Organization of Clinical Operations at a CRO

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• Organization of Clinical Operations at a CRO
• Anil Kane, Ph.D
• Patheon Inc.
• akane_at_patheon.com

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Outsourcing Clinical Manufacturing

• Outsourcing Pharmaceutical Industrys strategic
  
• tool
• Outsourcing increased dramatically since 1990s
• Today pharma companies outsource 20-40
• of the development budget
• Approx. 60 of R D spent on clinical trials
• hence clinical supply management critical to
• development budget / time.

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Outsourcing - Clinical Manufacturing
Pharmaceutical outsourcing in the US is now
over US 30 billion - Arthur D.Little
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Outsourcing Clinical Manufacturing
Sponsor / contractor relationship

• Past
• Master / slave relationship
• CROs at the whim of sponsors
• Today a paradigm shift
• Sponsor / CRO strategic partnership
• stronger and long term relationship
• risk / profit sharing opportunities

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Drivers to Outsourcing Clinical Manufacturing

• to accelerate drug development
• enhance competitiveness
• access world class technology / global
  manufacturing
• infrastructure
• utilize expertise / experience of a CRO
• focus internally on core competencies

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Drivers to Outsourcing Clinical Manufacturing

• Lower capital investment, higher ROI (capital
  risk)
• cover gaps in capacity
• access to focused flexible manufacturing
  infrastructure
• ensure a more tidy regulatory process

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Drivers to Outsourcing Clinical Manufacturing

• Contractors have a vast experience working with
  many more
• molecules and complexities than many individual
  
• pharmaceutical houses.
• Contractors offer creative solutions to their
  sponsors
• Contractors have approved vendors resulting in
  better quality
• assurance of RMs / PMs
• Contractors have regulatory experiences
• sites are FDA approved

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Drivers to Outsourcing Clinical Manufacturing

• Logistics of procurement advantage with a
  contractor
• Bulk procurement of RMs / PMs reduce overall
  costs for
• small clinical supplies

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Drivers to Outsourcing Clinical Manufacturing

• 55 Companies outsource to improve company focus
• 54 Companies rely on outsourcing to reduce or
  control
• operating costs
• 38 to free internal resources for other purposes
• 36 to gain access to world class capabilities
• 18 to reduce time to market
• 12 for risk sharing
• Survey The Outsourcing Institute
• a report Interphex 2004

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Outsourcing Clinical Manufacturing

• Disadvantages
• reduce organizational innovation
• shift knowledge to suppliers organization
• reduce control over activities
• need a close monitor
• regulatory risk
• Leaking Intellectual property pr being boxed
  in by third party
• providers

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Outsourcing Clinical Manufacturing
Sponsors

• Big Pharma
• Medium size pharmaceutical houses
• Biotech companies
• Virtual to small companies

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Outsourcing Clinical Manufacturing

• Evaluating a potential outsourcing partner a
  checklist
• Capability
• Experience
• Expertise
• Speed
• Track Record
• Capacity
• Right resources (equipment, personnel)
• Responsiveness to changing requirement

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Outsourcing Clinical Manufacturing

• Evaluating a potential outsourcing partner a
  checklist
• Quality
• Quality control procedures and processes in
  place.
• Continuous monitoring
• Compliance
• understanding of applicable regulations
• established QA plan
• archiving system

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Outsourcing Clinical Manufacturing

• Evaluating a potential outsourcing partner a
  checklist
• Financial considerations
• financial stability
• long term viability
• cost of services
• Culture
• ability to build a lasting, mutually profitable
  relationship
• with sponsor

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Outsourcing Services at CRO

• API characterization
• API Stability
• Preformulation
• Analytical Methods development
• Dosage Form Development
• Dosage form Stability
• Packaging Development
• Clinical Manufacturing
• Packaging
• Shipping
• Storage Distribution

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Clinical Supply
Active or placebo preparation used in clinical
programs for the determination of safety and /
or efficacy of a pharmaceutical formulation.

• Material for Toxicology studies / animal PK
  study
• Phase I II supply
• Phase III trials
• Phase IV supplies (generally from commercial
  supplies)

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Clinical Manufacturing Operations
Formulation Dev.
Project Management
Analytical Dev.
Business Dev.
Sales, Marketing
Manufacturing Packaging
Materials Mgt.
Quality Control
Services-IT Eng.
Quality Assurance
Regulatory CMC Group
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Clinical Manufacturing Operations
QC/ Release Testing
Project Planning
Clinical Manufacturing/ Packaging - GMP facility
Materials
Clinical Stability
Info from FD/AD
Shipment
Documentation
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Critical Steps in Outsourcing Clinical
Manufacturing

• Confidentiality Disclosure Agreement (CDA)
• prerequisite for any project discussion
• reviewed and signed by both parties legal
  counsel
• evaluate project feasibility

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Critical Steps in Outsourcing Clinical
Manufacturing

• Intellectual Property Rights
• ownership of IP
• Importance of contracts, assignments and
  licenses
• addressed through diligence and Good Contractual
  Practices

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Critical Steps in Outsourcing Clinical
Manufacturing

• Quality Audits
• Self Audit by contractors
• Sponsor audits
• cGMPs
• IQ/OQ/PQs of equipment, HVACs, Water etc.
• Training
• Corrective Action / Preventive action (CAPA)
  Plan
• Regulatory Inspection track records
• References

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Critical Steps in Outsourcing Clinical
Manufacturing

• Project Questionnaire
• completed by sponsor
• clear definition of project scope (activities,
  responsibilities
• timelines)
• useful tool to communicate project requirement /
  expectations
• to contractor
• Alternatively this is captured in Request for
  Proposal (RFP)

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Critical Steps in Outsourcing Clinical
Manufacturing

• Project Questionnaire should answer the following
  questions
• drug classification (toxicity, therapeutic class
  etc)
• availability of MSDS
• handling procedures / precautions
• special storage conditions / requirements
• phase of the clinical program
• cleaning verification requirement
• requirement of analytical method/s development,
  formulation
• development

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Clinical Manufacturing Plan / Proposal / Quote

• well laid out steps in the project execution
• detailed timeline for deliverables
• assumptions
• back up plan
• cost estimate for the project

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Clinical Manufacturing Operations
- Cleaning Verification Program - Master
Validation Plan - Product specific -
Contractor responsibility for compliance
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Clinical Manufacturing Operations
Effective Project Management key to a successful
partnership key to a successful execution /
timely completion key to building long term
relationship / future collaboration
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Clinical Manufacturing Operations

• Analytical Development Laboratories
• strong team of experienced analytical chemists
• skills in Preformulation to Analytical support
  for routine testing
• complete, flexible infrastructure to meet a
  variety of client / project
• requirement

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Clinical Manufacturing Operations

• Formulation Development / Process Development
• most projects need some development / tech
  transfer work
• prior to clinical manufacturing hence the
  requirement for
• formulation development infrastructure / pilot
  plant
• trained, experienced formulators / process
  development staff

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Clinical Manufacturing Operations

• Materials Management / Sourcing
• procurement of raw materials
• procurement of packaging materials
• experienced staff a key to sourcing materials
  in a timely
• manner

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Clinical Manufacturing Operations

• Manufacturing set up
• systems planning / scheduling manufacturing
  jobs
• feasibility of manufacturing a variety of dosage
  forms
• equipment / process trains for different scale
  of operations
• skilled, trained experienced operators for
  manufacturing /
• packaging

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Clinical Manufacturing Operations

• Packaging
• flexibility in packaging different dosage forms
• primary packaging
• secondary packaging
• clinical kit - packaging

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Clinical Manufacturing Operations

• Quality Assurance / Compliance
• SOPs
• Training Curriculum
• cGMP compliance
• Approval of documents Master Batch Records,
  Deviation
• reports, change controls, Reports etc.

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Clinical Manufacturing Operations

• Quality Control / Analytical Release Testing
• In-process Testing
• Bulk product release
• Packaged product release
• Generation of CofAs

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Clinical Manufacturing Operations

• Shipment of Clinical supplies
• experienced staff
• export procedures where applicable
• special requirements for shipment (refrigeration
  etc.)

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Outsourcing Clinical Manufacturing
Its all about building TRUST and long term
strategic relationship
Contractor
Sponsor C
Sponsor A
Sponsor B
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Outsourcing Clinical Manufacturing

• Myths about CROs
• Outsourcing to a CRO is more expensive
• Large CROs do not care about small companies.
• Big Pharma gets a priority
• Large CROs do not communicate effectively
• CROs are training grounds hence high turnover.
• CRO does not have the same passion for my
  development /
• clinical program

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Outsourcing Clinical Manufacturing

• Myths about Sponsors
• Large companies do not communicate effectively
• Small companies use the bidding process as a way
  of
• getting free consulting.
• Small companies always ask for more than they
  are willing
• to pay for.

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Outsourcing Clinical Manufacturing
Key Partnership Elements

• Dos
• Understand each others wants and needs
• Establish project milestones and/or service
  model
• Develop a sense of common purpose

• Donts
• Underestimate the need for information exchange
• Assume that information flows perfectly
• Keep apart functions that need to be
  co-ordinated
• Keep trouble a secret

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Sponsor CRO Relationship

• Key Elements for Success
• Mutual Trust and Respect
• Clarity in Responsibilities
• Clarity in contractual and payment terms
• Channel of Communication
• Minimal changes to team

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Sponsor CRO Relationship
Key Elements for Success

• Tolerance in diversity of opinion
• Efficient Project Management Tools
• Open / honest discussion for problem
• resolution
• Measure Progress

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The Right Capacity
The Right Services

The Right People
Outsourcing Clinical Manufacturing
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Outsourcing Clinical Manufacturing

• Good Clinical Trial Manufacturing Contractor has
  facilities and systems
• equivalent to those in Big Pharma
• Reasons for outsourcing time, capacity,
  infrastructure etc.
• Key to Success - Information Flow
• - Effective Project Management
• Repeat Business TRUST / RELATIONSHIP

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