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)

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.
 Guideline for Good Clinical Practice

Q3A(R2)
Document History

First History Date New

Codification Codification
November
2005

Q3 Approval by the Steering Committee under Step 2 and 15 Q3A

release for public consultation. March
1994

Q3A Approval by the Steering Committee under Step 4 and 30 Q3A

recommendation for adoption to the three ICH March
regulatory bodies. 1995

Q3 was renamed Q3A.

Q3A(R) Approval by the Steering Committee of the first Revision 7 Q3A(R1)

under Step 2 and release for public consultation. October
1999

Q3A(R) Approval by the Steering Committee of the first Revision 6 Q3A(R1)

under Step 4 and recommendation for adoption to the February
three ICH regulatory bodies. 2002

Current Step 4 version

Q3A(R2) Approval by the Steering Committee of the revision of 25 Q3A(R2)

the Attachment 2 directly under Step 4 without further October
public consultation. 2006

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 IMPURITIES IN NEW DRUG SUBSTANCES
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

ICH Harmonised Tripartite Guideline...........................................................i

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.............................................................................. ...................9
ATTACHMENT 2...............................................................................................10

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 IMPURITIES IN NEW DRUG SUBSTANCES

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)

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Impurities in New Drug Substances

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 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

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 Impurities in New Drug Substances

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. 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

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Impurities in New Drug Substances

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 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

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 Impurities in New Drug Substances

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
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.

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Impurities in New Drug Substances

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 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
Chemical Development Studies: Studies conducted to scale-up, optimise,
and validate the manufacturing process for a new drug substance.

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.
Extraneous Contaminant: An impurity arising from any source extraneous
to the manufacturing process.
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.

Identified Impurity: An impurity for which a structural characterisation has

been achieved.

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 Impurities in New Drug Substances

Identification Threshold: A limit above (>) which an impurity should be

identified.

Impurity: Any component of the new drug substance that is not the chemical
entity defined as the new drug substance.

Impurity Profile: A description of the identified and unidentified impurities

present in a new drug substance.

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: An agent with a strong affinity to a metal ion.

New Drug Substance: The designated therapeutic moiety that has not been
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.

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 storage. It may or may not actually appear in the new drug
substance.

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.
Qualification Threshold: A limit above (>) which an impurity should be
qualified.
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.
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.
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.
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).

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Impurities in New Drug Substances

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.

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 Impurities in New Drug Substances

ATTACHMENT 1
Thresholds

Maximum Reporting Identification Qualification

Daily Dose1 Threshold2,3 Threshold3 Threshold3
≤ 2g/day 0.05% 0.10% or 1.0 mg per 0.15% or 1.0 mg per
day intake (whichever day intake (whichever
is lower) is lower)
> 2g/day 0.03% 0.05% 0.05%

1
The amount of drug substance administered per day
2
Higher reporting thresholds should be scientifically justified
3

3
Lower thresholds can be appropriate if the impurity is unusually toxic

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 Impurities in New Drug Substances

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" Reported Calculated Total Daily Action
Result Result Intake (TDI) (mg) of the Identification Qualification
(%) (%) impurity (Threshold 0.10% (Threshold 0.15%
Reporting (rounded result in mg) exceeded?) exceeded?)
threshold
=0.05%
0.044 Not 0.2 None None
reported
0.0963 0.10 0.5 None None
0.12 0.121) 0.6 Yes None1)
0.1649 0.161) 0.8 Yes Yes1)
Example 2: 0.8 g Maximum Daily Dose
Reporting threshold = 0.05%
Identification threshold = 0.10%
Qualification threshold = 1.0 mg TDI
“Raw” Reported Calculated Total Daily Action
Result Result Intake (TDI) (mg) Identification Qualification
(%) (%) of the impurity (Threshold 0.10% (Threshold 1.0 mg
Reporting (rounded result in mg) exceeded?) TDI exceeded?)
threshold
=0.05%
0.066 0.07 0.6 None None
0.124 0.12 1.0 yes None1)2)
0.143 0.14 1.1 yes 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.

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 Impurities in New Drug Substances

ATTACHMENT 3
Decision Tree for Identification and Qualification

Is impurity greater
than identification
thresholdc?

Yes No No action

Any
Yes known human Yes Reduce to
Structure relevant risksd?
identified safe level
?

No
No

Reduce
to not more Yes No further
than (≤) action
identification
thresholdc?

Yes
No

Reduce
to not more Yes Greater than No
than (≤) qualification No action
qualification thresholdc?
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

Any
Reduce to Yes clinically No
safe level relevant Qualified
adverse
effects?

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Impurities in New Drug Substances

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 single-dose 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?

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