Q3 a r2_ step4

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INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN
USE

ICH HARMONISED TRIPARTITE GUIDELINE

IMPURITIES IN NEW DRUG SUBSTANCES
Q3A(R2
Q3A(R2)
Current Step 4 version
dated 25 October 2006

This Guideline has been developed by the appropriate ICH Expert Working Group
and has been subject to consultation by the regulatory parties, in accordance with the
ICH Process. At Step 4 of the Process the final draft is recommended for adoption to
the regulatory bodies of the European Union, Japan and USA.


Q3A(R2
Q3A(R2)
Document History
First
Codification

History

Date

New
Codification
November
2005

Q3

Approval by the Steering Committee under Step 2 and release
for public consultation.

15
March
1994

Q3A

Q3A

Approval by the Steering Committee under Step 4 and
recommendation for adoption to the three ICH regulatory
bodies.

30
March
1995

Q3A

Q3 was renamed Q3A.
Q3A(R)

Approval by the Steering Committee of the first Revision
under Step 2 and release for public consultation.

7
October
1999

Q3A(R1)

Q3A(R)

Approval by the Steering Committee of the first Revision
under Step 4 and recommendation for adoption to the three
ICH regulatory bodies.

6
February
2002

Q3A(R1)

25 October
2006

Q3A(R2)

Current Step 4 version
Q3A(R2)

Approval by the Steering Committee of the revision of the
Attachment 2 directly under Step 4 without further public
consultation.


ICH Harmonised Tripartite Guideline
Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting
on 7 February 2002, this guideline is recommended for
adoption to the three regulatory parties to ICH.
Attachment 2 has been revised on 25 October 2006.

TABLE OF CONTENTS

1.

PREAMBLE ........................................................................................................... 1

2.

CLASSIFICATION OF IMPURITIES ................................................................... 1

3.

RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES.................................................................................................... 2
3.1 Organic Impurities.......................................................................................... 2
3.2 Inorganic Impurities ....................................................................................... 2
3.3 Solvents ........................................................................................................... 3

4.

ANALYTICAL PROCEDURES.............................................................................. 3

5.

REPORTING IMPURITY CONTENT OF BATCHES .......................................... 3

6.

LISTING OF IMPURITIES IN SPECIFICATIONS ............................................. 4

7.

QUALIFICATION OF IMPURITIES .................................................................... 5

8.

GLOSSARY ............................................................................................................ 6

ATTACHMENT 1 .......................................................................................................... 8
ATTACHMENT 2 .......................................................................................................... 9
ATTACHMENT 3 ........................................................................................................ 10

i



1.
PREAMBLE
This document is intended to provide guidance for registration applications on the
content and qualification of impurities in new drug substances produced by chemical
syntheses and not previously registered in a region or member state. It is not
intended to apply to new drug substances used during the clinical research stage of
development. The following types of drug substances are not covered in this
guideline: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical,
fermentation product and semi-synthetic products derived therefrom, herbal
products, and crude products of animal or plant origin.
Impurities in new drug substances are addressed from two perspectives:

Chemistry Aspects include classification and identification of impurities, report
generation, listing of impurities in specifications, and a brief discussion of
analytical procedures; and
Safety Aspects include specific guidance for qualifying those impurities that
were not present, or were present at substantially lower levels, in batches of a
new drug substance used in safety and clinical studies.
2.
CLASSIFICATION OF IMPURITIES
Impurities can be classified into the following categories:
•

Organic impurities (process- and drug-related)

•

Inorganic impurities

•

Residual solvents

Organic impurities can arise during the manufacturing process and/or storage of the
new drug substance. They can be identified or unidentified, volatile or non-volatile,
and include:
•

Starting materials

•

By-products

•

Intermediates

•

Degradation products

•

Reagents, ligands and catalysts

Inorganic impurities can result from the manufacturing process. They are normally
known and identified and include:
•

Reagents, ligands and catalysts

•

Heavy metals or other residual metals

•

Inorganic salts

•

Other materials (e.g., filter aids, charcoal)

Solvents are inorganic or organic liquids used as vehicles for the preparation of
solutions or suspensions in the synthesis of a new drug substance. Since these are
1


generally of known toxicity, the selection of appropriate controls is easily
accomplished (see ICH Guideline Q3C on Residual Solvents).
Excluded from this document are: (1) extraneous contaminants that should not occur
in new drug substances and are more appropriately addressed as Good
Manufacturing Practice (GMP) issues, (2) polymorphic forms, and (3) enantiomeric
impurities.
3.

RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES

3.1
Organic Impurities
The applicant should summarise the actual and potential impurities most likely to
arise during the synthesis, purification, and storage of the new drug substance. This
summary should be based on sound scientific appraisal of the chemical reactions
involved in the synthesis, impurities associated with raw materials that could
contribute to the impurity profile of the new drug substance, and possible
degradation products. This discussion can be limited to those impurities that might
reasonably be expected based on knowledge of the chemical reactions and conditions
involved.
In addition, the applicant should summarise the laboratory studies conducted to
detect impurities in the new drug substance. This summary should include test
results of batches manufactured during the development process and batches from
the proposed commercial process, as well as the results of stress testing (see ICH
Guideline Q1A on Stability) used to identify potential impurities arising during
storage. The impurity profile of the drug substance batches intended for marketing
should be compared with those used in development, and any differences discussed.
The studies conducted to characterise the structure of actual impurities present in
the new drug substance at a level greater than (>) the identification threshold given
in Attachment 1 (e.g., calculated using the response factor of the drug substance)
should be described. Note that any impurity at a level greater than (>) the
identification threshold in any batch manufactured by the proposed commercial
process should be identified. In addition, any degradation product observed in
stability studies at recommended storage conditions at a level greater than (>) the
identification threshold should be identified. When identification of an impurity is not
feasible, a summary of the laboratory studies demonstrating the unsuccessful effort
should be included in the application. Where attempts have been made to identify
impurities present at levels of not more than (≤) the identification thresholds, it is
useful also to report the results of these studies.
Identification of impurities present at an apparent level of not more than (≤) the
identification threshold is generally not considered necessary. However, analytical
procedures should be developed for those potential impurities that are expected to be
unusually potent, producing toxic or pharmacological effects at a level not more than
(≤) the identification threshold. All impurities should be qualified as described later
in this guideline.
3.2
Inorganic Impurities
Inorganic impurities are normally detected and quantified using pharmacopoeial or
other appropriate procedures. Carry-over of catalysts to the new drug substance
should be evaluated during development. The need for inclusion or exclusion of
inorganic impurities in the new drug substance specification should be discussed.
2


Acceptance criteria should be based on pharmacopoeial standards or known safety
data.
3.3
Solvents
The control of residues of the solvents used in the manufacturing process for the new
drug substance should be discussed and presented according to the ICH Q3C
Guideline for Residual Solvents.
4.
ANALYTICAL PROCEDURES
The registration application should include documented evidence that the analytical
procedures are validated and suitable for the detection and quantification of
impurities (see ICH Q2A and Q2B Guidelines for Analytical Validation). Technical
factors (e.g., manufacturing capability and control methodology) can be considered as
part of the justification for selection of alternative thresholds based on manufacturing
experience with the proposed commercial process. The use of two decimal places for
thresholds (See Attachment 1) does not necessarily reflect the precision of the
analytical procedure used for routine quality control purposes. Thus, the use of lower
precision techniques (e.g., thin-layer chromatography) can be acceptable where
justified and appropriately validated. Differences in the analytical procedures used
during development and those proposed for the commercial product should be
discussed in the registration application.
The quantitation limit for the analytical procedure should be not more than (≤) the
reporting threshold.
Organic impurity levels can be measured by a variety of techniques, including those
that compare an analytical response for an impurity to that of an appropriate
reference standard or to the response of the new drug substance itself. Reference
standards used in the analytical procedures for control of impurities should be
evaluated and characterised according to their intended uses. The drug substance can
be used as a standard to estimate the levels of impurities. In cases where the
response factors of the drug substance and the relevant impurity are not close, this
practice can still be appropriate, provided a correction factor is applied or the
impurities are, in fact, being overestimated. Acceptance criteria and analytical
procedures used to estimate identified or unidentified impurities can be based on
analytical assumptions (e.g., equivalent detector response). These assumptions
should be discussed in the registration application.
5.
REPORTING IMPURITY CONTENT OF BATCHES
Analytical results should be provided in the application for all batches of the new
drug substance used for clinical, safety, and stability testing, as well as for batches
representative of the proposed commercial process. Quantitative results should be
presented numerically, and not in general terms such as “complies”, “meets limit” etc.
Any impurity at a level greater than (>) the reporting threshold (see Attachment 1)
and total impurities observed in these batches of the new drug substance should be
reported with the analytical procedures indicated. Below 1.0%, the results should be
reported to two decimal places (e.g., 0.06%, 0.13%); at and above 1.0%, the results
should be reported to one decimal place (e.g., 1.3%). Results should be rounded using
conventional rules (see Attachment 2). A tabulation (e.g., spreadsheet) of the data is
recommended. Impurities should be designated by code number or by an appropriate
descriptor, e.g., retention time. If a higher reporting threshold is proposed, it should

3


be fully justified. All impurities at a level greater than (>) the reporting threshold
should be summed and reported as total impurities.
When analytical procedures change during development, reported results should be
linked to the procedure used, with appropriate validation information provided.
Representative chromatograms should be provided.
Chromatograms of
representative batches from analytical validation studies showing separation and
detectability of impurities (e.g., on spiked samples), along with any other impurity
tests routinely performed, can serve as the representative impurity profiles. The
applicant should ensure that complete impurity profiles (e.g., chromatograms) of
individual batches are available, if requested.
A tabulation should be provided that links the specific new drug substance batch to
each safety study and each clinical study in which the new drug substance has been
used.
For each batch of the new drug substance, the report should include:
•
•
•
•
•
•
•

Batch identity and size
Date of manufacture
Site of manufacture
Manufacturing process
Impurity content, individual and total
Use of batches
Reference to analytical procedure used

6.
LISTING OF IMPURITIES IN SPECIFICATIONS
The specification for a new drug substance should include a list of impurities.
Stability studies, chemical development studies, and routine batch analyses can be
used to predict those impurities likely to occur in the commercial product. The
selection of impurities in the new drug substance specification should be based on the
impurities found in batches manufactured by the proposed commercial process. Those
individual impurities with specific acceptance criteria included in the specification for
the new drug substance are referred to as "specified impurities" in this guideline.
Specified impurities can be identified or unidentified.
A rationale for the inclusion or exclusion of impurities in the specification should be
presented. This rationale should include a discussion of the impurity profiles
observed in the safety and clinical development batches, together with a
consideration of the impurity profile of batches manufactured by the proposed
commercial process. Specified identified impurities should be included along with
specified unidentified impurities estimated to be present at a level greater than (>)
the identification threshold given in Attachment 1. For impurities known to be
unusually potent or to produce toxic or unexpected pharmacological effects, the
quantitation/detection limit of the analytical procedures should be commensurate
with the level at which the impurities should be controlled. For unidentified
impurities, the procedure used and assumptions made in establishing the level of the
impurity should be clearly stated. Specified, unidentified impurities should be
referred to by an appropriate qualitative analytical descriptive label (e.g.,
“unidentified A", “unidentified with relative retention of 0.9”). A general acceptance
criterion of not more than (≤) the identification threshold (Attachment 1) for any

4


unspecified impurity and an acceptance criterion for total impurities should be
included.
Acceptance criteria should be set no higher than the level that can be justified by
safety data, and should be consistent with the level achievable by the manufacturing
process and the analytical capability. Where there is no safety concern, impurity
acceptance criteria should be based on data generated on batches of the new drug
substance manufactured by the proposed commercial process, allowing sufficient
latitude to deal with normal manufacturing and analytical variation and the stability
characteristics of the new drug substance. Although normal manufacturing variations
are expected, significant variation in batch-to-batch impurity levels can indicate that
the manufacturing process of the new drug substance is not adequately controlled
and validated (see ICH Q6A Guideline on Specifications, Decision Tree #1, for
establishing an acceptance criterion for a specified impurity in a new drug
substance). The use of two decimal places for thresholds (See Attachment 1) does not
necessarily indicate the precision of the acceptance criteria for specified impurities
and total impurities.
In summary, the new drug substance specification should include, where applicable,
the following list of impurities:

Organic Impurities
•

Each specified identified impurity

•

Each specified unidentified impurity

•

Any unspecified impurity with an acceptance criterion of not more than (≤) the
identification threshold

•

Total impurities

Residual Solvents
Inorganic Impurities
7.
QUALIFICATION OF IMPURITIES
Qualification is the process of acquiring and evaluating data that establishes the
biological safety of an individual impurity or a given impurity profile at the level(s)
specified. The applicant should provide a rationale for establishing impurity
acceptance criteria that includes safety considerations. The level of any impurity
present in a new drug substance that has been adequately tested in safety and/or
clinical studies would be considered qualified. Impurities that are also significant
metabolites present in animal and/or human studies are generally considered
qualified. A level of a qualified impurity higher than that present in a new drug
substance can also be justified based on an analysis of the actual amount of impurity
administered in previous relevant safety studies.
If data are unavailable to qualify the proposed acceptance criterion of an impurity,
studies to obtain such data can be appropriate when the usual qualification
thresholds given in Attachment 1 are exceeded.
Higher or lower thresholds for qualification of impurities can be appropriate for some
individual drugs based on scientific rationale and level of concern, including drug
class effects and clinical experience. For example, qualification can be especially
important when there is evidence that such impurities in certain drugs or therapeutic
classes have previously been associated with adverse reactions in patients. In these
5


instances, a lower qualification threshold can be appropriate. Conversely, a higher
qualification threshold can be appropriate for individual drugs when the level of
concern for safety is less than usual based on similar considerations (e.g., patient
population, drug class effects, clinical considerations). Proposals for alternative
thresholds would be considered on a case-by-case basis.
The "Decision Tree for Identification and Qualification" (Attachment 3) describes
considerations for the qualification of impurities when thresholds are exceeded. In
some cases, decreasing the level of impurity to not more than the threshold can be
simpler than providing safety data. Alternatively, adequate data could be available in
the scientific literature to qualify an impurity. If neither is the case, additional safety
testing should be considered. The studies considered appropriate to qualify an
impurity will depend on a number of factors, including the patient population, daily
dose, and route and duration of drug administration. Such studies can be conducted
on the new drug substance containing the impurities to be controlled, although
studies using isolated impurities can sometimes be appropriate.
Although this guideline is not intended to apply during the clinical research stage of
development, in the later stages of development the thresholds in this guideline can
be useful in evaluating new impurities observed in drug substance batches prepared
by the proposed commercial process. Any new impurity observed in later stages of
development should be identified if its level is greater than (>) the identification
threshold given in Attachment 1 (see the “Decision Tree for Identification and
Qualification” in Attachment 3). Similarly, the qualification of the impurity should
be considered if its level is greater than (>) the qualification threshold given in
Attachment 1. Safety assessment studies to qualify an impurity should compare the
new drug substance containing a representative amount of the new impurity with
previously qualified material. Safety assessment studies using a sample of the
isolated impurity can also be considered.
8.
GLOSSARY
Studies:
Chemical Development Studies Studies conducted to scale-up, optimise, and
validate the manufacturing process for a new drug substance.
Impurity:
Enantiomeric Impurity A compound with the same molecular formula as the drug
substance that differs in the spatial arrangement of atoms within the molecule and is
a non-superimposable mirror image.
Contaminant:
Extraneous Contaminant An impurity arising from any source extraneous to the
manufacturing process.
Products:
Herbal Products Medicinal products containing, exclusively, plant material and/or
vegetable drug preparations as active ingredients. In some traditions, materials of
inorganic or animal origin can also be present.
Impurity:
Identified Impurity An impurity for which a structural characterisation has been
achieved.
Threshold:
Identification Threshold A limit above (>) which an impurity should be identified.
Impurity:
Impurity Any component of the new drug substance that is not the chemical entity
defined as the new drug substance.

6


Profile:
Impurity Profile A description of the identified and unidentified impurities present
in a new drug substance.
Intermediate:
Intermediate A material produced during steps of the synthesis of a new drug
substance that undergoes further chemical transformation before it becomes a new
drug substance.
Ligand:
Ligand An agent with a strong affinity to a metal ion.
Substance: The designated therapeutic moiety that has not been
New Drug Substance
previously registered in a region or member state (also referred to as a new molecular
entity or new chemical entity). It can be a complex, simple ester, or salt of a
previously approved drug substance.
Forms:
Polymorphic Forms Different crystalline forms of the same drug substance. These
can include solvation or hydration products (also known as pseudo-polymorphs) and
amorphous forms.
Potential Impurity: An impurity that theoretically can arise during manufacture or
Impurity
storage. It may or may not actually appear in the new drug substance.
Qualification:
Qualification The process of acquiring and evaluating data that establishes the
biological safety of an individual impurity or a given impurity profile at the level(s)
specified.
Threshold:
Qualification Threshold A limit above (>) which an impurity should be qualified.
Reagent:
Reagent A substance other than a starting material, intermediate, or solvent that is
used in the manufacture of a new drug substance.
Reporting Threshold: A limit above (>) which an impurity should be reported.
Reporting threshold is the same as reporting level in Q2B.
Solvent: An inorganic or an organic liquid used as a vehicle for the preparation of
solutions or suspensions in the synthesis of a new drug substance.
Impurity:
Specified Impurity An impurity that is individually listed and limited with a
specific acceptance criterion in the new drug substance specification. A specified
impurity can be either identified or unidentified.
Material:
Starting Material A material used in the synthesis of a new drug substance that is
incorporated as an element into the structure of an intermediate and/or of the new
drug substance. Starting materials are normally commercially available and of
defined chemical and physical properties and structure.
Impurity:
Unidentified Impurity An impurity for which a structural characterisation has not
been achieved and that is defined solely by qualitative analytical properties (e.g.,
chromatographic retention time).
impurity:
Unspecified impurity An impurity that is limited by a general acceptance criterion,
but not individually listed with its own specific acceptance criterion, in the new drug
substance specification.

7


ATTACHMENT 1
Thresholds
Maximum
Daily Dose1

Reporting
Threshold2,3

Identification
Threshold3

≤ 2g/day

0.05%

0.10% or 1.0 mg per day 0.15% or 1.0 mg per day
intake (whichever is intake (whichever is
lower)
lower)

> 2g/day

0.03%

0.05%

Qualification
Threshold3

0.05%

1

The amount of drug substance administered per day

2

Higher reporting thresholds should be scientifically justified

3

Lower thresholds can be appropriate if the impurity is unusually toxic

8


ATTACHMENT 2
Illustration of Reporting Impurity Results for Identification and Qualification in an
Application
The attachment is only illustrative and is not intended to serve as template how
results on impurities should be presented in an application file. Normally raw data
are not presented.
Example 1:

0.5 g Maximum Daily Dose
Reporting threshold = 0.05%
Identification threshold = 0.10%
Qualification threshold = 0.15%

"Raw"
Result
(%)

0.044
0.0963
0.12
0.1649

Reported
Result
(%)
Reporting
threshold
=0.05%
Not reported
0.10
0.121)
0.161)

Example 2:

Calculated Total Daily
Intake (TDI) (mg) of the
impurity
(rounded result in mg)

Identification
(Threshold 0.10%
exceeded?)

Action
Qualification
(Threshold 0.15%
exceeded?)

0.2
0.5
0.6
0.8

None
None
Yes
Yes

None
None
None1)
Yes1)

0.8 g Maximum Daily Dose
Reporting threshold = 0.05%
Identification threshold = 0.10%
Qualification threshold = 1.0 mg TDI

“Raw”
Result
(%)

0.066
0.124
0.143

Reported
Result
(%)
Reporting
threshold
=0.05%
0.07
0.12
0.14

Calculated Total Daily
Intake (TDI) (mg)
of the impurity
(rounded result in mg)

Action
Identification
Qualification
(Threshold 0.10%
(Threshold 1.0 mg
exceeded?)
TDI exceeded?)

0.6
1.0
1.1

None
yes
yes

None
None1)2)
Yes1)

1) After identification, if the response factor is determined to differ significantly from
the original assumptions, it may be appropriate to re-measure the actual amount of
the impurity present and re-evaluate against the qualification threshold (see
Attachment 1).
2) To verify if a threshold is exceeded, a reported result has to be evaluated against
the thresholds as follows: when the threshold is described in %, the reported result
rounded to the same decimal place as the threshold should be compared directly to
the threshold. When the threshold is described in TDI, the reported result should be
converted to TDI, rounded to the same decimal place as the threshold and compared
to the threshold. For example the amount of impurity at 0.12% level corresponds to a
TDI of 0.96 mg (absolute amount) which is then rounded up to 1.0 mg; so the
qualification threshold expressed in TDI (1.0 mg) is not exceeded.

9


ATTACHMENT 3
Decision Tree for Identification and Qualification
Is impurity greater
than identification
thresholdc?

No

Yes

Structure
identified?

No action

Any
known human
relevant risksd?

Yes

No

Reduce
to not more than
(≤) identification
thresholdc?

Reduce to
safe level

No

Yes

No further
action

Yes

No

Reduce
to not more than
(≤) qualification

Yes

thresholdc?

Greater than
qualification
thresholdc?

No

Consider patient population and duration of use
and consider conducting:
•
Genotoxicity studies (point mutation,
chromosomal aberration)a
•
General toxicity studies (one species, usually
14 to 90 days)b
•
Other specific toxicity endpoints, as
appropriate

Reduce to
safe level

Yes

Yes

Any
clinically
relevant adverse
effects?

10

No

Qualified

No

No action


Notes on Attachment 3
a)

If considered desirable, a minimum screen (e.g., genotoxic potential), should be
conducted.
A study to detect point mutations and one to detect chromosomal aberrations,
both in vitro, are considered an appropriate minimum screen.

b)

If general toxicity studies are desirable, one or more studies should be designed
to allow comparison of unqualified to qualified material. The study duration
should be based on available relevant information and performed in the species
most likely to maximise the potential to detect the toxicity of an impurity. On a
case-by-case basis, single-dose studies can be appropriate, especially for singledose drugs. In general, a minimum duration of 14 days and a maximum
duration of 90 days would be considered appropriate.

c)

Lower thresholds can be appropriate if the impurity is unusually toxic.

d)

For example, do known safety data for this impurity or its structural class
preclude human exposure at the concentration present?

11

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