FDA Coming Attractions What You Need To Know

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FDA Coming Attractions What You Need To Know

• Current Trends and Industry Practices
• Thursday, September 28, 2006
• PDA Dinner Meeting

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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
• FDAs New Regulatory Framework
• Quality by Design
• New Approaches to Inspections

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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 weve not seen is how FDA management reviews
  will monitor performance, what acceptance
  criteria FDA has set for goal accomplishment, and
  how the Agencys continuous improvement program
  will be implemented with all these initiatives.

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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

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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
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FDAs 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?

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For FDA, will the future be increasingly defined
by a declining drug pipeline, growing product
complexity, and diminishing resources?
Innovation /Stagnation FDA 2004
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High Expectations and Major Obstacles
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For a decade, the enforcement strategy has seen
drug recalls climb and the FDAs ability to
perform inspections decrease.
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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.
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Common Inspection Observations underscore product
and process control as key concerns for FDA.
Source Robert Coleman, FDA National Expert
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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 2s?
Product Quality gt 5s? Are we not trapped in a
corrective action crisis and wasting
resources?
Ajaz S. Hussain, Ph.D. 28th Annual Midwest
Biopharmaceutical Statistical Workshop
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ICH Q8 and Quality By Design

• A Discussion

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

Variability
Manufacturing Process
Product
Raw Materials
Locked Process Variables
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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
Product
Raw Materials
Input Response
Endpoint Response
Measurement Dependant Variables
Therapeutic Response
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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.

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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.

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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.

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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.

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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.

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Risk Based Site Selection for Inspection

• A New Approach to Inspections

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

• Because there has been a decrease in FDAs
  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

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A Risk-Based Framework for Prioritizing Sites for
CGMP Inspection
PRODUCT
PROCESS
FACILITY
SITE RISK
3 Decision Modules 1) Product, 2) Process, 3)
Facility
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FY2006 Site Selection Risk Model Being Used to
Guide Inspection Activities.
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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)

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Facility Risk Score
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Product Risk Score
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Process Risk Score
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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.)
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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.
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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

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As One Senior FDA Official Described the New
Approach to Inspections

• In our risk based approach to pharmaceutical
  inspections, we dont inspect to find problems
  but if problems are there, we will find them.

-Senior FDA Executive PDA/FDA Meeting, 2007
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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.

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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

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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.

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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

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The study examined completed first cycle NDA
reviews with a Regulatory Milestone by June 28,
2006. N564
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Original NDA Outcomes by NCE and Priority Status
were analyzed.
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The Study found 50 to 60 of the NDAs were not
approved on the first cycle, depending on
submission.
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Of those NDAs that were not approved on the first
cycle, about 99 were not approved during the
period of the study.
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The study also found on average 5.7 Sites
Submitted for Evaluation Per Original NDA
Submission
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The Percentage of Sites Submitted for Evaluation
by Domestic and Foreign Firm shows a large
foreign component to FDAs regulatory burden.
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Distribution of Foreign Sites Submitted for
Evaluation by Country underscores the complexity
of the burden.
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Pre-Approval Inspection OAI Rates by Visit by
Domestic and Foreign Firm Indicated Foreign Firms
did slightly better.
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Distribution of Process Profiles by Domestic and
Foreign Sites could be an indicator of why.
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Pre Approval Inspections by OAI Rates indicates
sterile products are in a higher risk category.
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NDAs with Fewer Sites for Evaluation Received
more Acceptable Recommendations
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Whereas Original New Drug Applications Submitting
More Foreign sites For Evaluation Received More
Acceptable Recommendations
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And, finally, sites with a Longer Operation
History had Higher Acceptable Rates
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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.

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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 FDAs 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.

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In Closing, perhaps Donald Rumsfeld said it best

• Reports that say that something hasnt 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 dont know we dont know.
• Plain English Campaigns premier Foot in Mouth
  trophy (December 2003)

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FDA Coming Attractions What you need to know

• Current Trends and Industry Practices
• Thursday, September 28, 2006
• PDA Dinner Meeting