34 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2021 P h a r mTe c h . c o m
As shown in Figure 1, if the 2° amine-derived nitrosamine
contains hydrogens on the alpha carbon of the amine, it
can undergo activation (oxidation) in vivo, which sets off a
series of reactions resulting in the formation of an alkyl or
aryl diazonium. These are very reactive alkylating agents
and proposed to be the chemical entity for genotoxicity.
Compounds such as N-nitrosodiisopropylamine (NDIPA)
and N-nitrosoethylisopropylamine (NEIPA) are currently
and conservatively assumed to have carcinogenic potency
equivalent to that of NDEA even though carcinogenicity
data show significantly lower carcinogenic potency due
to the steric hinderance at the alpha position of the amine
preventing the formation of the mutagenic metabolite (dia-
zonium, Figure 1) (24–25).
Second, well-precedented LTL concepts from ICH M7(R1)
are currently and conservatively stated not to be appropriate
for NAs (5–6, 26). However, dose-time relationships have
been established for NAs, and example compounds were
used to develop the ICH M7(R1) framework (17–18, 24, 27–
28). These data can be used to better inform the appropri-
ateness of LTL concepts for NAs. For example, model com-
pounds are being used to validate the LTL concepts for NAs.
Third, regulatory guidance documents mention the use
of read-across/structure-activity analyses (SAR) to develop
AIs for NA impurities when no carcinogenicity data are
available. Data are being pulled together to provide addi-
tional guidance on the structural relationship for NAs and
carcinogenic potency (29–32).
Ongoing research and collaboration
The ability to mobilize experts in different aspects of drug
development and manufacturing to address the challenge
presented by NAs is the result of years of pre-competitive
collaboration among IQ member companies. Over the past
10 years, IQ members have developed compliant structures
and created a community of scientists and quality experts
committed to advancing innovation to develop new tech-
nologies and respond to new challenges. As more is learned
about NAs, whether about the likelihood of their formation,
or new safety findings, the Consortium's ability to quickly
engage with a broad range of experts—on a precompetitive
basis—promises to provide industry with valuable infor-
mation that can be applied to protect patient safety and
product quality.
References
1. ICH, M7(1) Assessment and Control of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk,
Step 4 version (2017).
2. R. Kroes, et al., Food Chem Toxicol 42 (1) 65–83 (2004).
3. FDA, Guidance for Industry, Control of Nitrosamine Impurities in
Human Drugs (2020).
Quality Collaboration
Figure 1. Formation N-nitrosamines from secondary amines and mechanism for mutagenesis (8, 33).
FIGURE
COURTESY
OF
THE
AUTHORS.
