1. Risk Based CMC Review Advisory Committee for Pharmaceutical Science October 22, 2003 Vilayat A. Sayeed, Ph.D. OGD, FDA

2. Risk Based CMC Review General Principle Scope Drug Substance Attributes for risk qualification Drug Product Attributes for risk qualification

3. General Principle Followed for Developing DS/DP Attributes Probability of Detection Complexity Complexity* Low High Low DS/DP characterization *DS/DP characterization Mechanism of product performance Mechanism of product performance Manufacturing technology Manufacturing technology Medium High Medium Low Risk

4. Risk Based CMC Review Scope Eligible: Synthetic Drug substances Not Eligible: Radiopharm Oligonucleotides Oligonucleotides Peptides Peptides Fermentation Fermentation Biotech Biotech Semi-Synthetic Semi-Synthetic Plant/Animal Origin Plant/Animal Origin

5. Risk Based CMC Review Scope IR oral solids oral solutions non sterile topical solutions non sterile topical solutionsand sterile solution of simple salts

6. Risk Based CMC Review Drug Substance Attributes b Physical and Chemical Characterizations b Specification b Stability

7. Risk Based CMC Review Drug Substance Attributes Physical and Chemical Characterizations b Structural and Physicochemical properties are well known b Characterization can be achieved by commonly available analytical techniques eg: UV, IR, NMR, MS, elemental analysis

8. Risk Based CMC Review Drug Substance Attributes Specification Conforms to Contemporary Standards eg: b FDA Guidance b ICH Guidance Impuritues: b Indentified b Controlled b Qualified

9. Risk Based CMC Review Drug Substance Attributes Stability b Stable at room temp b Stored at CRT b Stable to light, Air & Moisture b Degradation mechanism is known and profile well controlled. b Analytical method stability indicating and validated

10. Risk Based CMC Review Drug Product Attributes Marketing History Marketing History Dosage form Characteristics Release and Stability Assessment

11. Risk Based CMC Review Drug Product Attributes Marketing History Has the DP been on market for five years, with two years real time stability data available on a minimum of three commercial batches?

12. Risk Based CMC Review Drug Product Attributes Dosage form Characteristics Dosage Form Strength Physical Attributes

13. Risk Based CMC Review Drug Product Attributes Strength IR Solids: Strength per unit NLT 1 mg or 1% w/w Oral/topical solutions drug substance concentration in drug vehicle is LT 50% and sterile solutions of simple salts drug substance concentration in drug vehicle is LT 75%

14. Risk Based CMC Review Drug Product Attributes Differences in physical attributes of ingredients used in manufacture of drug product are reported to have no impact on product performance. Physical Attributes

15. Risk Based CMC Review Drug Product Attributes Release and Stability Assessment Release & Stability Specifications Product Degradation Profile Product Storage

16. Risk Based CMC Review Drug Product Attributes Release and Stability Specification Drug product specification conform to contemporary standards.

17. Risk Based CMC Review Drug Product Attributes Product Degradation Profile Drug product degradation profile predictable and degradants are controlled. No know toxic impurities or degradants

18. Risk Based CMC Review Drug Product Attributes Product Storage The drug product stored at CRT and required no special packaging.

19. Risk Based CMC Review Drug Product Attributes Drug product to qualify as candidate for low risk assignment Marketing History Dosage form Characteristics Release and Stability Assessment

20. Acknowledgement Drug Substance Working Group b Eric Duffy b Paul Schwartz b Marie Kowblansky b Scott Furness b Mayra Pineiro-Sanchez b Rao Puttagunta b Haripada Sarker Drug Product Working Group b Devinder Gill b Dan Boring b Liang Zhou b Sheldon Markofsky