23 September 2010

EMA/CHMP/SWP/431994/2007 Rev. 3
Committee for Medicinal Products for Human Use (CHMP)
Safety Working Party (SWP)

Questions and answers on the 'Guideline on the limits of

genotoxic impurities'

Agreed by Safety Working Party (SWP) September 2010

Adoption by CHMP 23 September 2010

Keywords Impurities; Genotoxicity; Threshold of toxicological concern (TTC);

Structure activity relationship (SAR)

Background
The aim of this question-and-answer document is to provide clarification and harmonisation of the
'Guideline on the limits of genotoxic impurities' (EMEA/CHMP/QWP/251344/2006), published in 2006.

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Questions and answers
Question 1. The guideline does not need to be applied retrospectively to authorised products
unless there is a specific cause for concern. What might constitute "a cause-for-concern" in
terms of application to currently marketed products?

If a manufacturing procedure for API remains essentially unchanged a re-evaluation with respect to the
presence of potentially genotoxic impurities is generally not needed. However, new knowledge may
indicate a previously unknown cause for concern. One example is the mesylate salt drug substances
for which a few years ago, a concern regarding the potential for formation of genotoxic alkyl mesylates
was raised. This concern resulted in the Production Statement requesting a specific evaluation of the
potential for formation of these highly toxic products now included as part of the PhEur monographs for
all the mesylates salts.

Question 2. The guideline indicates that it is necessary to reduce a known or suspected

mutagenic impurity to as low as reasonably practicable (ALARP) even if the level is below
the threshold of toxicological concern (TTC), i.e. in the decision tree ALARP considerations
precede TTC considerations. If the level is already known to be below the TTC (which is a
very conservative value), why is it necessary to reduce it even further? On a practical basis
this would often involve developing analytical methods that have limits of quantitation
around or below 1ppm level. The effort and resource this can take, and the possibility that
it is not actually achievable, does not seem commensurate with the perceived risk.

If the level of a mutagenic impurity is below the threshold of toxicological concern (equivalent to a
clinical dose 1.5 g/day) it is not necessary to apply ALARP considerations unless it is a structure of
very high concern, e.g. N-nitroso, aflatoxins-like and azoxy-compounds.

Question 3. The guideline states: When a potential impurity contains structural alerts,
additional genotoxicity testing of the impurity, typically in a bacterial reverse mutation
assay, should be considered.

i) If an impurity triggers a mutagenic structural alert, will a negative result in an Ames test
on the impurity (conducted to regulatory acceptable standards) be sufficient to conclude
that the compound is of no concern with respect to genotoxicity and no further
qualification studies will be required?

ii) Is the absence of a structural alert sufficient to show that the impurity is of no concern?

iii) Is it acceptable to control impurities with a structural alert by assuming they will be
positive (without resorting to any testing) and ensuring the level remains below the
appropriate TTC value?

i) Yes, a negative Ames test (conducted to regulatory acceptable standards) will overrule a structural
alert and no further studies would be required providing the level remains below ICH Q3A/B limits.

ii) Yes, the absence of a structural alert based on a well-performed assessment (e.g. through
application of commonly used QSAR assessment software such as DEREK or MCASE) will be sufficient
to conclude that the impurity is of no concern with respect to genotoxicity and no further qualification
studies or justification will be required.

iii) Yes, genotoxicity testing is not obligatory when a potential genotoxic impurity is controlled at the
TTC level, unless it belongs to a class of very potent genotoxic carcinogens (N-nitroso and azoxy
compounds, or a aflatoxin-like compound).

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Question 4. What would be an appropriate strategy to qualify a new impurity that arises
during Phase III or with a commercial product? For example, would it be acceptable that a
new unidentified impurity, discovered at the 0.05-0.09% range requires no action to be
taken? Would an impurity discovered in the 0.10 to 0.15%, even if it triggers a structural
alert, be fully qualified by testing the active ingredient containing this impurity in an Ames
test?

In line with the ICH guideline, no action is generally required for a new unidentified impurity found at
levels below the ICH identification threshold. When an impurity is found above the ICH identification
threshold, but below the qualification threshold, and the structure gives rise to a structural alert, this
can be negated by carrying out an Ames test on the active ingredient containing the impurity as long
as the impurity is present at a minimum concentration of 250 g/plate (estimated detection limit for
most relevant mutagens in Ames test, see Kenyon et al., Reg Tox & Pharm, 2007, 75-86). If the
structure cannot be elucidated, then no action is generally required. Above the ICH qualification
threshold, then the ICH guidance should be followed.

Question 5. The guideline states that A TTC value higher than 1.5 g /day may be
acceptable under certain conditions e.g. short-term exposure.. Is the CHMP in agreement
with the principles of staged TTC dependent on the duration of clinical exposure, i.e.
higher levels allowed for marketed drugs used to treat acute conditions, e.g. antibiotics. If
yes, what levels would be acceptable?

TTC values for genotoxic impurities above 1.5 g /day will be treated on a case-by-case basis. For
short-duration treatments, the acceptability of higher levels will be in line with the principles outlined in
the CHMPs answer to question 6.

Question 6. The wording of the guideline implies that it is intended to cover an issue not
covered specifically by ICH Q3A/B guidelines. The scope of the ICH guidelines does not
include clinical development prior to NDA or MAA submission. However, experience across a
range of pharmaceutical companies indicates that some regulatory authorities are applying
the genotoxic impurity guideline during clinical development. In case the scope should
include application to clinical development, can the CHMP advise on how genotoxic
impurities should be controlled during the development stage?

According to the scope of the guideline, it mainly applies to genotoxic impurities in new active
substances which includes new active substances in both, MAA submissions as well as clinical trial
applications. In fact, the CHMP Guideline on the Requirements to the Chemical and Pharmaceutical
Quality Documentation Concerning Investigational Medicinal Products in clinical trials
(CHMP/QWP/185401/2004) states that For impurities in IMPs, a justification that the product is safe
for its intended use, considering the anticipated exposure of volunteers and patients, respectively, will
be required., and further on a brief justification of the specifications and acceptance criteria for
impurities should be provided based on safety and toxicity data.

The CHMP agrees with the use of a staged TTC concept during clinical development.

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The acceptable limits for daily intake of genotoxic impurities are 5, 10, 20, and 60g/day for a duration
of exposure of 6-12 months, 3-6 months, 1-3 months, and less than 1 month, respectively. For a
single dose an intake of up to 120 g is acceptable. Compared to the proposal of a staged TTC in the
Mueller et al (Reg Tox & Pharm, 2006, 44, 198211) paper these values incorporate a dose rate
correction factor of 2 to account for deviations from the linear extrapolation model.

Duration of exposure

Single dose 1 month 3 months 6 months 12 months

Allowable daily intake 120 g 60 g 20 g 10 g 5 g

Question 7. The guideline text implies that the indicated TTC value of 1.5 g /day is a level
that can be applied to each individual genotoxic impurity in a drug substance. Could this be
confirmed?

When more than one genotoxic impurity is present in the drug substance, the TTC value of 1.5 g/day
can be applied to each individual impurity only if the impurities are structurally unrelated.

In case of structural similarity, it can be assumed that the impurities act by the same genotoxic mode
of action and have the same molecular target. and thus might exert effects in an additive manner. In
such a situation, a limitation of the sum of the genotoxic impurities at 1.5 g/day is recommended.
This might be practically not achievable with reasonable efforts in particular when the maximum daily
dose is very high and thus may demand application of lower group limits. Justifications should be made
on a case-by-case basis taking into consideration issues such as:

Maximum daily dose of the active substance;

Therapeutic indication;

Step of the synthesis at which the genotoxic impurity(ies) arise;

Capability of the manufacturing process (purification steps) to eliminate these impurities;

Capability of the analytical procedure to control these impurities.

In cases where routine use of more powerful detection methods would be difficult, one could consider
using such methods during development or testing of the first commercial batches, in order to
demonstrate that the actual values are sufficiently below the TTC. In such a case, skip testing could be
considered instead of routine testing, providing that the Competent Authorities, based on a risk
assessment, consider the approach as acceptable.

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Question 8. The European Pharmacopoeia Commission Policy for dealing with potentially
genotoxic impurities was issued in March 2008. This policy is to be applied during
elaboration and revision of pharmacopoeial monographs. It provides very pragmatic
guidance on how the CHMP guideline can be applied to active substances described in
existing monographs. Can the same principles, as outlined within this policy, apply to
established drug substances, which do not have pharmacopoeial monographs?

Yes. For active substances included in medicinal products authorized by the competent authorities
before implementation of the CHMP guideline, the specifications as described in the dossier for
marketing authorization should be followed. Action is needed only where there is study data
demonstrating genotoxicity of the impurity. The existence of structural alerts alone is considered
insufficient to trigger follow-up measures unless it is a structure of very high concern, e.g. N-nitroso,
aflatoxins-like and azoxy-compounds. If a new synthetic route is used that may give rise to different
potentially genotoxic impurities or to higher levels of previously recognized potentially genotoxic
impurities then the situation should be discussed with the competent authority.

Question 9. What is a reasonable policy for setting specifications for potentially genotoxic
impurities which are theoretical or actual impurities in a drug substance manufacturing
process?

Different possible scenarios can be identified and the applicable policies to be applied for each of them
are described below:

Example 1 A potential genotoxic impurity

The definition for a potential genotoxic impurity is derived from the definition for Potential impurity:
an impurity that theoretically can arise during manufacture or storage. It may or may not actually
appear in the (new) drug substance (ICH Q3A, Glossary).

If a potential genotoxic impurity is just a theoretical impurity i.e. based on theoretical considerations
but not found in practice as demonstrated by studies during development of the manufacture, the
impurity does not need to be included in the drug substance specification.

Example 2 A (potentially) genotoxic impurity actually formed or introduced prior to the

final step of the synthesis

If a (potentially) genotoxic impurity is formed or introduced in a step before the final synthesis step, it
is considered possible to not include this impurity in the drug substance specification if it is controlled
by a suitable limit in a synthesis intermediate and if it is unambiguously demonstrated by analysis
results (use of spiking experiments are encouraged) that presence of this impurity does not exceed 30
% of the limit, derived either from TTC or otherwise defined acceptable limit etc, in the drug
substance. If these conditions are not fulfilled, this impurity has to be included in the drug substance
specification and the test has to be carried out on a routine basis.

Should a genotoxic impurity not be controlled at the intermediate stage, then the scenario of example
3 applies.

Example 3 - A (potentially) genotoxic impurity is formed or introduced in the last synthesis

step

If a (potentially) genotoxic impurity is formed or introduced in the final synthesis step, it should be
included in the specifications. However, it is considered possible to apply skip testing if the level of the
impurity does not exceed 30 % of the limit, derived from either TTC or otherwise defined acceptable
limit etc, in the drug substance. Data should be presented for at least 6 consecutive pilot scale or 3

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consecutive production scale batches. If this condition is not fulfilled, a routine test in the drug
substance specification is needed.

The following definitions apply:

Genotoxic impurity: an impurity that has been demonstrated to be genotoxic in an appropriate

genotoxicity test model, e.g. bacterial gene mutation (Ames) test.

Potentially genotoxic impurity: an impurity that shows (a) structural alert(s) for genotoxicity but that
has not been tested in an experimental test model. Here potentially relates to genotoxicity, not to the
presence or absence of this impurity.

References
M.O. Kenyon, J.R. Cheung, K.L. Dobo, W.W. Ku: An evaluation of the sensitivity of the Ames assay to
discern low-level mutagenic impurities. Reg Tox & Pharm, 2007, 75-86.

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