Technology to meet the needs of patients around the world Dr. Michael Thien, Senior Vice President Global Science, Technology and Commercialization Merck & Co., Inc.
Our Past Scientific approach applied Across all issues With various depths based on scientific know how Focus was on process performance Filed result was often Single parameter ranges Process descriptions Emphasis on ranges, focused on process capability Traditional Approach 2
Paradigm Shifts Recent emphasis on science, patient, disciplined framework refocuses the science Identify what s critical to the patient Understand process risks to patient needs Use great science to more holistically understand and manage risks 1 st principle Models Multi-variable parametric space Etc Create pro-active means of controlling critical aspects of process Incl. PAT Create means to continuously improve process with scientific approach Quality by Design Target Product Profile Critical Quality Attributes Risk Assessment Design Space Control Strategy Life Cycle Management Six Sigma Methodology Concept Design Optimize Verify DMAIC Lean Lean Six SIgma Design for Six Sigma (DFSS) Note: This does not replace Science 3
Our initial experience (2006) JANUVIA mono therapy product development and launch 2006 Followed QbD principles Approved in > 60 markets world-wide Experiences after 5 years of production Very robust process, very few atypicals on a highvolume product Allowed to increase volumes multi-fold from initial forecasts to satisfy patient needs Successful tech transfer to support expansion of production to other manufacturing sites Significant efficiency gains through Real-Time Release Testing FTE 6.0 5.0 4.0 3.0 2.0 1.0 0.0 RTR Economics - FTE's 2007 2008 2009 2010 2011 2012 PP FTE Savings Total FTE for RTR Based on this success we had appetite for more Year Increased scope of QbD and PAT applications for in-line products (API) Increased complexity of applications (combination product) 4
API Synthesis improvement (QbD for in-line product) 1 st Gen Process Alternate Chemistry Process Intermediate A Intermediate B Hydrogenation Fixed: IPA, FB & Water Isolated Freebase Final API 2-step process Transamination Non-Isolated Freebase Variable: IPA, FB, Water, DMSO, & IPAc Final API Through process Not viable without QbD/PAT as enabler F F 45wt% H 3 PO 4 F F O O NH 2 O NH 2 Transaminase N + N N N + F N N PLP F N N CF 3 CF 3 Flexibility in Rxn & Workup O Requires PAT/QbD/LSS as Assures Quality for the Patient 5
Combination Product/Bi-layer Tablet Fixed dose combination tablet for the treatment of T2DM patients also requiring lipid lowering management. Strengths: 100/10, 100/20, 100/40 Sitagliptin/Simvastatin Product 100/10 mg 100/20 mg 100/40 mg Film Coating Simvastati n granule Sitagliptin DC blend (JANUVIA) PAT-enabled feed-back controlled process Active A and excipients PAT feed back High shear granulation Blending lubricant Drying Lubing PAT feed back Milling lubricant Lubing Bilayer Compression PAT feed back PAT feed back Film Coating Coating dispersion Active B and excipients QbD benefits realized: Scale independent process Feedback control via PAT allows efficiencies Modeling accepted in lieu of formal stability study for a package Zero observations in Pre-approval inspection Finished tablets 6
But: The foundation markets Foundation Markets: US, Japan, EU, Canada Our World is changing Patient Unmet medical needs Higher bars on differentiation, safety Supply Chain Reliable, compliant supply Customer Pricing pressure Requirements for specific populations Geriatric, pediatric have not stood still 7
Our new paradigm can address some of it Foundation Markets: US, Japan, EU, Canada Our World is changing Patient Unmet medical needs Higher bars on differentiation, safety Supply Chain Reliable, compliant supply Customer Pricing pressure Requirements for specific populations Geriatric, pediatric [ Target Product Profile CQAs Risk Assessment Design Space Control Strategy The QbD paradigm: - assumes we know the process answer - focuses on patient, not customer Life Cycle Management Quality Management system/ Quality Risk Managment and Lean Six Sigma 8
But we must address the need for innovation Foundation Markets: US, Japan, EU, Canada Our World is changing Patient Unmet medical needs Higher bars on differentiation, safety Supply Chain Reliable, compliant supply Customer Pricing pressure Requirements for specific populations Geriatric, pediatric General roadmap for technology innovation Identify General Needs Identify Specific Needs Translate to Technical Criteria Identify Technical Options Options Risk/Benefit Assessment Develop and create operating space Create Reliable Manufacturing Scheme Allow for Continuous Improvement 9
We already have a lot of the tools Identify General Needs Identify Specific Needs Translate to Technical Criteria Identify/Create Technical Options Options Risk/Benefit Assessment Develop and create operating space Create Reliable Manufacturing Scheme Allow for Continuous Improvement } } } } } } Target Product Profile CQAs Risk Assessment Design Space Control Strategy Life Cycle Management Identifying needs and options remains a key issue 10
And the world is bigger than it used to be The World Economic Pyramid Individual annual income (2005 USD in Purchasing Power Parity) We ve just been talking about this Mature markets: > $20,000 Emerging markets: $3,260 to $20,000 but how about this? Survival Markets: < $3,260 Source: World Resource Institute 2007, http://earthtrends.wri.org/updates/node/50 11
Challenges of Emerging Markets BRIC+TK+ others Geographical South-East Asia/South America =>70-90 % of growth expected here Compound annual growth rates (CAGR) 1 2011-2015 US, Europe, Japan 0-4% China 19-22 % India 11-14% Who are these new customers? These new customers bring different challenges Huge pricing challenges In some cases, existing generic therapies Very different consumer habits Very different supply models Supply Chain integrity issues Distribution and Logistics issues Local Manufacturing Requirements => All will require new technologies Sources: 1: Pharmtech.com, June 2011 12
1 Customers & Markets From Customers to Technologies Patients providers payers regulators society Established Markets: Aging population, poor adherence, integration: diagnosis & treatment, novel treatments Emerging Markets: Needs-based products, throughput, lower costs, local presence, logistics & access 2 Our Business Franchise strategies, geographical strategies, core business growth, adjacent business growth 3 Product Requirements Low-cost API, fixed-dose dose comb., adherence-friendly pkg., diagnostics on paper, verification 4 Manufac. & Supply Technologies Equipment designs, process control technology, packaging, logistics tech. 5 Information Technologies (Production & Information) Communication, information, enterprise technology SIPAT 13
End in Mind: Anatomy of a Tech Roadmap Mock Up Example: Solid Oral Dosage Forms RM to Bulk Product Tech Road Map (Note: Bulk Product to Customer would be covered on another map as we have structr Major Tech Category Market Segments Products/Franchises of Focus & Their Plans i.e.. Commercial Strategy Premium/Existing Mkts Emerging Mkts Middle Class Bottom of the Pyramid Year 1H2011 2H2011 1H2012 2H2012 1H2013 2H2013 1H2014 2H2014 1H2015 2H2015 MK-XXXX Products/Technologies In-Use Clinical MK-YYYY Projects not funded Clinical MK-ZZZZ Projects Funded/In Progress BG MK-XXXX Technology in Commercialization BG MK-YYYY AcqR BD India 7.2 BD China Dragon X BD Turkey Korea - TTTJ BD Phoenix 2 Innovation BoP Product/Service Innovation BoP Product Innovaion BoP Product Sandwich in Business & Organization Models Physical Technologies Business & Organizational Models RM Technologies API Technologies Grand Challenge Pilot BGx Operating Model External Development Exp Low Cost API Tech Exp Blah Blah Exp Blah Exp Blah Exp Blah Exp Balh BoP Product Development Partner Network Exp Blah Formulation Tech Exp Blah Dotted Lines Indicate Connections Between Commercial & Technology Work Color is Type of Activity Required Exploratory, Vs. Incremental Innovation
Examples of Frugal / Reverse Innovation Developed & Adopted first in Developing World, then moves to Developed World General Electric Disrupting Itself $1K portable ECG Device developed in India, 1/5 to 1/10 th cost of conventional device $15K Portable Ultrasound Device developed in China, 1/7 th to 1/25 th cost of conventional device Both now sold in USA Eco-friendly $2500 Tata Nano Offering a better alternative to 2-wheelers Sachets (soaps, shampoos, detergents..) ~ 5 cents / shampoo sachet 15
Putting it all together: Quality by Design + Customer & Technology Innovation Mock Up Example: Solid Oral Dosage Forms RM to Bulk Product Tech Road Map (Note: Bulk Product to Customer would be covered on another map as we have structr Premium/Existing Mkts Emerging Mkts Middle Class 1H2011 2H2011 1H2012 2H2012 1H2013 2H2013 1H2014 2H2014 1H2015 2H2015 MK-XXXX BG MK-XXXX BG MK-YYYY AcqR Clinical BD Clinical India 7.2 BD MK-YYYY Identify general needs MK-ZZZZ Identify and create technical options China Dragon X BD Turkey Korea - TTTJ BD Phoenix 2 Products/Technologies In-Use Projects not funded Projects Funded/In Progress Technology in Commercialization Target Product Profile CQAs Risk Assessment Design Space Target product profile to include customer and contextual needsunique needs for new customers (dosing, combination products, packaging, etc.) Control strategies: Advanced in some manufacturing sites Basic in others Always supporting lean/six sigma Bottom of the Pyramid Business & Organizational Models RM Technologies API Technologies Formulation Tech Innovation Innovaion Grand Challenge Pilot BoP Product BGx Operating Model External Development Development Partner Network Exp Low Cost API Tech Exp Blah Blah Exp Blah Exp Blah Exp Blah Exp Balh Exp Blah Exp Blah BoP Product/Service Innovation BoP Product BoP Product Control Strategy Life Cycle Management Life cycle management: Can we prepare for Technology transfers? Customization? Volume changes? 16
Imagine the possibilities Mobile Apps At Home Patient Education & Health Checks Smart reminder packaging Medication Reminders Health Portal Conventional packages with 2D bar code 17
Conclusion QbD is powerful paradigm for supporting patient Needs to be inclusive of the customer needs, wants and likes Add the ability to inject innovation (via integration of technology roadmap) and we can address our changing world QbD and innovation are not mutually exclusive QbD approach can enable innovation 18