Small-molecule Drug Development: Selecting And Working With Contract Manufacturing Organizations (CMOs).

1. Small-molecule Drug Development: Selecting And Working With Contract Manufacturing Organizations (CMOs). James M. Hamby, R.Ph., Ph.D. Director of Business Development Ash Stevens, Inc. 18655 Krause Street Riverview, MI 48103 Tel: (734) 282-3370 ext. 1144 Email: jhamby@ashstevens.com Web: www.ashstevens.com

2. Ash Stevens Inc.:an Established, Stable API Contractor • Early-Stage Development Through Commercial Manufacturing Of APIs • Eleven FDA Approved Commercial APIs: • Velcade (5/03), Vidaza (5/04), and Clolar (12/04) • cGMP Compliant Operations • Provider Of Contract Research Services To The Federal Government (NIH &NCI) • Dun and Bradstreet Rating of “4A1”

3. Chemistry Milestones for an NDA Phase II/III Parametric Studies Validated Analytical Methods; Starting Material, Intermediate, and Product Specifications; Packaging FDA PAI One Validation Batch Complete Protocol for Two Additional Batches Mfg. Batch Definition Unit Operations Scale of Batch Development Candidate Approval to Market Phase I “Manageable” Process Process Hazard Review Cleaning Procedures Scientifically Sound Analytical Methods Stability Program Stability Studies Including Three Lots of API NDA Filing Validatable Process One Batch Prior To Filing Development Report Impurities Identified 12 Months Stability – 3 Batches (API Shipping and Storage Only)

4. cGMP Compliance • ICH Guidelines And US 21 CFR 210-211 Regulations Mandate That The Sponsor Company Is Responsible For Assuring Compliance With cGMP Regulations • Therefore, It Is Incumbent Upon The Sponsor To Ensure That Third Party Generated Data Is Of The Highest Quality And That The Sponsor Can Defend The Integrity Of The Data And The Process

5. Managing Drug Development • Ideal Situation Is to Have An In-House Drug Development Team Experienced At Working With CMOs • CMC Consultants And CRO’s • Experienced CMO (Turnkey)

6. Key Steps In Identifying A CMO • Due Diligence-Identifying Potential CMO Partners • Preparing the Technical Package (RFPs) • Evaluating the Proposal • Site Visit • Quality Systems Audit

7. Due Diligence • Provide Enough Time To Do Thorough Due Diligence • Avoid “I Need It Yesterday” And Unrealistic Expectations • Understand Your Project the Process, Timelines And Costs • Chemical Manufacturing Tradeshows (InformEx, ChemOutsourcing) • Rep Visits

8. Due Diligence • Good Fit For Project Needs And Strategy • Capacities And Capabilities • Reputation For Quality And Delivering On Time and On Budget (# Of NCE API Approvals, References) • Regulatory Inspection History • Financial Stability • Location And Accessibility

9. The Request For Proposal (RFP) Technical Package

10. The Request For Proposal (RFP): • CDA In Place • Share All Pertinent Information (Better Quality Quote) • Provide Full Experimental Details And Yields • Clearly Communicate Required Deliverables, Quantities, And Timelines

11. The Request For Proposal (RFP): • Describe Intended Use Of Material (e.g. 500g For GLP Tox. And 3 Kg cGMP For Phase I Studies) • Define General Purity Specifications For Deliverables (e.g. >95% Pure For GLP Tox. Material)

12. Proposal/Quote Assessment

13. Proposal/Quote Assessment • Comments And Strategy Section • All Costs and Work Clearly Defined • Risk-Based Proposals • Start Date • Intellectual Property

14. Early-Stage Project: Initial Tasks • Process Feasibility and Evaluation • Preliminary Process Development • Demonstration Batch (250-500g, non-GMP) • Initial Phase I GMP Batch (1-5 Kg) • Analytical Development

15. CMO: Site Visit

16. CMO Site Visit • Meet “Key” People, Explain Expectations And Requirements, Timelines (A Team Vs. B Team) • Project Manager Key Person • Communication & Resolution Of Problems • EHS&S, Housekeeping & Cleanliness • Tech Transfer: Scale-up From Grams To Kilograms, non-GMP vs. GMP • Hours Of Operation And Vacation Schedules • Quality Systems (Audit?)

17. CMO Site Visit • Modern Equipment And Facility, But Be Conscious Of The Wow Factor • Confidentiality: Chemical Structures Written on Hoods or Glassware, Client Names Or Client Compound Numbers Visible, Numbers Written On Hand or Scraps Of Paper, • How Busy Is The CMO, Are They Flexible • How Much Does the CMO Value Your Business (Win/Win)

18. Early-Stage Strategy: Proof Of Concept ASAP And Exit/Partner

19. Early-Stage Development Project • Developing An In-licensed Drug Or A Drug From In-house Discovery Effort • Discovery Route: Milligrams To A Few Grams • Strategy: Proof Of Concept; Find A Development Partner Or Sell Company • 1-5 Kg GMP Required For Phase 1-2b (IND Path) • Partner: Approval ASAP And Commercialize (NDA Path)

20. Early-Stage Development Project • Sponsor Strategy: Hammer Out GMP API By The Discovery Route To Save Time And Money. • Often A Risky Strategy • Rarely Is The Discovery Route Amenable To GMP Scale-up • High Probability Of Encountering Chemistry Issues

21. Early-Stage Development Project • Partner May Need To Reinvent The Process For Plant Scale Production • The Lack Of A Robust GMP Process Can Effect The Value Of A Deal • An Experienced CMO Can Help The Sponsor Optimize The Their Strategy

22. The Challenge Time/ Reliability Cost Quality

23. Comprehensive Medicinal Chemistry Vol. II (Strategy And Drug Research) Vol. Editor Walter Moos, Publisher Elsevier, Chapter 2.05, Pages159-173 “The Role of the Chemical Development, Quality, and Regulatory Affairs Team in Turning a Potent Agent into a Registered Product” Stephen A. Munk, Ph.D. Ash Stevens Inc., Detroit, MI