Quality by Design in

Pharmaceutical Manufacturing

Rakhi B. Shah, Ph.D.

U.S. Food and Drug Administration

Disclaimer: The views expressed in this presentation are the personal

opinions of the speaker and do not necessarily represent the views of FDA

AAPS-Chicago 2009
 Overview

Quality & Quality by Design (QbD)

Design Space
Quality Risk Management
QbD Case study (Fishbone, FMEA, DoE)
Continuous Quality Monitoring
Real Time Release
Questions based Review (QbR)
Challenges to Implementing QbD
Integrated Approaches

AAPS-Chicago 2009
 What is Quality by Design (QbD)?

Quality
Acceptably low risk of failing to achieve the desired clinical
attributes

Pharmaceutical Quality
= f {drug substance, excipients, manufacturing..}

QbD
Product and process performance characteristics
scientifically designed to meet specific objectives, not merely
empirically derived from performance of test batches (Janet
Woodcock, 2004)

AAPS-Chicago 2009
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
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

Winkle, FDA AAPS-Chicago 2009

 Recalls
550
17
39 15
16
Number

15 20 316 45
246 290 236
0
3 4 8
154
16 275
100 103 179 188
89 154 138

162 178 164 162 145 187 168 169

122 143 130 128
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Fiscal Year
Class III Class II Class I

361 Human drug recalls in FY 2006:

Class 1 (45), Class II (188), Class III (128)
AAPS-Chicago 2009
 cGMP Deficiencies on Foreign
Inspection data in 2006

Analytical method validation

Production/process control

Lab records/reports
Process validation protocol

Equipment maintenance
Equipment design/qualification

Lack of or Inadequate SOPs

Production records/reports

Laboratory controls
Failure/OOS investigations
0 5 10 15 20 25 30 35 40

AAPS-Chicago 2009
 Why QbD?
Higher level of assurance of product quality

Cost saving and efficiency for industry & regulators

Facilitate innovation
Increase manufacturing efficiency
Reduce cost/product rejects
Minimize/eliminate potential compliance actions
Enhance opportunities for first cycle approval
Streamline post approval changes & regulatory processes
More focused inspections
Opportunities for continual improvement

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 Quality by End-product Testing

10/30 out of
Drug Substance 10,000,000
Assay
Uniformity
Impurity
Unit Operations
Mixing Dissolution Meet
Compression Res Solvents Spec? Yes
Coating
Moisture
Metal No
Excipients

CFR 314.70

Yu, DIA 2006 AAPS-Chicago 2009

 Quality by Design

Clinical
Drug Substance relevance

Unit Operations
Mixing QbD Always Meet
Compression
Coating
Spec
Assay
Uniformity
Excipients Impurity
Dissolution

Yu, DIA 2006 AAPS-Chicago 2009

How does QbD relate to Performance?
Quality by design assures in vitro product performance
In vitro product performance provides assurance of in
vivo product performance in some cases
In vivo
dissolution

In vitro
dissolution

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 Risk Management
Brainstorming
RISK ASSESSMENT Flow charts
Fault tree analysis
Cause and effect diagram
Risk identification Process maps
Others..

Risk Analysis
FMEA
FMECA
Risk ranking
Risk Evaluation Others..

DoE
RISK CONTROL Statistical Process
controls

Process sensors
RISK REVIEW Data flow optimization
SOPs/Manuals
Others..

Modified from ICH Q9

 Constituents of QbD
Control Responses Process Parameter
(measurement) Control Strategy (set points)
Key Quality and Process
Parameter
Development and
Customer feedback
Complaints
Risk Management Manufacturing
Experience
OOS Critical to Quality Attributes
(measured material attribute)
Expe es ign
rim lD
ental Formulation Process enta
Desi
gn xperim els
Fund Experiments Development E o d
amen n talM
t al M o e
dels Initial Risk Assessment undam
F
Physicochemical Characterization Physicochemical Characterization
of API of the Excipients
Target Product Profile
Product Design based on User requirement
Emi, EFPIA 2008
QbD for Industry & Regulatory Agency
Industry
Develop scientific
understanding of critical
process & product attributes
Design controls & testing
based on limits of scientific
understanding at development
stage
Utilize knowledge gained over
the products lifecycle for
continuous improvement
Regulatory agency
Assess scientifically product
& manufacturing process
design & development
Evaluate & approve product
quality specifications in light
of established standards
(eg. Purity, stability, content
uniformity, etc)
Evaluate post-approval
changes based on risk and
science
AAPS-Chicago 2009
 Quality Roadmap
Product quality/performance
achieved by effective and Process
efficient manufacturing
processes

Process Continuous
Design Analytical real time
Space Technology assurance of
quality

Product
Performance
Product specifications based on
mechanistic understanding of how
formulation and process variables impact
product performance

Lyon, FDA AAPS-Chicago 2009

 ICH Q8 Design Space
Definition:
The multidimensional The Pharmaceutical Universe
combination and interaction of
input variables (e.g., material Knowledge Space
attributes) and/or process
parameters that have been
demonstrated to provide
Design Space
assurance of quality
Established experimentally

Traditional one dimensional Modelled

process range doesnt meet Q8
definition and will not lead to Khan, FDA
regulatory flexibility
AAPS-Chicago 2009
 Regulatory Flexibility
Working within the design space is not considered a
change
Proposed by applicant and approved by regulator
Degree of regulatory flexibility is predicted on the level
of relevant scientific knowledge provided
Opportunities to facilitate
risk-based regulatory decisions (reviews & inspections)
manufacturing process improvements, within the approved
design space described in the dossier, without further
regulatory review
reduction of post-approval submissions
real-time release, leading to a reduction of end-product
release testing

AAPS-Chicago 2009
 Reducing Product Variability

Reduced
Product
Design Variability
Space
Process
Input (or Process Step) Product
Raw materials (or Intermediate)

Input Monitoring of
Process Process Parameters
Variability Parameters or Attributes

Process Controls/PAT

Nasr, FDA AAPS-Chicago 2009

 Design Space Determination
First-principles approach
combination of experimental data and mechanistic
knowledge of chemistry, physics, and engineering
to model and predict performance

Statistically designed experiments (DOEs)

efficient method for determining impact of
multiple parameters and their interactions

Scale-up correlations
a semi-empirical approach to translate operating
conditions between different scales or pieces of
equipment

Any combination of the above

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 Designing a Robust Process

PROCESS UNDERSTANDING
Low High
Problems
detected after they
High potential
occur, through
for failures product testing and
CONTROL
PROCESS

Low inspection

Reproducible
process within Robust &
High narrow operating reproducible
ranges process

Nasr, FDA AAPS-Chicago 2009

QbD Dossier-An Industry View

EFPIA, 2006 AAPS-Chicago 2009

 QbD Case-study
Iterative risk assessment:
Inc
re a

QRAs (lab, monovariate) se
dp
roc

Fishbone diagrams e ss
un
d ers
FMEA-1 tan
d ing
reaction monitoring (lab)

DoEs (lab)  MVDA

FMEA-2

reaction monitoring (plant)

DoEs (plant)  MVDA

FDA-Novartis CRADA AAPS-Chicago 2009

 Fishbone (Ishikawa) Diagram

Raw materials Manufacturing

Size
Blending
Diluent
API
Granulation
LOD Coating
Disintegrant
Compression

Tablet
dissolution
Operator
Sampling

Method Temp
Instrument RH

Location

Analytical Plant

FDA-Novartis CRADA AAPS-Chicago 2009

 Failure Mode Effect Analysis
(FMEA)
RPN* = Probability X Impact X Detactability

Variable Failure P Impact I Detectability D RPN*

Mode (p)

Mesh Broken 1 Comp, psd, 5 Operator, 4 20

size screen flow batch record
LOD Low LOD 1 PSD, fines, 2 Near infra-red 1 2
flow

*RPN is Risk Priority Number

FDA-Novartis CRADA AAPS-Chicago 2009

Reaction Monitoring Lab and
Commercial Scale

Near Infra-
red probe

FBD with NIR probe

Commercial scale
Lab scale
FDA-Novartis CRADA AAPS-Chicago 2009
Design of Experiments (DoE)
A systematic, planned approach to solving problems
by gaining information through carefully planned
experiments or studies

These studies have adequate statistical properties to

be able to
-accurately measure the effects of formulation &
process factors on the key response variable(s)
(i.e.,dissolution, content uniformity, etc.)

-be able to tell if these factor effects are real

(above the noise level) and if so to accurately
quantify these effects.

AAPS-Chicago 2009
 Design Space on a full scale
DoE

F low high A
Out of specification
high high high high

low
L JG D
low
low high
high high

Response
Full Scale
Design Space
low high low

E low B I
high high
K
low 2
low
ble
ria
H low high C Variable 1 Va
low low

Design Space
23 factorial DoE

FDA-Novartis CRADA AAPS-Chicago 2009

 Continuous Quality Monitoring

Raw Materials Granulation Fluid bed drying Blending Compression

520095_GR_A.M 4:5 - Sc ores [c omp. 1] (Aligned) +3 Std.Dev 520095_D R_A.M 1 - Scores [comp. 1] ( Aligned) +3 Std.Dev 520095_C O_A.M 1 - Scores [comp. 1] ( Aligned) +3 Std.Dev
t[1] (Avg) t[1] (Avg) t[1] (Avg)
-3 Std.Dev -3 Std.Dev -3 Std.Dev
t[1] (Aligned): 1000016_A t[1] (Aligned): 665002T_A t[1] (Aligned): 665001T_A

4 4.00
6 6.0 0
5 5.00
3 3.00
5 5.0 0
4 4.00
2 2.00 4 4.0 0
3 3.00
1 1.00
3 3.0 0 2 2.00
0 0.00
2 2.0 0 1 1.00
-1 - 1.00
t[1]
t[1]

1 1.0 0 0 0.00

t[1]
-2 - 2.00 -1 -1.00
0 0.0 0

-3 - 3.00 -2 -2.00
-1 -1. 00
-4 - 4.00 -3 -3.00
-2 -2. 00
-5 - 5.00 -4 -4.00
-3 -3. 00
-6 - 6.00 -5 -5.00
-4 -4. 00
-7 - 7.00 -6 -6.00

0 1 2 3 4 5 6 7 8 9 10
0 11 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
-7 -7.00
Ti me ($Ti me) Ti me ($Ti me)
-1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Ti me ($Ti me)

520095_C O_A - batch level.M2 (PCA- X), FinalMonitor

t[Comp. 1]/t[Comp. 2]
520095_D R_A - batch level.M2 (PCA- X), Unti tled
520095_D R_A - batch level.M2 (PCA- X), Unti tled
t[Comp.
t[Comp.1]/t[Comp.
1]/t[Comp.2]2]
520095_GR_A
520095_GR_A- -batch
batchlevel.M1
level.M1(PCA-
(PCA-X),
X),Unti
Untitled
tled
t[Comp.
t[Comp.1]/t[Comp.
1]/t[Comp.2]2]

20 2 0. 0 0

88 88.0
.000
10
10 1100 .00
. 00
66 66.0
.000
10 1 0. 0 0

44 44.0
.000
55 55..0000

22 22.0
.000
0 0 .0 0

t[2]
t[2]

t[2]
t[2]
t[2]

00 00.0
.000 00 00..0000

-2
-2 -2
- 2..00
00
- 10 - 10 .00
-5
-5 -- 55..00
00
-4
-4 -4
- 4..00
00

-6
-6 -6
- 6..00
00
-- 10
10 -- 1100..00
00 - 20 - 20 .00
-8
-8 -8
- 8..00
00

-1
- 100 00 10
10
t[1] -4 0 -3 0 -20 -10 0 10 20 30 40
t[1] -- 20
20 -1
- 100 00 10
10 20
20
t[1] t[1]
t[1]

Ellipse
Ellipse:: Hot
Hotelli
elling
ng T2
T2 (0.9
(0.95)
5)

Ellipse
Ellipse:: Hot
Hotelli
elling
ng T2
T2 (0.9
(0.95)
5) Ellipse : Hot elli ng T2 (0.9 5)

520095_C O_A - batch level.M3 (PLS), Assay

YPred[Comp. 8]( YVar A1110-L20-O105-Assay_-_Liquid)/YVar(YVar A1110-L20- O105-Assay_-_Liquid)

y= 1.001* x-0.127
R2=0.9799
1 01 1 01 .0 0

YVar(A1110-L20- O105- Assay_- _Liquid)

1 00 1 00 .0 0

99 9 9. 00

98 9 8. 00

98 9 9 100 10 1

YPred[8]( A1110-L20-O105-Ass ay_-_Liquid)

RMSEE = 0.11 8192

FDA-Novartis CRADA AAPS-Chicago 2009

 Real Time Monitoring
Batch Fingerprint/Golden Batch - Predicted scores for t[1]
5
4
3
2
1
0
t[1]

-1
-2
-3
-4
-5
-6
M1

-7
-1 0 1 2 3 4 5 6 7 8 9 10 11 1 2 13 14 15 16 17 18 19 20 21 22 23
Time/Maturity ($Time)

3 std. dev. Average Batch -3 std. dev. 1003412

SIMCA-Batch On-Line View 2.1 - 7/29/2005 12:48:56 PM

1
Contribution

-1

-2
09636_EXHFILTERDP

009636_PRODUCTDP
2009636_DEWPOINT

52009636_EXHTEMP

YA52009636_INTEMP
A52009636_ATMPRS

9636_BYPASSTEMP

A52009636_EXHLEL
A52009636_AIRVOL

FDA-Novartis CRADA AAPS-Chicago 2009

 Real Time Release
The ability to evaluate and ensure the acceptable quality
of in-process and/or final product based on process data.
Typically, the PAT component of RTR include a valid
combination of assessed material attributes and process
control
In real time release, material attributes are measured
and controlled along with process parameters. Material
attributes can be assessed using direct and/or indirect
process analytical methods
As defined in the PAT guidance builds on parametric
release of heat terminally sterilized drug products
It is comparable to alternative analytical procedures for
final product release

PAT guidance, 2004 AAPS-Chicago 2009

Challenges to implementing QbD-
FDA perspective
Implementation Challenges
Putting new concepts/approaches into practice
Diversity of products
Different regulatory processes (NDA, ANDA, BLA)
Expectations for QbD based submission while addressing
traditional requirements (dual processes)
Integration of review and inspection

Broad spectrum of approaches to development,

manufacturing, and quality operations across industry

Implementing while harmonizing

Heavy workload and limited resources

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Challenges to implementing QbD-
Industry perspective

Culture Change
Information in application
Role of industry scientists in regulatory discussions

Business Challenges
Remove silos across business units
additional investment during development to achieve
efficiency and lower manufacturing cost over entire lifecycle

Management Support
Business case

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 Generic Industry Perspective

Generic drug manufacturing companies:

-Exist to make affordable drug therapies available to all
-Companies, staff, volumes and revenues are smaller
-Fixed bioequivalence targets
-Regulatory requirements to duplicate formulation of innovator
-Lack of access to innovator development data

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Question based Review for
Generics

Quality by Quality
Design Overall
Summary
QbR
Questions

Novel Risk Post Approval

Assessment Changes

Yu, DIA, 2006 AAPS-Chicago 2009

Examples of QbD questions under QbR
Define target product quality profile
What attributes should the drug product possess?

Design and develop product and manufacturing process to meet

target product quality profile
How was the product designed to have these attributes?
Why was the process selected?

Identify and control critical raw material attributes, process

parameters, and sources of variability
How were critical process parameters identified, monitored, and
controlled?
The process is monitored and adapted to produce consistent
quality over time
What are in-process tests and/or controls that ensure each step is
successful?
Yu, DIA, 2006 AAPS-Chicago 2009
 Integrated Approach
Industry
Integrate across business
units (e.g. R&D,
manufacturing,quality)
Integration across
disciplines (e.g. chemists,
engineers, statisticians)
Incorporate Quality
Systems to manage the
new approach
Regulatory agency
Integrate review,
inspection and
compliance
Incorporate multi-
disciplinary CMC review
(e.g. chemists,
pharmacists, engineers)
Implement Quality
Management System
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 Conclusions
Aspects Traditional QbD

Pharmaceutical Empirical; univariate Systematic; multivariate

development experiments experiments
Manufacturing Fixed; validation on 3 initial Adjustable within design
process full-scale batches; focus on space; continuous verification;
reproducibility focus on control strategy &
robustness
Process control In-process testing for go/no- PAT utilized for feedback &
go; offline analysis w/slow feed forward, real time
response
Product Primary means of quality Part of the overall quality
specification control; based on batch data control strategy; based on
desired product performance
Control Mainly by intermediate and Risk-based; controls shifted
strategy end product testing upstream; real-time release
Lifecycle Reactive to problems & Continuous improvement
management OOS; post-approval enabled within design space
changes needed
AAPS-Chicago 2009
 Conclusions

QBD methodologies with the identification and justification

of target product profiles, and product and process
understanding to obtain preset specifications, with
appropriate control strategies can ensure a state of
control.

This provides a possibility for continuous improvement

with real time release and reduced supplement burden.

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 Questions?

 Rakhi.shah@fda.hhs.gov

 1-301-796-0132

AAPS-Chicago 2009