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
Itis systematic approach to development,
begins with predefined objectives,
emphasizes on product and process
understanding & process Control based on
sound science and QRM (Quality risk mgt)
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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
Incorporate risk management
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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
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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 Drug
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Always encouraged by Regulators.
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
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Manage product lifecycle, including continuous improvement
WHAT ARE THE STEPS/ELEMENTS IN A QUALITY BY DESIGN
APPROACH?
1. Target
product
profile
2. Critical
6. Risk
quality
Management
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 affecting pharmacokinetic
characteristics (dissolution)
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Drug product quality criteria (sterility, purity, stability, drug release)
appropriate for intended marketed product
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.
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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)
Examples of material attributes: impurity profile, porosity,
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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,
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Dissolved oxygen, Medium constituents, Feed 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 subject to
regulatory assessment and approval 13
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
Determine significance of effects
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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
The associated methods and frequency of monitoring and 15
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.
DOE helps in identification of optimum conditions, CMA, CPP, Design space 16
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
Risk predictive models 18
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