Chemical DevelopmentLead Candidate to IND, and Beyond

Richard Donaldson, Ph.D.VP Chemical Development

Ricerca Biosciences, LLC

May 23, 2007

What is Drug Development?

BiologicalTarget

ChemicalCompound

Lead

Idea

DevelopmentCandidate

From IP to IND

DiscoveryChemistry

DiscoveryBiology

DevelopmentChemistry

DevelopmentBiology

Development Chemistry, IND

• Timeline: 9-14 Months to CMC Section

• Scalable Process Identified

• Analytical Methods Developed

• Tentative Specifications Determined

• Regulatory Starting Materials Identified

• Stability

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)

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

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

DC, IND, Month 9

• GMP-Grade Lot Stability Study Start (1-3 Yr)

• Chemistry Campaign Report Completed

• IND CMC Section Completed

• IND Filed

IND to NDA R&D

• Clinical R&D

• Development Chemistry

• Regulatory Compliance

• Continued Biology Testing

IND to NDA Issues

• Manufacturing Cost

• Process Scalability

• Analytical Method Development

• Stability

• Packaging and Storage

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

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)

DC, Phase I/II Process Alternatives

O

cat OsO4, NaIO4

O

OH

OH

O N

Benzene

-H2O

HN+

Options: Toluene, Cyclohexane

Analytical DC, Phase I/II

• Analytical Methods Upgraded

• Impurities and Metabolites ID

• Analytical Methods Documentation

• Drug Product Formulation Studies

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

DC, Phase III

• Validation Protocol

• Critical Variable Ranges Determined

• Development Report

• Process Validation, 3 Lots at >10% Scale

• Campaign Documentation

• Pre-Approval Inspection

NDA Approval - The Ultimate Goal

• FDA Approval

• Commercial Sourcing Strategy

• Commercial Launch Amounts

• Raw Material Sources Identified

• Commercial Partner in Place

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

Chemical DevelopmentLead Candidate to IND, and Beyond

Richard Donaldson, Ph.D.VP Chemical Development

FEBRUARY 5, 2007