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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: [email protected]: 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