QUALITY BY DESIGN IN
PHARMACEUTICAL
DEVELOPMENT
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CONTENTS
Definition
Introduction
Principles of QbD
Key aspects of QbD
ICH Q8 Guidelines
ICH Q9 Guidelines
ICH Q10 guidelines
Applications
Conclusion. 2
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DEFINITION
The pharmaceutical Quality by Design ( QbD ) is a
systematic approach to development that begins with
predefined objectives and emphasizes product and
process understanding and process control, based on
sound science and quality risk management. Quality by
Design is emerging to enhance the assurance of safe,
effective drug supply to the consumer, and also offers
promise to significantly improve manufacturing quality
performance.
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QbD means designing and developing formulations and
manufacturing processes to ensure predefined product quality .
Thus , QbD requires an understanding and controlling
formulation and manufacturing process variables influence
product quality .
Relevant documents from International Conference on
Harmonization of Technical Requirements for registration of
pharmaceuticals for human use ( ICH ) , ICH Q8 for
Pharmaceutical Development , along with ICH Q9 for Quality
Risk Management , and ICH Q10 for Pharmaceutical quality
system . 4
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INTRODUCTION
Quality by Design ( QbD ) was first described by Joseph
M. Juran . The fundamental premise behind QbD is that
quality can be designed in processes through systematic
implementation of an optimization strategy to establish
through understanding of the response of the system
quality to given variables , and the use of control
strategies to continuously ensure quality .
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In order to describe Quality by Design , We must know
what is mean by quality .
Quality in manufacturing is a measure of excellence or a
state of being free from defects , deficiencies , and
significant variation .
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The pharmaceutical industry is one of the most strictly
regulated and its products are of excellent quality .
However , there are issues suggesting that pharmaceutical
development and manufacturing can be improved .
Defects in pharmaceutical product quality can be
encountered such as low manufacturing process yield or
more dangerously some which may affect the therapeutic
performance of the drug .
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The quality of a pharmaceutical product can be defined as
an acceptably low risk of failing to achieve the desired
clinical attributes of the drug .
It is recognized that reasonable product quality in the
pharmaceutical industry sometimes comes with the price
of great effort and cost .
Implementation of the QbD concept is important for all
products , including generics and biotechnological
products. 8
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PRINCIPLES OF QBD
Risk and knowledge based decisions.
Systematic approaches for process development.
Continuous improvement.
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PHARMACEUTICAL QUALITY BY DESIGN
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1.Describes the use , safety , and efficacy of the product.
2.Design and develop product and manufacturing
processes.
3.Identify critical quality attributes , process parameters ,
and source of variability.
4. Establish a control strategy for the entire process.
5.Control manufacturing processes to produce consistent
quality over time .
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ELEMENTS OF QBD
Elements of QbD involves following steps
Quality characterstics of product that will ensure safety and efficacy , and QTPP
Identify of Critical Quality Attributes (CQA) for drug substance , excipients , drug products
To perform risk assessment linking material attributes and process parameters to CQAs
To established design space linking between input variables and process parameters and CQAs
Using elements such as control of input material , product specification , in process controls , in
process.
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Life cycle management continuous improvement
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TARGET PRODUCT PROFILE ( TPP )
The TPP provides a statement of overall intent of the drug
development program , and gives information about the
drug at a particular time in development .
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QUALITY TARGET PRODUCT PROFILE ( QTPP )
The QTPP is a prospective summary of the quality
characteristics of the product that ideally will be achieved
to ensure the desired quality , taking into account safety
and efficacy of the drug product.
The QTPP is a essential element of A QbD approach and
forms the basis of design of the generic product.
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QTPP is a quantitative substitute for aspects of clinical
safety and efficacy .
Quality target product profile ( QTPP )
➢ Dosage form
➢ Route of administration
➢ Strength
➢ Release or Delivery of the drug
➢ Pharmacokinetic characteristics
e.g Dissolution . 15
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CRITICAL QUALITY ATTRIBUTES ( CQA )
ICH Q8 defines CQA as physical , chemical , biological
or microbiological properties or characteristics that
should be within an appropriate limit or range to ensure
the desired product quality .
CQA has been used by some to describe elements of the
QTPP ( such as dissolution ) and to describe mechanistic
factors ( such as particle size and hardness ) that
determine product performance.
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CONTROL STRATEGY AND PRODUCT LIFE CYCLE
The control strategy is related to the level of process
understanding at a given time , and evolves as
manufacturing experience increases .
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DESIGN SPACE
The multidimensional combination and interaction of
input variables ( e.g. Material attributes ) and process
parameters that have been demonstrated to provide
assurance of quality . Working within the design space is
considered to be change . Movements out of the design
space is considered to be change and would normally
initiate a regulatory post approval change process .
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DESIGN OF EXPERIMENTS ( DOE )
DOE is a structured and organized method to determine
the relationship among factors that influence outputs of a
process .
When DOE is applied to pharmaceutical process , factors
are the raw material attributes ( e.g particle size ) and
process parameters ( e.g speed and time ) , while outputs
are the critical quality attributes such as blend uniformity
tablet hardness , thickness and friability .
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ICH Q8 PHARMACEUTICAL DEVELOPMENT
The aim of pharmaceutical development is to design a
quality product and its manufacturing process to
consistently deliver the intended performance of the
product .
The information and knowledge gained from
pharmaceutical development studies and manufacturing
experience provide scientific understanding to support the
establishment of the design space , specification , and
manufacturing controls . 20
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The pharmaceutical development section should describe
the knowledge that establishes that the type of dosage
form selected and the formulation proposed are suitable
for the intended use .
This section should include sufficient information in each
part to provide an understanding of the development of
the drug product and its manufacturing process .
At a minimum , those aspects of drug substances,
excipients , container closure systems , and control
strategies justified . 21
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COMPONENTS OF THE DRUG PRODUCT
1 . Drug substance
The physicochemical and biological properties of the drug that
can influence the performance of the drug product and its
manufacturability , or specifically designed into the drug
substance .
e.g. 1 Solid state properties should be identified and discussed .
2 physicochemical and biological properties that might need to
be examined include solubility, water content, particle size,
crystal properties, biological activity, and permeability. These
properties are interrelated and might need to be considered in
combination.
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2 Excipients
The excipients chosen, their concentration, and the characteristics
that can influence the drug product performance (e.g. Stability ,
bioavailability ) or manufacturability should be discussed relative to
respective function of each excipients .
This should include all the substance used in the manufacture of the
drug product , whether they appear in the finished product or not
( e.g. Processing aids ). Compatibility of the excipients with other
excipients ( e.g. Combination of preservatives in a dual preservative
system ) should be established . The ability of excipients
( e.g. Antioxidants , penetration enhancers , disintegrants , release
controlling agents ) should be demonstrated . 23
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DRUG PRODUCT
1. Formulation development
A summary should be provided describing the development of the
formulation , including identification of those attributes that are
critical to the quality of the drug product, taking into consideration
intended usage and route of administration .
2. Physicochemical and biological properties
The physicochemical and biological properties relevant to the
safety , performance or manufacturability of the drug product
should be identified and discussed
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MANUFACTURING PROCESS DEVELOPMENT
Appropriate equipment used for the intended product should be
discussed .
It should provide basis for process improvements , process
validation , continuous process verification and any process
control requirements .
It should identify any critical process parameters that should be
controlled . ( e.g. Granulation end point ) to ensure that the
product is of the desired quality .
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CONTAINER CLOSURE SYSTEM
The choice for selection of the container closure system for the
commercial product should be discussed . Consideration should be
given to the intended use of the drug product and suitability of the
container closure system for the storage and transportation for bulk
drug product.
The choice of primary packaging material should consider e.g.
Choice of materials, protection from moisture and light,
compatibility of the materials of construction with dosage form ,
safety of materials of construction .
If a dosing device is used ( e.g. Dropper pipette , pen injection
device, dry powder inhaler ), it is important to demonstrate that a
reproducible and accurate dose of product is delivered under testing
condition . 26
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MICROBIAL ATTRIBUTES
The selection and effectiveness of preservative system in
products containing antimicrobial effectiveness of product
that are inherently antimicrobial .
For sterile products, the integrity of the container closure
system as it relates to preventing microbial
contamination.
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COMPATIBILITY
The compatibility of the drug product with reconstitution
diluents ( e.g. Precipitation , stability ) should be
addressed to provide appropriate and supportive
information for the labelling .
Admixture or dilution of products prior to administration
( e.g. Product added to large volume infusion containers )
might need to be addressed .
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ICH Q9 QUALITY RISK MANAGEMENT
This guideline provides principle and examples of tools
for quality risk management that can be applied to
different aspects of pharmaceutical quality . These aspects
include development , manufacturing, distribution, and
the inspection and submission or review processes
throughout the lifecycle of drug substances , drug
products , biological and biotechnological products (
including use of raw materials , solvents , excipients ,
packaging and labelling materials in drug products .
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PRINCIPLES OF QUALITY RISK MANAGEMENT
Two primary principles of quality risk managements are
1. The evaluation of the risk to quality should be based
on scientific knowledge and ultimately link to the
protection of the patient .
2. The level of effort , formality and documentation of
the quality risk management process should be
commensurate with the level of risk .
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GENERAL QUALITY RISK MANAGEMENT PROCESS
QRM is a systematic process for the assessment , control ,
communication and review of risks to the quality of the
drug product across the product lifecycle .
Decision nodes are not shown in the diagram because
decisions can occur at any point in the process . These
decision might be to return to the previous step and seek
further information , to adjust the risk management
process based upon information that supports such a
decision. 31
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General quality risk management process
Product Process Process scale up Manufacturing
development development & tech transfer
Product
Process
knowledge Process
understanding Risk control history Clinical
Risk trials
assessment Risk Product Risk review
assessment quality
Excipients control Continual
Process design
and drug strategy improvemen
space
t
substance
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Quality Risk Management
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QRM RESPONSIBILITIES
Take responsibility for coordinating quality risk
management across various functions and departments of
their organization.
Assure that a quality risk management process is defined
and reviewed and that adequate resources are available.
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INITIATING A QRM PROCESS
Quality risk management should include systematic
processes designed to coordinate , facilitate and improve
science-based decision making with respect to risk .
1. Define the problem or risk question .
2. Assemble background information or data on the
potential hazard relevant to risk assessment .
3. Identify a leader and necessary resources .
4. Specify a timeline , deliverables and appropriate level of
decision making for the risk management process. 35
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RISK ASSESSMENT
Risk assessment consists of the identification of hazards and
the analysis and evaluation of risks associated with exposure
to those hazards .
Quality risk assessments begin with a well defined problem
description or risk question.
For risk assessment purposes , three fundamental questions
are often helpful .
1. What might go wrong ?
2. What is likelihood it will go wrong ?
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3. What are the consequences ?
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RISK CONTROL
Risk control includes decision making to reduce and accept risks . The
purposes of risk control is to an acceptable level. The amount of effort
used for risk control should be proportional to the significance of the
risk . Decision makers might use different processes , including benefit-
cost analysis , for understanding the optimal level of risk control .
Risk control might focus on the following questions .
1. Is the risk above an acceptable level ?
2. What can be done to reduce or eliminate risks ?
3. What is the appropriate balance among benefits , risks and resources ?
4. Are new risks introduced as a result of the identified risks being
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controlled .
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RISK COMMUNICATION
Risk communication is the sharing of information about
risk and risk management between the decision makers
and others . Parties can communicate at any stage of the
risk management process . The result of the quality risk
managements process should be appropriately
communicated and documented .
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RISK REVIEW
The output of the risk management process should be
reviewed to take into account new knowledge and experience
. Once a quality risk management process has been initiated ,
that process should continue to be utilized for events that
might impact the original quality risk management decision ,
whether these events are planned
( e.g. Results of product review, inspections , audits , change
control ) or unplanned ( e.g. Root cause from failure
investigations , recall ) . The frequency of any review should
be based upon the level of risk . Risk review might include
reconsideration of risk acceptance decisions . 39
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ICH Q 10 PHARMACEUTICAL QUALITY SYSTEM
This guidelines applies to the systems supporting the development
and manufacture of pharmaceutical drug substances ( i.e. API )
and drug products , including biotechnology and biological
products, throughout the product life cycle .
The elements of ICH Q 10 should be applied in a manner that is
appropriate and proportionate to each of the product lifecycle
stages , recognising the differences among , and the different goals
of each stage .
The product lifecycle includes the following technical activities
for new and existing products . 40
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The product lifecycle includes the following technical activities
for new and existing products .
1 Pharmaceutical development .
a) Drug substance development
b) Formulation development
c) Manufacture of investigational products
d) Delivery system development
e) Manufacturing process development and scale-up
f) Analytical method development.
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2 Technology transfer
a) New product transfers during development through manufacturing .
b) Transfers within or between manufacturing and testing sites for
marketed products .
3 Commercial manufacturing
a) Acquisition and control of materials
b) Provision of facilities , utilities , and equipment.
c) Production
d) Quality control and assurance
e) Release
f) Storage
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g) Distribution
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4 Product discontinuation
a) Retention of documentation
b) Sample retention
c) Continued product assessment and reporting .
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ICH Q 10 OBJECTIVES
1. Achieve product realisation
2. Establish and maintain a state of control
3. Facilitate continual improvement.
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Opportunities to impact risk using Quality
Risk Management
Q9
Design
Process
Materials Manufacturing
Facilities
Distribution
Q8 Patient
Q10 45
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INDUSTRIAL VIEWS
Putting new concept / approaches into practice.
Broad spectrum approaches for development ,
manufacturing and quality operations across industry.
Implementing while harmonizing.
Heavy workload and limited resources .
Additional investment to achieve efficiency .
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APPLICATIONS
1. For enhancement of the solubility and dissolution of
class 2 BCS drug using polymeric surfactants and
crystallization inhibitors i.e. development of controlled
release tablets.
2. QbD used for quality control analysis of API and drug
products.
3. QbD is used for improve the quality of product.
4. QbD is used for pharmaceutical fields like analysis,
formulation, design and technology development . 47
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CONCLUSION
Ensures robust commercial manufacturing methods for
consistent production of quality drugs.
Ensures the consumers that therapeutic equivalent generics
are manufactured every single time.
QbD methodology helps in identifying and justifying target
product profiles, product and process understanding.
Helps in continuous improvement.
There is a need for vigorous and well funded research
programs to develop new pharmaceutical manufacturing 48
platforms.
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REFERENCE
A review article on Quality by Design in pharmaceuticals
by Hardik patel , Shraddha Parmar , Bhavna Patel .
A review on design of experiments ( DOE ) .
A article on ICH Q8 Pharmaceutical Development.
A articles on ICH Q9 Quality Risk Management.
A Article on ICH Q10 pharmaceutical Quality System.
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THANK YOU
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