FDA Coming Attractions What You Need To Know

1. FDA Coming Attractions What You Need To Know Current Trends and Industry Practices Thursday, September 28, 2006 PDA Dinner Meeting

2. Agenda • How Did We Get Where We Are • The Reinvention of FDA • The Business Case for Change • Restructuring for Quality • What are the Key Trends • FDA’s New Regulatory Framework • Quality by Design • New Approaches to Inspections

3. Office of Pharmaceutical Science More Staff assigned to implement QbD Office of Drug Quality Assurance Established to accommodate new vision for CMC review process Office of Biotechnology Products Adapting quality by design principles to large molecules Office of Generic Drugs Instituted Question-based reviews and adopted CTD formats Office of Testing and Research More Resources to understanding PAT as analytical tools ORA and Office of Compliance Pharmaceutical Inspectorate What we’ve not seen is how FDA management reviews will monitor performance, what acceptance criteria FDA has set for goal accomplishment, and how the Agency’s continuous improvement program will be implemented with all these initiatives. The Reinvention of FDA: A Framework for Continuous Improvement…

4. FDA Reorganization to maximize resources using science and risk based tools Question-Based Reviews for Generics Pilot CMC submission, ongoing dialogue CTD formats for submissions, promotion of e-submissions Quality by Design Regulatory Flexibility Proposed Risk Based Inspections Instituted Pharmaceutical Inspectorate The Journey so Far..

5. Prior Focus on: End product and in-process testing Follow the validated procedure All deviation are equal Change is Bad New focus Cost of Quality (Flexible Regulatory Approaches) Quality by Design (lower risk of operations) Continuous Improvement (Optimize change management) cGMPs for the 21st Century Risk-based orientation Science-based policies Integrated quality systems Public Health Protection International Cooperation Mass revocation of 7 CMC and stability guidelines, replacing them with ICH guidance documents. Q8: Pharmaceutical Development Q9: Risk Management Q10: Pharmaceutical Quality System Clearly the momentum for change is strong, but will the new regulatory and manufacturing concepts take hold? Drivers

6. FDA’s business case for change, they claim, is to loosen the regulatory bonds that constrain industry. • Adjust level of regulatory scrutiny commensurate with public health risk • A risk based approach to product quality regulation set the stage: Pharmaceutical cGMPs for the 21st Century • This initiative aims at ensuring that regulatory review, compliance and inspection policies are based on state of the art pharmaceutical science, and do not impede rapid adoption of new technological advanced by the pharmaceutical industry. • The Big Question: • How much risk is enough, and are we already trapped in a corrective action crisis?

7. For FDA, will the future be increasingly defined by a declining drug pipeline, growing product complexity, and diminishing resources? Innovation /Stagnation: FDA 2004

8. High Expectations and Major Obstacles

9. For a decade, the enforcement strategy has seen drug recalls climb and the FDA’s ability to perform inspections decrease.

10. The new definition of FDA regulation will drive toward targeted enforcement and flexible regulation as….. ….Drug Product Quality Defects Are Tied to Product and Process Design Issues.

11. Common Inspection Observations underscore product and process control as key concerns for FDA. Source: Robert Coleman, FDA National Expert

12. But as we seek to control risk with QbD, Risk Management and Quality Systems, how much risk are we willing to take versus the cost of quality? For many products and processes: Process Quality at about “2σ”? Product Quality > “5σ”?: Are we not trapped in a “corrective action crisis” and wasting resources? Ajaz S. Hussain, Ph.D. 28th Annual Midwest Biopharmaceutical Statistical Workshop

13. ICH Q8 and Quality By Design A Discussion

14. Quality by Design will become a major element in the future for new products as well as existing products.

15. A key strategy for the FDA is to reduce the number of supplemental applications for review, while providing industry with regulatory flexibility to make changes.

16. Example: Traditional IQ, OQ and PQ for validation is costly and often impedes continuous improvement. Emphasis on full-scale replication Validation lots viewed as evidence of process reproducibility prior to commercial launch Encourages fixed processing conditions, discourages process improvement The new strategy will require industry reinvention at multiple steps. Variability Manufacturing Process Raw Materials Product Locked Process Variables

17. Process Validation Guidance Revision Design Design/Development Phase Confirm Commercialization Phase Monitor and Assess Maintain and Optimize Knowledge to be gained during production The new paradigm may actually reduce non-value added activities such as numerous approvals, over-documentation and over-testing Manufacturing Process Raw Materials Product Input Response Endpoint Response Measurement Dependant Variables Therapeutic Response

18. CMC Pilot Program is One Step in This Direction. • Objectives: • Participating firms submitted CMC information based on QbD • FDA Implemented Q8, Q9 and Q10, PAT during the review. • Target: 12 Original or supplement NDA • Status: 1 approved, 2 under review, 8 to be submitted • Submission Criteria • More relevant scientific data • An expanded Pharmaceutical Development • A Comprehensive Quality Overall Summary • A Proposed CMC regulatory Agreement.

19. The project aligns nicely with ICH Q8 – Regulatory Flexibility. • Proposed by Applicant, Approved by Regulator • Based on Product Knowledge and Process Understanding • Flexibility predicated on level of knowledge • Risk-based regulatory decisions (reviews and inspections) • Manufacturing process improvements in design space without further regulatory review • Reduction of post-approval submissions • Real-time quality control, leading to a reduction of end-product testing.

20. For now, however, it is a voluntary pilot project, with no regulatory mandate. But will it become standard practice? • Examples of proposed flexibility • In-process testing in lieu of end-product testing • Real time release in lieu of end-product testing • Minimize regulatory burden of post-approval changes. Annual report for post-approval changes within established design space.

21. While there are potential benefits, do the benefits outweigh the potential business risks? • Benefits of the Pilot Program • FDA and Industry Explore ways to implement Q8, Q9, PAT and PQAS • Better establish what is a risk based assessment • Gain experience to develop a guidance on QbD • Intent: Higher quality, fewer product rejects/recalls, enhanced public protection.

22. The transformation to QbD in the CMC Pilot, however, is not without challenge. Will it offer faster approvals? • First Law of Marriage: For every action there is an equal and opposite reactions, some time not so equal. The reaction can be disproportionate to the action, causing an escalation of the problem. • Level of detail in submission demonstrating product knowledge, could delay approval. More to look at. Provides company with greater risk exposure if known risks are not addressed. • Cultural changes needed in both FDA and Industry, so industry is not penalized for using QbD • More resources to review the data, where are they coming from. Based on anticipation of fewer supplements to review. Will Congress see it the same way? • What is valuable and feasible and how much risk is acceptable? FDA investigators tend to think 100% perfect quality/risk, whereas businesses users are focused on product approvals and operating efficiency.

23. Risk Based Site Selection for Inspection A New Approach to Inspections

24. Overworked and understaffed, FDA inspection resources must focus on a new inspection model. • Because there has been a decrease in FDA’s capacity for inspections, sample collections, and sample analyses: • increase in number of facilities, especially foreign • increase in number, diversity, and complexity of drugs and processes as pharmaceutical science advances • Bring the inspectional level in line with public health risk • Establish an agency-wide consistent approach to the inspection processes

25. A Risk-Based Framework for Prioritizing Sites for CGMP Inspection PRODUCT PROCESS FACILITY SITE RISK 3 Decision Modules: 1) Product, 2) Process, 3) Facility

26. FY2006 Site Selection Risk Model Being Used to Guide Inspection Activities.

27. A Plain Language Summary of the Influence of the Factors • A site will be less frequently selected for inspection if… • It has been inspected recently and has few or no previous violations of GMPs and a smaller volume of product (facility weight) • It make non-sterile, OTC drugs, and/or other product types that are not associated with a high frequency of recalls and for serious defects (product weight) • It makes products judged to be relatively straightforward to manufacture with consistent quality, and not vulnerable to contamination (process weight)

28. Facility Risk Score

29. Product Risk Score

30. Process Risk Score

31. Process Score Product Placed in Profile Category (e.g.) Process Control Aerosol Dispersed Med. (e.g.) Non-sterile liquid (e.g.) Aerosol Dispersed Medication Delayed Release Tablets Extended Release Tablets Large Volume Parenteral Modified Rel. Hard Gelatin Caps Non-sterile Liquid Non-Sterile Ointments Non-sterile Powder Prompt Release Hard Gelatin Caps Prompt Release Tablets Small Volume Parenteral Soft Gelatin Capsules Sterile Liquid Sterile Ointment Sterile Powder Suppositories Transdermal Patch Contamination Vulnerability Parenteral (e.g.) Non-sterile ointment (e.g.)

32. Because of resource constraints, FDA will focus on sites most likely to merit monitoring. Distribution of FY2006 Site Risk Scores: Tier 1 Some sites may go 6 years without inspection.

33. The Model is in its infancy, and may require Re-Invention because.. • Factors were selected on the basis of • Relevance to product quality risks (Severity) • Availability of data sources • The Model is not a predictor of ‘good’ or ‘bad’ sites, or of OAI outcome • Assign weights • Empirically derived • Expert judgment • Current policy emphasis

34. As One Senior FDA Official Described the New Approach to Inspections… • “In our risk based approach to pharmaceutical inspections, we don’t inspect to find problems; but if problems are there, we will find them.” -Senior FDA Executive: PDA/FDA Meeting, 2007

35. Continuing CDER Refinement of the risk-based model may require new and different forms of data gathering. • Challenge • Data: Current factors selected on the basis of available information and lagging indicators. • Model is not a predictor of good or bad sites • There exists a potential to move toward “predictive indicators” of compliance and behavior.

36. Dramatic changes in financial performance. Profits declining, yet operating margin increasing CEO announces double production in a facility operating at capacity, no new CAP-EX projects planned Website shows recruitment of VP of Quality 6 times in 2 years Merger and Acquisitions Other economic indicators Potential Predictive Indicators of Compliance may eventually draw upon available public information.

37. The New Approach to Inspections will also free up FDA resources to focus on Pre-Approval Inspections. • But has the PAI Program reached the end of its useful life? • FDA Has a Solution: • PAI Inspections will: • Depend on the process being used by the manufacturer in the NDA. • Incorporate risk based concepts, and will customize scope and depth of pre-approval inspection.

38. Over the Past 5 years, the PAI program has revealed some interesting data. • FDA Study • FDA reviewed original NDA submissions from FY2000-FY2005 (n-628) • They were profiled as Approved, Approvable, Not Approved, Withdrawn and Refusal to File • FDA looked at data by Priority NCE, Priority non-NCE, Standard NCE

39. The study examined completed first cycle NDA reviews with a Regulatory Milestone by June 28, 2006. N=564

40. Original NDA Outcomes by NCE and Priority Status were analyzed.

41. The Study found 50% to 60% of the NDAs were not approved on the first cycle, depending on submission.

42. Of those NDAs that were not approved on the first cycle, about 99% were not approved during the period of the study.

43. The study also found on average 5.7 Sites Submitted for Evaluation Per Original NDA Submission

44. The Percentage of Sites Submitted for Evaluation by Domestic and Foreign Firm shows a large foreign component to FDA’s regulatory burden.

45. Distribution of Foreign Sites Submitted for Evaluation by Country underscores the complexity of the burden.

46. Pre-Approval Inspection OAI Rates by Visit by Domestic and Foreign Firm Indicated Foreign Firms did slightly better.

47. Distribution of Process Profiles by Domestic and Foreign Sites could be an indicator of why.

48. Pre Approval Inspections by OAI Rates indicates sterile products are in a higher risk category.

49. NDAs with Fewer Sites for Evaluation Received more Acceptable Recommendations

50. Whereas Original New Drug Applications Submitting More Foreign sites For Evaluation Received More Acceptable Recommendations