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


Agenda :- 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


The Reinvention of FDA: A Framework for Continuous Improvement… :- 3 - The Reinvention of FDA: A Framework for Continuous Improvement… 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 Journey so Far.. :- 4 - The Journey so Far.. 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


Clearly the momentum for change is strong, but will the new regulatory and manufacturing concepts take hold? :- 5 - Clearly the momentum for change is strong, but will the new regulatory and manufacturing concepts take hold? 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 Drivers


FDA’s business case for change, they claim, is to loosen the regulatory bonds that constrain industry. :- 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?


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


High Expectations and Major Obstacles :- 8 - High Expectations and Major Obstacles


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


The new definition of FDA regulation will drive toward targeted enforcement and flexible regulation as….. :- 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.


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


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? :- 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


ICH Q8 and Quality By Design :ICH Q8 and Quality By Design A Discussion


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


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. :- 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.


The new strategy will require industry reinvention at multiple steps. :- 16 - The new strategy will require industry reinvention at multiple steps. 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 Manufacturing Process Locked Process Variables Product Raw Materials Variability


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


CMC Pilot Program is One Step in This Direction. :- 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.


The project aligns nicely with ICH Q8 – Regulatory Flexibility. :- 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.


For now, however, it is a voluntary pilot project, with no regulatory mandate. But will it become standard practice? :- 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.


While there are potential benefits, do the benefits outweigh the potential business risks? :- 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.


The transformation to QbD in the CMC Pilot, however, is not without challenge. Will it offer faster approvals? :- 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.


Risk Based Site Selection for Inspection :Risk Based Site Selection for Inspection A New Approach to Inspections


Overworked and understaffed, FDA inspection resources must focus on a new inspection model. :- 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


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


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


A Plain Language Summary of the Influence of the Factors :- 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)


Facility Risk Score :- 28 - Facility Risk Score


Product Risk Score :- 29 - Product Risk Score


Process Risk Score :- 30 - Process Risk Score


Process Score :- 31 - Process Score Product Placed in Profile Category (e.g.) Aerosol Dispersed Med. (e.g.) Non-sterile liquid (e.g.) Process Control Parenteral (e.g.) Non-sterile ointment (e.g.) Contamination Vulnerability 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


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


The Model is in its infancy, and may require Re-Invention because.. :- 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


As One Senior FDA Official Described the New Approach to Inspections… :- 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


Continuing CDER Refinement of the risk-based model may require new and different forms of data gathering. :- 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.


Potential Predictive Indicators of Compliance may eventually draw upon available public information. :- 36 - Potential Predictive Indicators of Compliance may eventually draw upon available public information. 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


The New Approach to Inspections will also free up FDA resources to focus on Pre-Approval Inspections. :- 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.


Over the Past 5 years, the PAI program has revealed some interesting data. :- 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


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


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


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


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


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


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


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


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


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


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


NDAs with Fewer Sites for Evaluation Received more Acceptable Recommendations :- 49 - NDAs with Fewer Sites for Evaluation Received more Acceptable Recommendations


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


And, finally, sites with a Longer Operation History had Higher Acceptable Rates :- 51 - And, finally, sites with a Longer Operation History had Higher Acceptable Rates


So What Does This All Mean? :- 52 - So What Does This All Mean? FDA is under resource constraints and has adopted risk-management models to make sure the Agency targets its resources better. It appears the FDA is employing traditional risk analysis to construct its model using lagging indicators, but may reinvent as data become available to use Predictive Indicators. Sharing QbD with FDA may potentially slow down approvals, but by submitting the information you take the initiative to manage FDA expectation. Whether the business benefits outweigh the risks, there is no easy answer.


Time will tell.. :- 53 - Time will tell.. Time will tell how industry will benefit in terms of faster product approval, lower costs of quality, and increased productivity. Where we need to work together is by establishing metrics by which to monitor FDA’s performance, and work toward a common goal. In the area of PAI inspections, it appears that applications with fewer sites and foreign firms tend to do slightly better. By understanding what drives FDA, we can best work with the FDA. We need to be careful, however, in defining how much risk we as an industry are willing to take. Continuous improvement must be balanced with what is valuable and feasible, otherwise we run the risk of getting trapped in a corrective action crisis.


In Closing, perhaps Donald Rumsfeld said it best: :- 54 - In Closing, perhaps Donald Rumsfeld said it best: “Reports that say that something hasn’t happened are always interesting to me, because as we know, there are known knowns; there are things we know we know. We also know there are known unknows; that is to say we know there are some things we do not know. But there are also unknown unknowns – the ones we don’t know we don’t know. Plain English Campaign’s premier “Foot in Mouth” trophy (December 2003)


FDA Coming Attractions What you need to know :FDA Coming Attractions What you need to know Current Trends and Industry Practices Thursday, September 28, 2006 PDA Dinner Meeting