Transcript REGULATORY AFFAIRS

‫الشوائب في األدوية الجديدة‬
Impurities in New Drug Substances
ICH Topic Q3A (R) – Revised Guidelines in Oct-2006.
CONTENTS
1. Preamble
2. Classification of Impurities
3. Rationale for the Reporting and Control of Impurities
3.1 Organic Impurities
3.2 Inorganic Impurities
3.3 Solvents
4. Analytical Procedures
5. Reporting Impurity Content of Batches
6. Specification Limits for Impurities
1. Preamble
Impurities in new drug substances are addressed from two
perspectives:
Chemistry Aspects includes
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classification and identification of impurities,
report generation,
setting specifications, and
a brief discussion of analytical procedures;
and
Safety Aspects includes specific guidance for qualifying impurities
that were not present in batches of new drug substance used in
safety and clinical studies and/or impurity levels substantially
higher than in those batches. Threshold limits are defined at or
below which, qualification is not needed.
2. CLASSIFICATION OF IMPURITIES
Impurities may be classified into the following
categories:
– Organic Impurities (Process- and Drug-Related)
– Inorganic Impurities
– Residual Solvents
Source of Impurities
impurities may arise during the manufacturing process
and/or storage of the new drug substance
[a] Organic Impurities; They may be identified or
unidentified, volatile or non-volatile, and include
· Starting Materials
· By-Products
· Intermediates
· Degradation Products
· Reagents, Ligands and Catalysts
Solvents are organic or inorganic liquids used during the
manufacturing process
[B] Inorganic impurities; may derive from the
manufacturing process. They are normally known
and identified and include:
· Reagents, Ligands and Catalysts
· Heavy metals or other residual metals
· Inorganic Salts
3. RATIONALE FOR THE REPORTING
AND CONTROL OF IMPURITIES
3.1 Organic Impurities
The applicant should summarize those actual and potential
impurities most likely to arise during the synthesis,
purification, and storage of the new drug substance.
The applicant should summarize 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
results of intentional degradation studies used to identify
potential impurities arising during storage.
3.2 Inorganic Impurities
Inorganic impurities are normally detected and quantitated
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 specifications should be discussed.
Limits should be based on pharmacopoeial standards or
known safety data.
4. ANALYTICAL PROCEDURES
Organic impurity levels can be measured
by a variety of techniques, including;
those which compare an analytical
response for an impurity to that of an
appropriate reference standard or to the
response of the new drug substance
itself.
- Use Diode-Array Detector
- Use LC/MS or GC-MS
Assay of impurities, how?
• [1] Known impurities; use RS
substance sold by USP or EuPharm. Or
use working standard
• [2] Unknown impurities; measured as if
it is the principle drug (use correction
factor or not)
5. REPORTING IMPURITY CONTENT OF BATCHES
• Batches of  Clinical study, safety, stability studies.
• Report what?;
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Identified impurity(ies)
Un-identified impur.
Total impurities
Analytical method used (with validation)
Tabulated data (impurities amount)
Representative chromatogram(s) to show impurity peak(s)
and the anal. method performance (impu-separation)
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. SPECIFICATIONS FOR IMPURITIES
Obtain Specs of Known and unknown
impur. From;
[1] USP or BP
[2] Drug supplier/manufacturer
Limit of impurities  from USP/BP or
supplier, +Chromatogram +and method
of separation. (Potential impurities).
The new drug substance specifications should
include, where applicable,
limits for:
Organic Impurities
1. Each Specified Identified Impurity
2. Each Specified Unidentified Impurity at a level greater
than (>) the qualification/identification threshold
· Any Unspecified Impurity, with a limit of not more than (_) the
qualification/identification threshold
1. Total Impurities
Residual Solvents
Inorganic Impurities
Limit of impurities
As per ICH Guidelines;
[1] Get the cited limit of impurities (known, unknown,
total) from USP or BP or EurPharm
[2] From Supplier or manufacturer
[3] If not available in official monographs apply the
below rule;
Maximum Daily Dose
Qualification Threshold and
Identification Threshold
Reporting Threshold *
2 g / day
0.1% or 1 mg per day intake
(whichever is lower)
0.05%
>2 g / day
0.05%
0.03%