M7(R2) Assessment and Control of 
DNA Reactive (Mutagenic) 
Impurities in Pharmaceuticals to 
Limit Potential Carcinogenic Risk 
Questions and Answers 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
July 2023 
ICH-Multidisciplinary
   
M7(R2) Assessment and Control of 
DNA Reactive (Mutagenic) 
Impurities in Pharmaceuticals to 
Limit Potential Carcinogenic Risk 
Questions and Answers 
Guidance for Industry 
 
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U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
July 2023 
ICH-Multidisciplinary 
  Contains Nonbinding Recommendations 
FOREWORD 
 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) has the mission of achieving greater regulatory harmonization worldwide to 
ensure that safe, effective, and high-quality medicines are developed, registered, and maintained 
in the most resource-efficient manner.  By harmonizing the regulatory expectations in regions 
around the world, ICH guidelines have substantially reduced duplicative clinical studies, 
prevented unnecessary animal studies, standardized safety reporting and marketing application 
submissions, and contributed to many other improvements in the quality of global drug 
development and manufacturing and the products available to patients.  
 
ICH is a consensus-driven process that involves technical experts from regulatory authorities and 
industry parties in detailed technical and science-based harmonization work that results in the 
development of ICH guidelines.  The commitment to consistent adoption of these consensus-
based guidelines by regulators around the globe is critical to realizing the benefits of safe, 
effective, and high-quality medicines for patients as well as for industry.  As a Founding 
Regulatory Member of ICH, the Food and Drug Administration (FDA) plays a major role in the 
development of each of the ICH guidelines, which FDA then adopts and issues as guidance to 
industry.
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
PREFACE ...................................................................................................................................... 1 
I.  INTRODUCTION (1) ....................................................................................................... 2 
II.  SCOPE OF GUIDANCE (2) ............................................................................................ 3 
III.  GENERAL PRINCIPLES (3) .......................................................................................... 3 
IV.  CONSIDERATIONS FOR MARKETED PRODUCTS (4) ......................................... 4 
V.  DRUG SUBSTANCE AND DRUG PRODUCT IMPURITY ASSESSMENT (5) ...... 4 
VI.  HAZARD ASSESSMENT ELEMENTS (6) ................................................................... 4 
VII.  RISK CHARACTERIZATION (7) ................................................................................. 6 
VIII.  CONTROL (8) ................................................................................................................... 8 
IX.  DOCUMENTATION (9) ................................................................................................ 10 
X.  ILLUSTRATIVE EXAMPLES (10) ............................................................................. 11 
XI.  GLOSSARY (11) ............................................................................................................. 11 
REFERENCES ............................................................................................................................ 12 
 
 
  Contains Nonbinding Recommendations 
M7(R2) Assessment and Control of DNA Reactive (Mutagenic) 
Impurities In Pharmaceuticals to Limit Potential Carcinogenic Risk 
Questions and Answers 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can 
use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To 
discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title 
page.   
 
 
 
PREFACE 
 
Since the International Council for Harmonisation (ICH) guidance for industry M7 Assessment 
and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential 
Carcinogenic Risk (ICH M7) was finalized, worldwide experience with implementation of the 
recommendations for DNA reactive (mutagenic) impurities has given rise to requests for 
clarification relating to the assessment and control of DNA reactive (mutagenic) impurities. 
 
This question and answer (Q&A) document is intended to provide additional clarification and to 
promote convergence and improve harmonization of the considerations for assessment and 
control of DNA reactive (mutagenic) impurities and of the information that should be provided 
during drug development, marketing authorization applications, and/or master files submissions.  
 
The scope of this Q&A document follows that of the ICH guidance for industry M7(R2) 
Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit 
Potential Carcinogenic Risk (ICH M7(R2)) (July 2023).2  
 
Sponsor is used throughout the Q&A document and should be interpreted broadly to refer to the 
marketing authorization holder, the filing applicant, the drug product manufacturer, and/or the 
drug substance manufacturer. 
 
 
 
1 This guidance was developed within the Expert Working Group (Multidisciplinary) of the International Council for 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been 
subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been 
endorsed by the ICH Assembly at Step 4 of the ICH process, May 2022.  At Step 4 of the process, the final draft is 
recommended for adoption to the regulatory bodies of the ICH regions.  
2 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
1  I.  INTRODUCTION (1)3 
 
In general, the Food and Drug Administrations guidance documents do not establish legally 
enforceable responsibilities. Instead, guidances describe the Agencys current thinking on a topic 
and should be viewed only as recommendations, unless specific regulatory or statutory 
requirements are cited. The use of the word should in Agency guidances means that something is 
suggested or recommended, but not required. 
 
Q1.  Note 1 provides general guidance on the relationship of ICH M7(R2) with the ICH 
guidances for industry Q3A Impurities in New Drug Substances (Revision 2) (ICH 
Q3A) (June 2008) and Q3B(R2) Impurities in New Drug Products (ICH Q3B(R2)) 
(August 2006). The use of both mutagenic potential and genotoxic potential in Note 1 
is confusing. Are these terms considered interchangeable? (1.1) 
 
No. The terms mutagenic potential and genotoxic potential are not interchangeable.  Mutagenic 
potential refers to the ability of a compound to induce point mutations (i.e., bacterial reverse 
mutation assay), and genotoxic potential refers to mutagenic, clastogenic, or aneugenic potential. 
ICH M7(R2) focuses specifically on mutagenicity. 
 
Q2.  What are the expectations for evaluation of the mutagenic potential for an impurity 
where the amount of impurity is less than or equal to 1 milligram (mg) daily dose? 
(1.2) 
 
In the context of ICH M7(R2), (quantitative) structure-activity relationships ((Q)SARs) are 
considered an appropriate initial evaluation of mutagenic potential of an impurity at a daily dose 
of less than or equal to 1 mg. When a structural alert is identified, a follow-up in vitro evaluation 
(e.g., bacterial reverse mutation assay) could be conducted, or the impurity could be controlled 
by threshold of toxicological concern (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. 
 
Q3.  What are the expectations for evaluation of the genotoxic potential for an impurity 
where the amount of impurity exceeds 1 mg daily dose? (1.3) 
 
In the context of Note 1 of ICH M7(R2) , 1 mg refers to an absolute amount of an impurity, 
irrespective of the identification or qualification thresholds outlined in ICH Q3A and Q3B(R2). 
 
In cases where the amount of impurity is less than 1 mg daily dose for chronic administration, 
and an impurity generated negative predictions in two appropriate (Q)SAR systems, a minimum 
screen of genotoxicity studies (point mutation and chromosomal aberration) could be considered. 
 
3 The numbers in parentheses reflect the organizational breakdown of the document endorsed by the ICH Assembly 
at Step 4 of the ICH process, May 2022. 
2   
Q4.  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 warranted? (1.4) 
 
No. 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/day, further genetic toxicity testing is not warranted. 
 
 
II.  SCOPE OF GUIDANCE (2) 
 
Q5.  Are semisynthetic drug substances and drug products included in the scope of ICH 
M7(R2)? (2.1) 
 
Yes, for certain cases. If a semisynthetic drug substance, as defined in the ICH guidance for 
industry Q11 Development and Manufacture of Drug Substances (November 2012), is 
manufactured using steps that could introduce mutagenic impurities or degradation products 
(e.g., postmodification of a fermentation product, late-stage introduction of a linker), a risk 
assessment is warranted.  
 
The following compounds used in the manufacturing process of semisynthetic drug substances 
and drug products should be considered within the scope of the application of ICH M7(R2): 
 
  Chemically synthesized intermediates and actual impurities therein 
  Reagents  
 
 
III.  GENERAL PRINCIPLES (3) 
 
Q6.  Should nonmutagenic, carcinogenic impurities be controlled according to ICH 
M7(R2)? (3.1) 
 
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 the scope of ICH M7(R2) (e.g., 
acetamide, hydroxylamine). 
 
Q7.  Should mutagenic, noncarcinogenic impurities be controlled according to ICH 
M7(R2)? (3.2) 
 
No. Mutagens that are demonstrated to be noncarcinogenic in appropriate and well-conducted 
animal bioassays will be classified as Class 5 impurities. 
 
 
3  IV.  CONSIDERATIONS FOR MARKETED PRODUCTS (4) 
 
Q8.  What does significant increase in clinical dose mean in section IV.C., Changes to 
the Clinical Use of the Marketed Products, (4.3)? (4.1) 
 
Any increase in dose of the active pharmaceutical ingredient that would increase any mutagenic 
impurity to levels above the acceptable limits is considered significant (see Tables 2 and 3 in 
ICH M7(R2) and the ICH guidance for industry M7(R2) Addendum: Application of the 
Principles of the ICH M7 Guidance to Calculation of Compound-Specific Acceptable Intakes 
(July 2023)).  
 
In such cases a reevaluation of the mutagenic impurity limits is recommended.   
 
 
V.  DRUG SUBSTANCE AND DRUG PRODUCT IMPURITY ASSESSMENT (5) 
 
Q9.  No Q&A drafted on this section. (5.1) 
 
 
VI.  HAZARD ASSESSMENT ELEMENTS (6) 
 
Q10.  What information and/or documentation should be provided to regulatory agencies 
to sufficiently demonstrate validation of (Q)SAR models that are developed in-house 
or are not commonly used? (6.1) 
 
Section VI (6) of ICH M7(R2) states that (Q)SAR models utilizing these prediction 
methodologies should follow the general validation principles set forth by the Organization for 
Economic Co-operation and Development (OECD) (OECD Validation 2007). 
 
In the context of ICH M7(R2), the OECD principles of (Q)SAR validation are:  
 
1)  A defined endpoint  The model should be trained using experimental data generated 
according to the standard OECD protocol for the in vitro bacterial reverse mutation assay. 
 
2)  An unambiguous algorithm  The algorithm used to construct the model should be 
disclosed. It should be clear whether the model is considered statistical (constructed via 
machine learning) or expert rule based (created from human expert-derived knowledge). 
 
3)  A defined domain of applicability  It should be described whether a test chemical falls 
within the models applicability domain and how the applicability domain is calculated. 
The user should be warned when the model does not have enough information to make a 
reliable prediction on a chemical. 
 
4)  Appropriate measures of goodness-of-fit, robustness, and predictivity  The model 
should be evaluated and shown to be sufficiently predictive of bacterial reverse 
mutagenicity. Standard validation techniques that should be used are recall, cross-
4  validation, and external validation. Evidence that the model has not been over-fit should 
also be provided. 
 
5)  A mechanistic interpretation  Is there adequate information to allow an assessment of 
mechanistic relevance to be made (e.g., specific descriptors)? 
 
For any system as a minimum recommendation to demonstrate how each model follows these 
principles and to understand how a (Q)SAR model was developed and validated, the sponsor is 
expected to provide the OECD (Q)SAR Model Reporting Format (QMRF) (OECD QMRF 2017) 
on request by the regulatory agency. This template summarizes and reports key information on 
(Q)SAR models, including the results of any validation studies as well as provides 
supplementary information on applicability of the model to a given chemical. Agencies may 
request this information depending on the experience of the specific agency with the specific 
models.  
 
Q11.  When an out-of-domain or noncoverage result is obtained from one of the two 
(Q)SAR models as described in ICH M7(R2), can the impurity be classified as a 
Class 5 impurity? (6.2) 
 
No, an out-of-domain or noncoverage result from one of the two (Q)SAR models warrants 
additional assessment to classify the compound as a Class 5 impurity. 
 
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): 
 
1)  Comparison to structurally similar analogs for which bacterial reverse mutation assay 
data are available (read-across approach).   
 
2)  Expert review of the chemical structure to determine if there is potential for the chemical 
to react with DNA. 
 
3)  (Q)SAR output from an additional validated model (see Question Q10 (6.1)) of the same 
methodology (i.e., expert rule based or statistical) that generates a prediction that is 
within its applicability domain. 
 
Q12.  In a case where an impurity is demonstrated to be negative in an Ames test but 
positive in a clastogenicity study (e.g., chromosomal aberration test), how would the 
impurity be classified per ICH M7(R2) classification system? (6.3) 
 
If an impurity tests negative in an Ames assay, it is considered a Class 5 impurity. Addressing 
positive results in a clastogenicity assay is out of the scope of ICH M7(R2). 
 
5  Q13.  Please clarify the rationale for the tests included under Note 3 as a follow-up to 
investigate the in vivo relevance of in vitro mutagens. (6.4) 
 
If an impurity is positive in the Ames test, and levels of the impurity cannot be controlled to an 
appropriate acceptable limit, an in vivo follow-up test with mutagenic endpoint (mutagenicity) 
should be used. The other follow-up tests outlined in Note 3 are also acceptable when scientific 
rationale (as indicated in Note 3) is provided to support their uses.  
 
For any of the above tests, adequate exposure should be demonstrated in line with the ICH 
guidance for industry S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals 
Intended for Human Use (June 2012). 
 
 
VII.  RISK CHARACTERIZATION (7) 
 
Q14.  If an Ames positive impurity is subsequently tested in an appropriate in vivo assay 
and the results are negative, is that sufficient to demonstrate lack of in vivo 
relevance? (7.1) 
 
Yes. A well-conducted and scientifically justified in vivo study (see Question Q13 (6.4) in this 
document) is sufficient to demonstrate lack of in vivo relevance. If the results of the in vivo 
study are negative, the impurity can be assigned to ICH M7(R2) Class 5. 
 
Q15.  If an Ames positive impurity cannot be controlled to an acceptable limit and is 
subsequently tested in an appropriate in vivo assay and the results are positive, does 
that support setting compound-specific impurity limits? (7.2) 
 
When a mutagenic impurity cannot be controlled to the TTC (or less than lifetime (LTL) based 
limit), results from an appropriate in vivo assay could complement the available data for a weight 
of evidence approach to support a higher limit on a case-by-case basis. However, in vivo gene 
mutation assays alone are currently not validated to directly assess cancer risk because the 
endpoint is mutation and not carcinogenicity (i.e., they are used for hazard identification). 
 
Q16.  Can an LTL approach be applied to acceptable intakes (AIs) or permissible daily 
exposures (PDEs) using the same ratio as in Table 2? (7.3) 
 
The LTL approach can be applied to compounds with exposure limits based on the TTC or a 
compound/class-specific AI. However, this approach is not applicable to PDEs as linearity of 
dose duration response is not considered sufficiently demonstrated for threshold-related 
mechanisms. Higher levels of exposure for short-term exposure (30 days or less) may be 
acceptable on a case-by-case basis. 
 
6  Q17.  Why was HIV disease moved to the Treatment duration of >10 years to lifetime in 
the clinical use scenarios Table 4? How should this change be implemented? (7.4) 
 
The treatment duration category was changed because of advances in the clinical treatment of 
HIV disease. To avoid disruption of supply of HIV drugs already on the market, this change will 
not be applied to currently marketed products. For example, when a new drug substance supplier 
is proposed, the AI would remain at 10 micrograms (g)/day in cases where the drug substance 
produced by this supplier, using the same route of synthesis, is a component of an existing drug 
product marketed in the specific region (see ICH M7(R2) section IV.A (4.1)). 
 
For HIV treatment-related regulatory submissions 18 months after the date that ICH M7(R2) 
reached Step 4, the 1.5 g/day or other appropriate AI will be applied in the following situations: 
 
  New drug substances and new drug products during their clinical development and 
subsequent applications for marketing 
 
  Changes to the drug substance synthesis resulting in new impurities or increased 
acceptance criteria for existing impurities 
 
  Changes in the formulation, composition, or manufacturing process resulting in new 
degradation products or increased acceptance criteria for existing degradation products 
 
  Introduction of a new source of the drug substance through a drug master file (DMF) 
from a DMF holder that has not had a previously accepted DMF in the relevant region 
 
  Changes made to a specific synthetic step as described in ICH M7(R2) section IV.A (4.1) 
 
  A newly discovered Class 1 or Class 2 impurity, a structure in the cohort of concern, or 
new relevant impurity hazard data, as described in ICH M7(R2) section IV.D (4.4) 
 
Q18.  Does Table 2: Acceptable Intakes for an Individual Impurity apply when three or 
more Class 2 or Class 3 impurities are specified in the drug substance specification? 
(7.5) 
 
Yes. In this scenario, a limit for each individual impurity should be listed in the drug substance 
specification as per limits provided in Table 2 (e.g., greater than 10 years to lifetime not more 
than (NMT) 1.5 g/day). Additionally, a limit for total mutagenic impurities should be listed in 
the drug substance specification as per limits provided in Table 3 (for example greater than 10 
years to lifetime NMT 5 g/day).    
 
As stated in the guidance, compound-specific or class-related acceptable limits (Class 1) and 
degradation products, which form in the drug product, are excluded from total mutagenic 
impurity limits. 
 
 
7  VIII.  CONTROL (8) 
 
Q19.  When is it appropriate to use an Option 4 control strategy? (8.1) 
 
Use of Option 4 is appropriate when a mutagenic impurity has a negligible risk of being present 
in the final drug substance. The risk can be considered negligible if predictive purge calculations 
based on scientific principles (e.g., impurity reactivity or solubility) result in impurity levels less 
than 1 percent of TTC or AI. When predictive purge calculations result in impurity levels greater 
than 1 percent of TTC or AI, measured purge factors (i.e., spike and purge data) showing 
impurity levels less than 10 percent of TTC or AI should be provided to justify Option 4 control. 
The process-relevant conditions should be considered for the purge calculation and the 
generation of analytical data. The acceptability of Option 4 will be assessed by authorities on a 
case-by-case basis, including additional requests for supporting information. See also Question 
21 (8.3) in this document for impurities introduced in the last step. 
 
Q20.  When predictive purge calculations are used for Option 4 control, what elements 
should be considered? (8.2) 
 
When using predictive purge calculations for Option 4 control, the following elements should be 
considered:  
 
  Predictive purge calculations should be based on the drug substance manufacturing 
process as described in the application and should consider reactivity, solubility, 
volatility, and other factors of the impurity in each step. The predictive purge calculation 
should use conservative values and methodology because predictive purge often does not 
rely on experimental confirmation. Example predictive purge calculation approach based 
on scientific principles has been described (Teasdale et. al. 2013; Barber et. al. 2017). 
Predictive purge calculations can be paper based or software based.  
 
  The amount of information (i.e., impurity reactivity or solubility data, spike and purge 
data under the process-relevant conditions) to justify a predictive purge calculation 
approach should be guided by knowledge of the manufacturing process, risk to the final 
drug substance, and the stage of drug development.  
 
  A predictive purge calculation justification submitted in an application could range from 
a high-level summary to detailed information on the calculation (e.g., scientific 
justification for individual purge factors) and other supporting data. More detailed 
information on the calculation is expected when the predicted level of the impurity in the 
drug substance approaches the TTC or AI. Even if not submitted, information on how 
each individual purge factor is derived should be available upon request. 
 
8  Q21  What is meant by for impurities introduced in the last synthetic step, an Option 1 
control approach would be expected unless otherwise justified in section VIII.B 
(8.2), Considerations for Control Approaches? (8.3) 
 
For mutagenic impurities introduced or generated in the last synthetic step, given the proximity 
to the final product, Option 1 control approach is preferred. However, Option 2 and Option 3 
control approaches may be possible when appropriately justified. The control strategy may be 
influenced by the presence of a subsequent recrystallization step, a highly effective purification 
operation (e.g., chromatography, well-defined crystallization), the reactivity (e.g., highly reactive 
reagents such as thionyl chloride) and physical characteristics of the impurity (e.g., low boiling 
point such as methyl chloride), and the availability of data (analytical data supporting the purge 
assessment). In most cases, for mutagenic impurities introduced or generated in the last synthetic 
step, the justification of an Option 4 control approach solely based on prediction is not sufficient 
and supporting analytical data should be provided (see Question Q19 (8.1)). 
 
Q22.  Is periodic verification testing (i.e., skip testing) allowed for Option 2 and Option 3 
control approaches? (8.4) 
 
No. Periodic verification testing is not appropriate for Option 2 and Option 3 control approaches. 
In ICH M7(R2) section VIII.A (8.1), periodic verification testing is only discussed as a control 
strategy when using Option 1 control approach. 
 
The Option 1 periodic verification testing strategy references the ICH guidance for industry Q6A 
Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New 
Drug Products: Chemical Substances (ICH Q6A) (December 2000). The Option 1 periodic 
verification testing concept (per ICH Q6A) should generally be implemented after approval and 
applies to testing in the final drug substance. 
 
Q23.  If batch analysis data on the drug substance for a mutagenic impurity is consistently 
less than 30 percent TTC or AI in multiple batches, is that sufficient to justify no 
specification of that impurity in the control strategy? (8.5) 
 
No. Batch data alone demonstrating that a mutagenic impurity is consistently less than 30 
percent TTC or AI is not sufficient to apply an Option 4 control strategy. 
 
However, if there is negligible risk of the impurity to be present in the drug substance, an Option 
4 control strategy may be considered with appropriate justification. See Questions Q19 and Q20 
(8.1 and 8.2) for recommendations on supporting an Option 4 control strategy. 
 
Q24.  What scale considerations are relevant when generating analytical data in support 
of control Options 3 and 4? (8.6) 
 
Lab scale experiments are typically sufficient when generating measured purge factors or when 
defining in-process control points. These studies should employ conditions representative of the 
final process as described in the application and should consider the potential impact of scale and 
equipment-related differences between the laboratory and production environment (e.g., the 
9  effects of mixing on impurity levels in heterogeneous systems, the quality of liquid-liquid phase 
separations). In the case of observed scale dependencies, confirmatory testing on batches 
manufactured at pilot or commercial scale may be advisable. There is no expectation to perform 
spiking studies at pilot or commercial scale. 
 
 
IX.  DOCUMENTATION (9) 
 
Q25.  If (Q)SAR predictions are made during drug development, should they be repeated 
for the marketing application? (9.1) 
 
(Q)SAR models developed for use under ICH M7(R2) are generally updated regularly with new 
bacterial reverse mutagenicity assay data and more refined structural alerts. A Sponsor is not 
expected to update its (Q)SAR assessment during drug development unless there is a safety 
concern such as when newly available bacterial reverse mutagenicity assay data and/or 
mechanistic knowledge suggest that the prediction is incorrect. As an example, in cases where 
there is reason to question the outcome of a negative prediction (e.g., an aromatic amine is 
present, but the model gave a negative prediction), a reassessment is recommended. It is 
recommended that the sponsor rerun (Q)SAR predictions before the initial marketing application 
to ensure predictions reflect the most current data available. If the marketing application is later 
submitted in other regulatory jurisdictions, reassessment may be considered. Reassessment may 
also be considered if the predictions made for the initial global marketing application did not use 
a recent version of the software.  
 
In general, predictions generated with models developed before ICH M7s publication in 2014 
are considered unacceptable.  
 
Q26.  For marketing applications, what content and common technical document (CTD) 
placement recommendations could improve the clarity of an ICH M7(R2) risk 
assessment and control strategy? (9.2) 
 
In Module 2, a brief summary of the ICH M7(R2) risk assessment and control strategy should be 
included (sections 2.3 and 2.6). 
 
In Module 3, the ICH M7(R2) risk assessment and control strategy should be provided in detail. 
This type of information is recommended to be placed in the CTD locations per the ICH 
guidances for industry M4Q: The CTD  Quality (August 2001) and related M4: The CTD  
Quality: Questions and Answers/Location Issues (June 2004)(e.g., 3.2.S.3.2 Impurities or 
3.2.S.4.5 Justification of Specification for drug substance; 3.2.P.5.5 Characterization of 
Impurities or 3.2.P.5.6 Justification of Specification for drug product). A table summary of the 
ICH M7(R2) hazard assessment and ICH M7(R2) impurity control strategy is recommended to 
improve clarity.  
 
  Information recommended for an ICH M7(R2) hazard assessment table includes impurity 
chemical structure, individual (Q)SAR results (positive/negative predictions, out of 
domain), bacterial reverse mutagenicity assay results (positive/negative, if available), 
10  ICH M7(R2) impurity class (1 to 5) assignment, and supporting information (e.g., 
information/links for bacterial reverse mutagenicity assays, literature reports, (Q)SAR 
expert analysis). The in silico systems used (name, version, endpoint) can also be noted. 
 
  Information recommended for an ICH M7(R2) impurity control strategy table includes 
impurity origin (e.g., synthetic step introduced, degradant), ICH M7(R2) class, purge 
factors (e.g., measured or predicted), ICH M7(R2) control option (1 to 4), control strategy 
(i.e., including in-process or compound testing rationale), and supporting information 
(e.g., information/links for justifications, calculations). The maximum daily dose, TTC, 
and proposed duration of treatment can also be noted. 
 
  Additionally, it is recommended that compound code names be cross-referenced, if 
Module 3 and Module 4 (including toxicity study reports) use different compound 
naming conventions. 
 
In Module 4, full safety study-related information on impurities (e.g., bacterial reverse 
mutagenicity assay reports, (Q)SAR reports, other genotoxicity test reports, additional testing) 
should be included to support the risk assessment and control strategy. This information is often 
placed in section 4.2.3.7.6 Impurities (see the ICH guidance for industry M4S: The CTD  
Safety (August 2001) for additional information) and can be cross-referenced to Module 3 by 
hyperlinks. 
 
 
X.  ILLUSTRATIVE EXAMPLES (10) 
 
No Q&A drafted on this section. 
 
 
XI.  GLOSSARY (11) 
 
No Q&A drafted on this section.
11  Contains Nonbinding Recommendations 
REFERENCES 
Literature 
 
Amberg A, et. al., 2019, Principles and Procedures for Handling Out-of-Domain and 
Indeterminate Results as Part of ICH M7 Recommended (Q)SAR Analyses, Regul Toxicol and 
Pharmacol, 102:5364. 
 
Teasdale A, Elder D, Chang S-J, Wang S, Thompson R, Benz N, and Sanchez Flores I, 2013, 
Risk Assessment of Genotoxic Impurities in New Chemical Entities: Strategies to Demonstrate 
Control, Org Process Res Dev, 17:221230. 
 
Barber C, et. al., 2017, A Consortium-Driven Framework to Guide the Implementation of ICH 
M7 Option 4 Control Strategies, Regul Toxicol and Pharmacol, 90:2228. 
 
International Council for Harmonisation (ICH) Guidances for Industry1 
 
ICH guidance for industry M4: The CTD  Quality: Questions and Answers (June 2004) 
 
ICH guidance for industry M4Q: The CTD  Quality (August 2001) 
 
ICH guidance for industry M4S: The CTD  Safety (August 2001) 
 
ICH guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) 
Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk (March 2018) 
 
ICH guidance for industry Q3A Impurities in New Drug Substances (Revision 2) (June 2008) 
 
ICH guidance for industry Q3B(R2) Impurities in New Drug Products (August 2006) 
 
ICH guidance for industry Q6A Specifications: Test Procedures and Acceptance Criteria for 
New Drug Substances and New Drug Products: Chemical Substances (December 2000) 
 
ICH guidance for industry Q11 Development and Manufacture of Drug Substances (November 
2012) 
 
ICH guidance for industry S2(R1) Genotoxicity Testing and Data Interpretation for 
Pharmaceuticals Intended for Human (June 2012) 
 
ICH guidance for industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals (March 
2010) 
 
 
1 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
12  Organization for Economic Co-operation and Development (OECD) Guidance Documents 
 
OECD Validation, 2007, Test No. 69: Guidance Document on the Validation of (Quantitative) Structure-
Activity Relationship ((Q)SAR) Models (available at 
http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2007)2&doclang
uage=en) 
 
OECD (Q)SAR Model Reporting Format (QMRF), 2017, Joint Research Center QSAR Model Database: 
User Support and Tutorial (available at 
https://publications.jrc.ec.europa.eu/repository/bitstream/JRC107491/kjna28713enn.pdf) 
13