The potential for
N
-nitrosamine impurities in
pharmaceutical products presents a challenge for the quality management
of medicinal products.
N
-Nitrosamines are considered
cohort-of-concern compounds due to the potent carcinogenicity of many
of the structurally simple chemicals within this structural class.
In the past 2 years, a number of drug products containing certain
active pharmaceutical ingredients have been withdrawn or recalled
from the market due to the presence of carcinogenic low-molecular-weight
N
,
N
-dialkylnitrosamine impurities. Regulatory
authorities have issued guidance to market authorization holders to
review all commercial drug substances/products for the potential risk
of
N
-nitrosamine impurities, and in cases where a
significant risk of
N
-nitrosamine impurity is identified,
analytical confirmatory testing is required. A key factor to consider
prior to analytical testing is the estimation of the daily acceptable
intake (AI) of the
N
-nitrosamine impurity. A significant
proportion of
N
-nitrosamine drug product impurities
are unique/complex structures for which the development of low-level
analytical methods is challenging. Moreover, these unique/complex
impurities may be less potent carcinogens compared to simple nitrosamines.
In the present work, our objective was to derive AIs for a large number
of complex
N
-nitrosamines without carcinogenicity
data that were identified as potential low-level impurities. The impurities
were first cataloged and grouped according to common structural features,
with a total of 13 groups defined with distinct structural features.
Subsequently, carcinogenicity data were reviewed for structurally
related
N
-nitrosamines relevant to each of the 13
structural groups and group AIs were derived conservatively based
on the most potent
N
-nitrosamine within each group.
The 13 structural group AIs were used as the basis for assigning AIs
to each of the structurally related complex
N
-nitrosamine
impurities. The AIs of several
N
-nitrosamine groups
were found to be considerably higher than those for the simple
N
,
N
-dialkylnitrosamines, which translates
to commensurately higher analytical method detection limits.
A workshop entitled “Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis” was held at the 2018 Genetic Toxicology Association annual meeting. The objectives of the workshop were to provide an educational forum and use case studies and live multiple-choice polling to establish the degree of similarity/diversity in approach/opinion of the industry experts and other delegates present for some of the more challenging decision points that need to be considered when developing a compound-specific exposure limit (ie, acceptable intake or permissible or permitted daily exposure). Herein we summarize the relevant background and case study information for each decision point topic presented as well as highlight significant polling responses and discussion points. A common observation throughout was the requirement for expert judgment to be applied at each of the decision points presented which often results in different reasoning being applied by the risk assessor when deriving a compound-specific exposure limit. This supports the value of precompetitive cross-industry collaborations to develop compound-specific limits and harmonize the methodology applied, thus reducing the associated uncertainty inherent in the application of isolated expert judgment in this context. An overview of relevant precompetitive cross-industry collaborations working to achieve this goal is described.
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