1.

ICH Q3AR Guideline

Impurity Testing Guideline
Impurities in New Drug Substances
ICH Step 5
Comments for its application

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Impurities in New Drug Substances ICH Q3AR

1. Preamble
The Guideline provides guidance for registration application on the content and
qualification of impurities in new drug substances produced by chemical synthesis.
Does not apply for new drug substances used during the clinical research.
Impurities are addressed from two perspectives:
Chemical Aspects
classification
identification
report generation
setting specification
analytical procedures
Safety Aspects
Guidance for qualifying impurities
- which were not present
- were present at substantially lower levels
in batches of a new drug substance used in safety and clinical studies

2. Classification of Impurities

Classification

Organic impurities (process- and drug -related)

Inorganic impurities

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

Starting materials
By-products
Intermediates
Degradations products
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Reagents, ligands, catalysts

Inorganic impurities are normally known and identified.

Excluded
Excluded are extraneous contaminants which should not occur and are generally
addressed as GMP issues: polymorphic form, a solid state property, enantiomeric
impurities.

3.

Rationale for Reporting and Control Impurities

.

3.1

0rganic Impurities

Summary of actual and potential impurities most likely to arise during

synthesis,
purification,
storage.
The summary should be based on scientific appraisal of
chemical reactions involved in synthesis,
impurities associated with raw materials and
possible degradation products.
Included only those that may reasonably expected.
Summary of laboratory studies conducted to detect impurities in new drug
substance
Summary should include test results of batches:
manufactured in development process
from proposed commercial process.
of stress testing used to identify potential impurities arising during storage
comparison impurity profile development and commercial process

3.

Rationale for Reporting and Control Impurities

Studies conducted to characterise structure of actual impurities present at level

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( > ) than identification threshold, response factor of drug substance, described.

Any impurity ( > ) than identification threshold in any batch manufactured by

proposed commercial process should be identified.

Degradation products ( > ) than identification threshold observed at recommended storage conditions should be identified.

If identification not feasible, summary of laboratory studies of unsuccessful effort

should be included in application.

Identification of ( ) identification threshold generally not necessary

3. Rationale for Reporting and Control of Impurities

3.2

Inorganic Impurities

Detected and quantitated using pharmacopoeial or other appropriate

procedures. Inclusion or exclusion of inorganic impurities should be
discussed.

3.3

Solvents

According pharmacopoeial procedure.

4. Analytical Procedures

Requirements for analytical procedures

Documented evidence that the analytical procedures are validated and suitable
for detection and quantitation of impurities.
Differences in analytical procedures used during development and proposed for
commercial product should be discussed.
Quantitation limit for analytical procedure not more than ( ) reporting threshold

Organic impurity levels can be measured by:

comparison of analytical response for an impurity to that
- of an appropriate reference standard
- of the new drug substance itself.

Reference standards used should be evaluated and characterised according to

intended use.
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It is considered acceptable to use drug substance to estimate levels of impurities.

Are response factors not close, applicable provided a correction factor is applied
or impurities are overestimated.
Acceptance criteria and analytical procedures used to estimate identified or
unidentified impurities are often based on analytical assumptions, they should be
discussed.

5. Reporting Impurity Content of Batches

Analytical results of all batches used for

clinical
safety
stability testing
representative of proposed commercial process.

Presentation of quantitative results

Any impurity > reporting threshold
and total impurities reported with analytical procedures
Below 1.0% two decimal places ( 0.06%) above 1.0% one decimal place (1.3%)
Rounding using conventional rules

Impurities should be designated by

code number
or an appropriate descriptor e.g. retention time.
All impurities (>) reporting threshold should be summed and reported as total
impurities

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5. Reporting Impurities Content of Batches

If analytical procedures change during development, reported results should

be linked with the procedure used with appropriated validation information.
Representative chromatograms should be provided. Representative impurity
profiles (e.g. spiked samples) should be available if requested

For each batch, 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

Specifications
Specifications should include a list of impurities.
Prediction of those likely to occur in commercial product
- Stability studies
- Chemical development studies
- Routine batch analyses
Those with specific acceptance criteria are referred to as specified impurities.
Specified impurities can be
identified or
unidentified
and should be individually listed in the specifications.
A rationale for the inclusion or exclusion in the specification should be presented.
Discussion of the impurity profiles observed in the safety and chemical development
batches together with a consideration of the impurity profile of material
manufactured by proposed commercial process.

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6.

Listing of Impurities in Specifications

Specified identified impurities should be included

along with specified unidentified impurities estimated to be
to be present ( > ) identification threshold
For unidentified impurities the procedure used and
assumptions made in establishing the level of the impurity
should be clearly stated. Unidentified impurities should be
referred e.g. unidentified A.
General acceptance criteria of ( ) identification threshold for any unspecified impurity
Acceptance criterion for total impurities
Limits not higher than level justified
by safety data, no lower than achievable by the
manufacturing process and analytical capability.
Impurity specifications should be based on data of actual
batches allowing sufficient latitude to deal with
manufacturing and analytical variation and stability
characteristics.

6.

Listing if Impurities in Specifications

Specification should include:

Organic impurities
each specified identified impurity
each specified unidentified impurity
any unspecified impurity, with an acceptance criterion of ( )
identification threshold
total impurities

Residual Solvents:

Inorganic impurities

Mass balance as far as possible.

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7. Qualification of Impurities
Qualification
Establishing the biological safety of an individual impurity or a given impurity profile
at levels specified.
Any impurity tested in safety or clinical studies
considered qualified.
Impurities which are metabolites present in animal or
human studies are qualified.

Thresholds
Maximum
Daily Dose

Reporting
Threshold

2g/day

0.05%

Identification
threshold

Qualification
threshold

0.10% or 1.0 mg /day 0.15% or 1.0 mg /day

intake (whichever is intake (whichever is
lower)
lower)

Higher or lower threshold limits based on scientific rationale including drug class effects
and clinical experience.

adverse reaction in patients (lower)

patient population }
higher
drug class effects }
higher
clinical experience }
higher

7.

Qualification of Impurities II

Qualification when thresholds are exceeded

If threshold exceeded, Decision Tree for Safety Studies.

Studies will depend on number of factors

- patient population
- daily does
- route and duration of drug administration

Studies conducted on new drug substance, containing the impurities.

Studies with isolated impurities are acceptable.

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7.

New Impurities

New impurity > identification threshold should be identified

New impurity > qualification threshold should be qualified
Threshold exceeded Decision Tree for Safety Studies.
New drug containing impurity compared with previously qualified material,
Studies using isolated impurity are acceptable

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