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A Review on quality by design approach (QBD) for Pharmaceuticals

Article in International Journal of Drug Development and Research · March 2015

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Open Access Contents
Int. J. Drug Dev. & Res.
| January - March 2015 | Vol. 7 | Issue 1 | ISSN 0975-9344 |
www.ijddr.in

A Review on quality by design approach (QBD) for Pharmaceuticals

Vemuri Pavan Kumar

A
bstract:
Quality by Design is the modern approach for quality of pharmaceuticals. It describes use of
N. Vishal Gupta* Quality by Design to ensure quality of Pharmaceuticals. In this review, the Quality by Design is
described and some of its elements identified. Process parameters and quality attributes are
Pharmaceutical Quality Assurance identified for each unit operation. Benefits, opportunities and steps involved in Quality by

Full Length Original Research Paper

Group, Department of Design of Pharmaceutical products are described. It is based on the ICH Guidelines Q8 for
pharmaceutical development, Q9 for quality risk management, Q10 for pharmaceutical
Pharmaceutics, JSS College of
quality systems. It also gives application of Quality by Design in pharmaceutical
Pharmacy, JSS University, development and manufacturing of pharmaceuticals. The aim of the pharmaceutical
Sri Shivarathreeshwara Nagara, development is to design a quality product and its manufacturing process to consistently
Mysore - 570015 deliver the intended performance of the product. Quality cannot be tested into products
but quality should be built in by design. It includes the Quality target product profile, critical
quality attributes and key aspects of Quality by Design. It also gives comparison between
Corresponding Authors: product quality by end product testing and product quality by Quality by Design. The
e-mail: [email protected] foundation of Quality by Design is ICH Guidelines.

Keywords: Quality by Design (QbD), Process Analytical Technology (PAT), Quality target
product profile, Critical quality attributes

variables that are emerged during development

INTRODUCTION
Page 52

stages will serve as a source for QRM. Before

The basic concept of QbD is “The Quality cannot conducting the development studies the QTPPs of
be tested into the product, but it should be built the product must be determined and having the
into it.” The design space is defined as a final product quality in mind and evaluation is
manufacturing area of the product including performed to obtain the desired quality of
Equipment,Material, and Operators and product. The QTPP of product includes design
Manufacturing Conditions. The design space space, specifications and manufacturing
should be well defined prior to regulatory controls.[1-3]
approval. Working with design space is not Design [4, 5]
considered as a change, but working out of - Product is designed to meet patient needs
design space is considered as a change. Different and performance requirements.
variables are monitored for their effect of product - Process is designed to consistently meet
quality when the manufacturing is done out of product quality attributes.
design space. All these variables are assessed and - Impact of starting raw materials and process
conclusions will be drawn which serves as a tool to parameters on product quality is understood.
QbD. All these data are included in the regulatory - Critical sources of process variability are
submission dossier identified and controlled.
The pharmaceutical product formulation can be - The process is continually monitored and
developed based on the data obtained from updated to allow for consistent quality over
product development studies. The process time.

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 Definition [ICH Q 8(R1)] Opportunities [7, 8]
A systematic approach to development that
Efficient, agile, flexible system
begins with predefined objectives and
Increase manufacturing efficiency, reduce
emphasizes product and process understanding costs and project rejections and waste
and process control, based on sound science and
Build scientific knowledge base for all
N. Vishal Gupta et al; A Review on quality by design approach (QBD) for Pharmaceuticals

quality risk management. [6] products

Definition [FDA PAT Guidelines, Sept. 2004]
Better interact with industry on science issues
A system for designing, analyzing and controlling
Ensure consistent information
manufacturing through timely measurements (i.e.
Incorporate risk management
during processing) of critical quality and STEPS INVOLVED IN QUALITY BY DESIGN PRODUCTS
performance attributes of new and in-process [7-9]

materials and processes, with the goal of ensuring 1. Development of new molecular entity
final product safety. [5, 6]
Preclinical study
The concept of “Quality by Design” (QbD) was
Nonclinical study
defined as an approach which covers a better
Clinical Study
scientific understanding of critical process and
Scale up
product qualities, designing controls and tests
Submission for market Approval
based on the scientific limits of understanding 2. Manufacturing

Page 53
during the development phase and using the
Design Space
knowledge obtained during the life-cycle of the
Process Analytical Technology
product to work on a constant improvement
Real time Quality Control
environment. QbD describes a pharmaceutical 3. Control Strategy
development approach referring to formulation
Risk based decision
design and development and manufacturing
Continuous Improvement
processes to maintain the prescribed product
Product performance
quality. Guidelines and mathematical models are Seven steps of quality by design start up plan
used to ensure the establishment and use of the 1. Hire an independent Quality by design
knowledge on the subject in an independent and expert.
integrated way. Benefits of QbD [1,3,5,6] 2. Audit your organization and process with the

QbD is good Business expert conducting a gape analysis.

Eliminate batch failures 3. Hold a basic quality by design workshop with

Minimize deviations and costly investigations all your personal.

Avoid regulatory compliance problems 4. Review the expert’s report and

Organizational learning is an investment in the recommendation.
future 5. Draft an implementation plan, timelines and

QbD is good Science estimated costs.

Better development decisions 6. Assign the resources (or contract out).

Empowerment of technical staff 7. Retain the independent expert as your
“Project Assurance” advisor.

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 Quality by design (QbD) and well understood QUALITY TARGET PRODUCT PROFILE [10, 11]
product and processes [4,7,8] A summary of the drug development program

All critical sources of variability are identified described in terms of labeling concepts and it
and explained. mainly focus on the safety and efficacy.

Variability is controlled by the process.  Description

Product quality attributes can be accurately  Clinical Pharmacology
and reliably predicted over the design space  Indications and Usage
established for materials used, process  Contraindications
parameters, environmental and other  Warnings
conditions.  Precautions

Full Length Original Research Paper

To gain enhanced knowledge of product  Adverse Reactions
performance over a range of material  Drug Abuse and Dependence
attributes, manufacturing process options  Over dosage
and process parameters considering  Dosage and Administration

Appropriate use of quality risk management  How Supplied
principles.  Animal Pharmacology and/or Animal
QbD BY PHARMACEUTICALS [8-10] Toxicology
Even though the pharmaceutical industry has  Clinical Studies
Page 54

focus on quality, it has failed to keep up with other A natural extension of Target Product Profile for
industries in terms of manufacturing efficiency and product quality – Quality characteristics
productivity. (attributes) that the drug product should possess in
Current scenario in the Pharmaceutical Industry: order to reproducibly deliver the therapeutic

Cost of revalidation benefit promised in the label guide to establish

Off-line analysis for in-process - need based formulation strategy and keep the formulation

Product specifications as primary means of effort focused and efficient. It facilitates
control identification of what’s needed/critical for the

Unpredictable Scale up issues patient/consumer in the Quality Target Product

Inability to understand failures Profile (such as Critical Quality Attributes, CQAs)
Systematic approach to development:
Identifies risks and best approaches to

That begins with predefined objectives manage.

Emphasizes products and process
Uses tools/enablers in an optimized fashion
understanding (such as integration of QbD and bio

Process control (Figure 1) pharmaceutics)

Generates and enables knowledge sharing.

An iterative, learning, life-cycle process for
optimizing decision-making and the
therapeutic outcomes for the patient benefit.
A drug product designed, developed and
Figure 1: Process control
manufactured according to Quality Target

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noncommercial use, provided the original work is properly cited.
 Product Profile with specification (such as Certain Key Aspects of QBD [15-17]
dissolution/release acceptance criteria) consistent • The Target Product Quality Profile (TPQP)
with the desired in vivo performance of the Target Product Quality Profile (TPQP) is a tool for
product. setting the strategic foundation for drug
CRITICAL QUALITY ATTRIBUTES [12-14] development — “planning with the end in mind.”
N. Vishal Gupta et al; A Review on quality by design approach (QBD) for Pharmaceuticals

It is necessary to identify the quality More recently an expanded use of the TPP in
attributes that are critical, i.e. those defining development planning, clinical and commercial
purity, potency and surrogate for Bioavailability decision making, regulatory agency interactions,
Criticality etc. It is based on the impact of quality and risk management has started to evolve.
attribute/ parameter on the safety, efficacy & • Drug Substance and Excipient Properties
quality (manufacturability) of theproduct. To consistently achieve the drug-product quality

Establish a link between CPP & CQAs: specified in the label, the drug substance needs
Identification of attribute or parameters that to be thoroughly characterized with respect to its
can be used as a surrogate for clinical safety physical, chemical, biological, and mechanical
& efficacy (important to patient) (Figure 2). properties such as solubility, polymorphism,

Manufacturability is also an attribute stability, particle size, and flow properties.
(important to business) that is critical to • Formulation Design and Development
quality. Not all prototype formulations can be evaluated

Page 55

The level of criticality may differ for an API in human subjects, which mean that developing
manufacturing process relative to a drug sensitive in vitro dissolution methods is crucial to an
product manufacturing process effective development program.

API is one component of a drug product and • Manufacturing Process Design and
one step further away from the patient Development
continuum of Criticality. Several levels of Process development and formulation design
criticality may be used to describe multiple cannot be separated because a formulation
levels of risk. cannot become a product without a prescribed

As attribute or parameter boundaries process. Process design is the initial stage of
approach edges of failure, the level of process development, in which an outline of the
critically increased with the risk. commercial manufacturing processes is
documented, including the intended scales of
manufacturing. The outline should include all the
factors that need to be considered for the design
of the process, including facility, equipment,
material transfer, and manufacturing variables.
Other factors to consider during process
development are the QTPP and CQAs
Product quality by end product testing vs QbD
[17,18]

Figure 2: Decision Tree to Decide CQAs

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 Comparison is shown between product qualities Product.
by end product testing vs. quality by design  End product testing might be reduced.
(Figure 3, 4). Designed to facilitate continuous improvement
[17,18]

 Process control strategy: control of the

process.
Figure 3: Flow-chart for Product Quality by End  Performance and continuous process
Product Testing
improvement.
 Real-time process feedback Process
improvements within design space

Full Length Original Research Paper

Knowledge builds with experience Leverage
information/new technologies to improve
process efficiency Key opportunity to
continuously improve the process. E.g.
increased supply, more efficiency
Figure 4: Simplified flow-chart of QBD process ICH Q8, Q9, Q10 GUIDELINES: THE FOUNDATION OF
QbD [2,3,6,18]
Successful adoption[17,18]
ICH Guidelines Q8 for Pharmaceutical
 Regulatory flexibility to accommodate quality
Page 56

Development, Q9 for Quality Risk Management,

by design submissions
Q10 for Quality systems are foundation of QbD
 Common dossier accepted worldwide by
(Figure: 5)
regulatory agencies
 Post-approval changes within pre-defined
design space can be implemented with
regulatory flexibility
 Laws and processes in place to protect
intellectual property (IP)
Designed to consistently meet desired product
quality [17-19]
Figure 5: The Foundation of QbD
 Design space concept
Quality by Design relative to ICH [20,21]
 Experimentally defined process operating
- Concepts aligned
space basedon scientific principles.
- Design Space - Key to understanding
 Critical process parameters identified.
- Process robustness
 Critical - impact product quality.
- Design of Experiments (DOE)
 Space - operating range yielding acceptable
- Quality management Quality management
product Space.
Critical Concept: Design Space [19-21]
 Critical process parameters are consistently
Multidimensional combination with interactions
controlled.
Multidimensional interactions put variables (e.g.
 Product of process is always desired quality
raw material attributes) and process parameters
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noncommercial use, provided the original work is properly cited.
 - Demonstrated to provide assurance of quality • QbR contains the important scientific and
- Defined by applicant and reviewed by regulatory review questions
regulator • Evaluate whether a product is of high quality
- Defined regulator • Determine the level of risk associated with the
- Once design space is approved, regulatory manufacture and design of this product.
N. Vishal Gupta et al; A Review on quality by design approach (QBD) for Pharmaceuticals

post approval change requirements will be • 416 applications received using QbR by June
simplified 2007
- approval Inside vs. outside design space • Successful in ensuring that questions address
Inside space issues
- Regulatory flexibility to operate within the • regarding QbD
design space Regulatory space. BENEFITS OF IMPLEMENTING QbD FOR FDA
APPLICATIONS OF QUALITY BY DESIGN (QbD) • Enhances scientific foundation for review
[7,8,10,22-29] • Provides for better coordination across
Quality by design (QbD) – a comprehensive review,
systematic approach to pharmaceutical • compliance and inspection
development and manufacturing Advancement • Improves information in regulatory submissions
in the pharmaceutical development and • Provides for better consistency
manufacturing by Qbd can be explained against • Improves quality of review (establishing a

Page 57
traditional approach QMS for CMC)
In Pharmaceutical Development • Provides for more flexibility in decision making
To design a quality product and a manufacturing • Ensures decisions made on science and not
process to consistently deliver the intended on empirical information
performance of the product • Involves various disciplines in decision making
In life cycle management • Uses resources to address higher risks
Continual improvement enabled within design Benefits to Industry
space o Ensures better design of products with less
QbD IN CMC REVIEW OFFICES problems in manufacturing
Office of New Drug Quality Assessment (ONDQA) o Reduces number of manufacturing

Science-based assessment supplements required for post market

Restructured organization and reorganized changes –rely on process and risk
staff – understanding and risk mitigation

premarket staff and post market o Allows for implementation of new technology

CMC Pilot to improve manufacturing without regulatory

A number of applications submitted scrutiny

Lessons learned o Allows for possible reduction in overall costs of

Evaluation of information manufacturing –less waste

Implementation of PMP o Ensures less hassle during review –reduced
Office of Generic Drugs (OGD) deficiencies –quicker approvals

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 o Improves interaction with FDA –deal on a o Established for one or more unit operation(s)
science level instead of on a process level or up to complete process
o Allows for continuous improvements in o Working within the design space: not
products and manufacturing process. considered as a change.
Pharmaceutical Development Quality by design approach in coating process
Widely used in pharmaceutical development and o Quality cannot be tested into product but it
manufacturing (Figure: 6). should be built in product. Parameters that
affect the coating process are given below
(Figure: 8).

Full Length Original Research Paper

Figure 6: Pharmaceutical developments

Used in PAT
A system for designing, analyzing and controlling
manufacturing through timely measurement of
Page 58

critical quality performance attributes of raw and

in process materials and processes with the goal Figure 8: Parameters of the coating process
of ensuring final product quality (Figure : 7).
Quality target product profile for the ANDA
product
The Quality Target Product Profile (QTPP) is “a
prospective summary of the quality characteristics
of a drug product that ideally will be achieved to
ensure the desired quality, taking into account
Figure 7: Off-line & On-line Analysis Design Space
safety and efficacy ofthe drug product.”
o Multidimensional combination of and
Before developing the product, the quality
interaction of input variables and process
characteristics of the product are identified.
parameters that have been demonstrated to
Based on the desired characteristics the design
provide Quality Assurance
space is utilized to evaluate variable of quality
o Linkage between process inputs (inputs
target product profile from which the critical
variables and process parameters) and
quality attributes as derived. The data obtained
critical quality attributes
from evaluation will serve as a source for risk
o Proposed by Applicant
assessment. The finding of risk assessment is
o Subject to regulatory assessment and
examined and optimized process is developed to
approval
produce the products of desired quality.
o Implementation before or after MA

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noncommercial use, provided the original work is properly cited.
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Page 59
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