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Industry Perspective on Lifecycle Management and Post-Approval Changes Focus on Quality by Design
FDA/PQRI Conference on Evolving Product Quality Sep. 16-17, 2014 Michael Kimball Executive Director, Transdermal Development Actavis plc Salt Lake City, Utah
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Disclaimer
The views expressed herein are strictly those of the presenter and are not necessarily
the views of Actavis plc or its affiliates
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Topics . . .
Scientific Perspective on Prior-Approval Supplement Process (PAS)
Quality by Design
Prior Knowledge
Quality Target Product Profile (QTPP)
Risk Assessment
Examples
Equipment Change Case Study - Drying Oven
A Transdermal Patch Case Study
Process Analytical Technology (PAT) Case Study
Final Thoughts
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“Resting on what's considered great has always been a
recipe for decline.”
- Robert K. Cooper
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Post-Approval Changes – Scientific Perspective
“Simply stated: Is the drug product made after the change equivalent to the drug product made before the change?” -- Guidance for Industry: Changes to an Approved NDA or ANDA (2004)
Science and Risk-Based Approach
Future of Guidances (SUPAC, etc.)?
Dosage Form Complexity
Modified Release
QbD Integration with Post-Approval Change Process
QTPP
Risk Assessment
PAT
Other Tools
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QbD Definition
QbD defined: “A systematic approach to
development that begins with predefined
objectives and emphasizes product and
process understanding and process control,
based on sound science and quality risk
management.” (ICH Q8)
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Overview of QbD
Target Design and Implementation
Understanding
Labeled Use
Safety and Efficacy
(TPP)
DEFINE Quality Target
Product Profile (QTPP)
DESIGN Formulation
and Process
IDENTIFY Key Quality
Attributes, Raw
Material Attributes and
Process Parameters
CONTROL
Materials and
Process
Lawrence Yu. Pharm. Res. 25:781-791 (2008)
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QbD, Scale-up, and Product Lifecycle
Business /
Therapeutic Need
Target Product
Profile
Quality Target
Product Profile
Process Design /
Experimentation
Risk
Management /
Control Strategy
Lab-Scale /
Formulation
Pilot Plant
Commercial
Plant
TPP Elements
Patient / Consumer Population
Labeling
Indication
Dosage Form
Route of Administration
QTPP Elements
Design Elements
CQA’s
CMP’s
Risk Assessment
Iterative Process
· Re-assess risk
· Design Space
Prior Knowledge
Design of
Experiments
Modelling
Pilot Plant Scale-up
R&D Focus
Post-Approval
· Lifecycle management
· Continual improvement
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Quality by Design
Complex / modified release dosage forms especially benefit from QbD
Quality Target Product Profile (QTPP)
Cornerstone of QbD
Generics: Design for Equivalence
Should include clinically-relevant specifications
Importance of prior knowledge
Comprehensive and appropriate
Framework of change assessment
Regulatory and scientific perspective
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QTPP: Appropriate and Comprehensive?
Scope of QTPP As Defined
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QTPP: Appropriate and Comprehensive?
Prior knowledge
Risk assessment
Appropriate process and product
characterization
May evolve during development
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Case Study: Equipment Change Success Story
Solid Oral Product: Drying Oven change from Gruenberg to Vacuum Oven
Different design and operating principle
Guidance -> PAS
QbD and Scientific Principles -> CBE 0
QTPP: Change did not impact and degradation profile improved
Equipment/Process
Parameter Gruenberg Oven Tenney Vacuum Oven Comment
Equipment
Manufacturer Thermal Products Solutions Thermal Products Solutions Same manufacturer
Drying Method
Wet granules are placed on
trays. Drying is accomplished by
heat convection from hot air flow to
the wet granules. Moisture is
carried away by air flow.
Wet granules are placed on
trays. Drying is accomplished by
heat conduction from fluid heated
racks to the wet granules. Moisture
is carried away by vacuum pump.
Convection versus
Conduction
Process Parameter
Inlet Temperature Set
Point 50ºC (45ºC to 55ºC) 50ºC (45ºC to 55ºC) No change
Vacuum Pressure N/A 40 Torr (30 to 50 Torr)
Addition of vacuum
setting for Tenney
vacuum oven
Drying Time Approximately 7 hours Approximately 7 hours No change
Drying End Point Until loss-on-drying is not more
than 0.5%
Until loss-on-drying is not more
than 0.5% No change
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Case Study: Transdermal Patch (Hypothetical)
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Background: Side View of a Typical
Transdermal Patch
Backing Film
Release Liner
Drug Reservoir Adhesive Layer
(Adhesive A)
Skin-Contact Adhesive Layer
(Adhesive B)
Each adhesive contains several constituents (i.e., polymers, diluent, tackifier, etc.)
Consider: post-approval change: removal of minor constituent from Adhesive A
In addition to Design Space, QbD-based development introduces other tools
that have potential to reduce regulatory burden
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Example QTPP: Transdermal Patch
QTTP Element Target Measure of Equivalency: Post-Change
Active Ingredient Match RLD Unchanged
Dosage Form
Film,
Controlled
Release
Unchanged
Dosage Form
Appearance and
Characteristics
Similar to RLD Unchanged
Patch,
rectangular Unchanged
Route of
Administration Transdermal Unchanged
Dosage Strength Match RLD Unchanged
Container
Closure System
Equivalent to
RLD Unchanged
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Example QTPP: Transdermal Patch, cont’d QTTP Element Target Measure of Equivalency: Post-Change
Drug Product
and Quality
Attributes
Appearance
Continued compliance with established specifications
Assay
Content
Uniformity
Identity
Residual
Solvents
Degradation
Liner Peel
Physical Tests
Drug Release
Microbial Limits
Cold Flow
Stability
At least 24 month
shelf life at 25˚C
(15 – 30˚C
permitted)
QbD - > Excipient compatibility, formulation challenge studies:
mechanistic understanding of degradation pathway(s)
Bioequivalence
1. Non-inferior
Adhesion
2. Non-inferior
Irritation/
Sensitization
3. Equivalent PK
Profile
1. Skin-contact adhesive is unchanged; lab assessment of patch
integrity
2. (see 1, and no components added)
3. In-vitro Franz cell testing (cadaver skin and/or synthetic
membranes)
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Formulation Understanding is Increasing
QbD -> Excipient Compatibility or Similar Formulation Challenge Studies
Mechanistic understanding of degradation and role each excipient plays
Stability documentation required?: “Customized based on risk assessment and
product sensitivities.” [1] (context of PAT)
Repeat excipient compatibility with modified adhesive?
(Simulated) Excipient Compatibility: Total Impurities and Degradation
Products, %
Time API +
Adhesive A
API +
Adhesive B
API +
Backing API + Liner API
Zero 0 0 0 0 0
2wk 25C 0 0 0 0 0
2wk 40C 0 0 0 0 0.4
2wk 60C 2.6 2.7 2.7 2.1 3.2
4wk 25C 0 0 0 0 0
4wk 40C 1.8 1.4 0.8 1.1 1.6
4wk 60C 4.3 4.2 4.1 4.5 3.9
1. Van Buskirk, et.al. Best Practices for the Development, Scale-up, and Post-approval
Change Control of IR and MR Dosage Forms in the Current Quality-by-Design Paradigm.
AAPS Pharmscitech Vol 15 no 3, June 2014
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In Vitro Release Testing (Franz Cell): API Diffusion
through Cadaver Skin, Before and after Change
0 3 6 9 12 15 18 21 24
Inte
rval
Flu
x (
µg
/cm
²/h
r)
Time (hrs)
Demonstrates non-
criticality of change
Advances in IVRT
Synthetic
Membranes
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Risk Assessment
QTTP Element Target Measure of Equivalency and Risk: Post-Change Risk Assessment
Active
Ingredient Match RLD Unchanged Low
Dosage Form Film, Controlled
Release Unchanged
Low
Dosage Form
Appearance and
Characteristics
Similar to RLD Unchanged Low
Patch,
Rectangular Unchanged
Low
Route of
Administration Transdermal Unchanged
Low
Dosage
Strength Match RLD Unchanged
Low
Stability
At least 24
month shelf life
at 25˚C (15 –
30˚C permitted)
QbD - > Excipient compatibility, formulation challenge
studies: mechanistic understanding of degradation
pathway(s)
Low
Bioequivalence
1. Non-inferior
Adhesion
2. Non-inferior
Irritation/
Sensitization
3. Equivalent
PK Profile
1. Skin-contact adhesive is unchanged; lab assessment of
patch integrity
2. (see 1, and no components added)
3. In-vitro Franz cell testing (cadaver skin and/or
synthetic membranes)
Low
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Risk Assessment
QTTP
Element Target Measure of Equivalency and Risk: Post-Change Risk Assessment
Drug
Product
and
Quality
Attributes
Appearance
Continued compliance with established specifications Low
Assay
Content Uniformity
Identity
Residual Solvents
Degradation
Liner Peel
Physical Tests
Drug Release
Microbial Limits
Cold Flow
Container
Closure
System
Equivalent to RLD Unchanged Low
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The Point Being . . .
Industry is embracing the tools offered by QbD-based development, meaningful and
intelligent risk assessment, and other recent advances in the science, which provide an
improved framework to reassess change guidance
“Mechanistic understanding and review of formulation design could reduce the need for
testing and expand the design space beyond past experience.” (emphasis mine) (R.
Lionberger)
How will this look moving forward?
PQRI white paper on IR and MR Dosage Forms (June, 2014)
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Use of Process Analytical Technology (PAT) to Mitigate
Risk for Scale-up, Site Change, and Equipment Change
OPQ: “Innovation is not increasing” [1]
Various uses in oral formulation processes
Endpoint semi-solid/liquid mixing processes
Solvent coating / extrusion processes (patches, oral thin films, etc.)
Others
1. Iser, Robert. Office of Pharmaceutical Quality. Global Drug Development and its Impact on CDER’s Drug
Review Process Symposium, June, 2014
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Endpoint Mixing Processes: Key Measures
Homogeneity
Viscosity
Time to dissolve or disperse components
Lends itself to Process Analytical Technology (PAT)
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Case Study: Realizing PAT in Process Development by Implementation of NIRS: Mitigate Risk for Scale-up, Site Change, and Equipment Change Work published in Sep/Oct 2013 issue of Pharmaceutical Engineering (Fowler, et. al.)
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Hydrogel Mixing: Realizing PAT in Process Development by Implementation of NIRS
IR spectrums recorded for each raw material
- Can be used for release, reference, investigations
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Case Study: Realizing PAT in Process Development by
Implementation of NIRS
Flat spectrum = homogeneity
Viscosity prediction / modeling
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Case Study: Realizing PAT in Process Development by Implementation of NIRS
Stage Pre-PAT
Process Mix #1 Mix #2 Mix #3
Stage 1 30 mins 21 mins 15 mins 22 mins
Stage 2 30 mins 28 mins 17 mins 4 mins
Stage 4 15 mins 12 mins 11 mins 5 mins
Cumulative Mix
Time 75 mins 61 mins 43 mins 31 mins
% of Control Mix
Time N/A 81% 57% 41%
Viscosity (cP) N/A 1,435 ~1,485 N/A
Result: Increased Process Understanding and Efficiency
Uniformity controlled via scale-independent method (NIR) =>
Mitigation of reporting requirement for significant scale or site change?
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Industry is embracing PAT – including generic Gx R&D
Great potential for risk mitigation in a variety of process, equipment, scale-up, and
site change scenarios
Consideration of PAT in lifecycle management and future/ongoing discussion of
change guidance
Perspective on Process Analytical Technology
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QbD Implementation Example: Risk Assessment - FMECA: Endpoint Batch Mixing Processes
Parameter Potential
Failure Mode Impact of Change
Potential Cause of Failure Controls S O D RPN
Risk Rating
Method of Investigation
Mixing Speed Too slow or fast
CU, viscosity, degradation
Equipment, Operator
BPR: inspection 7 5 3 105 H DoE
Final Mix Time
Too short or long
CU, viscosity, degradation Operator
BPR: inspection 7 5 3 105 H DoE
Fill Level Too low or high CU or spilling Operator BPR: visual 7 5 3 175 H
Constant in DoE
Mix Scale Too small or
large CU Operator BPR: visual 7 7 3 245 H DoE
Temp Too low or high CU,
degradation Friction, ambient
temp Visual 5 5 3 75 M Monitor in
DoE
Potential for greater utilization, especially with complex dosage forms
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Final Thoughts
Science and risk-based approach to lifecycle management is welcomed
As QbD and science advance, post-approval change process should improve
QbD tools, including PAT, and other recent advances in the science have
untapped potential to mitigate risk and streamline post-approval change process
Goal is to change the paradigm and improve the public health:
Traditional Development
Emphasis on Testing
No Risk Assessment
or DoE
Minimal Formulation Knowledge
PAS
Systematic Development
Emphasis on Design
Risk Assessment,
DoE
Substantial Formulation Knowledge
Annual Reportable,
CBE
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Thank You
Acknowledgements
PQRI
Gordon Johnston
Susan Rosencrance, U.S. Food and Drug Administration
Francois Menard, (former) Vice President, R&D, Watson Pharmaceuticals
Janie Gwinn, Director, Regulatory Affairs, Actavis plc
Michael Fowler, Principal Engineer, Actavis plc
