This document provides guidance on reporting and controlling impurities in new drug substances. It discusses the classification, identification, and qualification of organic, inorganic, and residual solvent impurities. Key points covered include identification thresholds for impurities, qualification thresholds, reporting thresholds, analytical procedures for detecting impurities, and reporting impurity levels in batches. The document also describes how to list impurities in specifications and evaluate impurities using a decision tree when thresholds are exceeded.
2. 1 Introduction to Q3A (R2).
2 Glossary
3 Classification of Impurities.
4 Rational for the Reporting and Control of Impurities.
5 Analytical Procedure.
6 Reporting Impurity Content of Batches.
7 Listing Of Impurities in Specification.
8 Qualification Of Impurities.
9 Decision Tree.
3. It provide guidance about the content of impurities in new
drug substances.
Biological/biotechnological, radiopharmaceutical, herbal
products, and crude products of animal or plant origin are
not included in this guidelines.
There are two aspects of impurities in new drug substances
1.Chemistry Aspects: include classification and
identification of impurities, report, and a brief discussion of
analytical procedures
2. Safety Aspects: it include qualifying those impurities that
were not present, or were present at lower levels, in batches
used in safety and clinical studies.
4. Identification Threshold: A limit above (>) than the
impurity identified.
Qualification Threshold: A limit above (>) which an
impurity should be qualified.
Reporting Threshold: A limit above (>) which an
impurity should be reported.
Ligand: An agent with a strong affinity to a metal ion.
Reagent: A substance other than a starting material,
intermediate, or solvent that is used in the
manufacture of a new drug substance
6. They arise during manufacturing process
During storage of the new drug substance.
can be identified or unidentified,
volatile or non-volatile,
Degradation products,
Reagents, ligands and catalysts.
7. These can result from the manufacturing process.
They are normally known and identified
They include: Reagents, ligands and catalysts,
Heavy metals or other residual metals, Inorganic
salts, Other materials (e.g., filter aids, charcoal)
Residual solvents
Solvents are inorganic or organic liquids used as vehicles
in synthesis of a new drug substance.
8. 1.Organic Impurities :
(application include)
How impurity is arise, it is during the synthesis, purification
or storage of the new drug substance.
Laboratory studies conducted to detect impurities in the new
drug substance.
Test results of batches manufactured to determine impurity
profile.
When identification of an impurity is not feasible, a summary
of the laboratory studies demonstrating the unsuccessful
effort should be included.
9. 2.Inorganic impurities
They are normally detected by using
pharmacopoeia and their acceptance criteria
should be based on pharmacopoeia
3. Solvents
The control of solvents residue in the
manufacturing process for the new drug
substance should be according to the ICH
Q3C Guideline for Residual Solvents.
.
10. ◦ The application should include analytical
procedure for the detection and quantification of
impurities
◦ Organic impurity levels can be measured by
comparing the results with an appropriate
reference standard.
11. ◦ All Analytical results of produced batches including clinical batch ,safety batch ,
stability batch and commercial batch should be provided in the application
◦ Quantitative results should be presented numerically, and not in general terms
such as “complies”, “meets limit” etc.
◦ 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%).
◦ 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
12. ◦ The specification for a new drug substance
should include a list of impurities.
◦ Those impurities which has specific acceptance
criteria in the specification are referred "specified
impurities“.
13. ◦ Qualification is the process for evaluating
impurity for biological safety or establish a
impurity profile at the specified levels.
◦ 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.
◦ The "Decision Tree for Identification and
Qualification" describes considerations for the
qualification of impurities when thresholds are
exceeded.
