Quality by Design ( QbD ) ( Chapter 4 ) 59

CHAPTER Quality by Design (QbD )

4

4.1 . QUALITY BY DESIGN ( QBD)

4.1 . 1 . Definition and Overview
A systematic approach for development of pharmaceutical products that begins
with predefined objectives and emphasises product and process understanding
and process control, based on sound science and quality risk management is
defined as Quality by Design ( QbD ).

The concept of QbD was developed by Dr. Joseph M. Juran , who believed that
quality should be designed into a product, and most quality problems are related
to the way in which a product was designed . Woodcock defined a high-quality
drug product as a contamination-free product that reliably produces the expected
therapeutic benefit to the consumer. The USFDA encourages risk-based
approaches and implementation of QbD principles in development ,
manufacturing, and regulation of drug product . FDA started emphasising on the
acceptance of QbD with the recognition that increased testing does not improve
product quality, and it should be built into the product.
QbD involves designing and developing
formulations and manufacturing processes that Labelled use safety and efficacy
ensure predefined product specifications. This
concept has been lately adopted in the
pharmaceutical industries through several
| Define quality target product profile
..
initiatives [e g , ICH Q81, Q92 and Q103, new Design formulation and process
.
regulatory documents Process Analytical
.
Technology ( PAT) FDAs cGMP for the 21st
Identify critical material attributes
Century ]. It aims to shift from the concept of and critical process parameters
Quality by Testing ( QbT, that was previously
implemented in the pharmaceutical industry )
Control materials and process
to a development that improves the
understanding of the processes and the Target Design - Implementation
products, and hence the product quality, Figure 4.1: Overview of QbD
process efficiency and regulatory flexibility.

4.1 . 2. Elements of QbD Program

In QbD approach to product development, an applicant identifies the desired
characteristics of quality from the patient’s viewpoint, and translates them into
the drug product Critical Quality Attributes (CQAs ). Then the applicant links the
formulation/ manufacturing variables with the CQAs to offer a drug product with
such CQAs to the patient.
60 Quality Assurance

QbD consists of the following elements:

1 ) Defining the quality target product profile,
2) Identifying the quality attributes,
3) Performing a risk ( assessment ) analysis,
4) Determining the critical quality attributes and critical process parameters,
5) Determining the design space, and
6) Identifying a control strategy.

4.1.2.1. Quality Target Product Profile ( QTPP)

According to ICH Q8( R2) guideline, QTPP is described as a prospective summary
of the quality characteristics of a drug product that ideally will be achieved to
ensure the desired quality, taking into account safety and efficacy of the drug
product . QTPP is a method used to establish the strategy for drug development.
Currently, it is used for planning, making clinical and commercial decisions,
interacting with regulatory agencies, and for risk management.
QTPP defines the properties of drug product that are essential to deliver
therapeutic benefits mentioned in the label. Under QTPP guidelines, formulation
strategies are established by the scientists to keep the formulation effort focused
and efficient. For example, QTPP of an immediate release solid oral dosage
form consists of the following:
1 ) Tablet characteristics, 2) Identity, 3) Assay and uniformity,
4 ) Purity or impurity, 5) Stability, and 6) Dissolution .
It is important to notice that under QTPP product performance elements that are
relevant to the patients should only be included. Other formulation related
properties ( e.g., tablet density, hardness, etc.) may be included as a specification
for process monitoring but not in QTPP. The QTPP should include dissolution but
not particle size, if particle size is critical to the dissolution of a solid oral product.

4.1.2.2. Critical Quality Attributes ( CQAs)

The next step after QTPP identification is the identification of relevant CQAs. A
CQA is defined as 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 .
[ Start

Prior Potential quality

knowledge attributes I QTPP I

Quality attribute No Is this a CQA ( from 1

I ' nsure Experimental work to
not a CQA patient perspective) increase knowledge

Yes
Apply suitable tool to
rank CQAs

Listof CQAs
Figure 4.2: Decision Tree to Decide CQAs
Quality by Design ( QbD ) ( Chapter 4 ) 61

.
In general , CQAs are related to raw materials ( e g., drug substances and
.
excipients ), intermediates (e.g , in-process materials), and drug products. CQAs
of drug product are the properties that are important for product performance,
such as the desired quality, safety, and efficacy ( figure 4.2). Thus, CQAs are
subsets of QTPP that can be altered by changing the formulation or process
variables. For example, quality attributes of the drug product including strength
and dosage form are included in the QTPP but not included in CQA as they
cannot be changed during drug development process. However, quality attributes
of the drug product including assay, content uniformity, dissolution , and
permeation flux are included in both QTPP and CQA as they can be altered by
formulation or process variables. Some examples of the CQAs of drug
substances and drug products are enlisted in table 4.1.
Table 4.1 : Typical CQAs for Drug Substances and Drug Products
For Drug Substances ( Chemical ) For Drug Products ( Tablet )
Appearance Appearance
Particle size Identification
Morphic forms Hardness
Water content Dosage uniformity
Residual solvents Physical form
Organic impurities Dissolution
Inorganic impurities Degradation products
Heavy metals Water content
Residue on ignition Assay
Assay Microbiological limits
CQAs for a formulation are identified through risk assessment according to the ICH
guideline Q9. These risk assessments are made by prior product knowledge, such as
the accumulated laboratory, non-clinical and clinical experience with a specific
product-quality attribute. This knowledge may also include relevant data from
similar molecules and data from literature references. This information provides a
foundation to establish a relation between the CQA to product safety and efficacy.

4. I .2.3.Quality Risk Management ( QRM )

According to FDA, risk management is a strategic safety program designed to
reduce product risk by using one or more interventions or tools. QRM is a
systematic process designed to assess, control , communicate , and review the
risks related to the quality of the drug product during the product lifecycle. A
process for a typical quality risk management is briefly given in figure 4.3.
As per the ICH Q9 guideline, QRM provides a structure to start and follow a risk
management process. Following are the important tools of QRM :
1 ) Failure Mode Effects Analysis ( FMEA ): It is one of the most common tools of
risk-assessment used in pharmaceutical industries. This systematic and proactive
method is used to identify and mitigate the possible failure in the process. Failure
mode indicates any errors or defects that may occur in a process, material,
design, or equipment. If failure modes are established, FMEA tool recognises the
effect of these failures and enlist them accordingly. By performing critical
studies of the consequences and by providing clear indication of the situation,
advancement can be made in the FMEA tool.
62 Quality Assurance

initiate Quality Risk Management "'"'

Process
Risk Assessment
| Risk Identification ]
Risk Analysis

[ Risk Evaluation ]
Unacceptable

Risk Control
Risk Reduction

Risk Acceptance

Output Result of the Quality Risk

Management Process

Risk Review
r Review Events ]
Figure 4.3: Overview of a Typical Quality Risk Management

2) Failure Mode, Effects and Criticality Analysis ( FMECA ): It is the

extended form of FMEA tool that can be used for investigating the degree of
severity of consequences, their chances of occurrence, and their detectability.
In FMECA tool, failure modes of the products are identified and their
criticality is evaluated, which is then translated into a risk. Corrective actions
are taken in case of unacceptable levels of risk. The results are further used to
assess failures and risks associated with manufacturing processes. FMECA
tool can also be used to establish and optimise maintenance plans
for repairable systems and/or to control plans and other quality assurance
procedures.
3) Fault Tree Analysis ( FTA ): It is used to deal with failure of the functionality of
a product or process. The obtained results are pictorially represented in the form
of a tree of fault modes, which are then used for investigating complaints or
deviation to identify their cause and to ensure that the improvement made will
overcome the issues and will not cause any further problem.
4 ) Hazard Analysis and Critical Control Points ( HACCP): It is used for
providing elaborated documentation for any process or product understanding
through identifying parameters to control and monitor. Hazard analysis is
useful for both safety and quality of a process or product. HACCP tool
includes hazard analysis, determination of critical control point , establishment
of critical limit, installation of a system to monitor critical control point, and
establishment of a record-keeping system. It is done to identify and manage
risks associated to physical, chemical and biological hazards.
A combination of quantitative and qualitative estimation of risk is obtained
as the output of a risk assessment. As part of FMEA, a risk score or Risk
Priority Number ( RPN ) may be allotted to the deviation or to the affected
stage of the process; this helps in categorising the deviation .
Quality by Design ( QbD ) ( Chapter 4 ) 63

For the calculation of RPN, Probability ( P), Detectability ( D), and

Severity (S), which are individually categorised and scored, are multiplied.
Rating scales usually range from 1 to 5.
RPN = Probability score x Severity score x Detectability score
Where, the score was defined prior to the risk analysis stage:
RPN is < 40 = Low risk
RPN is 40-99 = Intermediate risk
RPN is > 100 = High risk

4. I .2.4. Determination of Critical Process Parameters ( CPPs )

Any measurable input (such as input material attribute or operating parameter ) or
output ( process state variable or output material attribute ) of a process step that
needs to be controlled to achieve the desired product quality and process
consistency is stated as a critical process parameter.
A parameter is important when any alteration in it may cause the product to fail
to meet the QTPP. Therefore, whether or not a parameter is critical depends on
the changes made in them or how many changes one is willing to consider.
During the parameter classification, the first step is to establish the range of
interest which is called as Potential Operating Space ( POS ) . It indicates the
region between the maximum and minimum value of interest for each process
parameter. Thus, the criteria for identification of critical and non -critical
parameters are the following two:
1 ) A parameter is considered critical when there is a trend to failure within the
POS, and
2) A parameter is critical when there is evidence of interactions within the
Proven Acceptable Range ( PAR , the range of experimental observations that
establish an acceptable quality ).
The CCPs which are considered during tablet manufacturing along with CQAs
are given in table 4.2:
Table 4.2: Different Critical Process Parameters with Critical Quality Attributes
During Tahleting
Operations during Tableting Critical Process Critical Quality' Attributes
Parameters
Wet Granulation 1 ) Mixing time 1 ) Blend uniformity
2) Impeller speed 2) Granule size and distribution
3 ) Binder fluid addition 3 ) Moisture content
rate and time
4) Method of binder addition
5 ) Temperature
Drying 1 ) Drying time 1 ) Bulk/tapped density
2 ) Inlet air flow 2) Moisture content
3 ) Exhaust air temperature 3) Granules strength and
and flow uniformity
Milling 1 ) Milling speed 1 ) Flow properties
2) Screen size 2) Particle size distribution
3 ) Feeding rate 3 ) Bulk/tapped density
 Quality Assurance
64

Mixing 1) Mixer type

2) Mixing time Blend uniformity
3) Order of addition
Compression 1) Pre-compression force I ) Weight variation
2) Main compression force 2) Hardness
3) Dwell time 3) Friability
4) Hopper design 4) Content uniformity
5) Punch penetration depth 5) Assay
6) Roller type 6) Dissolution
7) Auger screw rate 7) Disintegration
8) Ejection force
Coating 1) Inlet air flow 1 ) Thickness
2) Time 2) Hardness
3) Temperature 3) % of Weight gain
4 ) Spray pattern and rate 4 ) Appearance
Surveillance Visit After certification, routine surveillance is carried out on a
6-12 month basis. The final visit in the certification cycle
is termed a renewal visit.
Renewal Assessment A recommendation is made from this review on certificate
renewal, along with any adjustment required to the on -
going surveillance plan. The renewal package is then
reviewed independently and if found satisfactory the
certification is renewed for another 3 year.

4. I .2.5. Design Space

According to the ICH Q8( R 2 ) guideline, design space is defined as the
multidimensional combination and interaction of input variables (e.g.,
material attributes ) and process parameters established to provide quality
assurance . Working within the design space is not included in a change, while
movement out of the design space is regarded as a change and would generally
start a regulatory post -approval change process. An applicant proposes the design
space and it is subjected to regulatory assessment and approval.
Design space may be established for a single unit operation, multiple unit operations,
or the entire process. But as per the FDA guideline, defining design space is not an
essential condition because the product and process understanding can be established
without a formal design space; however, such an approach regarding the design
space can be helpful for better understanding and overall control of a system.
Design space is criticality related to the results of risk assessment , which
determine the associated CQAs and CPPs. It includes the multivariate functional
relationships between CQAs and CPPs that impact them, and should include their
relation to or across unit operations. These relationships can be identified by
application of risk assessment, experimental design , modelling, and by using
literature and prior experience.
Design space can be determined by the following methods:
1 ) One-variable-at -a -time experiments,
2 ) Statistically designed experiments, and
3) Modelling approaches.
Quality by Design ( QbD ) ( Chapter 4 ) 65

The design space can be represented by graphs ( surface-response curves and

contour plots), linear combination of parameter ranges, equations, and models,
while the design space can be mathematically represented through equations
describing relationships between parameters for successful operation .

4. I .2.6.Control Strategy
According to the ICH Q10 guideline, a control strategy is defined as a planned
set of controls derived from current product and process understanding that
assures process performance and product quality . The controls include
parameters and attributes related to drug substances, drug product materials and
components, facility and equipment operating conditions, in -process controls,
finished product specifications , and the associated methods and frequency of
monitoring and control.
Input material controls, process controls and monitoring, design space around
individual or multiple unit operations, and/or final product specifications used to
ensure consistent quality are the factors included under control strategy. The
quality of finished drug products is tested by evaluating whether or not they meet
the specifications. Generally, it is expected that extensive in - process tests ( blend
uniformity or tablet hardness ) should be performed by the manufacturers.
In figure 4.4. a QbD-based control strategy for blending process is given. To
ensure the quality of a finished pharmaceutical product , it is essential to
understand and control formulation and manufacturing variables. The overall
quality of the product can be confirmed by testing the end product.
Start |

Prior Potential quality

knowledge attributes
|

Quality attribute No a CQA ( from Unsure Experimental work to

not a CQA patient perspective increase knowledge

Yes
Apply suitable tool to
rank CQAs

List of CQA
Figure 4.4: Example of Control Strategy for QbD Process

4.1.3. Tools
The tools for QbD include the following:
1 ) Prior Knowledge: The term prior knowledge has been widely used in
workshops, seminars, and presentations. In regulatory submissions, the
applicants attempt to use prior knowledge as an authentic reason for
substitution of scientific justifications or conducting necessary scientific
studies . Knowledge is defined as an awareness of someone or something
that can include information , facts, descriptions, and/or skills attained
through experience or education . The word prior in the term prior
66 Quality Assurance

knowledge indicates previous and also associates with ownership,

confidentiality , and not available to the public. Knowledge gained through
education or public literature is termed public knowledge. Prior knowledge
is the exclusive information, understanding, or skill that applicants acquire
through previous studies.
2) Design of Experiments ( DOE ): It is a structured and organised method of
determining relationship between the factors influencing process
outputs. DOE can offer returns that are four to eight times greater than the
cost of running the experiments in a fraction of time. Use of DOE in QbD
helps in achieving maximum information from a minimum number of
experiments. When DOE is applied to a pharmaceutical process, factors like
.
raw material attributes ( e.g., particle size), process parameters ( e g., speed
and time), and outputs are the CQAs such as blend uniformity, tablet
hardness, thickness, and friability. Each unit operation has many input and
output variables and process parameters, thus experimental investigation of
all of them is not possible. The results of DOE help in identifying optimal
conditions, critical factors influencing and not influencing CQAs, and the
existence of interactions and synergies between factors.
3) Process Analytical Technology ( PAT): It is defined as a system for
designing, analysing, and controlling manufacturing through
measurements, during processing of CQAs of raw and in process -
materials and processes, to ensure the final product quality . The PAT
aims to enhance understanding and control the manufacturing process, which
is consistent with our current drug quality system. Design space is the key
and critical process parameter ( primary focus of on-, in- or at-line PAT
applications ) identified from process characterisation studies and their
acceptable ranges. Principally , real -time PAT assessments provide the basis
for continuous feedback and improve process robustness. NIR is a tool for
PAT and is useful in Real Time Release Testing ( RTRT ) as it monitors the
particle size, blend uniformity, granulation , content uniformity,
polymorphism, dissolution and monitoring the process online, at the line and
offline, thus reducing the release testing of the product.
4) Risk Management Methodology: Quality risk management is defined as a
systematic process for the assessment, control, communication and
review of risks to the quality of the drug product across the product
lifecycle. Risk assessment tools are used based on prior knowledge and
.
primary experimental data for identifying parameters ( e g., process,
equipment , and input materials ) that can affect the product quality. The initial
list of potential parameters can be long, but can be modified and prioritised
through a combination of DOEs and mechanistic models. After identifying
the significant parameters, they are further studied through a combination of
DOEs, mathematical models, or studies that lead to mechanistic
understanding. This is done to achieve a higher level of process
understanding.
The pharmaceutical industry and regulators, with the help of the following
risk management tools and/or internal procedures , such as basic risk
Quality by Design ( QbD ) ( Chapter 4 ) 67

management facilitation methods ( flowcharts, check sheets, etc.), evaluate

and manage risks:
i ) Failure Mode Effects Analysis ( FMEA ),
ii ) Failure Mode, Effects and Criticality Analysis ( FMECA ),
iii) Fault Tree Analysis ( FTA ),
iv) Hazard Analysis and Critical Control Points ( HACCP ),
v) Preliminary Hazard Analysis ( PHA ), and
vi ) Risk ranking and filtering.

4.2. SUMMARY
The details given in this chapter can be summarised as follows:
1 ) A systematic approach for development of pharmaceutical products that
begins with predefined objectives and emphasises product and process
understanding and process control, based on sound science and quality risk
management is defined as Quality by Design ( QbD ).
. .
2 ) The concept of QbD was developed by Dr Joseph M Juran, who believed
that quality should be designed into a product, and most quality problems are
related to the way in which a product was designed.
3) According to ICH Q8( R 2 ) guideline , QTPP is described as a prospective
summary of the quality characteristics of a drug product that ideally will be
achieved to ensure the desired quality, taking into account safety and efficacy
of the drug product .
4 ) A CQA is defined as 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.
5) Failure Mode Effects Analysis ( FMEA ) is one of the most common tools
of risk-assessment used in pharmaceutical industries and is used to identify
and mitigate the possible failure in the process.
6) Failure Mode, Effects and Criticality Analysis ( FMECA ) is the extended
form of FMEA tool that can be used for investigating the degree of severity
of consequences, their chances of occurrence, and their detectability.
7) Fault Tree Analysis ( FTA ) is used to deal with failure of the functionality
of a product or process.
8) Hazard Analysis and Critical Control Points ( HACCP) is used for
providing elaborated documentation for any process or product
understanding through identifying parameters to control and monitor.
9) As part of FMEA, a risk score or Risk Priority Number ( RPN ) may be
allotted to the deviation or to the affected stage of the process; this helps in
categorising the deviation.
10) For the calculation of RPN, Probability ( P), Detectability ( D), and
Severity (S), which are individually categorised and scored, are multiplied.
11 ) During the parameter classification , the first step is to establish the range of
interest which is called as Potential Operating Space ( POS). It indicates the
region between the maximum and minimum value of interest for each
process parameter.
68 Quality Assurance

12) According to the ICH Q8( R2 ). design space is defined as the multidimensional
..
combination and interaction of input variables (e g , material attributes ) and
process parameters established to provide quality assurance.
13) According to the ICH Q 10, a control strategy is defined as a planned set of
controls derived from current product and process understanding that assures
process performance and product quality.
14 ) The term prior knowledge has been widely used in workshops, seminars,
and presentations.
15 ) Knowledge is defined as an awareness of someone or something that can
include information , facts, descriptions, and/or skills attained through
experience or education.
16) The word prior in the term prior knowledge indicates previous and also
associates with ownership, confidentiality, and not available to the public.
17 ) Knowledge gained through education or public literature is termed public
knowledge.
18 ) Design of Experiments ( DOE) is a structured and organised method of
determining relationship between the factors influencing process outputs.
19 ) Process Analytical Technology ( PAT) is defined as a system for designing,
analysing, and controlling manufacturing through measurements, during
processing of CQAs of raw and in-process materials and processes, to ensure
the final product quality.
20 ) Quality risk management is defined as a systematic process for the
assessment , control , communication and review of risks to the quality of the
drug product across the product lifecycle.

4.3 . EXERCISE
4.3. 1 . Very Short Answer Type Questions
1) What is QbD?
2) Give the overview of QbD .
3) Enlist the elements of QbD .
4) Define QTPP .
5) What are CQAs?
6) What is fault tree analysis?
7) Give the definition of design space .

4.3.2. Short Answer Type Questions

1) Write a note on critical quality attributes .
2) Write about the tools of QRM .
3) Discuss how critical process parameters are determined .
4) Write a note on control strategy .
5) Give a short review on the tools of QbD .

4.3.3. Long Answer Type Question

1 ) Write an exhaustive note on the elements of QbD program.