10/5/2015
Winning Strategies for Tech Transfer Projects:
Key Issues that Affect Successful Product Manufacture in “New” Facilities
- Presented By John M. Hyde, Chairman and Founder
Hyde Engineering + Consulting, Inc.
ISPE Rocky Mountain Chapter Fall Meeting
1 October 2015
Presentation Overview
• Drivers for Technology Transfer
• Tech Transfer Process:
• Product/Process Definition
• Process Modeling
• Process Fit Assessment
• Planningg
• Readiness Check & Execution
• Tour of Newly Constructed Indian CMO
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10/5/2015
Technology Transfer Drivers
• Scale up/Capacity:
• New Product Introduction
• Rapid Globalization of Core Products
• Redundant Sourcing of Strategic Products
• Quality/Technology:
• Remediation changes
• Rapid
R id Ad
Adoption
i off N
New T
Technologies
h l i
• New Market Entry
• Economics
Economics of Outsourcing
Economic considerations:
– Time to Market
– Alternative to large upfront capital expenditures
– Consolidation
Key Drivers: Cost of Goods
Market Demand
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Cost of Goods Reduction
– Reduced Operating Costs
• Lower Labor and Material costs – Economies of Scale
• Expenditure by CMO ‐
Expenditure by CMO at favorable terms to Owner
at favorable terms to Owner
• Contract ‐ limited flexibility for unplanned upside costs
– Reduced Costs of Quality
• Limited exposure to costs of quality – waste
• Reduced direct oversight by Owner Quality Function
Big Caveat: How does CMO fit seamlessly into Owner Operating and Quality models with minimal Owner Oversight?
Guidelines on Tech Transfer
– ISPE Good Practice Guide – Technology Transfer, 2003:
•
•
•
•
Planning and Success Criteria
Analytical Methods
Active Pharmaceutical Ingredient
Dosage Forms
– WHO Technical Series Report 961, Annex 7 – Guideline on transfer of technology in pharmaceutical manufacturing, 2011: •
•
•
•
•
Organi ation and Management
Organization and Management
Production Transfer
Quality Control: Analytical methods
Premises and Equipment
Qualification and Validation
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Technology Transfer Process Map
High Level View
Product Definition
Process Conformance
Process Re-Definition
Process Fit Assessment
Technology Transfer Planning
Transfer Readiness Check
Release and Execute
Concurrent Processes:
•Regulatory requirements review, planning, execution stream
•Analytical Methods review, transfer planning, execution stream
•Planning and Logistics management
•Quality management
•Marketing and Sales as needed
Technology Transfer Process Map
Product Definition
Product Definition
Packages to Be Sold
Markets/Countries Where Sold
Package
g List and BOM
Product Formulation by Market
QC Tests and Methods
•Release
•Stability
Purpose:
Understand everything
there is to know about the
product and manufacturing
process!
Raw Materials
•Specifications
•Sources
•Compendial Requirements
•Tests
Tests and Methods
Process Definition
•Process Flow Diagram
•Detailed Process Narrative
•CPPs/CQAs by Step
•Equipment and Instrumentation
•In-Process Tests and Methods
•Other (Quality History, CAPA’s, etc.)
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10/5/2015
Technology Transfer Process Map
Process Conformance / GAP Analysis
Process Conformance (Gap analysis)
Manufacturing and
Laboratory Documentation
Purpose:
Identifyy ggaps
p in product
p
supporting documentation
before it is moved. Avoid
surprises and unexpected
delays!
•Batch
Batch Records
•SOPs
•Method Validations
•Stability Studies
Process Validation Review
Supporting Studies
•Container Closure Integrity
•Extractable/Leachable
•Stopper Coring, Reseal
•Filters
Filt
•Etc., Etc.
Quality by Design (QbD) facilitates this process!
Regulatory Filing Review
Regulatory Commitments
Internal Quality Commitments
Technology Transfer Process Map
Process Conformance ‐ Regulatory Issues
• Which Agencies
– Manufacture, Sale and Distribution
• Prior Regulatory Agency Interaction (the Owner and CMO)
– Outstanding Observations
– Resolved Observations Dealing Directly With the Product, Process or Facility
– Potential Process Changes that may Require Potential Process Changes that may Require
Additional Regulatory Filing(s)
• Product or Process Specific Regulatory Issues
• Consistency of Manufacturing Process (Annual Reviews, Process Capability Monitoring, etc.) 5
10/5/2015
Technology Transfer Process Map
Process Re‐Definition
Process Optimization
New Technology Review
•Disposable vs. Re-Usable
•Separation Technologies
•Purification Resins/Filters
•Dosage Form (Vials vs. Syringe)
Process Cycle Time
•Single Step vs. Multi-Step
•Batch Size Optimization
•PAT vs. In-Process Tests
•Continuous vs. Batch
•Etc.,
Et Et
Etc.
Purpose:
Develop and select best
case for product transfer
success, quality, cost,
compliance. Adjust
product and process as
needed. Stay ahead of
the curve!
Process Development Plan
•Address known quality/cost issues
•Introduce higher quality or lower cost components
•Rationalize multiple formulations
•Extend patent protection?
Process Block Flow Diagram
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Process Model ‐ Inputs
All process model input required for the various unit operations is identified on single sheet Process Model – Process Calculations
• All detailed process calculations are captured on a single sheet
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Process Model – Output Block Flow Diagram
• The calculation results are summarized in a Block Flow Diagram format
Process Model – Utility Sizing
Utility Sizing based on Process Model and Production Schedule
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Technology Transfer Process Map
Process Fit Assessment
Process Fit Assessment
Develop Product Information Package
•Detailed Product Specifications
Purpose:
Process Flow Diagram as Desired
•Process
Provide as desired
•API and Drug Component Specs.
product and process
•Analytical Tests (In-Proc., Release, Stab.)
details to second site.
Submit to potential Receiving Sites
Receiving sites return proposals
Review and assess second
site proposed process.
•Develop evaluation criteria
Market Regulatory conformance Know what you’re
Quality / Management culture fit getting into!
Quality
Q
y Systems
y
Robustness
History/Reputation
Reliability/Financial stability
Technologies fit to Process
Capacity, Cost, Etc.
Perform Due Diligence inspections
Evaluate and Select Receiving Site
Selection of CMO
The Right CMO: • Communication & Responsiveness
– CMO functions as internal manufacturing site
– Decentralized decision making ‐ Operations and Quality
• Culture:
– Management ‘culture’ are strongly aligned and “Fit” to Owner’s culture
– Aligned Quality Systems –
Aligned Quality Systems CMO Procedures/Standards CMO Procedures/Standards
harmonized • Business Fit:
– Capacity and Costs
– Owner/CMO Integrated planning and logistics systems
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10/5/2015
Technology Transfer Process Map
Technology Transfer Planning
Technology Transfer Planning
Execute Quality Agreement
Execute Business Agreement
Prepare Project Execution Plan
Prepare Tech Transfer Plan
Prepare Validation Master Plan
Order/Modify/Transfer Equipment
Order raw materials and consumables
Prepare Analytical Laboratory
Prepare Regulatory Filings
Finalize artwork and copy
py
Purpose:
Prepare a detailed plan
that lists all deliverables,
assigns roles and
responsibilities, provides
timelines and milestones,
to provide basis for
checking readiness to
proceed and progress
toward goals. If you fail
to plan….!
Process & Utilities Readiness Check
• Equipment Scale – Process & Utilities
• Degree of Process Systems D
fP
S t
Automation
– Extent of Reliance on Software Algorithm Versus Manual Operations
– Degree of Process Data Collection Capabilities
• Process Containment Capabilities
• Sterilization and Cleaning Practices
• Segregation ‐ Plant and Clean Utilities
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10/5/2015
Facility Readiness Check
• HVAC Zoning
– Air Segregation Between g g
Functional Areas
– Appropriate Pressure Gradients
• Routing
– Adequate Corridors for “Supply” and “Return” of People and Materials
• Gowningg
– Appropriate Gowning Areas and Gowns
• Storage of In‐Process Materials
– Segregation by Lot and Product
Documentation/Personnel Readiness Check
• Documentation
– Batch records and SOP’s
– Address all Manufacturing, Laboratory and Facility Issues Including GMP, GLP, Safety, etc.
– Specific to Markets Served, e.g. WHO, EMA, FDA, etc.
• Training Program
Training Program
– Training Program for Manufacturing and Support Staff
– Documented Training Records
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10/5/2015
Methods Transfer Readiness Check
QC ‐ Analytical Methods (collection, management and testing)
and testing)
• Instrument and Procedure Validation
• Sample Collection and Tracking Methodologies
• Sample Storage Requirements
• Re‐Testing Policies and Criteria
• Requirements for Out‐Sourced Analyses
q
y
• Sample Segregation Requirements
• Laboratory Staff Qualifications
– Documented Training for Samplers and Analysts!
Validation Readiness Check
• Bases of Equipment and Facility Validation Practices
Facility Validation Practices
– Risk Basis
– Grouping of Equipment and Facility Systems
– Re‐Qualification
• Process, Sterilization and Cleaning Validation
Cleaning Validation
– Risk Basis
– Quality and Quantity of Lab and Pilot Scale Supporting Data, e.g., “Design Space” Understanding
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10/5/2015
Validation Readiness Check (cont.)
• Carryover Risk of Contaminants from Prior Products
– Value of Residue Removal and Fragmentation Studies
– Replacement of Elastomers?
– Dedication of Key Equipment
– Chromatography Resin and Ultrafiltration
Membrane Replacement and Storage
Membrane Replacement and Storage
– Pre Versus Post Viral Equipment Systems and Manufacturing Suites
– Raw Materials and Finished Goods Handling
• Facility Cleaning and Decontamination
Quality Systems Readiness Check
• Management of Change
– How are Change Requests Initiated?
g
q
– Who Approves of Change Requests
– How are Completed Changes Evaluated and Closed?
• Documentation of Change
– How is Change Recorded?
– Chronological, Departmental, Equipment Systems and Product Cross Referencing
• Evaluation of “Drift”
– Real‐Time Manufacturing Data to Assess Un‐Planned Change
– Basis for Re‐Qualification
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10/5/2015
Case Study – Indian CMO
• Facility Basics
− Total Facility Footprint is ~40,000 Sq. Ft., ~18,000 Sq. Ft. Classified Space
− Process Designed to Manufacture Microbial Based Bio‐
Therapeutics
− Process Systems are a Mix of Single‐Use and Re‐Usable Equipment
− Process is Designed to Manufacture Bulk Drug Substances
− Manufacturing Areas Include:
−
−
−
−
−
−
−
Media Prep
p
Seed and Production Fermentation and Harvest
Inclusion Body Dissolution and Refolding
Buffer Prep, Storage and Distribution
Primary Purification
Final Purification and Pegalation
Final Bulk Filling
Case Study – Indian CMO
• Media Preparation
– 150L Reusable Vessel for Prep of Fermentation Media, Nutrient Feed, Dextrose and Lysis Buffer Concentrate
Nutrient Feed, Dextrose and Lysis Buffer Concentrate
– Reusable Media Transfer Piping
• Fermentation
– 20L Seed and 250L Production Reusable Fermenters
– 50L Dextrose 150L Nutrient Reusable Vessels
– Reusable Lysis Buffer Hold Vessel
y
• Harvest
– Ultra Filter
– Disk‐Stack Centrifuge
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10/5/2015
Case Study – Indian CMO
• Upstream Purification
– Inclusion Body Dissolution
• 500L Reusable Vessel and Interconnecting Piping
– Ion Exchange Chromatography
• 5 Buffer Concentrate Bags, 1 Product Pool Bag
• 200L Reusable PW Dilution Vessel
• Upstream Purification Buffer Preparation
– 500L Buffer Prep Vessel and Transfer Piping
– Guanidine HCl Based Buffer Concentrates
Case Study – Indian CMO
• Downstream Purification
– Reaction and Refolding
• Two 500L Reusable Vessels and Interconnecting Piping
– Ion Exchange and Affinity Chromatography
• 10 Buffer Concentrate Bags, 1 Product Pool Bag
• 250L Reusable WFI Dilution Vessel
• Two 250L Reusable Pool Vessels
• Diafiltration
– 3 Diafiltration Skids
• 3 Buffer Concentrate and 1 Pool Bag per Skid
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10/5/2015
Case Study – Indian CMO
• Buffer Preparation
– 50L, 250L and 1,000L Reusable Vessels
– Preparation of Buffer Concentrates
Preparation of Buffer Concentrates
– Reusable Buffer Transfer Piping
• Buffer Hold
– 29 Bag Bins
– Storage of Buffer Concentrates
g
• 3x to 10x Solutions Diluted Inline with WFI
– Reusable Buffer Concentrate Transfer Piping to Upstream and Downstream Purification Operations
Technology Transfer Summary
Keys To Successful Tech Transfer:
• Knowledge Management ‐
Knowledge Management ‐ QbD
• Strong Product Understanding
• Strong Process Understanding ‐ CCP and CQA’s
• Document knowledge
• Project Management
• Capability and Preparation of CMO/ /
Receiving Site • Planning & Communication
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10/5/2015
Questions?
John M. Hyde
y
Chairman and Founder
Hyde Engineering + Consulting, Inc
Voice: +1.303.641.5468
EE‐mail:
mail: john.hyde@hyde
john hyde@hyde‐ec
ec.com
com
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