winning strategies for tech transfer projects
TRANSCRIPT
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Winning Strategies for Tech Transfer Projects:
Key Issues that Affect Successful Product Manufacture in “New” Facilities
Presented By - Presented By -John M. Hyde, Chairman and Founder
Hyde Engineering + Consulting, Inc.
ISPE Rocky Mountain Chapter Fall Meeting1 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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Technology Transfer Drivers
• Scale up/Capacity:• New Product Introduction• Rapid Globalization of Core Products
• Redundant Sourcing of Strategic Products• Quality/Technology:
• Remediation changesR id Ad i f N T h l i• Rapid Adoption of New Technologies
• 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 at favorable terms to Owner• Expenditure by CMO ‐ 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: • Organization and ManagementOrgani ation and Management
• Production Transfer
• Quality Control: Analytical methods
• Premises and Equipment
• Qualification and Validation
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Technology Transfer Process MapHigh Level View
Product Definition
Process ConformanceProcess 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 MapProduct Definition
Product Definition
Markets/Countries Where SoldPackage List and BOM
Packages to Be Sold
Purpose:Understand everythingg
Product Formulation by MarketQC Tests and Methods•Release•Stability
Understand everything there is to know about the product and manufacturing process!
Raw Materials•Specifications•Sources•Compendial Requirements•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.)
Tests and Methods
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Process Conformance (Gap analysis)
Manufacturing and Laboratory Documentation•Batch Records
Technology Transfer Process MapProcess Conformance / GAP Analysis
Purpose:Identify gaps in product
Supporting Studies•Container Closure Integrity•Extractable/Leachable•Stopper Coring, ResealFilt
Process Validation Review
Batch Records•SOPs•Method Validations•Stability Studies
y g p psupporting documentation before it is moved. Avoid surprises and unexpected delays!
Quality by Design (QbD) facilitates this process!
Regulatory Filing Review
•Filters•Etc., Etc.
Regulatory CommitmentsInternal Quality Commitments
• Which Agencies– Manufacture, Sale and Distribution
Technology Transfer Process MapProcess Conformance ‐ Regulatory Issues
• 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 RequirePotential 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.)
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Process Optimization
New Technology Review•Disposable vs. Re-Usable•Separation Technologies
Technology Transfer Process MapProcess Re‐Definition
Purpose:Develop and select best
Process Cycle Time•Single Step vs. Multi-Step•Batch Size Optimization•PAT vs. In-Process Tests•Continuous vs. BatchEt Et
•Separation Technologies•Purification Resins/Filters•Dosage Form (Vials vs. Syringe)
Develop and select best case for product transfer success, quality, cost, compliance. Adjust product and process as needed. Stay ahead of the curve!
•Etc., Etc.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 ‐ InputsAll 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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Process Fit Assessment
Develop Product Information Package•Detailed Product Specifications•Process Flow Diagram as Desired
Technology Transfer Process MapProcess Fit Assessment
Purpose:Provide as desired
Submit to potential Receiving Sites
•Develop evaluation criteriaMarket Regulatory conformanceQuality / Management culture fitQuality Systems Robustness
Process Flow Diagram as Desired•API and Drug Component Specs.•Analytical Tests (In-Proc., Release, Stab.)
Provide as desired product and process details to second site.
Review and assess second site proposed process. Know what you’re getting into!
Receiving sites return proposals
Q y yHistory/ReputationReliability/Financial stabilityTechnologies fit to ProcessCapacity, Cost, Etc.Perform Due Diligence inspections
Evaluate and Select Receiving Site
The Right CMO:
• Communication & Responsiveness
Selection of CMO
– 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 CMO Procedures/Standards– Aligned Quality Systems – CMO Procedures/Standards harmonized
• Business Fit:
– Capacity and Costs
– Owner/CMO Integrated planning and logistics systems
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Technology Transfer Planning
Prepare Project Execution Plan
Execute Quality AgreementExecute Business Agreement
Technology Transfer Process MapTechnology Transfer Planning
Purpose:Prepare Project Execution Plan 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
Prepare Analytical Laboratory
Prepare Validation Master Plan
Order/Modify/Transfer Equipment Order raw materials and consumables
Prepare Regulatory FilingsFinalize artwork and copy
Prepare Tech Transfer Plan
toward goals. If you fail to plan….!
py
• Equipment Scale – Process & Utilities
D f P S t
Process & Utilities Readiness Check
• Degree of Process Systems 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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• HVAC Zoning– Air Segregation Between
Facility Readiness Check
g gFunctional 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
Documentation/Personnel Readiness Check
– 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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QC ‐ Analytical Methods (collection, management and testing)
Methods Transfer Readiness Check
and testing)
• Instrument and Procedure Validation
• Sample Collection and Tracking Methodologies
• Sample Storage Requirements
• Re‐Testing Policies and Criteria
• Requirements for Out‐Sourced Analysesq y
• Sample Segregation Requirements
• Laboratory Staff Qualifications– Documented Training for Samplers and Analysts!
• Bases of Equipment and Facility Validation Practices
Validation Readiness Check
Facility Validation Practices– Risk Basis– Grouping of Equipment and Facility Systems
– Re‐Qualification
• Process, Sterilization and Cleaning ValidationCleaning Validation– Risk Basis– Quality and Quantity of Lab and Pilot Scale Supporting Data, e.g., “Design Space” Understanding
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• Carryover Risk of Contaminants from Prior Products
Validation Readiness Check (cont.)
– Value of Residue Removal and Fragmentation Studies
– Replacement of Elastomers?
– Dedication of Key Equipment
– Chromatography Resin and UltrafiltrationMembrane Replacement and StorageMembrane Replacement and Storage
– Pre Versus Post Viral Equipment Systems and Manufacturing Suites
– Raw Materials and Finished Goods Handling
• Facility Cleaning and Decontamination
• Management of Change– How are Change Requests Initiated?
Quality Systems Readiness Check
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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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 Prepp− 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 ConcentrateNutrient 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 Vessely
• Harvest– Ultra Filter
– Disk‐Stack Centrifuge
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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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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 Concentratesg
• 3x to 10x Solutions Diluted Inline with WFI
– Reusable Buffer Concentrate Transfer Piping to Upstream and Downstream Purification Operations
Keys To Successful Tech Transfer:
• Knowledge Management ‐ QbD
Technology Transfer Summary
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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John M. Hyde
Questions?
yChairman and Founder
Hyde Engineering + Consulting, Inc
Voice: +1.303.641.5468
E‐mail: john hyde@hyde‐ec comE mail: john.hyde@hyde ec.com