End to End Development. Tackling the Challenges of Today s Pharmaceutical Industry

Transcription

1 End to End Development Tackling the Challenges of Today s Pharmaceutical Industry John Curran Global CMC Regulatory Affairs Merck Manufacturing Division Oct

2 Scope of Presentation Development Challenges Define End to End Development Building the Business Case The Need for Speed (JANUVIA) Example of Development Challenges (SINGULAIR Oral Granules) Establishing End to End Development at Merck E2E Enablers Impact of End to End Development Questions and Discussions Oct

3 Group Discussion What are today s biggest challenges bringing a pharmaceutical product from concept to launch? Oct

4 Development Challenges Achieve Speed to Market(s)/Keep Formulation Development off the Critical Path Assure Robust Formulation, Process, Methods Meet Regulatory Requirements Gain/Capture Product and Process Knowledge Achieve Optimized Economics (Cost/Supply Chain) Oct

5 Requirements Outside Focus of This Presentation Identification/Qualification of a suitable Drug Candidate Design and Execution of Clinical Program Clinical Drug Supply Investigational Filings Oct

6 End to End Development A systematic approach* which looks holistically at product life cycle during the development phase, in order to efficiently and effectively position the drug product to best serve both the long term patient/market needs and provide optimum ROI for the company. Strongly enabled by Quality by Design principles Significantly leverages Strategic Sourcing Appropriately leverages Prior Knowledge and meaningful Market Projections * - The approach must have a foundation based on Scientific Excellence Oct

7 BUILDING THE BUSINESS CASE FOR END TO END DEVELOPMENT Oct

8 Potential Development Results (Best to Worst) Meet clinical outcomes; gain regulatory approval; successful worldwide market launch; robust, long term supply Failure to meet clinical outcomes Failure to achieve regulatory approval Regulatory approval; unable to launch Regulatory approval; successful launch; long term supply challenges/recalls Regulatory approval; launch; safety, efficacy, stability or manufacturing driven market withdrawals Oct

9 Audience Poll #1 Which is MOST IMPORTANT to you/your Company? 1. Regulatory Approval 2. Economics 3. Robustness (Process and Supply Chain) 4. Speed 5. Knowledge Oct

10 THE NEED FOR SPEED Oct

11 Competition/Rapid Market Entry Huge Competitive Advantage to be First- To-Market Followers need to show advantages over Pioneer Compound Significantly more difficult for late followers to gain market share without redefining market Oct

12 JANUVIA Initially behind competitor in development Strategies developed to erode competitor market share Competitor s clinical delays allowed JANUVIA to be first DPP-4 treatment approved for Type II Diabetes; JANUMET (combo with metformin) approval closely followed JANUVIA JANUVIA/JANUMET launch forecasts and initial sales significantly were greater than early projections* Competitor (ONGLYZA) gains approval as second market entry; facing challenges of implementing strategies to erode JANUVIA sales * Increased demand presented Supply Chain Challenges!!! Oct

13 High Speed Risks/Challenges Oct

14 Speed-Related Challenges Achieving Process Knowledge and Experience in Less Time Product/Process Optimization (quality, robustness, economics) Decision-making Based on Less Data (clinical, financial, formulation, sourcing, etc) Condensed Launch Preparation Timeline (site readiness, capacity planning, etc) Increased Regulatory Requirements for Approval (Worldwide) Oct

15 JANUVIA SUPPLY Assuring supply to meet increased demand involved: Order for additional outsourced raw material (lead time and scheduling considerations) Manufacture and release of drug substance (scheduling/capacity) Manufacture, release and packaging of tablets (scheduling/capacity) Distribution Oct

16 Example of Development Challenges SINGULAIR Oral Granules Oct

17 SINGULAIR Oral Granules Background Development through launch followed a traditional, formal milestone-driven strategy (~ ) Merck had successfully developed and launched filmcoated and chewable tablet formulations OG is a simple granulation manufactured and unit dose packaged in aluminum sachet (about the size of a sugar packet) Active ingredient (montelukast sodium) is light sensitive, hygroscopic and subject to oxidation The product was targeted for global marketing Strategy contained some elements of current E2E and QbD approaches Oct

18 Packaging Challenge To provide a unit of use presentation for the patient, a prescribed quantity of granulation needed to be packaged into an aluminum sachet, and the sachet needed to be sealed. Each sachet must deliver drug in accordance to standard dose uniformity requirements. Seal integrity was needed to minimize product exposure Merck did not have internal technology to perform unit dose packaging of sachets. Merck pipeline at that time did not include other granule products; internal capital investment for a single product was high. External packaging companies were evaluated and a suitable technology was identified to perform packaging for commercial supply. Supply and Quality Agreements were executed with this external party. Oct

19 ISSUE: Supply Chain Challenges (Economics) As a unit dose package, significant information was required or desired on the sachet (opening instructions, product name and dose, ingredients, Company name, etc). Required information on the sachet differed from market to market Since the product was to be global, information was required in multiple languages A set batch size was developed for granulation and packaging operations Market forecasts varied significantly from multiple batches to small portions of batches Issue identified during development after approval of package definition and development of product PGM estimate. CHALLENGE How to supply varying quantities of sachets to appropriate markets, printed in correct language with the required information without significant impact to PGM??? SOLUTIONS Consolidated number of sachet printing variations from >100 to <30; Modified packaging operations to allow sub-batch printed foil changeovers; Created release testing strategy which allowed for release of sub-batches based on full batch testing. Oct

20 Issue: Supply Chain (Logistics) Supply chain (initially sequential): 1. Manufacture granule 2. Release testing on granule 3. Bulk packaging of granule 4. Ship to external packaging site 5. Reblend granule 6. Package into sachets 7. Ship sachets to internal release site 8. Release test and final product release 9. Ship to distribution centers Complex supply chain and testing requirements resulted in a significant time cycle between charge of active (start expiry clock) and final delivery of finished product for distribution. Issue identified late in development program, following completion process development and site selection. CHALLENGE reduce cycle time to maximize remaining expiry upon receipt at distribution sites (many required min 75% of original expiry) SOLUTION Perform risk analysis to determine which steps can be done prior to completion of prior step; Optimize planning schedule to reduce downtime between steps Oct

21 End to End The Solution? Oct

22 ESTABLISHING END TO END DEVELOPMENT AT MERCK Oct

23 End to End Product Development Goals Achieve meaningful speed to market while assuring acceptable product performance, process robustness and regulatory approvability Strive for continual optimization (e.g. process economics) during development and post launch Leverage QbD approach to increase product knowledge Achieve strategic utilization of company owned resources/capacity for certain key operations while strategically outsourcing other fundamental or specialty operations Establish a company structure that assures consistent application of the defined approach Identify the long term project specific goals and requirements, and champion each development program to achieve this strategic vision Oct

24 Organizational Structure Early Development (MRL) Phase I IIA Commercialization (MMD) Phase IIB Launch and Initial N years of Supply Supply (MMD) Long term supply through product deletion or divestiture (includes External Manufacturing group) Oct

25 Business Processes Overview Business Processes create consistent ways of operating. These processes monitor (1) Early development (ED) projects (2) Transition from ED to Commercialization (3) Alignment of functional optimization plans (4) Transition to supply POC D R U G D E V E L O P M E N T P R O C E S S Preclinical Early Stage Clinical Late Stage Clinical Launch Long-term Supply Integrated Development and Supply Plan (IDSP) Early Development Line of Sight (LOS) 4 Supply Early Monitoring & Entry to Commercialization API, Pharm, Analytical, Operations, Human Health, Supply Chain Transition to Supply Oct

26 Business Processes Overview Line of Sight (LOS) What is LOS: View of product until five years after launch Examines the five major attributes affecting commercialization 1. Priority to Company/POS 2. Speed 3. Volume 4. Economics 5. Complexity Benefits of LOS: Creates alignment and shared understanding Highlights risks and immediate needs Serves as the basis for planning the IDSP Enables planning to Most probable and not Worst case ED Line of Sight (LOS) Supply Inputs include: Marketing forecasts Clinical/safety info/needs Key milestones Process development status POC Supply chain considerations Product cost information POS factors Regulatory/CMC requirement D R U G D E V E L O P M E N T P R O C E S S PCC I IIA IIB III Launch Long-term Supply Oct

27 Business Processes Overview Integrated Development & Supply Plan (IDSP) What is IDSP: A holistic plan for meeting LOS requirements Living document IDSP include: Development targets and timelines Risk mitigation plans Resource and facility needs Clinical supply strategy Launch supply strategy Regulatory/CMC strategy Transition to Supply IDSP enables: Tracking/measuring progress Team decision making Portfolio analysis and resource management Consistent communication with governance, partners, stakeholders ED Integrated Development and Supply Plan (IDSP) Line of Sight (LOS) Supply Inputs include: Marketing forecasts Clinical/safety info/needs Key milestones Process development status POC Supply chain considerations Product cost information POS factors Regulatory/CMC requirement D R U G D E V E L O P M E N T P R O C E S S Oct 2011 PCC I IIA IIB III Launch Long-term Supply 27

28 End to End Enablers Product Specific Development/Execution Team Cross functional team including Pharm, API, Analytical, Supply Chain, Regulatory and Marketing Functional subteams Dedicated Team Leader fully responsible for execution. Cross program governance structure Quality by Design QbD Continuum (applies to all Development Programs) Target Product Profile (TPP) Critical Quality Attributes (CQAs) Risk Assessments (DP, DS, Raw Materials, etc.) Development/Scale-up (Design Space determination, PARs) Control Strategy Product Life Cycle Management Understanding Regulatory Requirements/Expectations Strategic Sourcing (Internal and External) Oct

29 Merck Product Lifecycle Process Quality by Design Milestones PMF Strategy PMF Defined PMF Preliminary Market Formulation LOS Line of Sight IDSP Integrated Development & Supply Plan WMA filed LOS V1.0 IDSP V1.0 IDSP V2.0.,etc.. Product strategy Team Ownership Target Product Profile (TPP) Control strategy QbD Embedded into LOS QbD Strategy Review Control Strategy Review 1 Integrated QbD Execution Plans Across functions Control Strategy Review 2 Final Control Strategy Review Feedback Between: Supply Development Risk Assessment (RA) Functional Ownership Early Dev. RA API RA Late Dev. RA Design space definition / & risk assessment updates Cont. improvement / process monitoring Oct

30 Regulatory Complexities Changing expectations worldwide Emerging Market requirements Locking in on launch process Site selection/pai readiness Dead zone between filing and launch FSS/Site Stability Oct

31 Strategic Sourcing When and what operations to outsource or keep internal Selecting an appropriate facility/supplier/partner Executing technical and knowledge transfers Managing external providers Assurance of continued supply (multi-sourcing) Positioning for post-approval supply changes Oct

32 The Benefits of Employing an End to End Development Process Oct

33 JANUVIA/SINGULAIR Examples Would E2E Development Process Have Minimized These Issues? JANUVIA Supply Chain Tracking forecasts would have likely highlighted the potential for increased demand earlier if first to market, resulting in a more proactive capacity plan contingencies SINGULAIR Packaging Very likely the same decision to outsource packaging would have been reached; however LOS for Supply may have been better defined. SINGULAIR Economics LOS/IDSP would have alerted to needs for multiple printed foils allowing for consideration during package definition SINGULAIR Supply Chain Complexity Advanced assessment of supply chain would likely have highlighted the potential for an extended manufacturing cycle, allowing for optimization during development Oct

34 Regulatory/Sourcing Challenges E2E addresses these through: More proactive long term planning and awareness Detailed risk assessments and associated mitigation Required updates to plan when assumptions change Increased focus on product lifecycle Oct

35 Our Conclusion End to End Development A Recipe for Success Oct

36 Questions & Discussion Oct