the third annual regulatory and compliance symposium managing risks – from pipeline to patient
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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 - PowerPoint PPT PresentationTRANSCRIPT
The Third Annual Regulatory and Compliance SymposiumManaging Risks – From Pipeline to Patient
Meeting the Goals of the FDA’s QbD Initiative: Risk
Management and Pharmaceutical Development
Helen N. WinkleDirector, Office of Pharmaceutical
ScienceCenter for Drug Evaluation and
ResearchFood and Drug Administration
Anjali R. KatariaCo-Founder and CMO,
ConformiaPrincipal Investigator,
FDA-Conformia CRADA Study
Actual Focus of Current Initiatives
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 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 High cost for products due to
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 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 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 Quality is controlled by industry Manufacturers have extensive knowledge
about critical product and process parameters and quality attributes
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 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
1. Enhances scientific foundation for review2. Better coordination across review,
compliance and inspection3. Improvement in what is required for
regulatory submissions4. Better consistency5. Improved quality in review (establishing a
QMS for CMC)6. More flexibility in decision making7. Decisions made on science and not on
empirical information 8. Involves various disciplines in decision
making9. Uses resources to address higher risks
Benefits to Industry1. Design better product with less problems in
manufacturing 2. Reduce number of manufacturing supplements required
for post market changes – rely on process and risk understanding and risk mitigation
3. Allow for implementation of new technology to improve manufacturing without regulatory scrutiny
4. Possible reduction in overall costs of manufacturing – less waste
5. Less hassle during review – reduced deficiencies – quicker approvals
6. Better interaction with FDA – deal on a science level instead of on a process level
7. Allow for continuous improvements in products8. Better understanding of how APIs and excipients affect
manufacturing9. Relate manufacturing to clinical during design10. Better overall business model!
Next Steps 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
Company Confidential to Conformia, Inc
FDA – Conformia CRADAFindings from Part 1
Opportunities, Priorities and Challenges in Implementing FDA’s Desired State
August 23, 2007Anjali Kataria
Principal InvestigatorFDA-Conformia CRADA
Company Confidential to Conformia, Inc
CRADA Is Focused on Manufacturing Aspects Drug Development
Conformia research focus
Confidential FDA-Conformia CRADA Briefing Confidential 04/22/23 FDA-Conformia CRADA Briefing Confidential 15
Key Objectives & Outputs of CRADA
Analyze Root Cause: Identify existing root causes of bottlenecks in drug development resulting in inefficiency
Assess Guidelines: Describe gaps, perceptions, and usefulness of existing guidance related to pharmaceutical development.
Describe Current State Practices: Summarize current state of pharmaceutical development, challenges, opportunities, and top of mind issues facing development organizations.
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.
Educate: Increase familiarity of key initiatives, new technologies and future state possibilities
Company Readout: Identify current state practices / top of mind issues internal to participating companies.
Final Report / Benchmarking Briefing: Roll up results of all preliminary phase company participants ( Phase 1 )and loose comparison
FDA Briefings: Communicate to FDA current perceptions in understanding, expectations of future agency guidance; opportunities for streamlining guidance.
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.
Objective Expected Output
Confidential FDA-Conformia CRADA Briefing Confidential 04/22/23 FDA-Conformia CRADA Briefing 16
Research Agenda Was Split Into Two Parts
Research Pre-Clinical Clinical
CMC/Process development
Prepare Submission Approval Mfg Lot
release Distribution
PRODUCT / PROCESS DEVELOPMENT OPERATIONS
Registration Phase
I.PAT / QbD / ICH
Design Space
II.Information Management
VI.Communication / Decision Making
III.Regulatory Interaction
V.Collaboration Management
IV.Commercialization
Part 1 Part 2
Organization al Capabilities
Regulatory Perspective Feedback on current guidance/regulations Confidence in FDA Commitment
Implementation Plans Perceived Benefit
Process Capabilities
Technology Capabilities Systems & Tools Metrics
QbD Initiative Prior successes
Adoption of QbD Concepts
Skills and People Capabilities
RESEARCH
Topics completed; ready for final report
Confidential FDA-Conformia CRADA Briefing Confidential 04/22/23 FDA-Conformia CRADA Briefing Confidential 17
Participating Company Demographics
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:
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
Smaller LargerRelative Company
Size*
*Based on 2005 Annual Revenue, # of Employees, Number of Development Sites, Number of Commercial Sites
9 Participating Companies
Confidential FDA-Conformia CRADA Briefing Confidential 04/22/23 FDA-Conformia CRADA Briefing Confidential 18
1Ad-hoc /
Not enabled
3Partially Enabled
2Emerging
4Integrated Enterprise-
WideStages of Enablement
ProcessCapabilities
TechnologyCapabilities
OrganizationalCapabilities
Assessment Tool to Map Differences In Current Practices
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
No formal initiative Exists, but in multiple silos
Formalized; Initiative spans cross-functional groups
Stage 3 + FTE’s AssignedInitiatives integrated into daily operations
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 partnersClear Technology strategy
RegulatoryInteractions
Limited awareness of FDA initiative; no clear definitions and internal understanding of concepts
Interaction with regulatory bodies limited to regulatory and qualitySome 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 companyCross functional bi-directional sharing of ideas and perspective with FDA
Related FDA Initiatives
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1. Ad-hoc / Not enabled
3. Partially Enabled
2. Emerging 4. Integrated Enterprise-Wide
QbD Initiative
Management Support
Use of Systems/ Tools
QbD Definitions
Implementation Plans
Confidence in FDA Commitment
Prior Successes
Perceived Benefit
Elements of QbD
QbD approach applied consistently across development operations
Findings: Implementation of QbD Across Group is Moving in the Direction of Integrated Enterprise Wide
Awareness & Understanding
Process & System Capabilities
Implementation
Organizational
Source: Qualitative Analysis based on CRADA interviews
Confidential FDA-Conformia CRADA Briefing Confidential
QbD Initiatives in Place & Coming
% of Responses. N=95
Yes, we have one in place
today29%
No, but we will have one in
place in 1 year45%
No, but we will have one in
place in 5 years6%
No, but we will have one in
place in 3 years13%
We have no plans to have one in place
7%
74% of manufacturers say they either already have or will have in the next 12 months a QbD initiative in place
Source: AMR
Confidential FDA-Conformia CRADA Briefing Confidential
Top Priorities for Implementing QbD at Companies
Design Space Process, Formulation and Analytical Design Spaces Changes within Design Space / Notifications to agency
Product /Process Attributes Drug Substance and Drug Product attributes as determinants of
process end points
Risk Assessment Establishing the methodology and information required to present risk
assessment in a submission Linking risk assessment to control strategy
Prior Knowledge From previous submissions From internal information, successes, failures and learning's
Confidential 2104/22/23 CMC-IM Working Group
Confidential FDA-Conformia CRADA Briefing Confidential
Top Priorities for Implementing QbD at Companies cont.
Manufacturing Principles / Commercial Direction Post Approval Changes
Product/Process Lifecycle Management – Continual Improvement Feedforward and Feedback
On 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
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
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
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
Most companies had well documented development processes (roadmaps, technical briefs etc.)
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
Top obstacles include: 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
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