Know the Regulations:

Fostering the Quality-Based Sponsor/CMO Relationship

EJ Brandreth

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Welcome

EJ BrandrethSr. VP of Quality and RegulatoryAlthea Technologies, Inc

Chairman, PDA Biotech BoardDirector, Interphex BoardDirector, Biocom FDA Board

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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

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

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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

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The CMO World: Wide Range of Clients

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Big Pharma Virtual Biotech

Comprehensive QA Little QA

Custom Quality Agreement No Custom Quality Agreement

Financially Secure Small Funding

Lots of Experience with Submission Process

Less Experience with Submission Process

The CMO World: Wide Range of Projects

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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

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 stoppersViscosity 30-300 CPSClear to opalescent to flocculent, may be

opaque, blue, whiteSmall Molecules, Proteins, Plasmids,

Suspensions, Emulsions, Conjugates

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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

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Life in a CMO: With all those inspections…

SOPs are very well written (they’ve been independently reviewed 100+ times..)

No major gaps in systemsPersonnel provide great tours; SME’s

fluent in their systems

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Regulations and Culture

All Parties are Responsible and liable for CFR complianceRecent 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…

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Ownership Flow for Aseptic Filling at a CMO

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Sponsor/ CMO Relationship

Perspectives on the Partnership

1.Business-based approach; • Client and Vendor = Financial based

negotiations and decisions2.Quality-based approach;

• Sponsor QA and CMO QA = Compliance based negotiations and decisions

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The Partnership

Two over-arching considerations:1.Patient Safety Comes First2.cGMP Compliance Required

• Required for sponsor’s project.• From the CMO perspective, non-

compliance affects all products, not just that one client.

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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.

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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.

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Hot CMO Topics

Mold Incidental, or tip of an iceberg?

Visible Particles; overall reject rate100% 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

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Hot CMO Topics

Weak InvestigationsLack of Root Cause, too much “Operator Error” =

“Retrain”Lack of Data to support assumptions and

conclusionsLimited; 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?

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Hot CMO Topics

Shipping (Final Product) Under QuarantineBoth CMO and Sponsor are Responsible for

Adverse OutcomesRare Event; Urgent Need, Stock-Out SituationPer a Deviation, and Legal AgreementSterility Test Results Required prior to

shipmentVisual Inspection Completed prior to shipment

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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

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Thank you

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Althea Technologies11040 Roselle St.San Diego, CA 92121

Local Phone: 858-882-0123Toll-free: 1-888-425-8432Fax: 858-882-0133