1. 1 FDA Guidance for Industry: ANDAs: Impurities in Drug Substances www.Rx-360.org Published by US FDA’s Center for Drug Evaluation and Research June 2009

2. 2 FDA, CDER Guidance on Impurities in Drug Substances Purpose: –Applicable to drug substances produced by chemical synthesis when submitting: Original abbreviated new drug application (ANDAs) Drug master files (DMFs) including type II DMFs ANDA supplements for changes in synthesis or processing of drug substance –Provide guidance for establishing acceptable criteria for impurities –Provides consistency with ICH Q3A guidance for NDAs –Out of scope Fermentation products Radiopharmaceuticals Products of animal origin Biologics/Biotechnological Herbal products Peptides Semisynthetic products derived from fermentation products Oligonucleotide www.Rx-360.org

3. 3 Guidance Content Identification of impurities & acceptable criteria –Listing impurities in Drug Substance Specifications –Setting acceptable criteria for impurities Qualification of Impurities –Qualification thresholds –Qualification procedures www.Rx-360.org

4. 4 Definitions 1 Drug Substance Definition: an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates use in the synthesis of such ingredient. 2 Qualification: The process of acquiring and evaluating data that establish the biological safety of an individual impurity or a given impurity profile at the level(s) being considered. 1 21CFR314.3 2 Guidance for Industry: ANDAs: Impurties in Drug Substances www.Rx-360.org

5. 5 Identification of Impurities Listing of Impurities in Drug Substance Specifications based on: - Stability studies - Chemical development studies - Routine batch analyses Must be based on batch(es) manufactured by the proposed commercial process Rationale for inclusion as well as exclusion www.Rx-360.org

6. 6 Identification of Impurities-continued Types of impurities: www.Rx-360.org Type of Impurities: Identified Impurity? Unidentified Impurity? 1 Unspecified impurity < identified threshold? Total Impurities Organic Residual Solvents Inorganic impurities 1 ICH Q3A

7. 7 Impurity specified in USP? Monograph exists in the USP? Yes: - Utilize limit specified in monograph (official compendial limit) No: - Qualify the impurity - Level based on either reference list drug (RLD) or qualified level Acceptable Criteria for Impurities www.Rx-360.org

8. 8 Qualification of Impurities Qualified only if at least one of the following met: - The observed level and proposed acceptance criterion for the impurity < RLD - Impurity is a significant metabolite of the drug substance - The observed level and the proposed acceptance criterion adequately justified by scientific literature - The observed level and proposed acceptance criteria < safe levels from toxicity studies www.Rx-360.org

9. 9 Thresholds Based on maximum daily dose of drug substance Outlined in Q3A(R) Procedures Comparative Analytical Studies (CAS) Scientific Literature & Significant Metabolites (SLSM) Toxicity Studies (CAS & SLSM preferred) Qualification Thresholds & Procedures www.Rx-360.org

10. 10 Factors that could allow acceptance of studies to qualify the impurity: - Patient population - Daily dose - Route & duration of drug administration Qualification Procedure www.Rx-360.org

11. 11 Martin VanTrieste Advisory Board info@Rx-360.org +1 (805) 313-1524 www.Rx-360.org For More Information Thank you