by TTC. Negative results in either evaluation would classify the impurity under Class 5. The result of the bacterial reverse mutation assay overrules the (Q)SAR prediction. Additionally, impurities should not be assigned to Class 5 based solely on the absence of structural alerts by visual evaluation alone. There is an expectation that structural alert assessment will be conducted using (Q)SAR prediction.
The main point made in this Q&A is that (Q)SAR analysis is necessary in order to determine if an impurity has an alert for mutagenicity, and visual evaluation alone (which was conventional prior to the implementation of ICH M7) is currently not acceptable. Here again the emphasis is on the Ames test as the proper assay to perform in case testing is desired, and the results from this test overrule any (Q)SAR prediction.
2.4.1.3 Question 1.3
| Question | Answer |
|---|---|
| If an impurity generates negative predictions in two appropriate (Q)SAR systems and is present at a level less than or equal to 1 mg daily dose, is further genetic toxicity testing recommended? | No. If an impurity generates negative predictions in two appropriate (Q)SAR systems and is present at a level ≤1 mg/day, further genetic toxicity testing is not warranted. |
Interestingly, after Q&A 1.1 clearly explaining that the focus is on mutagenicity, the term used in this Q&A is “genetic toxicity testing” and not “mutagenic toxicity testing.” Does this mean that an impurity that is above the ICH Q3A/Q3B qualification threshold but has no (Q)SAR alerts and is found at less than 1 mg/day, there is no need for the Ames test or chromosomal aberrations? This is not clear, because the ICH Q3A and Q3B guidelines tell us that in order to qualify an impurity at a level above the qualification threshold you should test for mutagenicity (in the Ames test) and clastogenicity (in the chromosomal aberrations assay) in addition to general toxicity studies (one species, usually 14–90 days). The hope is that this topic will be further clarified in the final version of the Q&A document.
2.4.1.4 Question 1.4
| Question | Answer |
|---|---|
| What are the expectations for evaluation of the genotoxic potential for an impurity where the amount of impurity exceeds 1 mg daily dose? | In cases where the amount of impurity is >1 mg daily dose for chronic administration, regardless of the impurity classification, a minimum screen of genotoxicity studies (point mutation and chromosomal aberration) can be considered. |
This Q&A clarifies the situation where even if the impurity is a Class 4 or Class 5, if it is present at above 1 mg/day, you are compelled to perform an Ames test and a chromosomal aberrations assay in order to complete the qualification. The question that arises here is: What is the rationale behind requiring the Ames test in such a situation? If the entire basis of classifying impurities in the ICH M7 guideline is based on (Q)SAR analysis, and an impurity can be classified as being nonmutagenic, then why does this classification not prevail also when the level exceeds 1 mg/day? This is not a logical recommendation and here again the hope is that this topic will be further clarified.
2.4.2 Section 2 – Scope
The single Q&A in Section 2 relates to applicability of the ICH M7 on impurities in semisynthetic DPs.
2.4.2.1 Question 2.1
The relevant section in Section 2 of the guideline states that: “Assessment of the mutagenic potential of impurities as described in this guideline is not intended for the following types of drug substances and drug products: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation products, herbal products, and crude products of animal or plant origin.”
| Question | Answer |
|---|---|
| Are semisynthetic DSs and DPs included in the scope of ICH M7? | Yes, for certain cases. If a semisynthetic DS is manufactured using steps that could introduce mutagenic impurities or degradants (e.g. post‐modification of a fermentation product or late‐stage introduction of a linker), a risk assessment is warranted. The following compounds used in the manufacturing process of semisynthetic DSs and DPs should be considered within the scope of the application of ICH M7:Chemically synthesized intermediates and actual impurities thereinReagents |
This clarification is very important because there were cases where stakeholders considered, for instance, fermentation products, to be excluded from the scope of the ICH M7 guideline, even if they included synthetic steps following the fermentation process. This Q&A makes it clear that any manufacturing step that may introduce a chemical moiety that can be reactive enough to directly react with DNA brings the product within the scope of the application of ICH M7.
2.4.3 Section 3 – General Principles
The two Q&As in Section 3 relate to impurities which are nonmutagenic carcinogens or mutagenic noncarcinogens.
The relevant section in the guideline states the following (with emphasis on the critical phrase): “The focus of this guideline is on DNA reactive substances that have a potential to directly cause DNA damage when present at low levels leading to mutations and therefore, potentially causing cancer. This type of mutagenic carcinogen is usually detected in a bacterial reverse mutation (mutagenicity) assay. Other types of genotoxicants that are non‐mutagenic typically have threshold mechanisms and usually do not pose carcinogenic risk in humans at the level ordinarily present as impurities. Therefore to limit a possible human cancer risk associated with the exposure to potentially mutagenic impurities, the bacterial mutagenicity assay is used to assess the mutagenic potential and the need for controls. Structure‐based assessments are useful for predicting bacterial mutagenicity outcomes based upon the established knowledge. There are a variety of approaches to conduct this evaluation including a review of the available literature, and/or computational toxicology assessment.”
2.4.3.1 Question 3.1
| Question | Answer |
|---|---|
| Should nonmutagenic, carcinogenic impurities be controlled according to ICH M7? | No. Carcinogens that are negative in the bacterial reverse mutation assay do not have a DNA reactive mechanism of carcinogenicity and therefore are not in scope of the ICH M7 guidance (e.g. acetamide and hydroxylamine). |
This Q&A assists stakeholders understand that when impurities are negative in the Ames test but contained carcinogenic effects, they do not need to be controlled within the scope of the ICH M7 and should be controlled according to the ICH Q3A/Q3B guidelines. In such cases the carcinogenicity data may serve as the point of departure for calculation of an appropriate PDE as described in the ICH Q3C guideline.
2.4.3.2 Question 3.2
| Question | Answer |
|---|---|
| Should mutagenic, noncarcinogenic impurities be controlled according to ICH M7? | No. Mutagens that are demonstrated to be noncarcinogenic in appropriate and well‐conducted animal bioassays will be treated similarly to Class 5 impurities. |