Transcript The Third Annual Regulatory and Compliance Symposium

The Third Annual Regulatory and
Compliance Symposium
Managing Risks – From Pipeline to Patient
Meeting the Goals of the FDA’s
QbD Initiative: Risk Management
and Pharmaceutical Development
Helen N. Winkle
Director, Office of Pharmaceutical Science
Center for Drug Evaluation and Research
Food and Drug Administration
Anjali R. Kataria
Co-Founder and CMO, Conformia
Principal Investigator,
FDA-Conformia CRADA Study
Actual Focus of Current Initiatives
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Implementing changes in how FDA regulates
pharmaceutical products – or improvement in
our business processes
Necessity as move into 21st century
Paradigm shift
Evolution – not revolution
State of Pharmaceutical
Manufacturing
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In many cases, not state-of-art as compared to other
industries
Able to achieve reasonable product quality – but at a
great effort and cost
Little emphasis on manufacturing – mainly on
development although manufacturing is
approximately 25% of expenses
Factory/equipment utilization rate about 15%
For some products, waste as high as 50%
Inability to predict effects of scale up on final product
Inability to analyze or understand reasons for
manufacturing failures
Globally fragmented
Consequences
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High cost for products due to
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Low efficiencies in manufacturing
Waste
Manufacturing time requirements based on
testing, etc.
Drug shortages due to manufacturing
problems
Lack of improvements based on new
technologies
Slowed development/access for
investigational drugs
Need for intensive regulatory oversight
State of Regulatory Quality
Review Processes
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Oversight increased – reviewed every change made –
increased number of application supplements
Focused on chemistry but not on other important
areas (e.g., engineering)
Implemented numerous changes in process to
facilitate increasing review requirements (SUPAC,
BACPAC)
Issued numerous “how to” guidances (prescriptive)
All standards internally developed
PDUFA requirements speed up review process
More complex products along with new dosage forms
Increased emphasis on focused issues such as
counterterrorism, pandemic, counterfeiting
Consequences
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Too much work
Not enough staff
More and more information from sponsors
required (not always relevant)
No flexibility in regulatory process
Impossible to ensure consistency
Discouraged innovation on part of
manufacturer because of need for
supplements
Assumed all responsibility for product quality
The Desired State:
A Mutual Goal of Industry,
Society, and the Regulators
A maximally efficient, agile, flexible
pharmaceutical manufacturing sector that
reliably produces high quality drug products
without extensive regulatory oversight.
Janet Woodcock, M.D.
Characteristics of the
Desired State
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Quality is controlled by industry
Manufacturers have extensive knowledge about
critical product and process parameters and quality
attributes
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Knowledge comes from product development, prior
experience, studies, scientific and technical literature
Use that knowledge to understand product risk and risk
mitigation
Use that knowledge to determine appropriateness to make
manufacturing changes
Manufacturers control process through quality
systems over life cycle and strive for continuous
improvement
FDA’s role is to do initial verification and subsequently
audit
Moving Toward the
Desired State
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Philosophy – “Quality should be built into the
product, and testing alone cannot be relied
on to ensure product quality.”
Benefits of New Paradigm
to FDA
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Enhances scientific foundation for review
Better coordination across review, compliance and
inspection
Improvement in what is required for regulatory
submissions
Better consistency
Improved quality in review (establishing a QMS for
CMC)
More flexibility in decision making
Decisions made on science and not on empirical
information
Involves various disciplines in decision making
Uses resources to address higher risks
Benefits to Industry
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Design better product with less problems in manufacturing
Reduce number of manufacturing supplements required for
post market changes – rely on process and risk understanding
and risk mitigation
Allow for implementation of new technology to improve
manufacturing without regulatory scrutiny
Possible reduction in overall costs of manufacturing – less
waste
Less hassle during review – reduced deficiencies – quicker
approvals
Better interaction with FDA – deal on a science level instead
of on a process level
Allow for continuous improvements in products
Better understanding of how APIs and excipients affect
manufacturing
Relate manufacturing to clinical during design
Better overall business model!
Next Steps
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Evolution
There are definitely obstacles to change and a lot to
learn – gaps in science, knowledge, risk and risk
mitigation
Need to determine the applicability to risk
management to manufacturing process
What is appropriate information to submit in
application based on current product development
data?
Need appropriate guidance to guide industry and FDA
staff
Training, training, training
Will continue to work with industry and others to
learn – CRADA with Conformia is a perfect example
of how this is being done
FDA – Conformia CRADA
Findings from Part 1
Opportunities, Priorities and Challenges in
Implementing FDA’s Desired State
August 23, 2007
Anjali Kataria
Principal Investigator
FDA-Conformia CRADA
Company Confidential to Conformia, Inc
CRADA Is Focused on Manufacturing Aspects Drug
Development
Conformia research focus
Company Confidential to Conformia, Inc
Key Objectives & Outputs of CRADA
Objective
Expected Output
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Analyze Root Cause: Identify existing root
causes of bottlenecks in drug development
resulting in inefficiency
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Company Readout: Identify current state
practices / top of mind issues internal to
participating companies.
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Assess Guidelines: Describe gaps, perceptions,
and usefulness of existing guidance related to
pharmaceutical development.
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Final Report / Benchmarking Briefing: Roll up
results of all preliminary phase company
participants ( Phase 1 )and loose comparison
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Describe Current State Practices: Summarize
current state of pharmaceutical development,
challenges, opportunities, and top of mind issues
facing development organizations.
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FDA Briefings: Communicate to FDA current
perceptions in understanding, expectations of
future agency guidance; opportunities for
streamlining guidance.
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Identify Potential Future State: Define
requirements needed for companies to implement
Quality by Design (QbD) closed-loop, continuous
improvement, process understanding approach to
new drug development.
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FDA Reaction: Conformia to share FDA’s
feedback with participating companies.
FDA Workshops: Conduct Internal FDA
Seminars to educate FDA on key areas:
Development Process, QbD, Design Space, PAT.
Educate: Increase familiarity of key initiatives,
new technologies and future state possibilities
Confidential
4/6/2016
FDA-Conformia
FDA-Conformia
CRADA CRADA
Briefing Briefing
15
Confidential
Research Agenda Was Split Into Two Parts
RESEARCH
Research
PRODUCT / PROCESS DEVELOPMENT
PreClinical
Prepare
Submission
Clinical
OPERATIONS
Approval
Mfg
Lot
release
Distribution
CMC/Process development
Registration Phase
Part 1
I.
PAT / QbD / ICH
Design Space
II.
Information
Management
Part 2
III.
Regulatory
Interaction
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Process Capabilities
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Technology Capabilities
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Organization al Capabilities
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Regulatory Perspective
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Topics completed; ready for final report
4/6/2016
FDA-Conformia
FDA-Conformia
CRADA CRADA
Briefing Briefing
16
IV.
Commercialization
QbD Initiative
Prior successes
V.
Collaboration
Management
VI.
Communication /
Decision Making
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Adoption of QbD Concepts
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Skills and People
Capabilities
Systems & Tools
Metrics
Implementation Plans
Perceived Benefit
Feedback on current guidance/regulations
Confidence in FDA Commitment
Confidential
Confidential
Participating Company Demographics
Smaller
Relative Company
Size*
Larger
9 Participating Companies
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At Present 9 participating companies. (Will expand to 25
companies.)
7 of these have a biotech division participating in the study or are
a standalone biotech company. Designated by:
Collectively:
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350+ commercial products to market
Parallel and multi-site development activities occurring at all 9 companies
All 9 companies using CMOs in Development process / tech transfer
*Based on 2005 Annual Revenue, # of Employees, Number of Development Sites,
Number of Commercial Sites
4/6/2016
FDA-Conformia
FDA-Conformia
CRADA CRADA
Briefing Briefing
17
Confidential
Confidential
Assessment Tool to Map Differences In Current Practices
Related FDA Initiatives
3
Partially Enabled
4
Integrated EnterpriseWide
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Emerging
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Ad-hoc /
Not enabled
Ad-hoc processes
Exists, but in multiple
silos
Limited harmonization
across the enterprise;
some systems adopted as
standard
Single Process Frame for
development integrated
with external partners
Clear Technology strategy
Technology
Capabilities
No formal initiative
Exists, but in multiple
silos
Formalized; Initiative
spans cross-functional
groups
Stage 3 + FTE’s Assigned
Initiatives integrated into
daily operations
Organizational
Capabilities
Not very strong
Limited involvement or
support by Senior mgmt
“Top down” Sr. mgmt
support across the
organization
Executive Mgmt support
translated into formalized
initiatives
Regulatory
Interactions
Limited awareness of FDA
initiative; no clear
definitions and internal
understanding of concepts
Interaction with
regulatory bodies limited
to regulatory and quality
Some awareness and
efforts exist to adopt
initiatives
Open dialogue across
functions with regulatory
bodies; recognizing the
need for direction setting
and uniformity
Uniform definition of
concepts; clear plans
across the company
Cross functional bidirectional sharing of ideas
and perspective with FDA
Process
Capabilities
Confidential
4/6/2016
FDA-Conformia
FDA-Conformia
CRADA CRADA
Briefing Briefing
18
Confidential
Findings: Implementation of QbD Across Group is Moving
in the Direction of Integrated Enterprise Wide
1. Ad-hoc /
Not enabled
2. Emerging
3. Partially
Enabled
Awareness & Understanding
 QbD Initiative
 QbD Definitions
 Prior Successes
Process & System Capabilities
 Use of Systems/ Tools
 Elements of QbD
 QbD approach applied
consistently across
development operations
Implementation
 Implementation Plans
 Perceived Benefit
Organizational
 Management Support
 Confidence in FDA
Commitment
Source: Qualitative Analysis based on CRADA interviews
Confidential
4/6/2016
FDA-Conformia
FDA-Conformia
CRADA CRADA
Briefing Briefing
19
Confidential
4. Integrated
Enterprise-Wide
QbD Initiatives in Place & Coming
Source: AMR
No, but we will
have one in
place in 5 years
6%
We have no
plans to have
one in place
7%
Yes, we have
one in place
today
29%
No, but we will
have one in
place in 3 years
13%
% of Responses. N=95
74% of manufacturers
say they either already
have or will have in the
next 12 months a QbD
initiative in place
No, but we will
have one in
place in 1 year
45%
Confidential
FDA-Conformia CRADA Briefing
Confidential
Top Priorities for Implementing QbD at Companies
 Design
Space
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Process, Formulation and Analytical Design Spaces
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Changes within Design Space / Notifications to agency
 Product
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Drug Substance and Drug Product attributes as determinants of
process end points
 Risk
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Assessment
Establishing the methodology and information required to present risk
assessment in a submission
Linking risk assessment to control strategy
 Prior
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/Process Attributes
Knowledge
From previous submissions
From internal information, successes, failures and learning's
Confidential
4/6/2016
FDA-Conformia
CMC-IM CRADA
WorkingBriefing
Group
21
Confidential
Top Priorities for Implementing QbD at Companies
cont.
 Manufacturing
Principles / Commercial
Direction
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Post Approval Changes
Lifecycle Management –
Continual Improvement
 Product/Process
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Feedforward and Feedback
 On
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the Horizon:
The link between CMC specifications and clinical
endpoints
Confidential
FDA-Conformia CRADA Briefing
Confidential
Top Obstacles to Broader Implementation of QbD
by Companies
 Perceived
commitment of QbD by FDA across
Review, Field, and Policy Teams
 Lack
of harmonization of QbD across FDA,
EMEA, PMDA
 Lack
of executive leadership within companies
driving QbD “top down”
 Lack
of organized cross functional leadership
across lines of business
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Formulation, API, Analytical, Quality, Regulatory, Commercial Manufacturing
and Information Management all need to be involved
 Confusion
over core ICH Q8 / Q9 terminology
Confidential
FDA-Conformia CRADA Briefing
Confidential
Top Obstacles cont..
 Lack
of clear regulatory benefits / regulatory
flexibility
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Need to showcase a compelling business case
 Difficulty
accessing prior knowledge despite
significant investments in portals / online
document management
 Underdeveloped business process strategies to
support product / process lifecycle information
 No master formulation or master API repositories
of product/process science information
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Yet succeeding at QbD will require a master data management
strategy to support product/process attributes and prior knowledge
approaches.
Confidential
FDA-Conformia CRADA Briefing
Confidential
Overall Observations
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Most companies had well documented development processes
(roadmaps, technical briefs etc.)
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Top obstacles include:
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Poor information management supporting product/process lifecycle across
development
FDA’s perceived commitment to drive QbD across reviewers, inspectors and
policy team
Harmonization across PMDA, EMEA, FDA.
Dialogue between industry and agency is helping companies
translate concepts into practice / develop more case studies
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Though few companies had aligned these development process maps with
the FDA’s QbD approach such that key decision points
encompassed/aligned with QbD goals
FDA-Conformia-PhRMA Workshops for Cross Functional Senior Leadership
OPS Pilot Programs /Industry Meetings (ISPE, AAPS, PhRMA etc.)
More communication between FDA and Industry regarding FDA’s
implementation plans to support training of Reviewers and
Inspectors in this new paradigm will help move QbD forward
Confidential
FDA-Conformia CRADA Briefing
Confidential
Thank You
Confidential
FDA-Conformia CRADA Briefing
Confidential