chemical development
DESCRIPTION
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.TRANSCRIPT
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