Quality by Design is a systematic approach to development that begins with predefined objectives and emphasizes understanding of the product and process, efficient process control, and quality risk management to improve the overall manufacturing quality. Implementing the Quality by Design (QbD) principles in manufacturing has resulted in reduced operating costs, highly efficient manufacturing processes and better positioning companies to meet increasing regulatory expectations. QbD explains how to prioritize process parameters for screening designs, design robust processes using statistical design of experiments (DoE), bridge the bench and the commercial design spaces using mixing and scale-up calculations, quantify process risk, select suitable process analytical technology tools (PAT) and more. To know more about Quality by Design training worldwide, please contact us at - Email: support@invensislearning.com Phone - US +1-910-726-3695, Website: https://www.invensislearning.com

1. Quality by Design
Course Name : Quality by Design
Version : INVL_QBD_CW_01_1.0
Course ID :QMGT- 168

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About Invensis Learning
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“Live as if you were to die tomorrow. Learn as if you
were to live forever.”
- Mahatma Gandhi

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Agenda
 Introduction
 Some history and scene setting
 Relationship of QbD to ICH guidelines
 Overview and definition of QbD
 Design space
 Control strategy

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Quality by Design – The Origins
Quality by Design – coined by J M Juran (1904-2008)
- pioneer and evangelist for quality management techniques.
The Juran Trilogy - Quality Planning
- Quality Control
- Quality Improvement
Statistical approach owes more to
W Edwards Deming (and others)
“Cease dependence on inspection to achieve
quality. Build quality into the product in the first
place.”
“There is no substitute for knowledge."
"Experience by itself teaches nothing."

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History
 QbD techniques were adopted in many industries from
 1970’s onwards, particularly automotive and electronics.
 Quality planning principles are enshrined in the ISO9001 and ISO13485 for design and
manufacturing processes.
 Recent usage of the term stems from adoption by FDA for modernisation of review and approval
process pharmaceutical and biotechnology products.
 ICH*– developed a new set of guidelines for pharmaceutical development
*ICH = International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use

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ICH Guidelines
The ICH Vision as Described in Guidelines
A New Quality Paradigm
 Science and risk-based approaches to pharmaceutical product development, dossier submission,
review, inspection and post-approval change management
 Manufacturers empowered to effect continuous improvement and technical innovation throughout
the product lifecycle
 Efficient and consistent regulatory oversight across/between regions

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Q. Where should QbD be applied?
A. To all elements of a drug or biotechnology product
Pharmaceutical
Product
Formulation Device components
Container
Closure
System
Drug
Delivery
System
Drug
Substance
Excipientsform
Supply chain

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ICH Guideline Q8 defines QbD as…
A systematic approach to development that begins with predefined objectives &
emphasizes product and process understanding and process
control, based on sound science & quality risk management
..and Quality as the degree to which properties of a product,
system or process fulfil requirements
7

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What is QbD?
Quality by Design is….
 A scientific, risk based proactive approach to pharmaceutical product development
 A deliberate and structured design effort from first stages of conception and innovation through the
full product life cycle
 A complete understanding of how product attributes and process parameters relate to product
performance.

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Product development – definitions
General approach Quality Target Product Profile
-
-
-
-
Use and market related target requirements
Related to safety and efficacy
Intended use, dosage form, dosage strength
Quality criteria - sterility, purity, stability, etc.
Critical Quality Attribute
-
-
Physical, chemical, biological property
Should be within a defined range to ensure
product quality
Related to materials, intermediates, final
product.
-
Critical Process Parameter
- Parameter whose variability has an impact
on a CQA
- Should therefore be monitored or controlled
9
Define control
strategy
Define CPP of
manufacturing
process
Identify CQA -
components
Identify CQA -
product
Define QTPP

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Product development – minimum and QbD approach
“Quality by Design”
Systematically understand
and refine the product and
process
Risk assessment
Knowledge
Experimen
t
Minimalist approach
Quality target
product profile
Identify material attributes and
process parameters that affect
CQAs and the functional
relationships between them
Establish control strategy
e.g. design space
e.g. real-time release testing
Critical quality
attributes
Critical process
parameters
Continual improvement
Reduced variability
Innovation
Define control
strategy
Define CPP of
manufacturing
process
Identify CQA -
components
Identify CQA -
product
Define QTPP

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Stage-gated device design processes
Risk management Usability evaluation
LaunchStage 4:
Detailed
design &
output
creation
Stage 7:
Scale up &
transfer to
manufacture
Stage 1:
Requirements
definition &
capture
Stage 2:
Concept
creation &
selection
Stage 3:
Design
input
definition
Stage 5:
Design
verification
Stage 6:
Design
validation
Produce
First
tooling
Launch
Late stage
development
Early stage
development
Full
development
Discovery
Produce
Pre-clinical evaluation Phase 3 clinical evaluation

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Medical device stage gated device design process
Systematic analysis
& experimentation
Risk management
Usability evaluation
Launch
Stage 4:
Detailed
design &
output
creation
Stage 7:
Scale up &
transfer to
manufacture
Stage 1:
Requirements
definition &
capture
Stage 2:
Concept
creation &
selection
Stage 3:
Design
input
definition
Stage 5:
Design
verification
Stage 6:
Design
validation
Produce
First
tooling
Design
verification
Process
validation
Design
transfer
Design
planning
Design
inputs
Design
outputs
Design
validation
Change
control
Design space definition Control
strategy
QTPP CQA CPP? CPP
Systematic analysis &
experimentation
Experience gained in
production
Prior knowledge

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Design space
ICH 8 defines design space as:
The multidimensional combination and interaction of input
variables and process parameters that have been demonstrated to
provide assurance of quality.
For example:
Scientific investigation
– Experience?
- Design of experiment?
- Analytical model?
- Process validation?
Injection
moulded
medical
device
Knowledge
of design
space
Assembly process
Injection mould
process
Mould tools
Component drawings
(with tolerances)
Polymer specifications

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Design Space
Comments on Design Space
 Can a Design Space ever be complete?
 - Yes, if all parameters with a potential effect are investigated in all combinations.
In other words – Not really.
 - Risk management is needed to ensure itsrobustness of the Design Space
 Design Space does not need to go to the edge of failure – useful to know, but not mandatory
 Set of proven acceptable ranges is not a Design Space
 Design space should be verified at each scale of manufacture.

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Steps in development of a process Design Space
- Internal knowledge from
similar products and processes
External knowledge – peer
reviewed publications, etc.
Define QTPP
-
Define CQA
Use prior knowledge
to understand
variables and their
impact
Process risk
- Modelling may be OK, but
needs full verification and
justification
- Based on knowledge plus
additional tests where
needed
Iterative as experience is
gained.
assessment to
identify CPPs
-
Conduct and
evaluate DoE to
establish CPP/CQA
relationshipsRepeat as
necessary

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Analysis of variation
Can we analyse the relative contributions of the identified CPP and CQA to variability or failure of
the device?
Theoretical
 Tolerance analysis
 Sensitivity analysis
 Theoretical modelling of mechanisms
 Finite element analysis
Experimental
 Single factor experiments
 Designed experiments for multi-factor analysis
 Validation/ verification studies
Design
space

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Control strategy
Control strategy
 Needs to ensure that required quality is produced consistently
and is assured by combination of:
 In-process control and measurements
 Upstream process controls
 Input material controls
 Must be based on understanding of CPPs and the impact of
variability.
 Can enable adaptive process steps that vary according to input
materials.
 Can ultimately lead to real time release testing.
Control strategy

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Summary
 QbD is recommended for 21st century pharmaceutical development – and by extension to Container
Closure Systems
 QbD has less impact on MedTech product development processes since the requirements are close
to good design and manufacturing practices.
 QbD requires profound understanding of effects of, and interactions between, materials, products
and process parameters.
 QbD leads to a more flexible manufacturing environment, responsive to upstream variability
 CCS and drug delivery system component suppliers need to prepare to share information with
pharmaceutical clients.

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