IDA Ireland / PharmaChemical Ireland Symposium

1. IDA Ireland / PharmaChemical Ireland Symposium The Road to Integrated Development and Manufacturing Jacintha Griffin Wyeth Newbridge September 23rd 2009

2. Overview The Road to Integrated Development & Manufacturing • From technical transfer to Co-development • Pharmaceutical Development Centre (PDC) business case • PDC Newbridge – Capability, facility and approach to integrated development & manufacturing • Development and Manufacturing Model - Future Opportunities and Challenges

3. Wyeth NewbridgeThe Road to Integrated Development & Manufacturing Newbridge PDC Opens Newbridge PDC Construction Start New products organization & PDCs in Operation 2009 PDC Concept Approval 2008 Co-Development & Clinical Trial Supplies 2007 Technical Transfers & Process Optimisation 2005 2004 1992 - 2003

4. Pharmaceutical Development Centre (PDC)Integrated Development and ManufacturingBusiness Case and Fiscal Supports Critical Supports in Justifying Business Case for Development centre: • Proven technical capability of supporting a large portfolio of solid dosage products • Demonstrated capability in collaborating with corporate R&D - Co-development • Collaboration with the IMB for rapid application, audit and receipt of IMP licence • Process optimization for marketed product portfolio - “Quality by re-Design” • Changing regulatory environment – impact of ICH Q8, 9, 10 • Government, IDA mandate and support • R&D Tax Credit System & capability grants • 12.5% Corporation Tax • IP Royalty Scheme

5. PDC Charter and value proposition

6. PDC NewbridgeMulti-Purpose Multi- ProductcGMPModule • Pilot Scale 5-50kg • 1/10th the commercial scale of pipeline products • SmallScale (<5kg Suite) • ‘Smart Development’ • Smaller Batches - Higher Velocity / Throughput • Supports API Cost and Supply Constraints Full Scalability to pilot and commercial scales • Process Characterisation Laboratory • Active and Excipient Functional Characterisation • Dedicated Analytical Development Laboratory • Flexible and Modular Design • Multiple Product Capability • Flexible Containment to handle potent compounds • “Future Proofed” for Next Generation Technologies • PAT/Data Management Infrastructure • Process Analytical Infrastructure for Real Time Acquisition, Aggregation, Analysis of Data

7. Focus on Capability – Process Characterisation Molecular Particulate Bulk powder Final dosage form Spectroscopic: NIR Other chemical: Analysis to support physical characterisation (GQAD) Crystallographic: X-Ray Powder Diffraction (with Controlled Humidity Chamber) Microscopic: Scanning Electron Microscopy, Optical Microscopy, Image Analysis Thermal: Differential Scanning Calorimetry, Thermogravimetric Analysis Micromeritic: Specific Surface Area, Dynamic Vapour Sorption, Particle Size Analysis Mechanical: Texture Analysis Flow: Powder Rheometry Agglomeration: Air Jet Sieving Moisture: Loss on Drying, Water Activity Density: Bulk and Tapped Density, Helium Pycnometry, Envelope Density Coating Layer Thickness: Terahertz Pulsed Imaging Tablet Dimensions: Tablet Autotester

8. PAT & Data Management Infrastructure Process Char. Lab LIMS SAP ERP BMS PAT Tools 1 – 5kg & 5 – 50kg Equipment

9. Newbridge PDC Competencies • Cross Functional Team with Qualifications, Subject Matter Expertise and Practical Experience in: • Material Science • Powder Properties, Spectroscopic Techniques • Formulation Design • Pharmaceutics, Drug development, Pharmacokinetics • Process Design & Process Engineering • Process development • Analytical Method Design and Development • Spectroscopic Techniques, QbD for methods • Scale-up Expertise, Operational excellence and Lean manufacturing methodologies • Process Analytical Technology and Chemometrics expertise • IT, Automation and Data Management • Software Programming, Automation and Control Systems • Quality and Compliance • Regulatory understanding and application of CFR, GMP and ICH Q8, Q9 and Q10

10. Organisationalstructure to deliver success • NewProducts and Process Development (NPPD) • Accountable for all new product activities from Proof of Concept (PoC) Key operating principles: • “Quality by Design” and “Quality Risk Management” principles embedded • API and Drug product accountabilities • Broad scope – clinical relevance and manufacturing optimization • Smart Development - Do more with less API using QbD and DoEs • Drive Finished Product dosage to support standardized technology platforms • PDC network part of NPPD

11. New Products & Process Development (NPPD) and PDC Network New York PDC Phase 0, 1 Phase 2 Phase 3 Commercial Newbridge PDC Pipeline Newbridge, Ireland Corporate R&D 3rd Party Process Knowledge Pipeline Puerto Rico PDC Puerto Rico

12. Building blocks for integrated Development & Manufacturing • Using Quality Risk Management techniques to drive the level of development activities required to yield the highest level of scientific knowledge • Understand inputs - physical characterisation techniques • Structured development programme - Understand Design space and interdependencies through DOEs • Data management infrastructure - design allows for the ability to Acquire, Analyse, Archive and Report Product and Process Data • Advanced chemometrics and statistical modelling to interrogate and understand data • Process Analytical Technology (PAT) for real time monitoring, prediction and control of quality attributes • Elimination of science of scale through knowledge management, model creation & Management • Regulatory filing (Design & Control space) and elimination of post approval changes

13. PDC – Co-location with ManufacturingA Win - Win • Development co-located with manufacturing at commercial site - • Enhanced technical expertise to support both marketed and pipeline portfolios • Seamless knowledge transfer from late stage development through to commercial • Manufacturing requirements and input earlier into development programme • Influences standardized technology platform selection • Technical training and site upskilling • Reduction in regulatory complexity – Learn before filing • Deployment of PAT “with a purpose” – Pull not Push

14. Looking to the future • Future Opportunities • Leverage from Competence Centres/Clusters – Solid state Pharmaceutical cluster (SSPC) etc • Build RD&I reputation – IP, publications, conferences • Business Process Innovation • RTR & Continuous Manufacturing • Industry Challenges • Availability of personnel with cross functional skills • Alignment and harmonisation of regulatory requirements of EMEA / Japan / FDA & other global markets

15. Summary Build on manufacturing expertise and proven track record • Tech, transfers, scale up, operational excellence Build and deliver on business case • Drive an integrated & innovative approach to development and manufacturing • Focus on smart development and manufacturing excellence • Science driving compliance • Simple PAT solutions Grow a highly skilled, cross functional Team • Diverse backgrounds –formulation & process development, automation, statistics, chemometrics, analytics & engineering Overall result: • Enhanced process knowledge -Defined targets & ranges for CPP and CQA • Enhanced robustness, reduced COGs, elimination of scale up issues

16. Thank You • Questions?