Transcript Ash Stevens, Inc

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: [email protected]
Web: 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
Phase II/III
Development
Candidate
Phase I
Parametric Studies
Validated Analytical Methods;
Starting Material, Intermediate,
and Product Specifications;
Packaging
FDA PAI
Mfg. Batch Definition
Unit Operations
Scale of Batch
Stability Program
“Manageable” Process
Stability Studies
Process Hazard Review
Including Three Lots of API
Cleaning Procedures
Scientifically Sound Analytical Methods
NDA Filing
One Validation Batch Complete
Protocol for Two Additional
Batches
Approval
to Market
Validatable Process
One Batch Prior To Filing
Development Report
Impurities Identified
12 Months Stability – 3 Batches
(API Shipping and Storage Only)
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
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
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
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
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)
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
Cost
Quality
Comprehensive Medicinal Chemistry Vol. II
(Strategy And Drug Research) Vol. Editor Walter
Moos, Publisher Elsevier, Chapter 2.05, Pages 159173
“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