Althea Technologies' Sr. VP of Quality and Regulatory, EJ Brandreth, talks about life in the CMO world from the quality perspective. In this presentation, he discusses the regulations involved in biologics manufacturing and fill finish operations, and the importance of establishing a quality based partnership between CMOs and sponsors.

1. Know the Regulations:
Fostering the Quality-Based Sponsor/CMO
Relationship
EJ Brandreth

2. Welcome
EJ Brandreth
Sr. VP of Quality and Regulatory
Althea Technologies, Inc
Chairman, PDA Biotech Board
Director, Interphex Board
Director, Biocom FDA Board
CONFIDENTIAL

3. Regulations for Parenterals (PDA)
Some Key 21 CFR’s for CMO’s……
• Part 11 Electronic Records
• Part 200.10 Contract Facilities
• 210 & 211 cGMPs
• Part 600 Biological Products
• Part 601 Licensing
• Part 610 Biological Products Standards
• Part 820 Quality System Regulation
CONFIDENTIAL

4. CFR’s explain the What….but where is the How?
Points to Consider in the….
• FDA Guidance Documents…
• Guidance for Industry
• Guidance for Reviewers, Reviewers and Sponsors,
etc..
• FDA Program Documents: “Inspection of…” (SOP)
• ICH Guidelines
• PDA Technical Reports, Journals
CONFIDENTIAL

5. And a little of the Why…
• USP; below <1000> are mandatory
• WHO
• Federal Register
• Trade Articles; Journals
• Gold Sheet
• FDA Conference Presentations
• EIR’s, 483’s, Warning Letters (actually “what not to do.. ”)
daily emails
• FDA “Dear xxxxx…. “ Letters
CONFIDENTIAL

6. The CMO World: Wide Range of Clients
Big Pharma Virtual Biotech
Comprehensive QA Little QA
Custom Quality Agreement No Custom Quality Agreement
Financially Secure Small Funding
Lots of Experience with Submission Less Experience with Submission
Process Process
CONFIDENTIAL

7. The CMO World: Wide Range of Projects
Commercial Filling Phase 1
Biological Processing
Comprehensive History No GMP History
Process Understood New Process Knowledge
Deviations Rare Deviations Expected
Wide, Deep Investigations Limited Investigations
Tight Specifications Wide Specifications
Low Risk Moderate Risk
CONFIDENTIAL

8. The CMO World: Wide Range of Products
Defined Product? Yes! It’s….
2 to100 ml clear or amber vials, 13 or 20 mm
coated or uncoated stoppers
Viscosity 30-300 CPS
Clear to opalescent to flocculent, may be
opaque, blue, white
Small Molecules, Proteins, Plasmids,
Suspensions, Emulsions, Conjugates
CONFIDENTIAL

9. Life in a CMO
Showcase for Equipment
Weekly GMP audits by Clients
Constant Quality Input
Learn Best Practices Across the Industry
 Frequent EU GMP Audits by QPs
 Annual or Biennial FDA/EMA Inspections
CONFIDENTIAL

10. Life in a CMO: With all those inspections…
 SOPs are very well written (they’ve been
independently reviewed 100+ times..)
No major gaps in systems
Personnel provide great tours; SME’s fluent in
their systems
CONFIDENTIAL

11. Regulations and Culture
All Parties are Responsible and liable for CFR
compliance
Recent WL (12-NWJ-12, 2/17/2012); “You state you have
informed your clients on the importance of
validating the methods…You are responsible for
ensuring that the test methods used by your
firm are validated.”
Ownership is a
Meandering Stream…
CONFIDENTIAL

12. Ownership Flow for Aseptic Filling at a CMO
CONFIDENTIAL

13. Sponsor/ CMO Relationship
Perspectives on the Partnership
1. Business-based approach;
• Client and Vendor = Financial based
negotiations and decisions
2. Quality-based approach;
• Sponsor QA and CMO QA = Compliance
based negotiations and decisions
CONFIDENTIAL

14. The Partnership
Two over-arching considerations:
1. Patient Safety Comes First
2. cGMP Compliance Required
• Required for sponsor’s project.
• From the CMO perspective, non-compliance
affects all products, not just that one client.
CONFIDENTIAL

15. The Partnership
• Ideally the value of a true Partnership is formed;
the CMO and Sponsor succeed or fail together
• The CMO should be an extension of the
Sponsor’s Quality System (CFR 200.10)
• However, CMO quality systems are intricate and
interconnected – have to serve many different client
projects.
• BUT Sponsor gains advantage of established, robust
quality systems at CMOs.
CONFIDENTIAL

16. The Partnership
Quality Agreements:
• Defines who is responsible for what
• Defines timing of communications; error
reporting, OOS, FDA interactions, etc…
• Should address GMP details which need
specifics (e.g.: Sponsor determines Retain amount),
but simply repeating cGMPs is Fluff.
CONFIDENTIAL

17. Hot CMO Topics
 Mold
 Incidental, or tip of an iceberg?
 Visible Particles; overall reject rate
 100% Visual Inspection; Imperfect process, but
continuous drive towards zero
 Glass Particles; shedding phenomena
 Prevent/ Mitigate with knowledge of formulation
 Viral Contamination in Mammalian Systems
 PDA TRs for Control, and Emerging Analytical
Methods
CONFIDENTIAL

18. Hot CMO Topics
 Weak Investigations
 Lack of Root Cause, too much “Operator Error” =
“Retrain”
 Lack of Data to support assumptions and conclusions
 Limited; to one product, or one production suite, or
one test. Did not check to see if problem is actually
present in other systems/programs
 Corrective Actions; repeat offense?
 Preventive Actions; repeat offense?
PA Effectiveness program in place?
CONFIDENTIAL

19. Hot CMO Topics
Shipping (Final Product) Under Quarantine
Both CMO and Sponsor are Responsible for
Adverse Outcomes
Rare Event; Urgent Need, Stock-Out Situation
Per a Deviation, and Legal Agreement
Sterility Test Results Required prior to
shipment
Visual Inspection Completed prior to shipment
CONFIDENTIAL

20. Conclusion
While working within the Regulations, establish a Positive
Relationship with all three parties
 We all want Great Products Released
 We all have financial and scheduling pressures
 We all are held accountable to the Regulations
Foster the Relationship; Communicate, Document Every
Detail, Deliver
CONFIDENTIAL

21. Thank you
Althea Technologies
11040 Roselle St.
San Diego, CA 92121
Local Phone: 858-882-0123
Toll-free: 1-888-425-8432
Fax: 858-882-0133
CONFIDENTIAL