Complexity of the Process Pre-Submission Drug Development

1. Complexity of the ProcessPre-Submission Drug Development July 26, 2012 Rockville, MD

2. Obstacles to Generic Animal Drug Approvals • Third in our series of “Obstacles” presentations • April 2011: GADA detailed overall time to approval and the complexity of the process; joint BE and CMC subgroups were the result. • Significant investments are required before the processes begin, as discussed by the BE and CMC subgroups. • This presentation is intended to illustrate the complexity of the pre-submission drug development process.

3. Assumptions • Most of these activities occur prior to those detailed in the “obstacles” timeline • Pre-submission conferences may occur during these development activities (one or two, depending on complexity of the project)

4. Phases of Pre-submission Development • Product Selection • Sourcing • CMC • Biowaiver • BE Study

5. Product Selection The process for identifying prospective products varies significantly among Sponsors… • Evaluating patent and market exclusivity • Evaluating current market size (volume and $) • Assessing ability to penetrate that market/ potential market share

6. Product Selection • Access to pioneer product • Access to API • Access to excipients • “Product fit” with current capabilities • Manufacturing, packaging, marketing, customer base • Cost of goods • Market assessment impacts cost of goods • Purchase quantities • Batch size

7. This cost/benefit analysis must be performed to determine whether to move forward with a product

8. Sourcing • Reference Product • API • Excipients • Manufacturing facilities (in-house or CMO) • Analytical laboratories • Packaging/Final Market Container and Closure

9. Sourcing Considerations • Availability of Reference Products • API Selection: • Existing (V)DMF; other FDA manufacturing experience; alternate sources • Supplier Qualifications: • FDA Inspection; sponsor audit; business, supply and quality agreements; confirmatory testing

10. Sourcing Complexities • Upfront Development Costs • Development-scale Purchases • Minimum Annual Purchase Agreements • Supplier Continuity and Engagement • Supplier Disruption • Force majeure events • Regulatory/cGMP Compliance • Shortages, including starting materials and intermediates

11. Obtaining qualified suppliers is a critical factor in the early drug development process

12. CMC • Formulation development and optimization—QbD • Laboratory batches and stability • All method development and validation • Specification development • Sterilization process validation (if needed) • Process development • Product development report • Manufacturing equipment/facility construction or reconfiguration (if needed)

13. Biowaiver • Deformulate and reverse engineer reference formulation, or refer to pioneer label • Establish Q1, Q2, Q3 • pH determination • Buffer capacity • Source raw materials (API and excipients) • Obtain COAs • Develop labeling

14. BE Study • Formulation development/lab batch/stability • Bioanalytical method development/validation • Sourcing: • Site selection (test facility, analytical lab, statistician) • Test Animals • Seasonal/Regional Considerations • Pilot study – 6 to 9 months for: • Protocol development • Animal phase • Analysis/data • Statistical analysis

15. BE Study • Evaluate results, repeat if necessary • Acceptable pilot study and stability for lab batch results are required prior to manufacturing submission batch • Develop and submit pivotal BE protocol

16. Collectively, these five processes take years to complete, and the costs are quite significant… and this is before we’ve begun the pivotal drug development and regulatory review phase

17. Thank You!