Part of the MaRS Best Practices Series - Pre-Clinical development workshop Speaker: Rich Donaldson, Director Process Chemistry Ricerca BioSciences Once a clinical lead candidate has been identified, chemical development and biology testing are needed to gather the data required for IND filing. This work is best completed by coordination between chemistry and biology components. On the chemistry side, process research to develop a chemistry route that is sufficiently robust to synthesize test article for biology is the first requirement. Successful efficient scale-up to produce kilogram quantities of non-GMP and cGMP API is the ultimate goal. We explore how these various programs fit together from the chemistry perspective. Also some discussion of what analytical chemistry is needed for chemistry and biology support.

1. Chemical Development
Lead Candidate to IND, and Beyond
Richard Donaldson, Ph.D.
VP Chemical Development
Ricerca Biosciences, LLC
May 23, 2007

2. What is Drug Development?
Idea
Biological
Target
Development
Lead
Candidate
Chemical
Compound

3. From IP to IND
Development
Discovery
Chemistry Chemistry
Discovery Development
Biology Biology

4. Development Chemistry, IND
Timeline: 9-14 Months to CMC Section
•
Scalable Process Identified
•
Analytical Methods Developed
•
Tentative Specifications Determined
•
Regulatory Starting Materials Identified
•
Stability
•

5. DC, IND, Month 2
Process Benchmarking
•
Demonstration Sample (Preliminary Tox)
•
AC Method Development and Qualification
•
Reference Standard Prep and Characterization
•
Salt Screen Study (Optional)
•
Polymorph Screen (Optional)
•

6. DC, IND, Month 4
Toxicology Lot Preparation (1-3 Kg)
•
Analytical Methods Verified (GLP Release)
•
Tentative Specifications Verified
•
28-Day Tox. Studies Start
•
Regulatory Strategy in Place
•

7. DC, IND, Month 8
GMP-Grade Lot Preparation (5-10 Kg)
•
Stability-Indicating HPLC Method Developed
•
Impurity Profile Determined
•
Residual Solvents Method Developed (ICH)
•
GMP Analytical Release Testing
•

8. DC, IND, Month 9
GMP-Grade Lot Stability Study Start (1-3 Yr)
•
Chemistry Campaign Report Completed
•
IND CMC Section Completed
•
IND Filed
•

9. IND to NDA R&D
Clinical R&D
•
Development Chemistry
•
Regulatory Compliance
•
Continued Biology Testing
•

10. IND to NDA Issues
Manufacturing Cost
•
Process Scalability
•
Analytical Method Development
•
Stability
•
Packaging and Storage
•

11. DC, Phase I/II
Process Research (Robust Process, Plant)
•
Critical Variables Identified
•
Radiosynthesis, ADME
•
Impurities and Metabolites Synthesis
•
Phase II Campaign (10-50 Kg, Plant)
•
API Campaign Documentation
•

12. DC, Phase I/II Potential Showstoppers
Osmium Tetroxide, Alkyl Mercury, etc. (Toxic,
•
Waste Issues)
Benzene, aziridine, etc. (Carcinogenic)
•
Azides, Dinitroaromatics, etc. (Shock Sensitive)
•
Carbon Disulfide, Methylhydrazine, etc. (Extreme
•
Flammability)

13. DC, Phase I/II Process Alternatives
cat OsO4, NaIO4
O
OH
O
OH
Benzene
HN
+
-H2O
O N
Options: Toluene, Cyclohexane

14. Analytical DC, Phase I/II
Analytical Methods Upgraded
•
Impurities and Metabolites ID
•
Analytical Methods Documentation
•
Drug Product Formulation Studies
•

15. Phase I/II Common Issues
New Impurity
•
High Residual Solvent, Solvate or Entrainment
•
Trace Metal Impurities, Pd, Fe, Ni, Etc.
•
Scalability Issues, Temperature, Agitation, Etc.
•
Raw Material Sourcing, Quality
•
Rigorous QC Testing
•

16. DC, Phase III
Validation Protocol
•
Critical Variable Ranges Determined
•
Development Report
•
Process Validation, 3 Lots at >10% Scale
•
Campaign Documentation
•
Pre-Approval Inspection
•

17. NDA Approval - The Ultimate Goal
FDA Approval
•
Commercial Sourcing Strategy
•
Commercial Launch Amounts
•
Raw Material Sources Identified
•
Commercial Partner in Place
•

18. Keys to Drug Development Success
Anticipate and Expect Problems
•
Never too Early to Plan Ahead
•
Maintain Flexibility
•
Trade off Between $$ and Timing
•
Plan for Success
•

19. Chemical Development
Lead Candidate to IND, and Beyond
Richard Donaldson, Ph.D.
VP Chemical Development
FEBRUARY 5, 2007