Download - Chemical Development
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Chemical DevelopmentLead Candidate to IND, and Beyond
Richard Donaldson, Ph.D.VP Chemical Development
Ricerca Biosciences, LLC
May 23, 2007
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What is Drug Development?
BiologicalTarget
ChemicalCompound
Lead
Idea
DevelopmentCandidate
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From IP to IND
DiscoveryChemistry
DiscoveryBiology
DevelopmentChemistry
DevelopmentBiology
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Development Chemistry, IND
• Timeline: 9-14 Months to CMC Section
• Scalable Process Identified
• Analytical Methods Developed
• Tentative Specifications Determined
• Regulatory Starting Materials Identified
• Stability
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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)
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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
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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
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DC, IND, Month 9
• GMP-Grade Lot Stability Study Start (1-3 Yr)
• Chemistry Campaign Report Completed
• IND CMC Section Completed
• IND Filed
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IND to NDA R&D
• Clinical R&D
• Development Chemistry
• Regulatory Compliance
• Continued Biology Testing
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IND to NDA Issues
• Manufacturing Cost
• Process Scalability
• Analytical Method Development
• Stability
• Packaging and Storage
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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
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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)
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DC, Phase I/II Process Alternatives
O
cat OsO4, NaIO4
O
OH
OH
O N
Benzene
-H2O
HN+
Options: Toluene, Cyclohexane
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Analytical DC, Phase I/II
• Analytical Methods Upgraded
• Impurities and Metabolites ID
• Analytical Methods Documentation
• Drug Product Formulation Studies
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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
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DC, Phase III
• Validation Protocol
• Critical Variable Ranges Determined
• Development Report
• Process Validation, 3 Lots at >10% Scale
• Campaign Documentation
• Pre-Approval Inspection
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NDA Approval - The Ultimate Goal
• FDA Approval
• Commercial Sourcing Strategy
• Commercial Launch Amounts
• Raw Material Sources Identified
• Commercial Partner in Place
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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
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Chemical DevelopmentLead Candidate to IND, and Beyond
Richard Donaldson, Ph.D.VP Chemical Development
FEBRUARY 5, 2007