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

James M. Hamby, R.Ph., Ph.D.Director of Business DevelopmentAsh Stevens, Inc.18655 Krause StreetRiverview, MI 48103Tel: (734) 282-3370 ext. 1144Email: jhamby@ashstevens.comWeb: www.ashstevens.com

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”

Chemistry Milestones for an NDA

NDA FilingValidatable ProcessOne Batch Prior To FilingDevelopment ReportImpurities Identified12 Months Stability – 3 Batches(API Shipping and Storage Only)

FDA PAIOne Validation Batch CompleteProtocol for Two AdditionalBatches

Approvalto Market

Phase II/IIIParametric StudiesValidated Analytical Methods;Starting Material, Intermediate,and Product Specifications;Packaging

Phase I“Manageable” ProcessProcess Hazard ReviewCleaning ProceduresScientifically Sound Analytical Methods

Development Candidate

Stability ProgramStability StudiesIncluding Three Lots of API

Mfg. Batch DefinitionUnit OperationsScale of Batch

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

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)

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

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

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

Due Diligence

The Request For Proposal (RFP) Technical Package

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

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)

Proposal/Quote Assessment

Proposal/Quote Assessment

Comments And Strategy Section

All Costs and Work Clearly Defined

Risk-Based Proposals

Start Date Intellectual Property

Early-Stage Project: Initial Tasks

1. Process Feasibility and Evaluation

2. Preliminary Process Development

3. Demonstration Batch (250-500g, non-GMP)

4. Initial Phase I GMP Batch (1-5 Kg)

5. Analytical Development

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?)

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)

CMO Site Visit

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

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)

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

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

The Challenge

Time/Reliability

Quality

Cost

Comprehensive Medicinal Chemistry Vol. II(Strategy And Drug Research) Vol. Editor Walter Moos, Publisher Elsevier, Chapter 2.05, Pages 159-173

“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