The Third Annual Regulatory and Compliance Symposium Managing Risks – From Pipeline to Patient

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


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


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


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%


place in 5 years6%


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


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


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


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


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.


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


Thank You

Documents

The Third Annual Regulatory and Compliance Symposium Managing Risks – From Pipeline to Patient