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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 How Did We Get Where We Are ... – PowerPoint PPT presentation

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Title: 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

  • 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

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
  • Office of Generic Drugs
  • Instituted Question-based reviews and adopted CTD
  • Office of Testing and Research
  • More Resources to understanding PAT as analytical
  • 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.

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
  • 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?
  • 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
  • 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
  • Q8 Pharmaceutical Development
  • Q9 Risk Management
  • Q10 Pharmaceutical Quality System

FDAs business case for change, they claim, is to
loosen the regulatory bonds that constrain
  • 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
  • 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?
Innovation /Stagnation FDA 2004
High Expectations and Major Obstacles
For a decade, the enforcement strategy has seen
drug recalls climb and the FDAs ability to
perform inspections decrease.
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.
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?
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
Ajaz S. Hussain, Ph.D. 28th Annual Midwest
Biopharmaceutical Statistical Workshop
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
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.
  • Example Traditional IQ, OQ and PQ for
    validation is costly and often impedes continuous
  • 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
Raw Materials
Locked Process Variables
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
Raw Materials
Input Response
Endpoint Response
Measurement Dependant Variables
Therapeutic Response
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
  • Target 12 Original or supplement NDA
  • Status 1 approved, 2 under review, 8 to be
  • 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.
  • Proposed by Applicant, Approved by Regulator
  • Based on Product Knowledge and Process
  • Flexibility predicated on level of knowledge
  • Risk-based regulatory decisions (reviews and
  • 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?
  • 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?
  • 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?
  • 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
  • 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
  • A New Approach to Inspections

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
  • increase in number, diversity, and complexity of
    drugs and processes as pharmaceutical science
  • 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
3 Decision Modules 1) Product, 2) Process, 3)
FY2006 Site Selection Risk Model Being Used to
Guide Inspection Activities.
A Plain Language Summary of the Influence of the
  • 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
Product Risk Score
Process Risk Score
Process Score
Product Placed in Profile Category (e.g.)
Process Control
Aerosol Dispersed Med. (e.g.) Non-sterile liquid
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.)
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.
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
  • 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
Continuing CDER Refinement of the risk-based
model may require new and different forms of data
  • 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

Potential Predictive Indicators of Compliance may
eventually draw upon available public
  • Dramatic changes in financial performance.
    Profits declining, yet operating margin
  • CEO announces double production in a facility
    operating at capacity, no new CAP-EX projects
  • 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
  • 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

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. N564
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
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
The Percentage of Sites Submitted for Evaluation
by Domestic and Foreign Firm shows a large
foreign component to FDAs regulatory burden.
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.
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.
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
And, finally, sites with a Longer Operation
History had Higher Acceptable Rates
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..
  • 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

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)

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