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Anand D. Savkare et al. / International Journal of Advances in Pharmaceutical Research
IJAPR
Available Online through
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Review Article
ISSN: 2230 – 7583
QUUALITY BY DESIGN (QbD): A QUALITY IMPROVEMENT PERSPECTIVE FOR
PHARMACEUTICAL DEVELOPMENT
Anand D. Savkare* 1 , Nitin K. Mahajan 1 , Mitesh S. Hambardikar 2 , Vinayak Vadekar 1
1 Department of Pharmaceutics and Quality assurance techniques, N.D.M.V.P Samaj’s College of
Pharmacy, Gangapur Road, Nasik-02.
2 Department of Quality assurance techniques, TVES HLMC College of pharmacy, Faizpur
Received on 10 – 02 - 2012 Revised on 20 – 03- 2012 Accepted on 14– 05 – 2012
ABSTRACT
Quality by design (QbD) is a new modern perspective towards the qualitative pharmaceutical development. This is
a systemic approach to design and development of the pharmaceutical formulations and manufacturing processes
that ensures the predefined product quality. This QbD consists the chain of elements which on execution gives the
consistent quality over time. Implementation of QbD enables the assurance of pharmaceutical quality by
understanding and controlling formulation and manufacturing variables. Quality risk management (QRM) serves
the base for control strategy, which is only can attain by process understanding. This new paradigm of drug
development provides relief from regulatory framework that imparts flexibility, increase in efficiency by offering
important benefits by business point of view throughout the product’s life cycle. Continual improvement can be
achieve by QbD implementation as it is systematic way of product and process development.
Key Words: Quality By Design (QbD), Target Product Profile (TPP), Critical quality attribute (CQA),
Design Space, Control Strategy, Product lifecycle management
INTRODUCTION
The pharmaceutical development outcomes are the
basic platform for quality risk management (QRM).
It is important to recognize that quality cannot be
tested into products that is quality should built in by
design. The development relates with the changes in
the formulation and process of manufacturing
likewise the same thing is about the lifecycle
management which further can be looked upon as
opportunities for additional knowledge
improvement. Alternately that helps for
establishment of design space. Similarly, inclusion
of relevant knowledge gained from experiments
giving unexpected results can also be useful. Design
space is proposed by the applicant and to regulatory
assessment and approval. 1
Corresponding Author
Anand D. Savkare
E-Mail:- anandsavkare@rediffmail.com
Contact No: 9225816005
This QbD is a systematic approach which initiate
with the proper focus mainly on product and process
understanding scientifically that begins at start with
the predefined objectives. All this movement
towards quality of product based on sound science
and quality risk management. This segment of QbD
implementation stands for the efficiency of quality
product for customer satisfaction about its intended
use. This defines and control risk, creates reliable
knowledge & achieves optimum outcomes, by using
facts, multifunctional team work & systematic
methods to manage the process & decisions, helps in
meeting regulatory requirements, robustly method
development, meet commercial & quality
performance targets, & quality products for
customers. 2 The product with better quality and the
concerned manufacturing process is the basic idea of
pharmaceutical development which aimed to deliver
the product performance for its intended use. Thus,
to develop such a quality product requires the
scientific understanding of product and process
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Anand D. Savkare et al. / International Journal of Advances in Pharmaceutical Research
development is required which is collected through
pharmaceutical development. This step by step
programme finally supports the design space
establishment which accomplish the final quality
product and continual improvement throughout the
product lifecycle. 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 post approval change
process. 3
Critical quality attributes by patient perspective get
translates into the drug product quality attributes by
QbD concept. It supports the consistent production
of quality product with desired characteristics which
is implemented by the relationships between
formulation and manufacturing process variables
(including drug substance and excipient attributes
and process parameters) and product characteristics
are established and thus, the sources of variability
identified. The knowledge gathered from this all
over processing gives new flexible and robust
manufacturing process can be adapt for any scale
production of quality product that delivers a
consistent product over time. 4
ELEMENTS OF QUALITY BY DESIGN (QbD)
approach 1,5
QbD development process includes the following
elements that accomplish the following steps as per
fig. 1
1. To define the Target Product Profile
2. Determination of raw material Critical
Quality Attributes (CQAs)
3. To establish the relationship between the
drug and excipient attributes and the
process
parameters to the Critical Quality Attributes
4. To define the Design Space
5. Define the Control Strategy
6. Product lifecycle management & continual
improvement
GOAL STEPS FOR QUALITY BY DESIGN
(QbD) IMPLEMENTATION
To define the Target Product Profile
The target product profile describes the use,
safety and efficacy of the product that initiates
the development strategy. This target product
quality profile will be used by formulators as a
quantitative surrogate for aspects of clinical
safety and efficacy during product
development. 3
Determination of raw material Critical Quality
Attributes (CQAs)
The relevant knowledge gathered by formulation
personnel based on the prior experience about the
use of the drug substance and excipients alongwith
the related process unit operations and thus,
knowledge space get established. A risk assessment
undertaken for knowledge improvement and further
investigation support.
Establish the relationship between the drug and
excipient attributes and the process parameters to
the Critical Quality Attributes
By determining raw material critical quality
attributes, design a formulation that will meet the
target product profile. Following this a
manufacturing process should develop which have
these critical raw material that finally produce the
final drug product. During this stage, the correlated
critical attributes of both raw material and process
parameters should identify for which the risk
assessment undertaken to prioritize the critical
attributed concerned with both raw material and
process for verification of experiments.
Pharmaceutical Quality (Output) = f (drug substance,
excipients, Manufacturing process etc.)
For improvement in quality , it must be built into
the product. Thus, this is favored by
understanding the influence of both formulation
and manufacturing process variables on final
product quality. This is the input function ‘f’ in
the above equation.
To define the Design Space 7
As per ICH Q8 guidelines, the multidimensional
combination and interaction of input variables
(e.g., material attributes) and process parameters
that have been demonstrated to provide better
assurance of quality. Working within the design
space is not considered as a change. The
movement out of the design space is considered
to be a change and would normally initiate a
regulatory post approval change process. Design
space is proposed by the applicant and is subject
to regulatory assessment and approval. The
experiments undertaken when combined with
prior knowledge helps to establish a design space.
Design of experiments (DOE), risk assessment,
and process analytical technology (PAT) are tools
that may be used in the QbD process when
appropriate. They are not check-box
requirements. A design space is a way to
represent the process understanding which will be
establish (see fig.2). The process understanding
and design space collaborates the way to identify
and explain the all sources of variability and thus
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Anand D. Savkare et al. / International Journal of Advances in Pharmaceutical Research
way out from this variability by measuring and
controlling the critical process parameters
responsible for variability. Finally, this
assignment predicts the accurate and reliable
product quality attributes within specifications in
terms of quality. 5
Define the Control Strategy
The input material attributes (e.g. drug substance,
excipients etc.) are controlled by setting the target
on their impact on the process capability and end
product quality that designated as the in-process
controls or end-product controls. This is a
framework of process and formulation
understanding that follows the design space for
implementation of the process.
Quality risk management is a systematic process
for the assessment, control, communication and
review of risks to the quality of the drug product
across the product lifecycle. QRM ensures
conforming product quality according
specifications. Process understanding is key for
Quality Risk Management and QRM is the base
for any Control Strategy. (see fig.3)
Role of Quality risk management in
development 8
1. To design a quality product and its manufacturing
process to consistently deliver the intended
performance of the product
2. To enhance knowledge of product performance
over a wide range of material attributes (e.g.,
particle size distribution, moisture content, flow
properties), processing options and process
parameters
3. To assess the critical attributes of raw materials,
solvents, Active Pharmaceutical Ingredient (API)
starting materials, APIs, excipients, or packaging
materials
4. To establish appropriate specifications, identify
critical process parameters and establish
manufacturing controls (e.g., using information
from pharmaceutical development studies
regarding the clinical significance of quality
attributes and the ability to control them during
processing)
5. To decrease variability of quality attributes:
reduce product and material defects;
reduce manufacturing defects.
6. To assess the need for additional studies (e.g.,
bioequivalence, stability) relating to scale up and
technology transfer;
7. To make use of the “design space” concept
Supporting Statistical Tools
Statistical tools can support and facilitate quality
risk management. They can enable effective data
assessment which aid in determining the significance
of the data set, and facilitate more reliable decision
making. A listing of some of the principal statistical
tools commonly used in the pharmaceutical industry
are,
Control Charts
Design of Experiments (DOE)
Histograms
Pareto Charts
Process Capability Analysis.
Product lifecycle management & continual
improvement
A monitoring programme for verifying the
validity of process models should be established
and be based on a risk analysis of the model itself
and includes possible ways to verify the model by
another means. Continuous improvement is an
essential element in a modern quality system that
aims at improving efficiency by optimizing a
process and eliminating wasted efforts in
production. These efforts are primarily directed
towards reducing variability in process and
product quality characteristics. Quality by design
implements quality into the product and
manufacturing processes as well as continuous
process improvement. 9
This elaborates the changes in terms of
modification and improvement of the process
within the established design space by using the
collectively developed manufacturing data. This
stage justify the concepts covered under
development and rationale for the implementation
of quality-by-design concept are well accepted.
(FDA) 10
CONCLUSION
This Quality by Design concept (QbD) serves as
new modern reliable concept and as a next step
towards the pharmaceutical quality. This session
intensifies the benefits of QbD as, establishment
of target product profile that elaborates the target
for QbD in quantitative terms, identification and
establishment of mechanistic link between critical
material attributes and critical process parameters
and determination of control strategy for
incremental implementation of QbD elements in
corresponding process within design space. In
such a way, this modern paradigm could be
stands for essential benefits that leads to
development of a quality pharmaceutical product
with the continual improvement throughout the
product lifecycle.
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Anand D. Savkare et al. / International Journal of Advances in Pharmaceutical Research
Define Target Product
Profile
Products Quality Characteristics
ensuring safety and efficacy
Identification of Critical
Quality Attributes
(CQA’s)
e.g. drug substance, excipients
Risk Assessment
Material
Attributes
CQA’s
Process
Parameters
CQA’s
Design Space
Control Strategy
Using both Input material and
process controls established by
Quality Risk Management (QRM)
Life cycle Management
Continuous improvement
Fig. 1: Quality by Design (QbD) Steps (ICH Q8)
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Anand D. Savkare et al. / International Journal of Advances in Pharmaceutical Research
Fig 2. Design space determination
Where,
Large red square area : Ranges tested in design of experiment (DOE)
Oval area : Representing the design space
Small green square area : Portion of design space constrained for simplicity
Fig. 3. QbD steps for each unit operation
REFERENCES
1. ICH Q8 (R1), Pharmaceutical Development. Part
I: Pharmaceutical Development, 2008 available at
http://www.ich.org
2. Juran J. M., Juran’s quality by design: The new
steps for planning quality into goods and services
N.Y., 1992,1-2.
3. Lawrence. X. Yu, Raw A., Lionberger R. et al.,
U.S. FDA Question-based review for generic
drugs: A new pharmaceutical quality assessment
system. J. of Generic Med. 4, 2007, 239–248.
4. J. Woodcock. The concept of pharmaceutical
quality, Am. Pharm. Rev. Dec 2004, 1–3.
5. Lawrence. X. Yu., Lionberger R., Raw A. et al.,
Quality by Design: Concepts for ANDAs, The
AAPS Journal, Vol. 10, No. 2, June 2008, 268-
276.
6. Implementation of ICH Q8, Q9, Q10, ICH
Quality Implementation Training Workshop,
Product Development: Case Study Overview,
Oct. 2011.
7. Frank T., Brooks S., Murray K., Reich S.,
Sanchez E., Hasselbatch B., Obeng K.,
Creekmore R., PQRI Case Study (1): Defining
Process Design Space, Pharm. Tech., July 2011.
8. ICH Q9, Draft consensus guideline: Quality Risk
Management, 2008, available at
http://www.ich.org
9. http://www.pharmaqbd.com/QbDViewpoint.
10. ICH Q10, Draft consensus guideline:
Pharmaceutical Quality System, 2008, available
at http://www.ich.org
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