ICH Q3 (A) IMPURITIES IN NEW DRUG SUBSTANCES

EXECUTIVE SUMMARY OF ICH Q3 (A)

1. INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE IMPURITIES IN NEW DRUG SUBSTANCES Q3A(R2) By Mahrukh Mughal ( M.Phil 2021) Hamdard University Karachi Pakistan

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. Contents

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 . 1.Introduction

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 2. Defination

5. 03 types of impurities Organic impurity Inorganic impurity Residual solvents 3. CLASSIFICATION OF IMPURITIES

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. Organic impurity(process- and drug-related)

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. Inorganic impurities

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. 4.RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES

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. 4.RATIONALE FOR THE REPORTING(cont..) .

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. 5.ANALYTICAL PROCEDURES

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 6.REPORTING IMPURITY CONTENT OF BATCHES

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“. 7. LISTING OF IMPURITIES IN SPECIFICATIONS

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. 8.QUALIFICATION OF IMPURITIES

14. 9.Decision Tree

15. The End