The Third Annual Regulatory and Compliance Symposium Managing Risks – From Pipeline to Patient

1. The Third Annual Regulatory and Compliance SymposiumManaging Risks – From Pipeline to Patient Meeting the Goals of the FDA’s QbD Initiative: Risk Management and Pharmaceutical Development Helen N. Winkle Director, Office of Pharmaceutical Science Center for Drug Evaluation and Research Food and Drug Administration Anjali R. Kataria Co-Founder and CMO, Conformia Principal Investigator, FDA-Conformia CRADA Study

2. Actual Focus of Current Initiatives • Implementing changes in how FDA regulates pharmaceutical products – or improvement in our business processes • Necessity as move into 21st century • Paradigm shift • Evolution – not revolution

3. State of Pharmaceutical Manufacturing • In many cases, not state-of-art as compared to other industries • Able to achieve reasonable product quality – but at a great effort and cost • Little emphasis on manufacturing – mainly on development although manufacturing is approximately 25% of expenses • Factory/equipment utilization rate about 15% • For some products, waste as high as 50% • Inability to predict effects of scale up on final product • Inability to analyze or understand reasons for manufacturing failures • Globally fragmented

4. Consequences • High cost for products due to • Low efficiencies in manufacturing • Waste • Manufacturing time requirements based on testing, etc. • Drug shortages due to manufacturing problems • Lack of improvements based on new technologies • Slowed development/access for investigational drugs • Need for intensive regulatory oversight

5. State of Regulatory Quality Review Processes • Oversight increased – reviewed every change made – increased number of application supplements • Focused on chemistry but not on other important areas (e.g., engineering) • Implemented numerous changes in process to facilitate increasing review requirements (SUPAC, BACPAC) • Issued numerous “how to” guidances (prescriptive) • All standards internally developed • PDUFA requirements speed up review process • More complex products along with new dosage forms • Increased emphasis on focused issues such as counterterrorism, pandemic, counterfeiting

6. Consequences • Too much work • Not enough staff • More and more information from sponsors required (not always relevant) • No flexibility in regulatory process • Impossible to ensure consistency • Discouraged innovation on part of manufacturer because of need for supplements • Assumed all responsibility for product quality

7. The Desired State: A Mutual Goal of Industry, Society, and the Regulators A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight. Janet Woodcock, M.D.

8. Characteristics of the Desired State • Quality is controlled by industry • Manufacturers have extensive knowledge about critical product and process parameters and quality attributes • Knowledge comes from product development, prior experience, studies, scientific and technical literature • Use that knowledge to understand product risk and risk mitigation • Use that knowledge to determine appropriateness to make manufacturing changes • Manufacturers control process through quality systems over life cycle and strive for continuous improvement • FDA’s role is to do initial verification and subsequently audit

9. Moving Toward the Desired State • Philosophy – “Quality should be built into the product, and testing alone cannot be relied on to ensure product quality.”

10. Benefits of New Paradigm to FDA • Enhances scientific foundation for review • Better coordination across review, compliance and inspection • Improvement in what is required for regulatory submissions • Better consistency • Improved quality in review (establishing a QMS for CMC) • More flexibility in decision making • Decisions made on science and not on empirical information • Involves various disciplines in decision making • Uses resources to address higher risks

11. Benefits to Industry • Design better product with less problems in manufacturing • Reduce number of manufacturing supplements required for post market changes – rely on process and risk understanding and risk mitigation • Allow for implementation of new technology to improve manufacturing without regulatory scrutiny • Possible reduction in overall costs of manufacturing – less waste • Less hassle during review – reduced deficiencies – quicker approvals • Better interaction with FDA – deal on a science level instead of on a process level • Allow for continuous improvements in products • Better understanding of how APIs and excipients affect manufacturing • Relate manufacturing to clinical during design • Better overall business model!

12. Next Steps • Evolution • There are definitely obstacles to change and a lot to learn – gaps in science, knowledge, risk and risk mitigation • Need to determine the applicability to risk management to manufacturing process • What is appropriate information to submit in application based on current product development data? • Need appropriate guidance to guide industry and FDA staff • Training, training, training • Will continue to work with industry and others to learn – CRADA with Conformia is a perfect example of how this is being done

13. FDA – Conformia CRADAFindings from Part 1Opportunities, Priorities and Challenges in Implementing FDA’s Desired State August 23, 2007 Anjali Kataria Principal Investigator FDA-Conformia CRADA

14. CRADA Is Focused on Manufacturing Aspects Drug Development Conformia research focus

15. Key Objectives & Outputs of CRADA Objective Expected Output • Analyze Root Cause: Identify existing root causes of bottlenecks in drug development resulting in inefficiency • Assess Guidelines: Describe gaps, perceptions, and usefulness of existing guidance related to pharmaceutical development. • Describe Current State Practices: Summarize current state of pharmaceutical development, challenges, opportunities, and top of mind issues facing development organizations. • Identify Potential Future State: Define requirements needed for companies to implement Quality by Design (QbD) closed-loop, continuous improvement, process understanding approach to new drug development. • Educate: Increase familiarity of key initiatives, new technologies and future state possibilities • Company Readout:Identify current state practices / top of mind issues internal to participating companies. • Final Report / Benchmarking Briefing: Roll up results of all preliminary phase company participants ( Phase 1 )and loose comparison • FDA Briefings: Communicate to FDA current perceptions in understanding, expectations of future agency guidance; opportunities for streamlining guidance. • FDA Reaction:Conformia to share FDA’s feedback with participating companies. • FDA Workshops: Conduct Internal FDA Seminars to educate FDA on key areas: Development Process, QbD, Design Space, PAT. 8/8/2014FDA-Conformia CRADA Briefing Confidential Confidential 15

16. Research Agenda Was Split Into Two Parts RESEARCH PRODUCT / PROCESS DEVELOPMENT OPERATIONS Pre-Clinical Prepare Submission Lot release Research Clinical Approval Mfg Distribution CMC/Process development Registration Phase Part 1 Part 2 I. PAT / QbD / ICH Design Space II. Information Management III. Regulatory Interaction IV. Commercialization V. Collaboration Management VI. Communication / Decision Making • QbD Initiative • Prior successes • Adoption of QbD Concepts Process Capabilities Technology Capabilities • Systems & Tools • Metrics • Implementation Plans • Perceived Benefit • Skills and People Capabilities Organization al Capabilities Regulatory Perspective • Feedback on current guidance/regulations • Confidence in FDA Commitment Topics completed; ready for final report 8/8/2014FDA-Conformia CRADA Briefing Confidential 16

17. Participating Company Demographics At Present 9 participating companies. (Will expand to 25 companies.) 7 of these have a biotech division participating in the study or are a standalone biotech company. Designated by: Collectively: 350+ commercial products to market Parallel and multi-site development activities occurring at all 9 companies All 9 companies using CMOs in Development process / tech transfer Relative Company Size* Smaller Larger 9 Participating Companies *Based on 2005 Annual Revenue, # of Employees, Number of Development Sites, Number of Commercial Sites 8/8/2014FDA-Conformia CRADA Briefing Confidential Confidential 17

18. Assessment Tool to Map Differences In Current Practices 4 Integrated Enterprise-Wide 3 Partially Enabled 2 Emerging 1 Ad-hoc / Not enabled Related FDA Initiatives Stages of Enablement Ad-hoc processes Exists, but in multiple silos Limited harmonization across the enterprise; some systems adopted as standard Single Process Frame for development integrated with external partners Clear Technology strategy Process Capabilities Technology Capabilities No formal initiative Exists, but in multiple silos Formalized; Initiative spans cross-functional groups Stage 3 + FTE’s Assigned Initiatives integrated into daily operations Organizational Capabilities Not very strong Limited involvement or support by Senior mgmt “Top down” Sr. mgmt support across the organization Executive Mgmt support translated into formalized initiatives Interaction with regulatory bodies limited to regulatory and quality Some awareness and efforts exist to adopt initiatives Open dialogue across functions with regulatory bodies; recognizing the need for direction setting and uniformity Uniform definition of concepts; clear plans across the company Cross functional bi-directional sharing of ideas and perspective with FDA Limited awareness of FDA initiative; no clear definitions and internal understanding of concepts Regulatory Interactions 8/8/2014FDA-Conformia CRADA Briefing Confidential Confidential 18

19. Findings: Implementation of QbD Across Group is Moving in the Direction of Integrated Enterprise Wide 1. Ad-hoc / Not enabled 3. Partially Enabled 4. Integrated Enterprise-Wide 2. Emerging Awareness & Understanding • QbD Initiative • QbD Definitions • Prior Successes Process & System Capabilities • Use of Systems/ Tools • Elements of QbD • QbD approach applied consistently across development operations Implementation • Implementation Plans • Perceived Benefit Organizational • Management Support • Confidence in FDA Commitment Source: Qualitative Analysis based on CRADA interviews 8/8/2014FDA-Conformia CRADA Briefing Confidential Confidential 19

20. QbD Initiatives in Place & Coming Source: AMR 74% of manufacturers say they either already have or will have in the next 12 months a QbD initiative in place % of Responses. N=95 Confidential

21. Top Priorities for Implementing QbD at Companies • Design Space • Process, Formulation and Analytical Design Spaces • Changes within Design Space / Notifications to agency • Product /Process Attributes • Drug Substance and Drug Product attributes as determinants of process end points • Risk Assessment • Establishing the methodology and information required to present risk assessment in a submission • Linking risk assessment to control strategy • Prior Knowledge • From previous submissions • From internal information, successes, failures and learning's 8/8/2014CMC-IM Working Group Confidential Confidential 21

22. Top Priorities for Implementing QbD at Companies cont. • Manufacturing Principles / Commercial Direction • Post Approval Changes • Product/Process Lifecycle Management – Continual Improvement • Feedforward and Feedback • On the Horizon: • The link between CMC specifications and clinical endpoints Confidential

23. Top Obstacles to Broader Implementation of QbD by Companies • Perceived commitment of QbD by FDA across Review, Field, and Policy Teams • Lack of harmonization of QbD across FDA, EMEA, PMDA • Lack of executive leadership within companies driving QbD “top down” • Lack of organized cross functional leadership across lines of business • Formulation, API, Analytical, Quality, Regulatory, Commercial Manufacturing and Information Management all need to be involved • Confusion over core ICH Q8 / Q9 terminology Confidential

24. Top Obstacles cont.. Lack of clear regulatory benefits / regulatory flexibility Need to showcase a compelling business case Difficulty accessing prior knowledge despite significant investments in portals / online document management Underdeveloped business process strategies to support product / process lifecycle information No master formulation or master API repositories of product/process science information Yet succeeding at QbD will require a master data management strategy to support product/process attributes and prior knowledge approaches. Confidential

25. Overall Observations Most companies had well documented development processes (roadmaps, technical briefs etc.) Though few companies had aligned these development process maps with the FDA’s QbD approach such that key decision points encompassed/aligned with QbD goals Top obstacles include: Poor information management supporting product/process lifecycle across development FDA’s perceived commitment to drive QbD across reviewers, inspectors and policy team Harmonization across PMDA, EMEA, FDA. Dialogue between industry and agency is helping companies translate concepts into practice / develop more case studies FDA-Conformia-PhRMA Workshops for Cross Functional Senior Leadership OPS Pilot Programs /Industry Meetings (ISPE, AAPS, PhRMA etc.) More communication between FDA and Industry regarding FDA’s implementation plans to support training of Reviewers and Inspectors in this new paradigm will help move QbD forward Confidential

26. Thank You Confidential