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Quality by Design (QbD) Approach in Pharmaceuticals: Status, Challenges and

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2 Drug Delivery Letters, 2015, 5, 2-8

Quality by Design (QbD) Approach in Pharmaceuticals: Status, Challenges

and Next Steps

Lalit Singh and Vijay Sharma*

Shri Ram Murti Smarak College of Engineering and Technology, Pharmacy, Bareilly, India

Abstract: Traditional approach of formulating a new drug product is an exhaustive task and involves a
number of resources like man, money, time and experimental efforts. While, using this Quality by
Design (QbD) approach one can get the pharmaceutical product of desired (best) quality with minimiz-
ing above resources as well as knowing the influence of one factor over the desired associated process.
Hence aim of this study is the understanding of QbD approach to design product and manufacturing
process to get desired pharmaceutical product. QbD follows the concepts of ICH guidelines (Q8, Q9 &
Q10) which are essential for processing a pharmaceutical process. This review emphasizes on various
aspects of keynotes of QbD like ascertaining drug product quality profile, priorizing input variables for
optimization, modelization & validation of QbD methodology and in the last QbD validation, scale up and production as
well as the software used for QbD. Hence, QbD approach is not only useful in facilitating comprehension of the products
or process but also results in an excellent and economical product which follows federal compliance.
Keywords: ICH guidelines, product quality profile, quality by design.

INTRODUCTION FDA report “Pharmaceutical cGMPs for the 21st Cen-

FDA announced a new initiative in 2002 for risk man-
agement i.e. (cGMP for the 21st Century: A Risk based Ap-
proach) to modernize the FDAs regulation for maintaining
better pharmaceutical quality as well as setting up new regu-
latory framework focusing on QbD, risk management and
quality maintaining system. QbD needs good knowledge of
final product and in-process or process variables that affect
end-product quality. This newer concept being considered by
FDA in its current-GMP initiative, two main documents
were generated by International Conference on Harmoniza-
tion (ICH), to guide the quality i.e. ICH-Q8: (Pharmaceutical
Development) and ICH-Q9: (Quality Risk Management).
The pharmaceutical industry has been a highly regulated
industry in the past for many good reasons [1]. The major
hurdles in accomplishing quality in a product can be attrib-
uted to the cumulative variability in drug substance(s), ex-
cipients, process(es), packaging material(s), and so on, as
illustrated in (Fig. 1) (Sources of Variability). The pharma-
ceuticals have greatly improved the mortality and morbidity
rates, but purity, potency, delivery rate, and other properties
of medicine have been mitigated by various elements of risk
to the patients. Pharmaceutical regulations have clearly pro-
tected the population from much of the needless harm as
incurred early in the twentieth century; there has been a con-
cern more recently that overregulation may be associated
with stifling innovation that can improve pharmaceutical
quality even further [2].
*Address correspondence to this author at the Shri Ram Murti Smarak College
of Engineering and Technology, Pharmacy, Bareilly, India; Tel: 9458702561,
Fax: 0581-2582330; E-mail: vijaysrampur@gmail.com
tury: A Risk-Based Approach” has made it imperative to use
quality by design (QbD) approach in pharmaceuticals [3]. In
present century, pharmaceutical industry is still using manu-
facturing technologies that have been employed since 1940s
which mostly resulted in inefficient, overly expensive proc-
esses that were ultimately not in the best long-term interests
of patients. Even the industries did not make significant
changes in manufacturing process unless the significant
compliance or cost saving advantages could justify the high
costs and long cycle time that was needed to gain approval.
The quality may not be completely ensured with use of qual-
ity by testing (QbT) on finished product (Fig. 1) which was
used in early stage in good manufacturing practices (GMPs).
On the other hand, current good manufacturing practices
(cGMP) acknowledged the undesired impact of GMPs on
understanding manufacturing science and sought to set the
framework for additional guidance that encouraged risk- and
science-based understanding. Thus, it allows more freedom
to introduce innovations and improvements that will result in
enhanced quality, cost, or timing [4].
A new paradigm for regulation and time to market new
and improved medicines, to describe the comprehensive dis-
cipline, are required to shut down the quality problem [5].
Juran proposed the concept of QbD which was first outlined
in the 1960s. According to this concept, quality could be
something that may be planned rather than simply achieved
in (more often than not) a haphazard way [6].
The concept mentioned in the ICH-Q8 guideline, states
that “quality of product cannot be tested”. Systematic ap-
proach of QbD begins with predefined objectives and under-
standing of product and its process as well as process control
which was based on sound knowledge of science and quality

2210-303X/15 $58.00+.00 © 2015 Bentham Science Publishers

Quality by Design (QbD) Approach in Pharmaceuticals: Status, Challenges and Next Steps Drug Delivery Letters, 2015, Vol. 5, No. 1 3

risk management [7]. Formulation parameters (independent
variables) affect the product’s characteristics and are useful
in optimization of independent variables in order to monitor
the behavior of dependent variables in producing the opti-
mized product, under the given set of conditions. Thus, vari-
ables are included in QbD to ease the final best formulation
of drug [8].
changed to get drug product of desired characteristics. For
developing a quality drug product, and getting a relationship
between formulations and their manufacturing process vari-
ables including active pharmaceutical ingredients, excipients,
process variables, desired product characteristics and sources
of variability. This knowledge is then used to develop a
product of desired characteristics [10-13].
Although the idea of QbD is not new but it is still a sound
tool in the pharmaceutical industry, as it has capability to
profoundly change how drugs products are discovered, de-
veloped, manufactured and even regulated. Most crises or
failings around quality, as per Juran are simply related to
how processes were planned, set up, embedded and man-
aged. Knowledge management and quality risk management
are two of the primary enablers of QbD. They play a critical
role both in development and in the implementation of QbD.
They are instrumental in achieving final product, establish-
ing and maintaining a state of art for control, and lastly imi-
tating continual improvement [14].

BACKGROUND OF QUALITY BY DESIGN

Fig. (1). Various sources of variability.
Later in June 2007, Product Quality Lifecycle Implemen-
tation (PQLI) was laid down by the International Society for
Pharmaceutical Engineering (ISPE), in a workshop, which
was held in Europe in September. The PQLI was imple-
mented in US followed with the objective of coordinating
with the various regulatory agencies throughout the world to
encourage a common intellectual understanding of QbD. The
aim of PQLI is to strongly emphasize on ‘how to’ implement
guidance according to ICH-Q8, Q8 (R), Q9 and Q10 [9].
Hence, QbD for pharmaceuticals is a systematic, scientific,
risk-based, complete approach to develop the best optimized
pharmaceutical dosage form. Designing and development of
formulations and manufacturing processes with help of QbD
ensures predefined product quality objectives. QbD is also
useful in identification of characteristics (Fig. 2) that are
critical to quality. QbD analyze the effect of critical process
parameters i.e. independent variables and indicates how
these important and specific process variables should be
ICH-Q8: (pharmaceutical development) is the guideline
to understand the concept of QbD. It defines QbD as “QbD
is a systematic approach to design a product of predefined
quality and its production process to continually and consis-
tently delivering intended performance of the final product.
The data collected from pharmaceutical development studies
and manufacturing experiences, utilized for logical under-
standing for design space its specifications and process con-
trols, based on sound science and quality risk management”.
ICH-Q8:(R1) and ICH-Q8:(R2) guidance are the revision of
ICH-Q8, and an annex to ICH-Q8. It provides further
clarification of key concepts outlined in the core guideline
and describes the principles of QBD.
Since long time QbD have been used for various products
development like Design of Experiments is being used since
1920’s as factorial designs mainly in agricultural sciences,
later in fifties the technique was more accepted and became
popular for industrial applications. FMEA (Failure Modes
and Effects Analysis) was developed 1950s to study prob-
lems that arise from malfunctions of military systems. An
FMEA is often the first step of a system reliability study.
With further development in 1990 software were developed
in the QbD methodology.

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Fig. (2). Quality by testing.

4 Drug Delivery Letters, 2015, Vol. 5, No. 1
Because of these techniques for getting better product
rather best product the techniques were more highlighted in
the pharmaceutical fields. USFDA report on Pharmaceutical
cGMP for 21st century results in a strategic changes and
involvement of more statistical approach in any new
development or for betterment of the old products also,
thereby laying the groundwork for QbD methodology (Fig. 3).
The same ground further fruits in development of new
guidance document from FDA, i.e. process analytical technology
“PAT — A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance”.
Although the focus was more geared towards PAT, this
guidance document discussed many principles of QbD. In
2005, the concept of design space was introduced in
Common Technical Document (CTD) of ICH-Q8. This
Design Space was basically a method which concentrates on
differentiation between product attributes and process
parameters especially critical variables on which the focus
should be given. The approach used to decide the critical
variables is risk assessment. An ICH Q9 guideline includes
the tools that can be used to validate risk assessments and to
check risks that have been identified. ICH-Q10 is the next
approach, which address, development and manufacture of
Pharmaceutical drug substances systems. These guidelines
apply to pharmaceutical drug substances and drug products,
as well as biotechnology and biological products.
Lastly ICH-Q8 (R) gives details of the principles of QbD
and clarifies the key concepts described in ICH-Q8. The aim
of the annex is to show how concepts and tools could be
used in practice by the applicant for all dosage forms. Both
the guidelines, ICH-Q10 and Q8 (R) are still subjected to
revision [15].
QBD involves the following essential key aspects/elements
during pharmaceutical development:-
1) Explain target product quality profile.
2) Designing and development of product and
manufacturing processes.
3) Recognition of critical quality attributes, process
parameters, and variability sources.
4) Lastly controlling the manufacturing processes to
get consistent quality over time and so on.
Technical Elements of the QbD Process
QbD process consists following technical elements as
shown in figure 4: [16].
1) Critical Quality Attributes (CQAs) are very much
connected to clinical relevance because of their im-
pact on efficacy, safety, or reproducible therapeutic
effect.
2) Clinically relevant CQAs which is linked to critical
process parameters (CPPs), either directly or indi-
rectly.
3) One or more CPPs, which control the clinically rele-
vant CQA enabled by real time monitoring or by PAT.
4) Acceptance Criteria which is defined by dimensional
relationships between critical process parameters
Singh and Sharma
(CPPs) and Critical Quality Attributes (CQAs) in
such a way that enables the operational criteria to be
contained within a Design Space.
QbD for Pharmaceutical Products - Important Steps in
its Implementation [17]
Identification of Target Product Profile Quality character-
istic means prospective and dynamic summary of the quality
characteristics of a drug product that ensures the desired
quality, safety & efficacy.
1) First and foremost is to identify CQAs i.e. any
physical, chemical, biological, or microbiological
property or characteristic.
2) Defining and generating Process Design Space i.e.
performing risk assessment linking material attrib-
utes and process parameters to CQAs.
3) Establishing Design Space Linkage between input
independent variable, process parameter and CQAs.
4) Defining the Controlling methodology as planned
set of controls, derived from current product and
process understanding that assures process perform-
ance and product quality.
5) Process Validation involves understanding of the
manufacturing process.
6) Process monitoring is the process that is performing
within the defined acceptable variability that served
as the basis for the filed process design space.
Overall these steps may be summarized as [18]:
A. Ascertaining Drug Product Objectives
A quality target product profile QTTP is embarked upon
encompassing the fundamental information of the product to
be prepared or aspired as “goal-setting” exercise through
brain storming among the team members cutting across in-
dustrial disciplines.
B. Prioritizing Input Variables for Optimization
The critical material attributes CMA and critical parame-
ters CPP, which directly influence the CQA, represent the
product quality, are analyzed through the Ishikawa Fish dia-
gram and prioritization studies.
C. Design-guided Experimentation and Analysis
Response surface optimization carried out employing
experimental design is considered as a pivotal part of QbD
exercise. The experimental design helps in mapping the re-
sponses on the basis of the studied objectives, CQA being
explored, at high, medium or low levels of CMA.
D. Modelization and Validization of QbD Methodology
RSM is employed to relate a response variable or CQA to
the levels of input variables or CMAs/CPPs using the inter-
play of polynomial equations, the desired constraints/criteria
for optimum search and the design constraint.
Quality by Design (QbD) Approach in Pharmaceuticals: Status, Challenges and Next Steps
Fig. (3). Typical layout of QbD.
Fig. (4). Elements of QbD.
E. QbD Validation, Scale-up and Production
Validation of the QbD methodology is a crucial step that
forecasts about the prognostic ability of the polynomial
models studied. Qbd performance is corroborated after scal-
ing up the results obtained from validation to ensure the re-
producibility and robustness.
Various measures taken for assuring all of the above
summarized steps A-E are-
Target Product Profile
FDA gives guidelines for defining Target Product Profile
(TPP) [19]. As per these guidelines “The TPP is totally cor-
related to drug development program that provides knowl-
edge of drug during development. Generally, the TPP is use-
ful to develop a link for drug labeling, drug development
activities as well as to some concepts that are useful in the
drug labeling”. According to ICH-Q8 (pharmaceutical de-
velopment), pharmaceutical development should include
“Recognition of critical quality attributes of the drug product
with consideration of its intended use as well as route of ad-
ministration”, hence it becomes essential to consider the in-
tended usage and route of administration [20].
Drug Delivery Letters, 2015, Vol. 5, No. 1 5
Target Product Quality Profile
The target product quality profile (TPQP) is an essential
element of QbD approach. It provides an understanding of
product quality, safety, and efficacy. TPQP is useful and
used in designing and optimization of a formulation and
manufacturing process. ISPE and PQLI also call this the
Pharmaceutical Target Product Profile [21, 22].
Critical Quality Attributes
As per ICH, CQA is define as quality attribute that com-
prises of physical, chemical, biological or microbiological
characteristic and it is desired that these attributes should be
to be controlled (directly or indirectly) to give assurance that
product obtained will attain desired safety, efficacy, stability
and performance as well [23].
ICH-Q8 revision ICH-Q8 :( R1) states that all the above
mentioned quality attributes should be within appropriate
limit. CQAs give the assurance of product of desired quality
[24]. Elements of the TPQP can be described by CQA like
dissolution. In determination of product performance CQA is
used to observe the mechanistic variables such as particle
size and hardness. Hence both the aspects i.e. product per-
6 Drug Delivery Letters, 2015, Vol. 5, No. 1 Singh and Sharma

formance and product performance determinants, could be
explained by using TPQP [25, 26].
Comparison between End Product Testing and QbD
Testing of end product is used to confirm the quality of
the formulated product although it does not help to maintain
the consistency of the formulated product as well as process
control while in case of QbD product quality is ascertained
by observing the data from a number of small batches that
are supposed to be acceptable and fall under desired accept-
able limit [27, 28].
ucts. Each and every stage of product lifecycle should be
validated by using elements of Q10 in an appropriate and
proportionate manner. Principles of ICH-Q10 also used to
recognize the differences, and the different objectives of
each stage. These guideline applies in the process that help in
design, development and preparation of drug substances such
as API and drug products which includes biotechnology and
biological products, throughout the lifecycle of product [32].

ICH Guidelines
• Pharmaceutical Development (Q8)
ICH-Q8 is intended to provide guidelines of Pharmaceu-
tical Development of drug products as explained in the scope
of Module 3 of the CTD. While clinical trial stage of the
product the guidelines of ICH-Q8 are not applicable for the
data at the same time the principles in these guidelines are
important to consider clinical trials. ICH-Q8 guidelines are
also suitable for various other products but the application is
only possible after taking due approval from the appropriate
regulatory authorities. The annex provides further clarifica-
tion of key concepts outlined in the core Guideline. In addi- Fig. (5). Quality attributes governing quality of desired product.
tion, ICH-Q8 (R1) states that the annex explains the princi-
ples of quality by design (QbD) and this annex is not ment to
generate new standards but explains the concepts and tools
and their application by applicant in design space, outlined in
the parent Q8 document [29].

• Quality Risk Management (Q9)

ICH-Q9 Guideline is mainly concerned with the princi-
ples and examples of quality risk management (QRM). In
other word ICH-Q9 may be regarded as the document having
answers to all questions related with quality of product i.e.
parameters including designing, development, processing,
distribution, inspection/assessment and submission/review
processes throughout the lifecycle of drugs, drug products as
well as biological and biotechnological products, also in-
cludes raw materials, vehicles/solvents, additives and mate-
rial used for packing as well as labeling [30]. Risk assess- Fig. (6). Conventional versus QbD manufacturing process.
ment is one of the essential step require for ensuring the ef-
fective risk management. It reviews the materials, processes,
Noncritical Parameters
equipment used, storage conditions and intended use of the
product. The parameters used in the design space generation, are
In the risk assessment some of the questions like are ad- all critical but these not applied equally on the edges of de-
sign space and here comes some of the noncritical parame-
dressed:
ters which may not be captured in the design space, also pre-
Most vulnerable step which might go wrong? What is the sent ambiguity. Although noncritical process parameters are
probable nature and chances of occurrence, of risk? What not responsible for the failure in target product quality pro-
may be the results because of risk? etc. All of these decide file (TPQP) in the potential operating space and cause no
the step which should be addressed during QRM activities interactions with other parameters in the proven acceptable
for better control on the complete development process of range. Noncritical parameters can be monitored and con-
the product [31]. trolled easily [33, 34].

Pharmaceutical Quality System (Q10) Difference between Conventional Approach and QbD
ICH-Q10 Guideline describes quality of drug substances Approach
and its products (Fig. 5), which includes biotechnology and In case of Conventional approach, assurance of quality is
biological products, throughout the lifecycle of drug prod- subjected to its testing and inspection. It includes thorough
Quality by Design (QbD) Approach in Pharmaceuticals: Status, Challenges and Next Steps Drug Delivery Letters, 2015, Vol. 5, No. 1 7

Table 1. Comparison of the current state to the future desired QbD state.

Criteria Current state QbD state required

Pharmaceutical development Empirical; typical single variable experiments Systematic; multivariate experiments

Manufacturing process Rigid: avoids changes Flexible: changes can be made in design

By in-process testing
Process control Either in-process quality checks (IPQC) or off-line finished By using PAT for feedback and feed forward in real time
product quality checks

Based on performance of product in quality control

Product specification On behalf of previous experiences and batch data
checks

Control strategy Mainly by IPQC and end product testing Risk based controls shifted up-stream; real time release

Response after getting problem in IPQC or End product Design space itself have the provision of continual im-
Lifecycle management
testing, i.e. changes after approval are needed. provement of product during its development

data submission which includes coherent knowledge. All the
specifications are provided on behalf of previous experiences
i.e. batch history. Conventional approach is rigid and always
avoids changes. It focuses on reproducibility which often
avoids or ignores variation.
While in QbD approach, attempt is made to develop qual-
ity in the product and process by help of design (any) which
depend upon scientific knowledge of product and process.
Here, specifications are based on performance of the product
required. This approach is a flexible approach and changes
can be made in design for product quality improvement. It
focuses on lustiness to understand as well as to control the
variables (Fig. 6) [35].
Nasr summarized the differences between ‘‘current
state’’ and ‘‘desired state’’ as shown in Table 1 [36].
Software Used for Qbd
Software available for QbD includes Design Expert®,
MODDE®, Unscrambler®, JMP®, Statstica®, minitab® etc,
are at the software usually provide interface guide at every
step during the entire product development cycle. Software
provides support for chemo-metric analysis through multi-
variate technique like MNLRA, PCA, PLS etc. [18].
CONCLUSION
Now a days researcher utilizes QbD as an important tool
for getting the quality, QbD has eliminated the burden of
exhaustive and time consuming conventional approach with-
out compromising with quality of the product. Hence QbD is
an integral part of modern research in pharmaceutical indus-
try. All the concepts of ICH guidelines whether they are re-
lated to product development, quality risk management or to
pharmaceutical quality system, are essential for processing a
pharmaceutical process in QbD. QbD focus over all aspects
desired in an quality product like ascertaining drug product
quality profile, priorizing input variables for optimization,
modelization & validation of QbD methodology and in the
last QbD validation, scale up and production as well as soft-
ware used for QbD. Hence we can say that QbD is a useful
tool in the pharmaceutical research to facilitate comprehen-
sion of the product or process as well as to acquire an excel-
lent and economic product.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
The authors are thankful to Shri Dev Murti Ji, honorable
chairman, SRMS trust, Bareilly (U.P.) for inspiring us and
providing all necessary facilities.
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