QUALITY CAN NOT BE TESTED INTO PRODUCTS
IT HAS TO BE BUILT IN BY DESIGN : BY JOSEPH M
JURAN
QBD QUALITY BY DESIGN
Definition
Overview
Elements of QbD program
Tools
DEFINITION
It is systematic approach to
development,
begins with predefined
objectives,
emphasizes on product and
process understanding &
process Control based on sound
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BENEFITS OF QBD
Eliminate batch failures
Minimize deviations and costly investigations
Avoid regulatory compliance problems
Empowerment of technical staff
Increase manufacturing efficiency, reduce costs and
project rejections and waste
Build scientific knowledge base for all products
Provide Better interaction with industry on science
issues
Ensures consistent information
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Incorporate risk management
Reduce end-product testing
SIGNIFICANCE OF QBD
Quality by Design means –designing and developing
formulations and manufacturing processes to ensure
a predefined quality
Quality by Design requires – understanding how
formulation and manufacturing process variables influence
product quality .
Quality by Design ensures – Product quality with
effective control strategy 4
QBD APPROACH CAN BE USED FOR
Active pharmaceutical Simple dosage forms
Ingredients Advanced drug delivery
Materials including systems
Excipients Devices
Analytics Combination products
(e.g. theranostics- comb.
Of using one radioactive
drug & 2nd radioactive drg
to treat main tumor)
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KEY CHARACTERISTICS OF QBD
A tool for focused & efficient drug development
Provides Dynamic and systematic process
Relies on the concept that Quality can be built in as
a continuum
It is applicable to Drug Product and Drug Substance
development (chemicals / biologics)
It is applicable to analytical methods
Can be implemented partially or totally
Can be used at any time in the life cycle of the
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Drug
KEY ELEMENTS OF QBD
ICH Q8: Pharmaceutical Development discusses the various
elements of quality by design. These in combination with the
enablers forms the fundamental basis for the QbD approach to
development.
It involves the following key elements during pharmaceutical
development
Quality Target Product Profile (QTPP)
Identify the Quality Attributes
Determine the Critical Quality Attributes
Determine the Critical Material Attributes
Link raw material attributes and process parameters to CQA’s
Identify a Control Strategy & Design Space 7
Manage product lifecycle, including continuous improvement
WHAT ARE THE STEPS/ELEMENTS IN A QUALITY
BY DESIGN APPROACH?
1. Target
product
profile
6. Risk 2. Critical
Managemen quality
t attributes
5. Establish 3. Link MA’s
control & PP’s to
strategy CQA’s
4. Establish 8
Design
space
QUALITY TARGET PRODUCT PROFILE
The target product profile (TPP) has been defined as a
“prospective and dynamic summary of the quality
characteristics of a drug product that ideally will be
achieved to ensure that the desired quality, and thus
the safety and efficacy, of a drug product is realized”.
Considerations include
Clinical setting, route of administration, dosage form,
delivery systems
Dosage strengths
Container closure system
Therapeutic moiety release or delivery & attributes 9
affecting pharmacokinetic characteristics (dissolution)
CRITICAL QUALITY ATTRIBUTES
A 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.
CQAs are generally associated with the
Drug substance,
Excipients,
Intermediates (in-process materials) and
Drug product. 10
MATERIAL ATTRIBUTE
Material:
Raw materials, starting materials, reagents, solvents, process aids,
intermediates, API’s, packaging and labelling materials, ICH Q7A
Attribute:
A physical, chemical, biological or microbiological property
or characteristic
Material attribute:
Can be an excipient CQA, raw material CQA, starting material CQA,
drug substance CQA etc
A material attribute can be quantified
Typically fixed
can sometimes be changed during further processing (e.g. milling)
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Examples of material attributes: impurity profile, porosity,
specific volume, moisture level, sterility.
PROCESS PARAMETER
A process parameter whose variability has an impact on
a critical quality attribute and therefore should be
monitored or controlled to ensure the process produces
the desired quality (Q8R2)
CPPs have a direct impact on the CQAs
A process parameter (PP) can be measured and
controlled (adjusted)
Examples of CPPs for small molecule: Temperature,
addition rate, cooling rate, rotation speed
Examples of CPPs for large molecule: Temperature, pH,
Agitation, Dissolved oxygen, Medium constituents, Feed
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type and rate
DESIGN SPACE
Definition
The multidimensional combination and interaction of
input variables (e.g., material attributes) and
process parameters that have been demonstrated to
provide assurance of quality
Regulatory flexibility
Working within the design space is not considered a
change
Important to note
Design space is proposed by the applicant and is 13
subject to regulatory assessment and approval
DESIGN SPACE DETERMINATION
First-principles approach
Combination of experimental data and mechanistic knowledge
of chemistry, physics, and engineering to model and predict
performance
Non-mechanistic/empirical approach
statistically designed experiments (DOE’s)
linear and multiple-linear regression
Scale-up correlations
Translate operating conditions between different scales or
pieces of equipment
Risk analysis
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Determine significance of effects
any combination of the above
CONTROL STRATEGY
A planned set of controls
Derived from current product and process understanding
That assures process performance and product quality.
The controls can include Parameters and attributes related
to
Drug substance
Drug product materials
Components, facility
equipment operating conditions
In-process controls
Finished product specifications, and
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The associated methods and frequency of monitoring and
control (ICH10)
TOOLS:
DOE Design of experiments:
Method:
Choose experimental design (full factorial, optimal)
Conduct randomized experiments
Analyze data
Create multidimensional surface model
DOE Creates relationship between input and output
How factors jointly affect the output responses
Maximizing gain and minimizing resources
Material attributes like particle size of raw material or excipients and process
parameters (speed of press. Spray rate)
Critical quality attributes in process or materials or final drug product eg.
Blend uniformity, particle size particle size distribution of granules, tablet
assay, content uniformity, drug release etc. 16
DOE helps in identification of optimum conditions, CMA, CPP, Design space
RISK ASSESSMENT
Risk : Risk is defined as the combination of the
probability of occurrence of harm and the severity
of that harm.
Risk Assessment – A systematic process of
organizing information to support a risk decision to
be made within a risk management process.
It consists of the identification of hazards and the
analysis and evaluation of risks associated with
exposure to those hazards.
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PAT (PROCESS ANALYTICAL TECHNOLOGY)
System to design, analyze, control manufacturing through timely
measurements during processing of critical quality and performance
attributes of raw material and process materials to ensure final
product quality
Includes chemical, physical, microbiological, mathematical, risk
analysis
Can be part of control strategy
Provides continuous monitoring of CPPs, CMAs, CQAs
Ex: PAT Tablet Production
Compression functional tests (chemical/physical)
Validate process control
Control blending (particle size, disintegrant distribution)
Process focused 18
Risk predictive models
CONCLUSION
Quality by Design define target product quality
profile ,design and develop formulation and
process to meet target product quality profile,
Identify critical raw material attributes,
process parameters, and sources of variability.
PAT (Process analytical Tech), DoE, and risk
assessment are tools to facilitate the
implementation of QbD.
There is a need for vigorous and well funded
research programs to develop new
pharmaceutical manufacturing platforms. 19
