Winning Strategies for Tech Transfer Projects
- 1. 10/5/2015 1 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 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
- 2. 10/5/2015 2 Technology Transfer Drivers • Scale up/Capacity: • New Product Introduction • Rapid Globalization of Core Products • Redundant Sourcing of Strategic Products • Quality/Technology: • Remediation changes R 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
- 3. 10/5/2015 3 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
- 4. 10/5/2015 4 Technology Transfer Process Map High 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 Map Product Definition Product Definition Markets/Countries Where Sold Package List and BOM Packages to Be Sold Purpose: Understand everythingg Product Formulation by Market QC 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
- 5. 10/5/2015 5 Process Conformance (Gap analysis) Manufacturing and Laboratory Documentation •Batch Records Technology Transfer Process Map Process Conformance / GAP Analysis Purpose: Identify gaps in product Supporting Studies •Container Closure Integrity •Extractable/Leachable •Stopper Coring, Reseal Filt Process Validation Review Batch Records •SOPs •Method Validations •Stability Studies y g p p supporting documentation before it is moved. Avoid surprises and unexpected delays! Quality by Design (QbD) facilitates this process! Regulatory Filing Review •Filters •Etc., Etc. Regulatory Commitments Internal Quality Commitments • Which Agencies – Manufacture, Sale and Distribution Technology Transfer Process Map Process 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.)
- 6. 10/5/2015 6 Process Optimization New Technology Review •Disposable vs. Re-Usable •Separation Technologies Technology Transfer Process Map Process 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. Batch Et 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
- 7. 10/5/2015 7 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
- 8. 10/5/2015 8 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
- 9. 10/5/2015 9 Process Fit Assessment Develop Product Information Package •Detailed Product Specifications •Process Flow Diagram as Desired Technology Transfer Process Map Process Fit Assessment Purpose: Provide as desired Submit to potential Receiving Sites •Develop evaluation criteria Market Regulatory conformance Quality / Management culture fit Quality 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 y History/Reputation Reliability/Financial stability Technologies fit to Process Capacity, 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
- 10. 10/5/2015 10 Technology Transfer Planning Prepare Project Execution Plan Execute Quality Agreement Execute Business Agreement Technology Transfer Process Map Technology 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 Filings Finalize 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
- 11. 10/5/2015 11 • HVAC Zoning – Air Segregation Between Facility Readiness Check 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 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
- 12. 10/5/2015 12 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
- 13. 10/5/2015 13 • 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 Ultrafiltration Membrane 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
- 14. 10/5/2015 14 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
- 15. 10/5/2015 15 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
- 16. 10/5/2015 16 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
- 17. 10/5/2015 17 John M. Hyde Questions? y Chairman and Founder Hyde Engineering + Consulting, Inc Voice: +1.303.641.5468 E‐mail: john hyde@hyde‐ec comE mail: john.hyde@hyde ec.com