Regulatory Assessment of QbD

Elements in NDA Submissions

Experience and Considerations

Sarah Pope Miksinski, Ph.D.

Division Director (Acting)
FDA/CDER/OPS/ONDQA/DNDQA 2

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Outline

Pharmaceutical quality - background

Review of QbD elements in NDA submissions
Internal support
Process

FDA/EMA Pilot
Conclusions

What is Quality by Design (QbD)?

Systematic approach to
pharmaceutical development
and manufacturing
Begins with predefined objectives
Emphasizes product and process
understanding and process control
Based on sound science and
quality risk management
From ICH Q8(R2)
4

Quality
by
Design

Example QbD Approach - ICH Q8(R2)

Product
profile

CQAs

Risk
assessment

Design
space

Control
strategy

Continual
Improvement

Target the product profile

Determine critical quality attributes (CQAs)
Link raw material attributes and process
parameters to CQAs and perform risk
assessment
Develop a design space
Design and implement a control strategy
Manage product lifecycle, including
continual improvement
5

QbD Status - Industry

QbD has been widely adopted by innovator
pharmaceutical manufacturers for new products
Increasing use in biotech and generics

QbD has delivered to date:

Realization of the advantages of science and risk based
approach in pharmaceutical development, manufacturing
and regulatory review
Demonstrated increases in product quality and
manufacturing efficiency
Some flexibility for lifecycle management
Platform for scientific discussion and collaboration
between industry & regulators and amongst regulators
6

Quality Related Guidance and

Initiatives
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Guidance/Documents
7

2010

2011

2012

ONDQAs CMC Pilot Program

Initiated in July 2005
Objectives
o To provide participating firms an opportunity to submit
CMC information demonstrating QbD
o To enable FDA to implement new QbD concepts

Status Complete
o 9 original and 2(3) supplemental NDAs accepted
o 11 approved, 1 withdrawn (for non-CMC reasons)

Provided valuable experience for industry and FDA in

implementing QbD
o Elements of QbD in submissions
o Risk-based regulatory decisions were enabled

Learning has been incorporated into ICH Q8R

8

Internal Support of QbD within ONDQA

Internal searchable database for tracking QbD
elements in QbD-based applications (i.e. those
containing regulatory flexibility) launched
Database set up for Information Requests
regarding review of QbD elements
QbD CMC Lead position established
Extensive QbD Training (small and large group)
Established QbD Liaison mentoring role

Internal Support Continued

Increase in reviewer participation in inspections
Development of internal guidelines on review
considerations for QbD aspects
Collaborative research between ONDQA and
academia on QbD and PAT focused topics

10

Applications Containing QbD Elements

Same team-based review process and staffing for
applications with or without QbD elements

QbD Liaisons
CMC Leads
Secondary reviewers
Project management staff
Timelines (GRMPs)

Reviewers assigned based on workload and

expertise
Additional staff added to team as appropriate
11

NDA Reviews A Team-Based Process

All submissions are team-based reviews
ONDQA review team members

Primary reviewers Both CMC and Biopharmaceutics

QbD Liaison
ONDQA Project Manager
Supervisors (Branch Chief, Division Director)

Expanded team
Microbiology, statistical reviewers (as needed)
Office of Compliance (OC) Compliance Officer
Office of Regulatory Affairs (ORA) - Investigator

12

NDA Review Process

Kick-off meeting
Invite review team, ONDQA experts,
representatives from OC, ORA
Discuss potential product and process risks and
review precedence
Discuss review deliverables and anticipated
timing
Product Quality and Manufacturing (PQM) Memo
Communicated to OC and ORA
Periodic team meetings
13

NDA Review Process - Continued

Team-developed information requests
Pre-midcycle quality team meeting (all)
Pre-Discipline Review meeting (PDUFA V)
Others as needed and aligned with cases

Review response(s)
Conduct inspections
Reviewer input and frequent participation

Finalize review and recommendation

14

Product Quality and Manufacturing

Memo
ONDQA-prepared memo to aid in communicating
application-related information to OC and ORA
Prepared relatively early in the review cycle to help
with inspectional planning
Contents include: product description, process
summary, critical steps and controls, summary of
product and process-related risks
Currently prepared for:
Complex products and/or processes
Complex regulatory approaches (e.g., RTRT)
15

GRMPs - Timelines
QbD
Kick-off
Meeting

Periodic CMC
Review Team
Meetings

Prepare
PQM
Memo
Reviewer
Participation
in Inspection

16

Nontraditional QbD Examples

17

Example: Analytical Methods

Identify ATP

(Analytical Target Profile)

e.g. in terms of accuracy,
precision

ATP

Select Suitable
Analytical Method

Risk Assessment

Factors Affecting
Method Performance

Design Space
for Analytical
Method

Analytical Method
Implementation

18

e.g. Column type,

temperature, pH etc
for HPLC

Example Container Closure (CC)

Drug product moisture content: A CQA
- Limit set for maximal moisture content in
finished product

Mechanistic model to determine moisture

protection capacity of CC
- MVTR (Moisture Vapor Transmission
Rate) model
- Mass Transfer based

Design Space in terms of maximum

MVTR value
- Ensures moisture content remains below
acceptable limit at the end of shelf life

Example of Design Space Analysis for Tablet Packaging

Components
Container Packaging Measured
Design Space in
Closure Component MVTR Value terms of
System
@25C/60%RH Calculated MVTR
Value*
Bulk

Foil
Laminated
Bag

0.07 g/day

NMT 4.12 g/day

2-Count
Blister

Blister Film

0.02 mg/day

NMT 0.34 mg/day

* Predicted from MVTR model, assuming a 2 year shelf life

Note: Actual numbers not shown

19

FDA/EMA QbD Pilot

Aim Allow EU and US assessors to
exchange views on ICH Q8-10; facilitate
information sharing and harmonization
Scope Submissions that include enhanced
approach to pharmaceutical development

Design space
RTRT
Continuous processes, continuous verification
Post approval regulatory flexibility

20

FDA/EMA QbD Pilot

Two options
Parallel review 1 application submitted to both
agencies at same time (1 complete to date)
Consultative review application submitted to either
agency, with solicitations to other for advice during the
assessment (several ongoing)

Scope Submissions that include enhanced

approach to pharmaceutical development
Design space, RTRT
Continuous processes, continuous verification
Post approval regulatory flexibility
21

Preliminary Feedback- QbD Aspects

Close Agreement on:
QTPP and CQAs, Criticality
Design Space verification
Level of detail in manufacturing process
descriptions
QbD for Analytical Methods
Harmonisable aspects, but more work needs to be
done on:
NIR
Design Space development
Risk assessment detail in dossier
Large sample size acceptance criteria
22

22

Conclusions
Applications with QbD elements are fully integrated
into ONDQA work process and review practices
FDA/EMA QbD Pilot currently exploring parallel
assessment and collaborative review approaches
Team-based approaches successfully utilized
Approaches are being extended QbD-containing
applications
Consistently applied to expedited reviews

New avenues for application of QbD approaches

are emerging
23

Thank You!

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