This document discusses guidelines for classifying, reporting, controlling, and qualifying impurities in new drug substances. It defines types of impurities including organic, inorganic, and residual solvents. It provides thresholds for reporting, identifying, and qualifying impurities based on maximum daily dose. It also outlines specifications for listing impurities and qualification process. Analytical procedures and validation are also addressed.

1. IMPURITIES IN NEW DRUG SUBSTANCES
Q3A(R2)

2. INTRODUCTION
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.

3. DEFINITIONS
Impurity:
Undesirable element or substance that lowers the quality.
Identified Impurity:
An impurity for which a structural characterisation has been achieved.
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).

4. DEFINITIONS
Specified Impurity:
An impurity that is individually listed and limited with a specific
acceptance criterion in the drug substance specification. A specified
impurity can be either identified or unidentified.
Unspecified impurity:
An impurity that is limited by a general acceptance criterion, but not
individually listed with its own specific acceptance criterion, in the drug
substance specification.
Potential Impurity:
An impurity that theoretically can arise during manufacture or storage.

5. HIGHLIGHTS
 CLASSIFICATION OF IMPURITIES
 REPORTING AND CONTROL OF IMPURITIES
 ANALYTICAL PROCEDURES
 REPORTING IMPURITY CONTENT OF BATCHES
 LISTING OF IMPURITIES IN SPECIFICATIONS
 QUALIFICATION OF IMPURITIES

6. CLASSIFICATION OF IMPURITIES
Impurities can be classified into the following categories:
 Organic impurities (process- and drug-related)
 Inorganic impurities
 Residual solvents

7. CLASSIFICATION OF IMPURITIES
 Organic impurities (process- and drug-related)
Organic impurities can arise during the manufacturing process and/or
storage of the drug substance.
 Starting materials
 By-products
 Intermediates
 Degradation products
 Reagents, ligands and catalysts

8. CLASSIFICATION OF IMPURITIES
 Inorganic impurities
Inorganic impurities can result from the manufacturing process.
 Reagents, ligands and catalysts
 Heavy metals or other residual metals
 Inorganic salts
 Other materials (e.g., filter aids, charcoal)

9. CLASSIFICATION OF IMPURITIES
 Residual solvents
Solvents are inorganic or organic liquids used as vehicles for the
preparation of solutions or suspensions in the synthesis of a new drug
substance.

10. REPORTING AND CONTROL OF IMPURITIES
 Organic Impurities
 Identify the possible & potential impurities most likely to arise
during the synthesis, purification, and storage.
 Stress testing (ICH-Q1A on Stability) used to identify potential
impurities arising during storage.
 Any impurity at a level greater than (>) the identification threshold
should be identified.
 Any degradation impurity observed in stability studies at a level
greater than (>) the identification threshold should be identified.

11. REPORTING AND CONTROL OF IMPURITIES
 THRESHOLDS
Maximum Daily
Dose
Reporting
Threshold
Identification
Threshold
Qualification
Threshold
 2g/day 0.05%
0.10% or
1.0 mg per day intake
(whichever is lower)
0.15% or
1.0 mg per day intake
(whichever is lower)
> 2g/day 0.03% 0.05% 0.05%
 Reporting Threshold : A limit above (>) which an impurity should be reported.
 Identification Threshold : A limit above (>) which an impurity should be identified.
 Qualification Threshold : A limit above (>) which an impurity should be qualified.

12. REPORTING AND CONTROL OF IMPURITIES
 Inorganic Impurities
 Inorganic impurities are normally detected and quantified using
pharmacopoeia or other appropriate procedures such as sulphated
ash/Residue on ignition.
 No heavy metals test is recommended due to no longer available
from 1st January 2018.
 Metal(s) used/carryover should be identified and reported as per
pharmacopoeia or ICH-Q3D.

13. REPORTING AND CONTROL OF IMPURITIES
 Elemental Impurities
Metals are know to be toxic and do not provide any therapeutic
benefit so these should be monitored at specified levels.
Potential Sources of Elemental Impurities
 Metal catalysts and metal reagents are used
 Metals being used in reagents, water, starting materials or
excipients
 through interactions with processing equipment
 suspected of being leached from container closure system

14. REPORTING AND CONTROL OF IMPURITIES
Fishbone : Potential Sources of Elemental Impurities

15. REPORTING AND CONTROL OF IMPURITIES
 Metallic Impurities (Contd..)
Based on human health risk ICH classified the elemental impurities as
Class-1
•Significantly toxic
Class-2
•Toxic to a greater or lesser extent based on route of administration
Class-3
•Relatively low toxicity (high Permissible Daily Exposure)
Class-4
•PDE has not been established due to their low inherent toxicity and/or
regional regulations

16. REPORTING AND CONTROL OF IMPURITIES
 Metallic Impurities (Contd..)

17. REPORTING AND CONTROL OF IMPURITIES
 Residual 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.

18. ANALYTICAL PROCEDURES
 Analytical procedures shall be validated and suitable for the detection
and quantification of impurities (ICH Q2A Analytical Validation).
 Reference standards used in the analytical procedures for control of
impurities should be evaluated and characterised for intended use.
 The drug substance can be used as a standard to estimate the levels
of impurities.
 The quantitation limit for the analytical procedure should be not more
than () the reporting threshold.

19. REPORTING IMPURITY CONTENT OF BATCHES
 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 should
be reported.
 Results should be rounded using conventional rules.
 Impurities should be designated by code number or by an appropriate
descriptor, e.g., retention time.
 All impurities at a level greater than (>) the reporting threshold
should be summed and reported as total impurities.

20. LISTING OF IMPURITIES IN SPECIFICATIONS
Drug substance specification should include (where applicable):
 Organic Impurities
 Each specified identified impurity
 Each specified unidentified impurity
 Any unspecified impurity
 Total impurities
 Inorganic impurities
 Residual solvents

21. LISTING OF IMPURITIES IN SPECIFICATIONS
 Individual impurities with specific acceptance criteria should be
included in the specification are referred to as "specified impurities“.
 Note that specified impurities can be identified or unidentified.
 Specified identified impurities should be included along with specified
unidentified impurities estimated to be present at a level greater than
(>) the identification threshold.
 Specified, unidentified impurities should be referred to by an
appropriate descriptive label e.g., “unidentified A", “unidentified with
RRT of 0.9”.
 Unspecified impurity should be included with the acceptance criterion
of not more than () the identification threshold.

22. 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 level of any impurity present in 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.

23. DECISION TREE FOR IDENTIFICATION & QUALIFICATION OF IMPURITIES

24. NOTES
This procedure could not applied for the drug substances:
 Biological/biotechnological
 Peptide
 Oligonucleotide (genetics)
 Radiopharmaceutical
 Fermentation product and semi-
synthetic products derived therefrom,
herbal products
 Crude products of animal or plant origin

25. ? How to fix a limit for specified impurities?
 Limit can be fixed based on ICH Q6A recommended decision tree # 1.

26.  A Limit calculated on thresholds can also adopted.
Maximum Daily
Dose
Reporting
Threshold
Identification Threshold
Qualification
Threshold
 2g/day 0.05%
0.10%
or
1.0 mg per day intake
(whichever is lower)
0.15%
or
1.0 mg per day intake
(whichever is lower)
> 2g/day 0.03% 0.05% 0.05%

27. ? What is skip testing and which parameters can be assumed for skip
testing?
 Definition:
Skip testing is the performance of specified tests at predetermined
intervals, rather than on a batch-to-batch basis with the
understanding that those batches not being tested still must meet all
acceptance criteria established.
Selection of test parameters:
This concept may be applicable to, for example, residual solvents,
metallic impurities and microbiological testing (Q6A & Q3D).

28. ? Why the Identification & Qualification threshold limit is same for the
MDD >2g ?
Maximum Daily
Dose
Reporting
Threshold
Identification
Threshold
Qualification
Threshold
> 2g/day 0.03% 0.05% 0.05%
 The impurity at Identification threshold should be qualified, due to total daily
intake of impurity shall high due to higher dosage, hence the impurities will
be identified and qualified at the level of 0.05%.

29. ? What will be the limit for an impurity unknown & unidentified, if
surviving more than the identification threshold?
 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 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 are exceeded.