Читать книгу Mutagenic Impurities - Группа авторов - Страница 95

2.4.6.2 Question 6.2

Section 6 of the guideline says the following with respect to the interpretation of the (Q)SAR predictions: “If warranted, the outcome of any computer system‐based analysis can be reviewed with the use of expert knowledge in order to provide additional supportive evidence on relevance of any positive, negative, conflicting or inconclusive prediction and provide a rationale to support the final conclusion.”

Question	Answer
When an out of domain or noncoverage result is obtained from one of the two (Q)SAR models as described in ICH M7, can the impurity be classified as a Class 5 impurity?	No. Out of domain or noncoverage is not considered equivalent to Class 5. Additional assessment is warranted. Given that the relationship between chemical structure and DNA reactivity is well understood, it is unlikely that a structure with mutagenic potential would be associated with an out of domain result. However, expert review can provide reassurance in assignment of such impurities to Class 5. Expert review may include one or a combination of the following (Amberg et al. 2019):Comparison to structurally similar analogs for which bacterial reverse mutation assay data are available (read‐across approach).Expert review of the chemical structure to determine if there is potential for the chemical to react with DNA.(Q)SAR output from an additional validated model (see Question 6.1) of the same methodology (i.e. expert rule‐based or statistical) that generates a prediction that is within its applicability domain.

Question

Answer

When an out of domain or noncoverage result is obtained from one of the two (Q)SAR models as described in ICH M7, can the impurity be classified as a Class 5 impurity?

No. Out of domain or noncoverage is not considered equivalent to Class 5. Additional assessment is warranted. Given that the relationship between chemical structure and DNA reactivity is well understood, it is unlikely that a structure with mutagenic potential would be associated with an out of domain result. However, expert review can provide reassurance in assignment of such impurities to Class 5. Expert review may include one or a combination of the following (Amberg et al. 2019):Comparison to structurally similar analogs for which bacterial reverse mutation assay data are available (read‐across approach).Expert review of the chemical structure to determine if there is potential for the chemical to react with DNA.(Q)SAR output from an additional validated model (see Question 6.1) of the same methodology (i.e. expert rule‐based or statistical) that generates a prediction that is within its applicability domain.

In most cases it is the statistical (Q)SAR prediction that is out of domain. Comparison to structurally similar compounds will usually occur only when the stakeholder has in‐house data that will enable an expert review. In the absence of such data, an expert review by a chemist can determine if the out of domain moiety is sufficiently unreactive (i.e. non‐electrophilic) to consider it a Class 5 impurity. Using an additional (Q)SAR software frequently does not solve the problem, because an out of domain moiety in one software is often also not within the database domain of the additional software, and adding on additional prediction tools can sometimes just add more uncertainty rather than clarity.

Подняться наверх