5125/2021 Mutagenicity assessment of crug impuriias according tothe ICH M7 (R1) guideline andthe rle of expert review — ToxMinds
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THINKING AHEAD IN TOXICOLOGY
Mutagenicity assessment of drug impurities
according to the ICH M7 (RI) guideline and the
role of expert review
‘The evaluation of the genotoxicity potential of drug impurities has
been the focus of regulatory recommendations issued by the United
States Food and Drug Administration ('D.A, 2008), European
Medicines Agency (EMA, 2006 and 2010), and International
Conference for Harmonization (ICH, 2014, 2015). In 2017, the ICH
MT issued a revised guideline providing a framework for the
assessment and control of mutagenic impurities in pharmaceuticals,
In the absence of rcliable experimental mutagenicity and/or
carcinogenicity data the guideline recommends using computational
toxicology assessment to predict the outcome of the bacterial mutagenicity
assay (Ames test). This assessment should include two (QSAR prediction
methodologies, that complement each other. One methodology should be
expert rule-based and the second should be statistcal-based, The guideline
does not recommend any specific model, but it generally states that the
(QSAR models “should follow the general validation principles set forth
by the Organisation for Economic Co-operation and Development
(OECD}”. The most commonly used models in the pharmaceutical sector
are commercially available, e., Leadscope Genetox Expert Alerts and
Derek Nexus (Lhasa Limited) for the expert-rule based models, and CASE
Ultra from MultiCASE, Inc., and Sarah Nexus (Lhasa Limited) for the
statistical models.
The outcome of the two types of prediction should allow the assignment of
the impurity to one of the five ICH M7 classes as set in the guideline:
Class 1 (known mutagenic carcinogens); Class 2 (known mutagens with
‘unknown carcinogenic potential); Class 3 (compounds with alerting
structure, unrelated to the structure of the drug substance); Class 4
(compounds with alerting structure, same alert in drug substance or
compounds related to the drug substance, which have been tested and are
non-mutagenic); Class 5 (compounds with no structural alerts, or alerting,
structure with sufficient data to demonstrate lack of mutagenicity or
carcinogenicity). Impurities classified as class 4 or 5 do not require further
action, while the class | impurities have to be controlled “at or below
compound-specific acceptable limit”, and the class 2 or 3 impurities have
to be controlled at or below the Threshold of Toxicological Concern
limits
However, the (QSAR models adhering to the OECD principles do not
always provide clear positive or negative predictions. This may be due to
three main reasons, as deseribed by Arnley e* 2016), First, the model
ray consider the impurity as out-of-domain, since the structural features
of the impurity are not adequately covered by the model (third OECD
validation principle). Secondly, the prediction results may be categorized
as equivocal or indeterminate due to weak or conflicting evidence, such
that a definitive prediction cannot be made with adequate confidence.
Finally, a model may be technically unable to process certain types of
chemicals, ¢., metal complexes. In this frame, the ICH guideline
proposes to use expert knowledge “to provide additional supportive
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evidence for any positive, negative or inconclusive prediction and provide
a rationale to support the final conclusion
‘The expert review of ambiguous outcomes should examine the basis for
the prediction in order to identify reasons even for discarding the
prediction itself. Amberg et al (2016) have proposed a series of principles
and procedures to perform the expert review: it would be critical to 1)
determine whether there are shared alerts with known negative compounds
(e.g. from structurally similar compounds - ICH M7 class 4)], 2) provide
an assessment of the relevance of features or underlying data from the
statistical models, 3) identify potential analogues from public of in-house
sources, and 4) assess the strength of the single prediction, when only a
single methodology has generated a prediction.
A more recent article from Amber ef al. (2019) further supports the value
of the expert review and proposes to use additional QSAR models to
strengthen the results when the initial prediction is out-of-domain. In
addition, the authors present a thorough analysis of proprietary data to
help understanding the likelihood of misclassifying a mutagenic impurity
as non-mutagenic based on different combinations of (Q)SAR results, The
results clearly indicate that when the out-of-domain predictions are either
negative or indeterminate, the likelihood of misclassifying a mutagenic
impurity as non-mutagenic is similar to when there are two clear negative
results. Overall, the expert rule-based models scem to be the key driver of
the expert review when there are conflicting results
Itis evident that a well-established procedure for the assessment of the
‘genotoxicity potential of drug impurities has been put in place in the
pharmaceutical industry. However, there is still room for improvement and
even more so for those cases with conflicting results, For example, would
read across, as proposed by OECD and ECHA, be accepted as an
additional approach by regulatory agencies to assess the impurities? Also,
would the regulatory agencies promote the use of publicly available
(QSAR tools to meet the needs of small and medium enterprises of the
pharmaceutical sector? It should be noted that several publicly available
(QISAR models (e.g., Toxtree, US EPA TE.S.T, and CAESAR) have been
accepted by ECHA in the frame of the REACH regulation and EFSA
(Benigni et al., 2019) in the context of genotoxicity assessments.
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