Overview of Ricerca chemical development capabilities.

1. Chemical Development
Capabilities Presentation

2. Centrally Located on America’s North Coast
43-acre site near Cleveland, Ohio
Three main buildings:
• 260,000 square feet
• 125 well-equipped labs
• 4 cGMP kilo labs
• 6 general-purpose kilo labs
• Plant production facility
• 8 isolation/finishing suites
• 43 animal rooms
- 7 BSL2 Rated
• Cell culture suite
• Advanced LC/MS/MS lab

3. Focused on Our Clients’ Needs
• Established in 1986
• Annual growth rate of 20% for last four years
• Completed projects for >450 clients ─ virtual
biotech to global pharma
• Contributed to 8% of all US INDs filed by
biotechnology companies in 2007
• >100 APIs produced – KL and plant scale
• >200 quality audits passed
• Excellent process safety and environmental
compliance record

4. Our People – Experienced, Motivated, Collaborative
• Total company staff of 300
• >35% with Ricerca for >10 years
• Chemical Development (CD) staff
of 93
• Average industrial experience in CD
is >13 years
• >50% of technical staff hold
advanced degrees

5. Primary Services
Drug Development Biology Medicinal Chemistry
• Animal Models of Disease Chemical Development
• Drug Safety Assessment • Process Research &
- Toxicology Development
- Safety Pharmacology • Scale-up & Demonstration
• Pharmacokinetics • Analytical Methods
• Drug Metabolism Development & Compound
Characterization
- In vitro and In vivo
• API Preparation
• Bioanalytical Methods
• Technology Transfer
Development & Sample
Processing • Regulatory Support
• Regulatory Support • Project Management
• Project Management

6. Chemical Development – Our People
Motivated professionals working in
interdisciplinary teams to execute your project
Analytical Process Process Development
Chemistry Chemistry and Engineering
PhD 7 15 1
MS 21 7 3
BS 5 4 4
Technician 5
Operator 21
Total 33 31 29
Years of
Industrial > 13 > 13 > 22
Experience

7. Chemical Development – Our Strengths
• Organic Chemistry – expert in established reactions
with the ability to rapidly master new innovative
technologies
• Analytical Chemistry – diversified analytical
expertise applied to solve problems and support
development programs
• Process Development & Scale-up – rapid conversion
of a discovery route into a commercially-viable
process with demonstration in the pilot plant
• Custom Processing – rapid production of products
to support the development program

8. Chemical Development – Our Services
Process Chemistry
• Chemical route evaluation & selection
• Process research
• Process justification and robustness testing
Process Development & Engineering
• Process development
• Scale-up & demonstration
• Process optimization and cost analysis
• Process validation
• Technology transfer

9. Chemical Development – Our Services
Analytical Chemistry
• Methods development and validation – phase
appropriate
• Reference standard characterization
• Impurity & metabolite ID and characterization
• Forced degradation studies
• Photostability studies
• Storage stability studies
• Salt screening and selection
• Polymorph identification & characterization
• API release testing for research & commercial use

10. Chemical Development – Our Services
API Preparations & Manufacturing
• API preparation for preclinical use
• API preparation for clinical use using cGMP
controls
• Commercial API manufacturing – selective basis
• Preparation of reference standards, impurities, &
metabolites
• Radiolabeled synthesis – using cGMP controls
when needed
Regulatory Support
• CMC section preparation for IND filing
• Regulatory consultation

11. Putting It All Together – Project Management
• Multi-disciplinary team led by Project
Leader
• Project Leader is key client interface –
your “Go To” person
• Direct and frequent communication –
“the good, the bad, and the ugly”
• Direct access to team members
• Rapid and flexible response to project
scope changes

12. Drug Development Program - Phase I
Technology Input – Discovery Route
Preclinical to Phase I
• Chemical route assessment
• Chemical route modification
• API method development – purity (stability-indicating),
impurities, residual solvents, counter-ion, process residues
• API preparation and characterization for use in toxicology
studies
• Phase I process research – safety, reliability, scale-ability
• API preparation and characterization for Phase I clinical trials
• API physical and chemical characterization
• CMC documentation package preparation
IND Granted – Phase I Trials Successful!

13. Drug Development Program - Phase II
Phase II - API Chemical Development and Supply
• Applied process research and development
- Supported by economic modeling
- Establish commercially-viable API production process
• API process scale-up and demonstration
• API methods refinement
• API preparation and characterization for Phase II clinical
trials
• API production technology documentation
• Program is customized to meet specific client requirements
Phase II Trials Successful!

14. Drug Development Program – Phase III
Phase III – Validation and API Supply
• Process Justification – critical process parameters and critical
quality attributes
• Analytical Methods Validation for commercial use
• Process Validation
• NDA Lot Production – 3 Lots
• NDA Lot Storage Stability Program – 3 Lots
• Process Documentation for NDA submission
Commercial Launch and Production

15. Our Quality System
• Full compliance with the ICH Q7A Harmonized
Guidelines for current Good Manufacturing
Practices (GMPs) for Active Pharmaceutical
Ingredients (APIs)
• Excellent compliance record – passed audits by
>200 clients and US FDA
• Passed first US FDA PAI in late 2007
• System incorporates best practices developed
by interaction with our diverse client base
• Our challenge – balance compliance, cost, and
timing

16. Our Tools – Process Chemistry
Process Research Laboratories
• General purpose – mg to kg
• Processing scale - up to 12 liters
• Pressure range: FV to 50 psig
• Temp range: -78 to +200 ºC
Radiochemistry Labs - 4
• Licensed for 3H, 14C, 32P, 35S, 131I, 125I,
99Tc, 36Cl
cGMP Kilo Labs - 4
• HEPA-filtered air system
• Processing scale to 50 liters
• Temperature range: -78 to +200 ºC
• Dedicated single project use
General Purpose Kilo Labs - 6

17. Our Tools – Process Chemistry
Radiochemistry
cGMP Kilo Lab

18. Our Tools – Analytical Chemistry
FDA-, cGMP-, GLP-, ICH-, EPA-, and OPECD- Compliant
• Atomic spectroscopy AA, ETAAS, ICP
• Chromatography GC, LC, IC, GPC
• Microscopy Optical, Polarized, Hot-stage, Raman
• Microbiology LAL, Bioburden
• Molecular FTIR, FT-NMR, GC/MS, Raman
LC-MS/MS, LC-MS, UV
• Thermal analysis DSC, TGA, HSM, XRD
• X-ray analysis Combinatorial, Temp, Humidity
• Physical testing Particle size, Density, pka, logP, logD
• Water analysis KF, DVS, Static vapor
• Solubility Tecan, Safire, Nephelometric

19. Our Tools – Analytical Chemistry
Automated XRD
HPLC Systems
NMR Center

20. Our Tools – Plant Facility
Three-story cGMP facility
• Batch and continuous processing
• Isolation/finishing rooms
• Process and IPC testing labs

21. Our Tools – Plant Reaction Systems
Multipurpose Pilot Plants
Reaction Systems
• 17 reactors
• Total capacity = 17,000 liters
• Sizes from 40 to 3,000 liters
• MOC – GLS and 316SS
• FV to 400 psig
• - 55 to +165°C

22. Our Tools – Processing Support Equipment
Support Equipment
• Separations (Liquid/Liquid)
- Batch distillation – custom
design
- Thin-film/wiped film evaporator
• Separations (Solid/Liquid)
- Centrifuges
- Pressure/vacuum filters
• Flash Chromatography
- 40-kg SG cartridge
• Drying
- Rotary cone
- Vacuum shelf

23. Our Tools – Plant Facility
400-Liter GLS Reaction System
Shelf Dryer in Finishing Suite

24. A Proven Track Record
First Pharma ceutical P roject 19 87
Pharma ceutical P rojects > 220
APIs P roduced > 100
API Int ermedia tes Produce d > 30
APIs a nd Interme diate s Produced > 5 ,50 0 kgs
Technology Transfers 18
Most Complex API Project
16 chemical steps
1 chiral center – 100 kilograms

25. The Benefits We Bring
• Chemistry – Engineering synergy results in
development of robust practical process
• Experienced, motivated, and collaborative staff
that excels at executing challenging projects
• Continuity of API supply – preclinical to
commercial production – all at one site
• Collaborative partnership approach
• Proven capability to develop and transfer
technology to CMO (if needed)
• Commitment to quality and continuous
improvement

26. Project Profile - Background
• Young biotech company
• New indication for licensed-in compound
• Small molecule
• Limited process and analytical information
• Chemical route selected
• Process consisted of 4 reaction/isolation
segments
• Project requirements:
- Supply API for clinical program
- Develop manufacturing process

27. Project Profile - Outcome
• Original process benchmarked and used to
prepare initial API supply
• Process changes identified, tested, and reduced
to practice
• Significant process changes were:
- two processing segments combined into one
- cycle time for limiting step reduced by 5X
- productivity of limiting step increased by 4X
Net effect - throughput increased by 3X

28. Project Profile – Outcome
• Improved process successfully demonstrated at
400- liter scale
• Manufacturing cost reduced by 50%
• API supplied for clinical program through Phase IIB
• Complete analytical methods package developed
• Technology transferred to commercial partner
• Technology successfully demonstrated at 8,000-liter
scale
• Product launched worldwide in 2003