to synthesize a discrete sample for further testing. Additionally,
synthetic and analytical considerations that should be taken into
account during preparation of novel N-nitrosamines
for use in analytical or toxicological studies are discussed.
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