BY

Y
T
I
L
Y
N
A
I
U P THO
Q AN
IN R A

G
I
S
A

(Q

D
B

THE QUALITY MANTRA

Quality can not be

tested into products; it
has to be built in by
design
Joseph M Juran

WHAT IS QUALITY BY DESIGN?

You cant test quality into drug
products has been heard for
decades so whats new?
Its a culture - incorporates quality principles
as well as strong compliance function
Incorporates risk assessment and
management
Refocuses attention and resources on whats
important to the customer, i.e. the patients,
health professionals, payors and distribution
chain

QUALITY BY DESIGN
Continuous improvement is a hallmark of
quality by design
G. Taguchi on Robust Design: design changes during
manufacture can result in the last product produced
being different from the first product

In pharmaceutical manufacturing, we dont

want this patients and physicians must
count on each batch of drug working just
like the batches that came before

QUALITY BY DESIGN
In generic pharmaceutical manufacturing, there are
additional constraints
Fixed bioequivalence targets
Regulatory requirements to duplicate formulation of innovator drug
Lack of access to innovator development data

LEAD POINTS
1.

QbD Basic concept

2.

Steps in QbD

3.

DoE as a tool for QbD

4.

Example Torcetrapib

5.

Pros and cons

6.

Conclusion

WHAT IS QUALITY?

Quality
Requirements
= need or
expectations

Target Product
Quality Profile

Patient
Good pharmaceutical quality represents
an acceptably low risk of failing to achieve
the desired quality attributes.

DEFINITION: QUALITY BY DESIGN

Quality by Design is

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.

THE REVOLUTION IN QUALITY

THINKING

Quality by
Testing
and Inspection

Enhanced
product
knowledge
process
understanding

Quality by Design

quality assured by well designed product & process

INTRODUCED BY FDA IN 2002

ICH Q8
Pharmaceutical
Development
Management

ICH Q9

Quality Risk
Management

ICHQ10
Quality

Quality by
Design
Quality by Design GMP for the 21st
Century
Merck & Cos Januvia (2006) : first FDA
approved product

QUALITY BY DESIGN (QBD)

Myth : An expensive development tool !
Fact : A tool that makes product development
and commercial scale manufacturing simple !
Actually saves money !
How ?

OUTLINE
FDA initiatives for quality
The desired state
Quality by design (QbD) and design space (ICH
Q8)

Application of statistical tools in QbD

Design of experiments
Model building & evaluation
Statistical process control

FDAS INITIATIVE ON QUALITY

BY DESIGN
In a Quality-by-Design system:
The product is designed to meet patient requirements
The process is designed to consistently meet product
critical quality attributes
The impact of formulation components
parameters on product quality is understood

and

process

Critical sources of process variability are identified and

controlled
The process is continually monitored and updated to assure
consistent quality over time

o
Pr

g
n
i
nd

Quality
by
Design

Product Design

etc.

ance

Dosage fo
rm
,
st
ability,
formulation,
etc.

sta Process Controls

r
de
n
Process Pe
U
s
rformance
s
C
pk, robustn
ce
e ss ,

Unit operations, contr

ol
strategy, etc.

ed
ge

Product Quality Attributes

Pr
o
nt
e
m
e
v
ro
p
Im
s
u
o
u
d
n
ti
n
Co
u
c
Product Sp
Process
Parameters
ecificationst
Kn
Pro
ow
D
esdig
escireess
d PDro
ucnt
Perform
l

Pros and Cons

Scientific understanding

Holistic approach

Less data to manage

Meaningful data

recognised by

Fewer non conformances

authorities

Lean processes more

Culture change

cost efficient

Investment up front

Better control of process

Time to get to know

Continuous improvement

Managed based on risk

Patient first approach

Up to 30% savings*

New concept hard to

get buy in

Just starting to be

process and product

Difficult to apply
retrospectively

DESIGN SPACE (ICH Q8)

Definition: The multidimensional combination and
interaction of input variables (e.g., material
attributes) and process parameters that have
been demonstrated to provide assurance of
quality
Working within the design space is not
considered as a change. Movement out of the
design space is considered to be a change and
would normally initiate a regulatory postapproval change process.
Design space is proposed by the applicant and is
subject to regulatory assessment and approval

ICH Q9 QUALITY RISK MANAGEMENT

The primary objective is to find a harmful
event in the process

w
e
n
e
e
g
h
TFormalgua
Riskn
Management
a
lProcess

Initiate Quality Risk

Management Process

1.Risk

2. Risk

Assessment

Control

Output / Result of the Quality

Risk Management Process

4. Risk Review

CURRENT VS. QBD APPROACH

TO PHARMACEUTICAL
DEVELOPMENT
Current Approach

QbD Approach

Quality assured by testing and

inspection

Quality built into product &

process by design, based on
scientific understanding

Data intensive submission

disjointed information without
big picture

Knowledge rich submission

showing product knowledge &
process understanding

Specifications based on batch

history

Specifications based on product

performance requirements

Frozen process, discouraging

changes

Flexible process within design

space, allowing continuous
improvement

Focus on reproducibility often

avoiding or ignoring variation

Focus on robustness
understanding and controlling
variation

MAPPING THE LINKAGE

Input

Output
CQA1

M1
M2
Material Attributes

Critical
Quality
CQA2Attributes

CQA3

P1
P2
P3
Process
Parameters

Relationships:
CQA1 = function (M1)
CQA2 = function (P1, P3)
CQA3 = function (M1, M2, P1)

P2 might not be needed in the

establishment of design space

PHARMACEUTICAL
DEVELOPMENT & PRODUCT
LIFECYCLE
Product Design & Development

Process Design & Development

Manufacturing Development
Continuous Improvement

Candidate
Selection

Product
Approval

Pharmaceutical
Development & Product
Lifecycle

Statistical Tool

Product Design & Development:

Initial Scoping
Product Characterization
Product Optimization

Design of
Experiments
(DOE)

Process Design & Development:

Initial Scoping
Process Characterization
Process Optimization
Process Robustness

Model Building
And Evaluation

Manufacturing Development
and Continuous Improvement:
Develop Control Systems
Scale-up Prediction
Tracking and trending

Statistical
Process Control

BACKGROUND OF FDAS
PHARMACEUTICAL QUALITY
FOR THE 21ST CENTURY
INITIATIVE
In 2002, FDA identified a series of
ongoing problems and issues in
pharmaceutical manufacturing that
traditional approaches had not solved
FDA undertook an internal and external
assessment of the causes
As a result, the agency started a major
change initiative that is continuing
Stimulating more use of PAT was an

STATE OF REGULATION CIRCA 2002

Pharmaceutical manufacturing HIGHLY regulated (e.g.,
compared to foods, fine chemicals)
Cost of cGMP compliance very high
Despite this: process efficiency and effectiveness low (high
wastage and rework); and level of technology not
comparable to other industries

FUNCTIONAL CONSEQUENCES
Inability to predict effects of scale-up
Lack of agility usually takes years to
bring up a new production site
Operations fragmented around globe
Inability to understand reasons for
manufacturing failures

RESULT: FOR REGULATORS

Extensive oversight of manufacturing resource-intensive (in
era of cost reductions and increased mandates)
Expensive and time-consuming litigation and legal actions in
cGMP area
Need to deal with recalls and shortages of medically necessary
drugs

RESULT: FOR INDUSTRY

Culture: antithesis of continuous
improvement
Less focus on quality, more on
compliance
Regulatory burden high and costly,
but not viewed as contributing to
better science
Consequences of noncompliance:
potentially catastrophic
Lack of innovation: test but dont
tell

OUTCOMES
High cost of production for products due to
Low efficiencies in manufacturing
Waste
Long manufacturing cycle times based on testing requirements during
production
Drug shortages due to inability to manufacture
Lack of improvements based on new technologies
Slowed development/access for investigational drugs
Need for intensive regulatory oversight

FDA NEEDED TO MODERNIZE

PHARMACEUTICAL MANUFACTURING
REGULATION
More than 40 years ago, Congress required that all
drugs must be produced in accordance with Current
Good Manufacturing Practice (cGMP).
Requirement was intended to address significant
concerns about substandard drug manufacturing
practices by applying quality assurance and quality
control principles to drug manufacturing.
Last comprehensive revisions to the regulations
implementing cGMP requirements occurred over 25
years ago.
The initiative was started in August 2002 as the
Pharmaceutical cGMPs for the 21st Century - A RiskBased Approach initiative to enhance and modernize
the regulation of pharmaceutical manufacturing and
product quality to bring a 21st century focus to
this critical FDA responsibility.

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

Qbd on cleaning

GUIDANCE FOR INDUSTRY: QUALITY SYSTEMS

APPROACH TO PHARMACEUTICAL CGMP
REGULATIONS
Help manufacturers bridge between 1978
regulations and modern quality systems and
risk management approaches
Extends beyond CGMP expectations; however,
does not create requirements on manufacturers.
Implementation of this model should ensure
compliance and encourage use of science, risk
management and other principles of the 21st
Century Initiative.
When fully developed and effectively managed, a quality
Describes
comprehensive
quality system
model
system willalead
to consistent, predictable
processes
that
and
howthat
CGMP
regulations
QS elements
ensure
pharmaceuticals
arelink
safe,to
effective,
and
available for the consumer.

QUALITY SYSTEMS :
IMPLEMENTATION AND
INTERNATIONAL DEVELOPMENT AS
THE PQS
Manufacturers with a robust quality system and
appropriate process knowledge can implement
many types of improvements and take
responsibility for quality

Eliminate most of the burden of CMC post approval regulatory

submissions
Allow for more focused and fewer FDA inspections
Adoption by industry is starting to take hold fewer deviations, cost
savings in manufacturing

ICH adopted this concept as Q 10 Pharmaceutical

Quality System (PQS) to fulfill the ICH Quality Vision
Covers the product lifecycle from pharmaceutical development, tech
transfer, commercial manufacturing, to discontinuation
Focuses on the commercial manufacturing process, predicted by
development and utilizes knowledge for process improvement and
future development

INTERNATIONAL HARMONIZATION

In addition to Q10, Quality

Systems:
Q8 Pharmaceutical
Development
Q9 Quality Risk Management

HEPARIN WAS A WAKEUP CALL

Up to 30% contamination of
finished product
Present worldwide in various APIs:
many countries affected
Undetected by acceptance and
release testing
Persisted in drug supply until
serious adverse events triggered
investigation
Brought home the need for
vigilance throughout supply chain
and in all global settings

SIGNIFICANT CHALLENGES FOR BOTH

MANUFACTURERS AND FDA
Explosion of globalized
manufacturing
Increased complexity of supply
chains
Greater potential for exploitation
(e.g., counterfeits, terrorism)
Global regulatory system still
fragmented
(US) Erosion of inspectional
coverage over last several
decades
(US) Lack of modern IT (e.g.,

IMPROVEMENTS STARTED IN 21 ST CENTURY INITIATIVE ARE CRITICAL

Global harmonization of
manufacturing standards
Continuous improvement in
manufacturing science
Application of quality risk
management
Quality by design

ROLE OF THIS PAT WORKSHOP

Gathering of academics,
pharmaceutical industry, FDA, PAT
equipment manufacturers
Goal: update on use of the
technology, present case studies,
understand barriers to more
widespread adoption
Understanding of how PAT fits into
the future of quality by design

QUALITY BY DESIGN APPROACH

CAN BE USED FOR

API
Excipients
Analytics
Simple dosage forms
Advanced drug delivery
system
Devices

STEPS IN A QUALITY BY DESIGN

APPROACH?
2. CRITICAL
QUALITY
ATTRIBUTES
1.QUALITY
TARGET
PRODUCT
PROFILE

3. LINK
MAs AND PPs
TO CQAS

4. ESTABLISH
DESIGN
SPACE
6. PRODUCT
LIFECYCLE
MNGMNT

5. ESTABLISH
CONTROL
STRATEGY

STEP1 : QUALITY TARGET PRODUCT

PROFILE (QTPP)
Target Product Profile:
- a prospective and dynamic summary of the quality
characteristics of a drug product
- that ideally will be achieved to ensure that the desired
quality, and hence the safety and efficacy, of a drug
product is realized.
The TPP forms the basis of design of the product.

STEP 2. DETERMINE THE CRITICAL QUALITY

ATTRIBUTES (CQAS)
- DEFINITION

A critical quality attribute (CQA) is a

- physical, chemical, biological, or
microbiological property or
characteristic
- that should be within an appropriate
limit, range, or distribution
- to ensure the desired product quality.

STEP 2. DETERMINE THE CRITICAL

QUALITY ATTRIBUTES (CQAS)
Drug product CQAs are used to guide the
product and process development.
SOLID ORAL DOSAGE
FORMS:
Particle size
Polymorphic form
Water content
Residual solvent
Organic and inorganic
impurities

OTHER DELIVERY
SYSTEMS:
Include more product
specific aspects, such
as
Sterility for Parenteral,
Adhesive force for
transdermal patches.

STEP 3. LINK THE DRUG AND EXCIPIENTS

ATTRIBUTES AND THE PROCESS PARAMETERS TO
THE CQAS
tes

u
b
i
r
t
t
A
y
t
i
l
a
u
Q
Inputs to the process

I Chart
115
UCL=111.55

Individual Value

110

People

105
_
X=99.63

100

95

s
s
e ers
c
Pro met Equipment
ra I
a
P
90

LCL=87.71

60

62

64

66

68
70
72
Observation

74

76

78

80

I Chart

115

UCL=112.65

Individual Value

110
105
100

_
X=97.94

95

control variability
of the Output

90
85

LCL=83.23

80

40

42

44

46

48
50
52
Observation

54

56

58

60

I Chart

115

UCL=112.65

105
100

_
X=97.94

95
90
85

LCL=83.23

80
40

42

44

46

48
50
52
Observation

54

56

58

60

I Chart
120
UCL=116.68

Individual Value

115
110
105

_
X=102.37

100
95
90
LCL=88.05
20

22

24

26

28
30
32
Observation

34

36

38

40

I Chart
115
UCL=111.55

Individual Value

110

105
_
X=99.63

100

95

90

N
P
U
T
S
(X)

y = (x)

Measurement

62

64

66

68
70
72
Observation

74

76

78

UCL=114.17

110

Process

105
100
95

LCL=85.72

85
1

Materials

11

21

31

41
51
61
Observation

I Chart
UCL=111.17

Individual Value

105

_
X=98.76

100

95

Environment

90
LCL=86.35

85
80

82

84

86

88
90
92
Observation

94

96

98

71

81

91

OUTPUT

80

110

_
X=99.95

90

LCL=87.71
60

I Chart
115

Individual Value

Individual Value

110

100

4 DESIGN SPACE

STEP 5. CONTROL STRATEGY

Elements of a control strategy can include, but are
not limited to, the following:
Control of input material attributes based on an
understanding of their impact on process ability or
product quality
Product specification(s)
Controls for unit operations that have an impact on
downstream processing or end-product quality
In-process or real-time release in lieu of endproduct testing

STEP 5. DEFINE THE CONTROL

STRATEGY
The control strategy should describe
and justify how
in-process controls and
the controls of
- input materials
(drug substance and
excipients),
- container closure system,
- intermediates and
the controls of end products
contribute to the final product

TOOLS FOR RISK MANAGEMENT

Preliminary hazard analysis ( PHA)
Failure mode effect and criticality
analysis ( FMECA)
Risk ranking
Risk filtering

BETTER PROCESSES UNDERSTANDING

WILL LEAD TO PRODUCTS
WITH LESS VARIABILITY

What are the steps in a

Quality by Design approach?
2. CRITICAL
QUALITY
ATTRIBUTES
1.QUALITY
TARGET
PRODUCT
PROFILE

3. LINK
MAs AND PPs
TO CQAS

4. ESTABLISH
DESIGN
SPACE
6. PRODUCT
LIFECYCLE
MNGMNT

5. ESTABLISH
CONTROL
STRATEGY

DEFINITION OF DESIGN SPACE

The material attributes and process
parameters that assure quality.
The multidimensional combination
and interaction of input variables
(e.g. material attributes) and
process parameters that have been
demonstrated to provide assurance
of quality.

STEPS IN A QUALITY BY DESIGN

APPROACH?
2. CRITICAL
QUALITY
ATTRIBUTES
1.QUALITY
TARGET
PRODUCT
PROFILE

3. LINK
MAs AND PPs
TO CQAS

4. ESTABLISH
DESIGN
SPACE
6. PRODUCT
LIFECYCLE
MNGMNT

5. ESTABLISH
CONTROL
STRATEGY

CONTROL SPACE

Design Space

Knowledge
Space

Control Space

DESIGN OF EXPERIMENTS
(DOE)
Structured, organized method for determining the
relationship between factors affecting a process
and the response of that process
Application of DOEs:
Scope out initial formulation or process design
Optimize product or process
Determine
design
space,
including
multivariate
relationships

DOE
METHODOLOGY
(1) Choose experimental
design
(e.g., full factorial, doptimal)
A

(3) Analyze data

(2) Conduct randomized

experiments
Experimen
t

Factor A

Factor B

Factor C

(4) Create multidimensional

surface model
(for optimization or control)

www.minitab.com

A DOE IS USEFUL TO

Identify important factors

Establish process stability
Find best operating conditions

Graphical Analysis
Geo-Gram:
The geo-gram is a geometrical representation of the data.
The shape is determined by the number of factors ( i.e. 2
factors is a square, 3 factors is a cube), the number of
levels and the distance between levels.

SQUARE GEO-GRAM
35

+47

This defines the inference

space or the experimental
boundaries of your experiment
within your process.

Temp
B
-

41

50

Time
A

1a
Response surface plot

Contour plot

QbD

Literature
review

Preformulatio
n studies

formulation

QC and
Evaluati
on

Out
Product

Current approach: Quality assured by testing and inspection

Data intensive submission
Specifications based on batch history
Frozen process, discouraging changes
Focus on reproducibility often avoiding or ignoring
QbD
Approach:variation
Quality built into product & process by design, based on
scientific understanding
Knowledge rich submission showing product knowledge &
process understanding
Specifications based on product performance requirements
Flexible process within design space, allowing continuous
improvement
QbD
Focus
on robustness
understanding
replaces
QbT( Quality
by Testing) and controlling variation

Experimental Approach for

Identifying Parameters
Design of Experiments (DOE) is an efficient method
to determine relevant parameters and interactions
1.

Choose Experimental
Design
(e.g., full factorial, fractional )
2. Conduct Randomized
Experiments
3. Analyze Data
Determine significant
factors

MODEL BUILDING &

EVALUATION - EXAMPLES
Models for process development
Kinetic models rates of reaction or degradation
Transport models movement and mixing of mass or heat
Models for manufacturing development
Computational fluid dynamics
Scale-up correlations
Models for process monitoring or control
Chemometric models
Control models
All models require verification through statistical
analysis

Model Building & Evaluation Chemometrics

Chemometrics is the science of relating
measurements made on a chemical system or
process to the state of the system via
application of mathematical or statistical
methods (ICS definition)
Aspects of chemometric analysis:
Empirical method
Relates multivariate data to single
responses
Utilizes multiple linear regressions
Applicable to any multivariate data:
Spectroscopic data
Manufacturing data

or

multiple

QUALITY BY DESIGN &

STATISTICS
Statistical analysis has multiple
roles in the Quality by Design
approach
Statistically designed experiments
(DOEs)
Model building & evaluation
Statistical process control

A SHARED VISION OF QUALITY

GPhA supports the FDA CGMP initiative
Generic drug manufacturing companies:
Exist to make affordable drug therapies available to all
Companies, staff, volumes and revenues are smaller

It is completely appropriate that

regulatory requirements apply to all
companies small and large, as long as
regulatory guidance provides flexibility
in recognition of more limited resources
at smaller firms

SUGGESTED ACTIONS
Give credit for good performance
Continue to reduce unnecessary
supplements
Continue to develop the Pharmaceutical
Inspectorate
Reward process innovation
Eliminate unnecessary testing requirements
Address oversight of overseas API mfrs

Solid-State Polymorphism
Different crystalline forms of the same drug substance
(ICH Q6A)
Crystalline forms
Solvates (Hydrates)
Amorphous forms

Drug Product Bioavailability/Bioequivalence

Solubility/Dissolution

Pharmaceutical Solid Polymorphism

Mechanical Properties/
Hygroscopicity

Processability /
Manufacturability

Chemical Reactivity

Stability

Polymorphism and the Effect on Bioavailability

Form I

Intestinal
Membrane

Form II

Dissolution/Solubility
Limited Oral Absorption
(e.g. chloramphenicol palmitate)

Intestinal
Membrane

Solubility: Form II > Form I

Gastric Emptying or Permeation
Limited Oral Absorption
(e.g. ranitidine HCl)

Polymorphism and the Effect on Stability

Crystalline: Degradation: 0.5%
Amorphous: Degradation: 4.5%

Formulation I
X Crystalline/
Amorphous
Formulation II
Optimize the formulation mitigate degradation pathways
(e.g., adjust pH microenvironment to limit degradation,
anti-oxidant to limit oxidative degradation)

Crystalline: Degradation 0.6%

Amorphous Degradation 0.7%

Polymorphism and the Effect on Manufacturability

Paracetamol Form I

Paracetamol Form I I
Direct Compression

Wet Granulation

Paracetamol Form I
E. Joiris , Pharm. Res. 15 (1998) 1122-1130

Paracetamol Form I I

Intrinsic Properties
of Different Forms

Biopharmaceutical Properties

Selection and Control of

Polymorphic Forms?

Formulation
Variables

Manufacturing Process
Variables

Regulatory Considerations:
Can One Consider Polymorphs to be the Same Active?
CH3
S
NO2

N
H

C
N

Materials Science
J. Am. Chem. Soc. 122 (2000) 585-591

Form I

Form II

Drug Product
Safety/Effectiveness

QBD PARADIGM: POLYMORPHS

From ICH Q8: The physicochemical and biological

properties of the drug
substance that can influence the performance of the drug
product and its
manufacturability, or were specifically designed into the
drug substance
(e.g. solid state properties), should be identified and
discussed.
Expectation that sponsors justify in pharmaceutical
development the selection
and control of the polymorphic form (as applicable) to
achieve drug product performance characteristics, stability
and ensure manufacturability

FDA REGULATORY SCHEME

21 CFR 320.1(c), Food and Drugs, Definitions: Pharmaceutical
equivalent means drug
products in identical dosage forms that contain identical amounts
of the identical active
drug ingredient, i.e., the same salt or ester of the same
therapeutic moiety; do not
necessarily contain the same inactive ingredients; and meet the
Same Active Moiety
identical compendial or
other applicable standard of identity, strength, quality, and
purity, including potency.
Phosphate

Different Active Ingredients

Sulfate

FDA Regulatory Scheme: Pharmaceutical Alternatives

No Possibility for Therapeutic Equivalence for Different Salts

Co-Crystals

A
A

A
A

A
A

A
A

A+
A+ A+
CCCCA+
C-

CA+

A+

A+
C-

A+

Salts

CA+

G
A

G
A
A

Cocrystals

Crystalline Molecular Complexes:

Co- Crystal / Salt Continuum

A
A
A
A

Polymorphs

Crystalline Molecular Complexes:

Analogous to Polymorph Solvate
(Except other Component in Crystal
Lattice is a Solid (not Liquid))

Where Do Co-Crystals Fit in Our

Regulatory Scheme?
A
A

G
A

A
A

A
A

A+
A+ A+
CCCCA+
C-

CA+

A+

A+
C-

A+

CA+

Salts
Same Active Moiety
Different API

Co-crystals??
Where Do Co-Crystals Fit?
Is a New Regulatory
Class of Solids Needed?

A
A

A
A

A
A

A
A
A
A

Polymorphs
Same API

CASE STUDY API

TORCETRAPIB

The concept and application of quality by design

(QbD) principles has been and will undoubtedly continue to
be an evolving topic in the pharmaceutical industry.
However, there are few and limited examples that demonstrate
the actual practice of incorporating QbD assessments,
especially for active pharmaceutical ingredients (API)
manufacturing processes described in regulatory submissions.
We recognize there are some inherent and fundamental
differences in developing QbD approaches for drug
substance (or API) vs drug product manufacturing processes.
In particular, the development of relevant process understanding
for API manufacturing is somewhat challenging
relative to criteria outlined in ICH Q8 (http://www.ich.org/
cache/compo/2762541.html) guidelines, which are primarily
oriented toward application of QbD for drug product
manufacturing. J Pharm Innov (2007)
2:7186

In an effort to establish a consensus and develop consistency, industry

and regulators have frequently described quality by design (QbD) by
dividing it into three fundamental, interrelated concepts: control
strategy, design space, and criticality.1 Figure 1 describes a QbD
approach for developing design space, establishing control strategy,
and delineating criticality for an active pharmaceutical ingredient
(API) that essentially serves as a map for how these conceptual
elements were used to establish design space for the torcetrapib API
manufacturing process. A preliminary assessment of the QbD
strategy for the manufacture of the API typically begins early in
development when chemists and engineers evaluate synthetic route
selection as well as intermediate quality attributes (QAs) impacting
API specifications. As a default, established API specification limits
serve as a primary control standard for QAs and surrogate control in
the absence of a process control strategy and relevant intermediate
specifications.

Torcetrapib(CP-529,414,Pfizer) was adrugbeing developed

to treathypercholesterolemia(elevatedcholesterollevels) and
preventcardiovascular disease.

The API specification, by default, serves as a predictor of critical QAs

(CQAs) because the combination of their measurements may
directly correlate to potential impact to the safety and efficacy of
the drug product and thus to the
patient. API CQAs may include physical characteristics beyond such
things as the impurity specification of the API, e.g., particle size,
polymorphic form, and salt selection are Mrelevant for drug product
manufacture.3 The analytical
control strategy for an API manufacturing process that evolves during
development is routinely focused with the attention on the
formation and purge of impurities and their cascade effects on the
multiple process steps, including the
potential impact to the APIs CQAs. To establish design space, a formal,
prospective risk assessment is executed in accordance with ICH Q9
(B in Fig. 1). A process risk assessment is performed as a precedent
to formally develop a design space for the commercial
manufacturing process so that potential critical process parameters
(CPPs) can be identified. In general, a process risk assessment
considers prior knowledge, mechanistic understanding of the
chemistry,
and relevant chemical manufacturing experiences.

Starting and Raw Materials

Before parameters and ranges can be evaluated in any multivariate
designed experiment, the appropriate quality of SMs (or key
intermediates) and raw materials must be established. For the
torcetrapib manufacturing process,
some of the specifications of compound 4 were deemed CQAs because
of their direct impact on controlling the relative genotoxic impurities
in steps 5 and 6. In addition, ECF (raw material) is a commodity
chemical used in step 5 that is incorporated into the structure of the
API. Fate and purge development work, batch history, and
appropriate communications with vendors are a few methods to
establish appropriate specifications for SMs and raw
materials. Appropriate specifications were established for each of these
materials before any of the multivariate designs were initiated for
torcetrapib, and by default, some of these specifications were
deemed CQAs. The validity of
a multivariate experimental design used to establish a design space
depends on understanding the functional relationship between
these CQAs/specifications and the API CQAs.

CONCLUSION ON CASE STUDY

We have provided a case study of a QbD effort, including a risk
assessment, for the torcetrapib drug substance process.
Fundamentally, different from the drug product, API processes have
multiple steps. Understanding the functional
relationship between FAs, QAs, and process parameters as they
progress through the manufacturing process is the most universally
challenging aspect of QbD for API
development. Analytical specifications and control strategy aspects of
the QbD plan remain the foundation for change throughout the
evolution of the manufacturing process (from phase I to launch).
The role of the chemist and engineer during the course of development
is to effectively eliminate as many of the CQAs and CPPs as possible
from the commercial manufacturing process through continuous
improvement efforts.
Designed experiments generate the data required to establish a design
space for commercial manufacturing processes, while providing the
process understanding that facilitates sound business decisions.
First principles ofchemistry can expand this toolbox to include
kinetic models, computer predictive programs, and more diverse
concepts of prior knowledge.

SUMMARY:
Quality by Design (QbD) presents to the
industry , various pros like reduction in cost , a
better model ,hassle free processes better
interacted with FDA.
Along with that ,new technologies can be
implemented once a thorough understanding of
product is done.
For a manager ,It cuts down time to the industry
, if used effectively.
Thus , it brings about a worthwhile change in
every Pharmaceutical Operation and thus the
popularity of this subject and shift in the
paradigm is signified.

SUMMARY

The public expects their drugs to

be of reliable high quality
Tradition of empirical
development of formulation
and manufacturing process
makes reliability a challenge
Globalization introduces more
risks of quality problems
FDA introduced Pharmaceutical
Quality for 21st Century to

SUMMARY

Improved manufacturing science

(QbD), when paired with a
robust quality system, is the
key to reliable drug quality
Technologies such as PAT are
crucial to implementing the
knowledge gained from QbD in
a meaningful and efficient way
FDA encourages adoption of
these technologies, and is

CONCLUSION

Quality by Design and the

FDA CGMP Initiative make
excellent business and
scientific sense
The generic pharmaceutical
industry welcomes the
opportunity to work with
FDA