Impurities in New Drug SubstancesICH Topic Q3A (R) – Revised Guidelines in Oct-2006.

الجديدة األدوية في الشوائب

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 – 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 IMPURITIESImpurities 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 IMPURITIES3.1 Organic ImpuritiesThe 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 ImpuritiesInorganic 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?;

– 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 Impurities1. Each Specified Identified Impurity2. 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 threshold3. Total ImpuritiesResidual SolventsInorganic Impurities

Limit of impurities

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%

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;