Focus – Chemistry, manufacturing & controls
ICH Guideline M7 on mutagenic
impurities in pharmaceuticals
Author
David Snodin, Principal, Xiphora Biopharma Consulting,
UK.
Keywords
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ICH M7 guideline; Mutagenic impurity; Active pharmaceutical
ingredient (API); Scope; Nomenclature; M7 principles;
Structural alerts; Impurity classification; Compound-specific
limits; Threshold of toxicological concern (TTC); Lifetime limit;
Less-than-lifetime (LTL) limit; Quality; Drug substance; Clinical
development.
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ICH M7 document
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Abstract
The ICH M7 guideline on “Assessment and Control of
DNA-Reactive (Mutagenic) Impurities in Pharmaceuticals
to Limit Potential Carcinogenic Risk” is currently at Step 4.1
It supersedes the previous European Medicines Agency
(EMA) and US FDA guidance documents and has been
employed by regulators and industry for the past two to
three years. This article is intended to provide a brief
overview of the main provisions along with some
examples of topical issues.
potential is triggered only for impurities present at levels higher
than the relevant qualification threshold, and these limits can be
exceeded with adequate scientific justification.) For a mutagenic
active pharmaceutical ingredient (API) all impurities, mutagenic or
not, are controlled using ICH Q3A/B criteria. The ICH M7 guidance
applies to new drug substances and new drug products during
their clinical development and subsequent applications for
marketing. It is also relevant to submissions involving generic APIs
and to previously approved products in relation to changes in API
manufacturing, drug-product formulation and new indication(s).
The guidance is not intended to be used for evaluation of excipients
(including flavouring agents, colorants, and perfumes) contained
in existing marketed products, but is likely to be applied to the
assessment of any completely novel excipient.
Nomenclature. The guideline applies to the identification, evaluation
and control of DNA-reactive (ie, mutagenic) impurities or potentially
DNA-reactive impurities or DNA-reactive potential impurities. A
positive result (experimental or predicted) in a bacterial reverse
mutation assay (Ames’ assay) is used as a surrogate for DNAreactivity. Even if other (in vitro) assays for genotoxicity (for example
clastogenicity assays in mammalian cells) are positive, an Ames’negative impurity would be considered as non-DNA-reactive. This
explains the change in focus from “genotoxic” to “mutagenic”
impurities.
Features of the ICH M7 document include the following:
Guideline framework. The guideline is presented in nine sections
which can be summarised as follows:2
 Sections 1–4: Scope, general (toxicological) principles,
considerations for marketed products
 Section 5: Actual/potential/predicted impurities; degradation
impurities
 Section 6: Mutagenicity assessment – in-silico predictions and
bacterial reverse mutation assays (Ames’ testing)
 Section 7: Risk characterisation, based on TTC [threshold of
toxicological concern] limits [lifetime and less-than-lifetime],
compound-specific limits
 Section 8: Impurity control options (1–4), lifecycle management
 Section 9: Documentation and expectations for regulatory
submissions.
ICH M7: Scope. The same exclusions as for the ICH Q3 guidance
apply: biological iotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation, herbal, and crude products of animal
or plant origin. Drug substances and drug products intended for
advanced cancer indications as defined in the scope of ICH S9 are
also excluded. (In a draft Q&A for ICH S93 there is confirmation that
mutagenic impurities should be managed as described for nonmutagenic impurities in ICH Q3A/B; an assessment of mutagenic
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M7 principle #1: Structural alerts
Structural alerts are mentioned in the guidance but not defined.
A structural alert is a chemical motif (usually embedded in an
impurity chemical structure) considered to be potentially DNAreactive owing to its presumed electrophilic character. In addition,
compounds that can undergo metabolic activation to electrophilic
moieties are also alerting, the most common example being
aromatic amines in which P450-catalysed N-hydroxlation can lead
in many cases ultimately to the production of a reactive nitrenium
ion. “Classical” structural alerts which go back over 20 years are
used by most regulatory agencies; the US FDA employs the alerts
listed by Ashby & Paton in 1993.4 However, taking into account the
current state of knowledge,5 structural alerts can be broken down
into three broad categories in relation to the probable correlation
with mutagenic activity:
 High probability: “Cohort of concern” (CoC) relating to aflatoxinlike compounds, N-nitroso compounds and alkyl-azoxy
compounds
 Intermediate probability: This category covers an extremely wide
range of reactivity; examples are hydrazines, some epoxides
(unsymmetrical and/or sterically unhindered), azo compounds,
aliphatic and aromatic nitros; aromatic amines, some haloalkanes
and alkenes, boronic acids and derivatives
 Low probability: The main examples are: aldehydes, aromatic
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Table 1: Impurity classification in ICH M7.
Class
Definition
Control options
1
Known mutagenic carcinogens
At or below acceptable compound-specific limit
2
Mutagen with unknown carcinogenic potential (positive in
bacterial or in-vivo assay with no rodent carcinogenicity data)
At or below TTC or appropriate LTL limit
3
Alerting structure unrelated to drug-substance structure, with
no mutagenicity data
At or below TTC or appropriate LTL limit or conduct Ames’
assay or in-silico assessment. If non-mutagenic = Class 5; if
mutagenic = Class 2.
4
Alerting structure with same alert present in drug substance
or other appropriate reference compounds that have been
shown to be non-mutagenic
Non-mutagenic impurity; control as per ICH Q3A/B
5
No structural alerts, or alerting structure shown not to be
associated with mutagenicity or carcinogenicity
Non-mutagenic impurity; control as per ICH Q3A/B
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M7 principle #2: Threshold of toxicological concern (TTC)
such as the Vega systems (CAESAR, SarPy/IRFMN, ISS and KNN/
Read-Across models) developed in relation to substances
regulated by the ECHA may be sufficient, although commercial
systems such as Derek and Leadscope tend to provide more precise
predictions owing mainly to their larger “learning” datasets.9
Even so, false-negative or false-positive predictions cannot
be completely ruled out particularly for problematic impurities
such as aromatic amine. Sulfanilic acid (4-aminobenzensulfonic
acid) for example is likely to be a predicted mutagen, but it tests
negative in the Ames’ assay10
 An Ames’ bacterial reverse mutation assay can be undertaken as
necessary; miniaturised multi-well assay systems,11 if validated
against standard assays using appropriate reference compounds,
can be employed particularly in cases of low test-material
availability. In some cases a particular impurity may be extremely
difficult to isolate or synthesise in a sufficient amount to enable
“wet” testing. The result of an actual assay overrules any in-silico
prediction
 As previously noted, data from mammalian-cell assays are
discounted if the impurity is predicted with confidence to be
non-mutagenic and/or is an experimental non-mutagen (or noncarcinogen).
A classification scheme (see Table 1) has been developed on
the basis of known carcinogenic potential and/or known/predicted
mutagenic potential. Impurity control options are determined by the
particular categorisation. (The scheme is by no means comprehensive
or foolproof since, for example, the existence of mutagenic noncarcinogens such as methyl trans styryl ketone,12 sodium azide and
emodin13 is not mentioned.)
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N-oxides, carbamates (except ethyl and vinyl carbamate), Michael
acceptors (eg alpha, beta-unsaturated carbonyls), carboxylic acid
halides, sulfonic acid halides (except methanesulfonyl chloride).
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LTL = Less than lifetime.
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As implied by the name, the TTC (in relation to cancer) indicates a
patient’s exposure to a chemical substance at or below which any
adverse effects are unlikely to ensue. For pharmaceuticals, the
generic TTC lifetime limit is set at 1.5 µg/day, reflecting a cancer
risk of ≤1 in 10.5 [The derivation of the TTC is far from robust and no
appropriate publication is referenced in ICH M7 (in which the methods
used to determine the TTC are described as “very conservative”).]
Nevertheless, regulators have uncritically adopted the value cited
above for the cancer TTC (based on the publication of Kroes et al,
20046 using a non-transparent dataset) without any reassessment
for example by employing a clearly-defined dataset and appropriate
evaluation criteria.
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M7 principle #3: Impurity classification
The determination of bacterial mutagenic potential is a critical part of
ICH M7 and is based on a sophisticated and multi-layered procedure:
 The existence of impurity structural alerts alone is considered
insufficient to trigger follow-up measures, unless an alert is part of
the cohort of concern. If a structural alert is present, and assuming
no reliable public-domain data are available (for example from
Toxnet7 or ECHA8 – European Chemicals Agency) mutagenic
potential can be assessed by means of in-silico techniques using
two complementary systems (expert rule-based and statisticalbased) that are underpinned by datasets of known mutagenic and
non-mutagenic compounds.
Since the advent of ICH M7, regulatory assessors often request
an in-silico assessment even when no obvious structural alert is
present. For a simple structure use of open-source (free) software
M7 principle #4: Generic and compound-specific limits
 Generic limits. As mentioned earlier, the generic lifetime limit
for a mutagenic impurity is set at the cancer TTC of 1.5 µg/day.
Table 2: Generic limits for individual (multiple) mutagenic impurities.
Duration of treatment
≤1 month
>1–12 months
>1–10 years
>10 years
Total intake (µg/day)
120 (120)
20 (60)
10 (30)
1.5 (5)
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Focus – Chemistry, manufacturing & controls
Table 3: Lifetime and less-than-lifetime limits (µg/day) for alkyl mesilates and chloroalkanes.
Duration of treatment
≤1 month
>1–12 months
>1–10 years
>10 years
MMS
2544
424
212
31.8
EMS
8,320
1,386
693
104
IMS
200
33.3
16.7
2.5
MeCl
109,000
18,100
9,100
1,360
EtCl
145,000
24,100
12,100
1,810
2-CP
22,200
3,710
1,850
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to the drug substance). The risk of carryover into the drug substance
should be assessed for identified impurities that are present in
starting materials (especially if introduced late in the synthesis)
and intermediates, and impurities that are reasonably expected byproducts in the route of synthesis from the starting material to the
drug substance.
Drug-substance degradation products should be evaluated in a
similar manner. An assessment of degradation impurities in drug
products is triggered when levels exceed the relevant ICH Q3B
identification threshold. The various possibilities of generating
mutagenic impurities in the API or drug product mentioned above
are described in an ICH Q11 draft Q&A16 as “Hazard Assessment
Elements” and can differ if the starting material, reagents or reaction
conditions are changed.
A detailed evaluation of hazard assessment elements is now
required for each route of synthesis (RoS), integrating toxicological
information (particularly from in-silico predictions), chemical
knowledge and theoretical/actual purge factors.17,18 Such an
evaluation is distinctly more straightforward for an originator
company that has built up detailed knowledge of the synthetic
route throughout drug development compared to the situation of a
generics company that purchases its API and data package from a
third-party vendor.
ICH M7 sets out four possible control-strategy options (see
Table 4) at the MAA stage. Option 4 is most likely to be favoured by
companies, but the starting point for regulatory agencies would in
many cases be Option 1, the eventual strategy being agreed as part
of the drug approval process. If none of the options is feasible the
concept of ALARP (as low as reasonably practicable) can be applied
based on a benefit–risk analysis.
During clinical development, a risk-based approach based
on process chemistry fundamentals is encouraged to prioritise
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Generic less-than-lifetime (LTL) limits, which apply in clinical
trials and during marketing, have been developed based on
Haber’s law in relation to treatment durations of ≤1 month, >1–12
months, >1-10 years, >10 years. In Phase I clinical trials with dosing
up to 14 days only Class 1, Class 2 and CoC impurities need to
be controlled to acceptable limits. All other impurities would be
treated as non-mutagenic impurities. Similar but not identical
LTL limits are proposed for multiple mutagenic impurities (see
Table 2). For intermittent dosing, the LTL limits are based on the
total number of dosing days.
When two Class 2 or Class 3 specified impurities are to be
controlled, individual generic limits apply. For three or more
Class 2 or Class 3 impurities included in the drug substance
specification, total mutagenic impurities should be controlled
as shown in Table 2 for clinical development and marketed
products. Class 1 specified impurities, degradation impurities in
drug products and impurities with compound-specific limits do
not contribute to the multiple-impurity limits. For combination
products, each active substance is treated separately.
 Compound-specific limits. A few examples of compound-specific
limits are mentioned in ICH M7, an example being monofunctional
alkyl chlorides where a general lifetime limit of 15 µg/day is
proposed. Many more lifetime limits have been derived in an
addendum to ICH M7, ICH M7 (R1),14 employing two techniques:
determination of an acceptable intake (AI) by linear extrapolation
of carcinogenic potency data (eg, TD50, T25), and derivation of a
permitted daily exposure (PDE) as per ICH Q3C (R6) if a threshold
dose can be determined for a compound that has a non-mutagenic
mode of action in terms of carcinogenicity.
 Combining compound-specific limits with the LTL principle:
It’s permitted to use the implied LTL factors based on the
generic individual limits shown in Table 2 (80, 13.3 and 6.7 for
periods ≤1 month, >1–12 months, >1–10 years respectively) to
determine LTL compound-specific exposures (being capped at
a maximum of 0.5%). Examples are shown in Table 3 for alkyl
methanesulfonates (methyl methanesulfonate – MMS; ethyl
methanesulfonate – EMS and isopropyl methanesulfonate – IMS)
and chloroalkanes (chloromethane – MeCl; chloroethane – EtCl;
2-chloropropane – 2-CP).15
Analytical and quality aspects
An evaluation for mutagenic potential is required for both actual
impurities (reported/identified at the appropriate ICH Q3A
thresholds) and potential impurities (starting materials, reagents
and intermediates in the route of synthesis from the starting material
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Both scientific and regulatory approaches
are expected to evolve as experience
is gained, one clear manifestation
of this being the compound-specific
limits proposed for the first tranche of
substances evaluated by the ICH M7 (R1)
expert group
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Focus – Chemistry, manufacturing & controls
Table 4: Control strategies for mutagenic impurities.
Option
Description
1
Set acceptable generic or compound-specific specification limit in the API. Periodic testing can be applied if impurity is
consistently lower than acceptance criterion*
2
ICH M7-compliant specification limit set for a suitable precursor (eg, final intermediate)
3
Set specification level in suitable precursor at >ICH M7-compliant limit provided that fate/purge data indicate that the
concentration in the API is lower than the acceptance criterion.* No routine testing of API required
4
Sufficient compelling scientific information and fate/purge data to demonstrate that the level of the impurity in the API is
consistently lower than the acceptable limit. Process controls in lieu of analytical testing or specification-setting.
*≤30% of applicable ICH M7 limit.
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excreted in the urine as acetamide.20 Since acetohydroxamic acid
is administered therapeutically at 10–15 mg/kg/day21 patient
exposure to acetamide is estimated at 50–75 mg/day. Acetamide
is also a potential degradation product of atenolol, especially in
aqueous-solution products.
Due to an unfortunate initial misperception22 (recycled in
subsequent articles) concerning the mutagenicity status of
acetamide, an incorrect belief has become established, even in
some regulatory agencies, that acetamide should be controlled as a
mutagenic impurity. In fact acetamide is a non-mutagen (when tested
in Salmonella typhimurium strains TA97, 98, 100, 102 and 1535)23
and a PDE of 1–3 mg can be determined based on carcinogenicity
data for acetamide itself24 or on data from dimethylacetamide25
(acetamide being a metabolite of dimethylacetamide).
Alkyl sulfonates and chloroalkanes. For many years there has
been a widespread belief that mutagenic alkyl sulfonates are
potential impurities in sulfonic-acid salts of amine APIs, particularly
if the latter are synthesised using an alcohol (such as methanol,
ethanol or isopropanol) as solvent. In the case of mesilate salts
it was originally thought that a side-reaction between the solvent
(eg, ethanol) and the sulfonic acid (methanesulfonic acid) could
readily occur to produce ethyl methanesulfonate (EMS). Evidence
from numerous publications reporting the absence of EMS (or other
mesilate esters) was consistently discounted. Even though detailed
mechanistic, kinetic and experimental evidence is now available14
rebutting notions of alkyl-sulfonate formation, deficiency questions
on this topic still occur based on long-standing and embedded
false assumptions.
It is thus ironic that mutagenic chloroalkanes in hydrochloride
salts have attracted very little regulatory attention in spite of the
fact that a common method of synthesis (using an alcohol saturated
with HCl gas) generates significant amounts (percent levels) of
chloroalkanes. On the other hand, the chloroalkanes can be readily
purged (by washing the precipitated salt with solvent) and are of
relatively modest mutagenic/carcinogenic potency (see Table 3).
Impurities in ketone solvents. In ketone solvents such as acetone
and methyl isobutyl ketone (MIBK), low-level condensation reactions
can lead to the presence of various alpha, beta-unsaturated-ketone
impurities. The “classical” case relates to mesityl oxide (MsO;
4-methylpent-3-en-2-one; structurally alerting and so might be
considered as a potentially mutagenic impurity (PMI)) in acetone and
any API recrystallised from acetone is likely to attract a deficiency
question concerning carryover of MsO. Levels in fresh pharmaceuticalgrade acetone are extremely low (0–10 ppm)26 and MsO has been
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analytical efforts on those impurities with the highest likelihood of
being present in the drug substance or drug product.
In summary, controls on mutagenic impurities in APIs are based
on a two-fold strategy:
 Identification of impurities present at ≥ ICH Q3A identification
threshold (in most cases 1,000 ppm)
 Determination of hazard assessment elements focused for
example on starting materials, solvents, reagents (and impurities
therein), and potential by-products and degradation products,
and applying the 30% acceptance criterion (see Table 4) in a
targeted manner. Applicants are not expected to mount a “fishing
expedition” for impurities present at low-ppm levels.
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Four topical issues
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Qualification of degradation impurities in ophthalmic products.
When compared to the ICH Q3A/B guidance on impurities,
ICH M7 requirements are considerably more flexible and contain
a number of innovations, including: limits based on dose
rather than concentration (in line with toxicological principles);
use of structure-activity relationships and in-silico prediction
techniques; limits based on the duration of treatment. The latter
can be leveraged when attempting to qualify impurities present at
a higher level than the ICH Q3A/B qualification thresholds. This is
particularly helpful for ophthalmic products which often have short
treatment regimens of only three to five days with maximum daily
doses (MDDs) of 1–2 mg (expressed as applied dose, systemic
doses being much lower).
One example is naphazoline (MDD ≤1 mg as base over three
days for treatment of “red eye”) which is hydrolysed on prolonged
storage of the drug product to produce up to 5% of a ring-opened
degradation impurity (1-naphthylacetylethylenediamine).19 The latter
can be qualified on the basis of patient exposure being ≤50 µg/day,
significantly lower than the relevant ICH M7 LTL limit of 120 µg/day.
(In forced degradation studies, the primary hydrolysis product may
be converted to 1-naphthylacetic acid and ethylenediamine, both of
which are well characterised toxicologically.) Normally any impurity
exceeding the ICH Q3B qualification threshold (in this case 1%)
would need to be qualified using the standard toxicological-study
package, whereas the application of ICH M7 LTL thresholds enables
qualification to be achieved as a paper exercise.
Acetamide. Acetamide (acetic acid amide; CH3CONH2) is a
major metabolite of acetohydroxamic acid which is used to treat
patients with chronic urea-splitting urinary infection. Following
oral administration 9–14% of a dose of acetohydroxamic acid is
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Focus – Chemistry, manufacturing & controls
shown to be a non-mutagen in a number of independent Ames’
assays.27,28 Experimental data may not be available on unsaturatedketone impurities in MIBK, but in-silico evaluations using commercial
systems are highly likely to produce robust negative predictions for
mutagenic potential.
nih.gov/cpdb/
14. ICH M7 (R1). Application of the principles of the ICH M7 guideline to
calculation of compound-specific acceptable intakes. Available at:
www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/
Multidisciplinary/M7/M7_Addendum_Step_2.pdf
15. D Snodin, A Teasdale. ‘Mutagenic Alkyl-Sulfonate Impurities in Sulfonic
Acid Salts: Reviewing the Evidence and Challenging Regulatory
Perceptions’, Org Process Res Dev, 19 (11), 1465–1485, 2015.
16. ICH Q11. Development and manufacture of drug substances. Draft Q&A.
Available at: www.ich.org/fileadmin/Public_Web_Site/ICH_Products/
Guidelines/Quality/Q11/Q11_Q_A_Step_2.pdf
17. A Teasdale et al. Risk assessment of genotoxic impurities in new chemical
entities: strategies to demonstrate control. Org Process Res Dev, 17,
221-230, 2013. Available at: www.triphasepharmasolutions.com/
Resources/Literature%20Risk%20Assessment%20of%20Genotoxic%20
Impurities%20in%20New%20Chemical%20Entities%20Strategies%20
To%20Demonstrate%20Control.pdf
18. A Teasdale. ‘Explaining and demonstrating successful use of purging and
A
This short review is by no means a comprehensive account of
the many features of ICH M7. Topics such as options for in-vivo
mutagenicity assays,29 lifecycle management and applications for
clinical trial authorisations have not been discussed. With such
a complex guideline, both scientific and regulatory approaches
are expected to evolve as experience is gained (and hopefully
become more consistent), one clear manifestation of this being
the compound-specific limits proposed for the first tranche of
substances evaluated by the ICH M7 (R1)14 expert group. In addition,
some of the previously mentioned innovations in ICH M7 may
ultimately be carried over to guidance on non-mutagenic impurities
(as per ICH Q3A/B),30 one obvious possibility being application of
the LTL principle to drugs (such as antibiotics) that are normally
used for short-term treatment.
depletion strategies to control mutagenic impurities’, 2014. Available
at: www.lhasalimited.org/Public/Library/2014/Explaining%20and%20
PR
Concluding remarks
demonstrating%20successful%20use%20of%20purging%20to%20
control%20mutagenic%20impurities.pdf
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