Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management. Key aspects of QbD include establishing a Quality Target Product Profile (QTPP) that identifies critical quality attributes (CQAs), understanding critical material attributes (CMAs) and critical process parameters (CPPs), and implementing a control strategy for CQAs and CPPs. The ICH Q8 guideline introduced QbD, and it has been further developed through guidelines like ICH Q9 and Q10. Examples show how QbD has been applied scientifically in different pharmaceutical development and manufacturing processes.

1. Presented by
Mr. KAHNU CHARAN PANIGRAHI
Asst. Professor
(PHARMACEUTICS)
Quality by Design (QbD)
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2. • Introduction to Quality by Design (QbD)
• ICH Q8 guideline
• Regulatory and industry views on QbD
• Scientifically based QbD –examples of application
CONTENTS
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3. Introduction
Quality by Design (QbD)
is a concept first outlined by well-known quality expert Joseph M.
Juran.
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“Quality can be planned and most quality crises and
problems relate to the way in which quality was planned in
the first place.”
Juran on Quality by Design
(1992)
Quality- by-design (QbD) is a concept introduced by the International Conference
on Harmonization (ICH) Q8 guideline, as a systematic approach to development,
which begins with predefined objectives and emphasizes product and process
understanding and process control, based on sound science and quality risk
management.

4. • Predefined objectives make up the quality target product profile (QTPP), that is,
the summary of the drug product quality characteristics that ideally should be
achieved.
• According to the ICH Q8 guideline, QTPP is a prospective summary of the
quality characteristics of a drug product to ensure the desired quality, taking
into account safety and efficacy of that drug product.
• Through the scientifically based process of product development, critical
process parameters (CPPs), and critical quality attributes (CQAs) of the product
are identified.
• 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.
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5. 1. Which of the fallowing term best describe
QbD?
a) Systematic approach to product development
b) Emphasizes product and process control
c) Quality risk management
d) Predefined objectives and emphasizes product
and process understanding and process control,
based on quality risk management
Ans: d
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6. 2. Which of the fallowing represent initial step of
QbD?
a) Quality target product profile (QTPP)
b) critical quality attributes (CQAs)
c) Setting up CMA and CPP
d) design space development
Ans: a
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7. • A QTPP for immediate release tablets may include the
following requirements: assay, content uniformity, and
dissolution should be in accordance with the specifications to
assure safety and efficacy during the shelf life; tablets should
be robust in order to withstand transport and handling, and a
suitable size to aid patient acceptability and compliance.
• According to the defined QTPP, CQAs may include assay,
content uniformity, dissolution, and degradation products,
whereas CPPs could be the compression force and speed used
for tableting.
• Figure 1.1 shows a diagram of a QbD approach, combining
design space development and risk management tools.
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8. Elements of pharmaceutical quality by design
1. A quality target product profile (QTPP) that identifies the critical quality
attributes (CQAs) of the drug product
2. Product design and understanding including the identification of critical
material attributes (CMAs)
3. Process design and understanding including the identification of critical
process parameters (CPPs) and a thorough understanding of scale-up principles,
linking CMAs and CPPs to CQAs
4. A control strategy that includes specifications for the drug substance(s),
excipient(s), and drug product as well as controls for each step of the
manufacturing process
5. Process capability and continual improvement
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10. ICH Q8 guideline
• Over the years, pharmaceutical QbD has evolved with the issuance of IC
H Q8 (R2) (Pharmaceutical Development), ICH Q9 (Quality Risk
Management), and ICH Q10 (Pharmaceutical Quality System).
• The ICH Q8 guideline on scientifically based pharmaceutical
development serves to provide opportunities for pharmaceutical
manufacturers to seek regulatory flexibility and mitigation of some
activities required for product registration and/or subsequent post
approval change process.
• Even though the primary intention of the ICH Q8 document, and QbD
itself, was to provide guidance on the contents of section 3.2.P.2
(Pharmaceutical Development) for drug products defined in the scope of
Module 3 of the Common Technical Document (CTD), this concept is
now broadened to the whole drug product lifecycle.
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11. • The ICH Q8 guideline suggests that those aspects of drug substances,
excipients, container closure systems, and manufacturing processes
that are critical to product quality, should be determined and control
strategies justified.
• Some of the tools that should be applied during the design space
appointment include experimental designs, PAT, prior knowledge,
quality risk management principales etc.
• More details on quality risk management tools are provided in the ICH
Q9 guideline. QbD and quality risk management tools are often linked
to form a pharmaceutical quality system (ICH Q10 guideline).
• Pharmaceutical manufacturers are encouraged to describe the design
space in their submission by using a variety of terms, for example,
ranges of materials attributes and process parameters, complex
mathematical relationships, time dependent functions, multivariate
models, etc.
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12. 3. Which schedule of ICH guideline related to
pharmaceutical product development?
a) IC H Q7
b) ICH Q8
c) IC H Q9
d) ICH Q10
Ans. b
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13. 4. Which schedule of ICH guideline related to
quality risk management?
a) IC H Q7
b) ICH Q8
c) IC H Q9
d) ICH Q10
Ans. c
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14. 5. Which schedule of ICH guideline related to
Pharmaceutical Quality System?
a) IC H Q7
b) ICH Q8
c) IC H Q9
d) ICH Q10
Ans. d
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15. 6. Tools that is not to be applied during the
design space appointment.
a) Experimental designs
b) PAT
c) Quality risk management
d) All of the above
Ans: d
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16. • PAT is a system for designing, analyzing, and controlling manufacturing through
timely measurements (i.e. during processing) of critical quality and performance
attributes of raw and in- process materials and processes with the goal of
ensuring final product quality.
• PAT brought the possibility to evaluate and ensure the acceptable quality of in-
process and/or final product based on the measured process data, allowing real-
time release of the products.
Process Analytical Technology(PAT)
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• In order to ensure that a product of required quality is produced consistently,
various control strategies are designed.
• These strategies are based on product, formulation, and process understanding
and include control of the CQAs and CPPs. Control strategies can be
implemented for both real- time and end- product testing.

17. Failure Mode Effects Analysis (FMEA)
It is a methodology to identify and analyse all potential failure modes and their effects. The output is
a relative risk “score” for each failure mode, which is used to rank them on a relative risk basis.
S x O x D = Risk Priority Number (RPN)
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Severity of effect (S) Occurrence probability (O) Disirability(D)
Risk Assessment (
Risk assessment is a process in quality risk management which identify various critical
factor which effect the CQAs.

18. Temperature
Design of Experiments (DoE)
Sterility
Physical form
Mechanical properties
Purity
Dissolution
DOE is an critical component of QbD which uses stastical concept in order to
optimise the formulation considering all significant factors and build a relationship
between the input and output of a process The properties of products and
processes are affected by many factors:
Input factors Process Output responses
Raw material quality
Moisture level
Pressure
?
Mixing speed
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19. Each single input variable and multi-variables interaction can be
evaluated and their effects on each response variables can be
identified.
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2. DESIGN:
Choose the
experimental design
3. CONDUCT:
Run the experiments
and collect data
4. ANALYSE:
Analyze and
evaluate results
5. CONFIRM:
Validate
predicted
responses
1. PLAN:
Identify factors and
ranges to investigate

20. Input factors (X) Process
Model
Y=f(X)
Temperature
Sterility
Physical form
Mechanical properties
Purity
Dissolution
Output responses
(Y)
Raw material quality
Moisture level
Pressure
Mixing speed
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A relationship is established between the input and output
of a process

21. RIPS 21
7. Control strategies can be implemented for
which of the fallowing?
a)CMA
b)CPP
c)Both a and b
d)QTPP
Ans: c

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8. In quality by design PAT stand for:
a)Product Analytical Technology
b)Process Analytical Technology
c)Product Assessment Technology
d)Process Assessment Technology
Ans: b

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9. PAT is a system for designing, analysing and
controlling manufacturing through timely
measurements of which of the fallowing:
a)Critical quality and performance attributes of
raw and in- process materials and processes
b)Physical parameters affecting materials and
processes
c)Performance attributes of raw material
d)Performance attributes of processes
Ans: a

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10. Risk assessment is a tool applied for
which purpose?
a)Design space development
b)Risk identification
c)Process control
d)Quality risk management
Ans: d

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11. FMEA is a quality risk management tool which
represents:
a)Factor Mode Effects Analysis
b)Failure Mode Effects Analysis
c)Factor Mode Effects Assessment
d)Failure Mode Effects Assessment
Ans: b

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12. DOE is an critical component of QbD which
uses stastical concept in order to optimise the
formulation. It represents:
a)Design of element
b)Design of experiment
c)Development of experiment
d)Development of element
Ans: b

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13. DOE is an critical component of QbD applied for:
a)Establishing relationship between the input and
output of a process.
b)Development of product variable
c)Identifying CQA
d)Identifying CMA and CPP
Ans: a

28. Regulatory and industry views on QbD
• As defined by an FDA official (Woodcock, 2004), the QbD concept
represents product and process performance characteristics
scientifically designed to meet specific objectives, not merely
empirically derived from performance of test batches.
• QbD can facilitate innovation, increase manufacturing efficiency,
reduce cost/product rejects, minimize/eliminate potential
compliance actions, enhance opportunities for first cycle approval,
streamline post approval changes and regulatory processes, enable
more focused inspections, and provide opportunities for continual
improvement (Shah, 2009).
• The FDA has provided examples on implementation of QbD
concepts in abbreviated new drug applications (ANDA) for both
immediate and modified release dosage forms.
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29. • European Medicines Agency (EMA) representatives
(Korakianiti,2009) stressed that it is the properties of the
starting materials or the manufacturing process that
affect the quality of the pharmaceutical product.
• EMA templates and guidance documents used for the
assessment of any new drug application in the
centralized procedure include the possibility of design
space appointment.
• EMA, FDA, and ICH working groups have appointed the
ICH quality implementation working group (Q-IWG),
which prepared various templates, workshop training
materials, questions and answers, as well as a points- to-
consider document (issued in 2011) that covers ICH
Q8(R2), ICH Q9, and ICH Q10 guidelines.
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30. • Development and implementation of models include
definition of the model purpose, decision on the type of
modeling approach (e.g. mechanistic or empirical), selection
of variables for the model, understanding of the model
assumptions limitations, collection of experimental data,
development of model equations and parameters estimation,
model validation, and documentation of the outcome of the
model development.
• Design space verification includes monitoring or testing of
CQAs that are influenced by scale- dependent parameters.
Additional verification of a design space, which might be
triggered by changes (e.g. site, scale, equipment) is typically
guided by the results of risk assessment of the potential
impacts of the change(s) on design space.
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31. RIPS 31
Classification of models’ contribution in assuring product quality (according to
ICH Q-IWG document)

32. RIPS 32
QbD for industry and regulatory bodies

33. • FDA authorities state that QbD is to be fully implemented by
January 2013.
• There were several EMA marketing authorization applications
(MAA) with QbD and PAT elements (for the following
products: Avamys®, Torisel®, Tyverb®, Norvir®, Exjade®,
Revolade®, Votrient®, etc.).
• Pfizer was one of the first companies to implement QbD and
PAT concepts.
• The process performance index Ppk of the first QbD Pfizer
product was 1.2 (3–4 σ ) at launch and 1.8 (5–6 σ ) 6 months
after launch, which indicates that QbD results in robust
processes and is able to rapidly improve process capability.
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34. 14. As per FDA official (Saha, 2009), the QbD
concept represents:
a. QbD can facilitate innovation
b. increase manufacturing efficiency
c. minimize/eliminate potential compliance actions
d. All of the above
Ans: d
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35. 15. Who appointed ICH quality implementation
working group (Q-IWG)?
a) FDA
b) EMA
c) ICH
d) All the above
Ans: d
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36. 16. What are the schedule regarding QbD made
in 2011 by ICH quality implementation working
group (Q-IWG)?
a) ICH Q6,ICH Q7 and ICH Q8(R2) guidelines
b) Only ICH Q8(R2) guidelines
c) ICH Q8(R2), ICH Q9, and ICH Q10 guidelines
d) None of the above
Ans: c
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37. 17. Which company has first applied QbD ?
a) Dr Reddy
b) Glaxo smith
c) Sun pharma
d) Pfizer
Ans: d
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38. 18. According to FDA authorities state that QbD
is to be fully implemented by:
a) January 2012
b) January 2013
c) January 2014
d) January 2015
Ans: b
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39. 19. According to ICH Q-IWG document which
model assure product quality?
a. Low impact model
b. Medium impact model
c. High Impact model
d. Any model can be used
Ans: c
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40. 20. Design space verification includes:
a. Only Monitoring of CQAs that are influenced by scale-
dependent parameters
b. Only testing of CQAs that are influenced by scale
independent parameters
c. Monitoring or testing of CQAs that are influenced by
scale- dependent parameters
d. Monitoring or testing of CQAs that are influenced by scale
independent parameters
Ans: c
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41. Scientifically based QbD –examples of application
• The QbD approach was used to establish a relationship between the
CPPs, CQAs, and clinical performance of the drug (Short et al., 2011).
Both critical and noncritical attributes were used as inputs to the design
space, which was conditioned on quantitative estimates of ineffi cacy
and toxicity risk.
• A combined QbD and Discrete Element Model (DEM) simulation
approach was used to characterize a blending unit operation, by
evaluating the impact of formulation parameters and process variables
on the blending quality and blending end point(Adam et al., 2011).
• A quantitative approach was developed to simultaneously predict
particle, powder, and compact mechanical properties of a
pharmaceutical blend, based on the properties of the raw materials
(Polizzi and García-Muñoz, 2011).
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42. • An integrated PAT approach for process (co- precipitation)
characterization and design space development was reported (Wu
et al.,2011).
• QbD was applied in development of liposomes containing a
hydrophilic drug (Xu et al., 2011; 2012). The usage of risk
assessment facilitated formulation and process design, with the
eight factors being recognized as potentially influencing liposome
drug encapsulation efficiency and particle size (CQAs).
Experimental design was used to establish the design space,
resulting in a robust liposome preparation process.
• QbD principles were applied to an existing industrial fluidized bed
granulation process (Lourenço et al., 2012).
• QbD principles were used to investigate the spray drying process of
insulin intended for pulmonary administration (Maltesen et al.,
2008).
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43. • A multiparticulate system, designed for colon- specific
delivery of celecoxib for both systemic and local
therapy, was developed using QbD principles (Mennini
et al., 2012).
• The role of predictive biopharmaceutical modeling and
simulation in drug development, in the context of QbD,
was also presented (Jiang et al., 2011).
• The production bioreactor step of an Fc-Fusion protein
manufacturing cell culture process was characterized
following QbD principles (Rouiller et al., 2012).
• The QbD approach was used in the formulation of
dispersible tablets (Charoo et al., 2012). Critical
material and process parameters were linked to CQAs
of the product.
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44. ThankYou
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