QUALITY BY DESIGN IN PHARMACEUTICAL DEVELOPMENT

INTRODUCTION
Quality by design (QbD) is a systematic approach to performance based on intended clinical aspects, dosage
product development that begins with predefined strength, delivery mode,
objectives and emphasizes product and process
understanding and controls based on sound science
and quality risk management (ICH Q8). The emphasis
of QbD began with the recognition that increased
testing does not essentially improve product quality;
however, quality must be built into the product. The
regulatory agencies encourage risk-based approaches
and the adoption of QbD principles in drug product
development and manufacturing. At Piramal we are
applying QbD approach in product development,
which is characterized by following principles:

• Designing product and its manufacturing process to

meet patient needs with respect to safety and
efficacy

• Designing manufacturing process to consistently

produce product meeting pre-defined quality criteria

• Understanding impact of input parameters on

product quality to adequately build the controls at
the critical points in the process

QbD principally is a scientific, logical, and preemptive

scheme that will incorporate quality control into each
and every step of drug development and the
manufacturing process. It is a target-oriented
approach which we define Quality Target Product
Profile (QTPP) at initial stages of product
development. The QTPP describes the desired
pharmacokinetics, drug product quality criteria
and the container closure system. The next step is
identification of key elements of QbD as follows:

Critical Quality Attributes (CQA):

A CQA is a physical, chemical, biological, or

microbiological characteristic of an output drug
product that should be within an appropriate limit
to ensure the desired product quality. The quality
attributes of a drug product may include identity,
assay, content uniformity, degradation products,
residual solvents, drug release, moisture content,
microbial limits, and physical attributes such as
color, shape, size, odor, score configuration, and
friability. These attributes can be critical or not
critical. Criticality of an attribute is mainly based
upon its influence on the safety and efficacy in the
patient.

Risk Assessment:

There are many attributes of the drug substance

and excipients that could potentially impact the
CQAs of the intermediates and finished drug
product. It is impractical for the formulation
scientist to investigate all the identified material
attributes and process parameters during the
formulation optimization studies. Therefore, a risk
assessment would be valuable in identifying
material attributes and process parameters that
are critical. The assessment should be based on
scientific knowledge and expertise of the
formulation scientist. A material and process
attributes
are considered to be critical when a change in that Analysis (FMEA), Risk ranking and filtering etc. Risk
attribute can have a significant impact on the quality can be categorized depending upon likelihood and its
(CQA) of the output material. The risk assessment is impact on process or formula (Figure 1). Considering 3
performed through linking raw material attributes and different levels (high, medium, and low), decision on
process parameters to CQAs to arrive at the severity action/investigation required to mitigate that risk will
of risk using tools like Basic risk management methods be considered.
(flowcharts, check sheets, etc.), Failure Mode Effects

Risk is acceptable. Risk is unacceptable. Risk is

Further investigation Further investigation unacceptable.
High

may be needed in is needed to reduce Further

order to reduce the the risk investigation is
risk
Impact

Broadly acceptable Risk is acceptable. Risk is

Medium

risk. No further Further investigation unacceptable.

investigation is may be needed in Further
needed order to reduce the investigation is
risk

Broadly acceptable Broadly acceptable Risk is acceptable.

risk. No further risk. No further Further
investigation is investigation is investigation may be
needed needed needed in order to
Low

reduce the risk

Likelihood
Figure 1 Categorizing Risk levels depending upon Likelihood and impact.

Critical Material Attributes (CMA): Critical Process Parameters (CPP):

A CMA of a drug substance, excipient, and A CPP of manufacturing process are the parameters
in-process materials is a physical, chemical, which, when changed, can potentially impact
biological, or microbiological characteristic of an product CQA and may result in failure to meet the
input material that should be consistently within an limit of the CQA.
appropriate limit to ensure the desired quality of
Design Space:
that drug substance, excipient, or in-process
material. The CMA is likely to have an impact on As per ICH Q8, this is the multidimensional

CQA of the drug product. combination and interaction of input variables (e.g.,
material attributes) and process parameters that have Control Strategy:
been demonstrated to provide assurance of quality. A
Based on process and product understanding, during
design space may be built for a single unit operation
product development sources of variability are
or for the entire process. The design space could be
identified. Understanding the sources of variability
the direct outcome of analysis of the DoE data or
and their impact on processes, in-process materials,
other validated models. Working within the design
and drug product quality can enable appropriate
space is not considered as a change. Movement out
controls to ensure consistent quality of the drug
of the design space is considered to be a change and
product during the product life cycle.
would normally initiate a regulatory post approval
change process. Design space is proposed by the
applicant and is subject to regulatory assessment and
approval.

Control Strategy

Design sapace

Risk Updation

Optimization of variable levels DOE - Optimisation Design

Screening of variables
DOE - Screening Design
Operatin Space Factorial Design
2 level full functorial design # 3 level full factorial design: F =2
Risk Assessment F<3 # 2 level fractional factorial with
center point: F=3
Critical Process Parameters(CPPs) Placket Barman design
7<F<3 Response Surface
Critical Material Attributes (CMAs) Methodology
2 level fractional factorial design # Box Behnken design: 3<F<5
Critical Quallity Attributes (CQAs) 7<F<3 # Central composite design: 2<F<6

Quallity Target Product Profile (QTPP)

Mixture Design
# Simplex lattice design: 2<F<4
# Simplex centroid design: 3<F<5
# Constrained mixture design: 2<F<6

Figure 2 Schematic representation of elements involved in QbD based product development

Schematic representation of QbD approach in product to CQAs to arrive at the severity of risk using tools like
development is given in Figure 2. based on scientific Basic risk management methods (flowcharts, check
knowledge and expertise of the formulation scientist. sheets, etc.), Failure Mode Effects Analysis (FMEA),
A material and process attributes are considered to be Risk ranking and filtering etc. Risk can be categorized
critical when a change in that attribute can have a depending upon likelihood and its impact on process
significant impact on the quality (CQA) of the output or formula (Figure 1). Considering 3 different levels
material. The risk assessment is performed through (high, medium, and low), decision on
linking raw material attributes and process parameters action/investigation required to mitigate that risk will
be considered.

TOOLS APPLIED IN QBD APPROACH

Design of Experiment (DoE): effects and interactions and may also have quadratic and

This is a systematic approach applied to conduct cubic

experiments to obtain maximum output. We have

capability and expertize to perform DoE in product
development using software like Minitab and
Statistica.

Design of experiments- screening: Designs applied to

screen large number of factors in minimal number of
experiments to identify the significant ones. Main
purpose of these designs is to identify main effects
and not the interaction effects. For such studies
common designs used are Plackett-Burman and
fractional factorial design.

Design of experiments-optimization: Experimental

designs considered to carry out optimization are
mainly full factorial design, surface response
methodology (e.g. Central composite, Box-Behnken),
and mixture designs. These designs include main
terms require to obtain curvature. These designs
are only applied once selected factors are
identified, which seem to be contributing in
process or formulation.

Risk assessment methodology:

Cause and Effect Diagrams (fish bone/Ishikawa):

This is very basic methodology to identify multiple
possible factors for a single effect (Figure 3).
Various cause associated with single effect like
man, machine, material, method, system, and
environment need to be considered to identify
root cause.
 Fishbone Diagram

Environment Method Man

Temperature, Relative Preparation of Coating

Humidity(RH) and Differential Diapersion QA executives
Pressure (DP) of Area 1.Homozenization
2.Stirrering
3.Flltraton Oprator
Seal Coating Process
1. Spraying
Cleaning of Process area 2. Coatin Warehouse executives
g of Tablets Sampling
1. In-process
AHU Filter Cleaning
2. Analytical Scientist
Packeging
1.Bulk packing in Pilot-Plant Executive
HDPE container
Any Defect in Finished Product
Equlpments
Equipments cleaning Item used 1. Coating Pan
2. Over Head stirret
3. Homozenlzer Accessories
Line clearance from QA Excipients 1. SS containers
2. Tubing
Secondary Gowning Purified Water 3. Nozzle
Inlet air
Packaging materials Automization air
Manufacturing as per cGMP practices

Systems Material Machine

Primary branch represents effect, whereas major braches

Raman Spectrometer, Online Particle Size Analyzer etc. We
in diagram are associated with major causes and
are experienced in application of NIR
minor branches supports the possible detailed cause.

Failure Mode Effect Analysis (FMEA): This is an

important tool to evaluate potential failure modes in
any process. Quantification of risk by interaction of
probability functions of severity, occurrence, and
detectability of any event can be done. FMEA can be
effectively performed with good understanding of
process.

PAT:

Control Strategy: Assurance of product quality during

intermittent steps using Process Analytical Technology
(PAT) is recommended by regulatory authorities, which
is yet to be extensively accepted by the
pharmaceutical industry over conservative
methodologies. It involves advanced online
monitoring systems like NIR (Near IR), Handheld
and Raman Spectrometer to monitor processes
viz. blending and wet granulation. These
technologies further make assurance of
continuous improvement in process and product
quality through its life cycle.

To summarize, the aim of implementing

pharmaceutical QbD is to reduce variability and
defects in product, thereby enhancing efficiency
in product development and manufacturing. It
can be achieved by designing a robust
formulation and manufacturing process and
establishing clinically relevant specifications. The
key elements of pharmaceutical QbD can include
the QTPP, understanding of product and process
design, scale up, control strategy, and continual
improvement. Prior knowledge of various tools,
risk assessment, DoE and PAT is valuable to
facilitate QbD implementation.