Quality By Design

(QBD)&
Process Analytical
Technology
(PAT)
 Dr. Joseph M. Juran
QBD is a concept first developed by
the quality pioneer Dr. Juran.

He believed that quality should be

designed into a product.

Most quality crises and problems

relate to the way in which a product
was designed in the first place.
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Dr. Joseph M. Juran

“ Quality Cannot Be Tested

Into Products; It Has To Be
Built In By Design

Dr. Genichi Taguchi

“Continuous Improvements
Is A Hallmark Of Quality
By Design”
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 WHAT IS QUALITY?
Requirements= Need or expectations

QUALITY PATIENT

Target Product Quality Profile

‘Good pharmaceutical quality represents an acceptably low risk of

failing to achieve the desired quality atrributes.’

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WHAT IS QUALITY BY DESIGN ?
A systematic approach to development that begins with predefined objectives
and emphasizes product and process understanding based on sound science
and quality risk management.

According to FDA, QBD means ‘Designing and developing’ a product and

associated manufacturing processes that will be used during product
development to ensure that the product consistently attains a predefined
quality at the end of the manufacturing process.
 WHAT IS QUALITY BY DESIGN ?
USFDA encouraged risk-based approaches and adopted QBD principles in drug
product development, manufacturing and regulation.

They emphasized on QBD with the recognition when increased testing does not
necessarily improve product quality.
Quality must be built into the product.

Quality By Testing And Inspection Quality By Design

Enhance •Quality assured by well designed product and
process
•product knowledge
•process understanding

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 FDA INITIATIVE ON QBD
Over the years, pharmaceutical QBD has evolved with the issuance of:

ICH Q8 (R2)- Pharmaceutical Development Points to consider document

ICH Q9 – Quality Risk Management
ICH Q10- Pharmaceutical Quality System
QBD documents provide high level directions
with respect to the scope and definition of QBD
as it applies to the pharmaceutical industry.

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 FDA INITIATIVE ON QBD
Over the years, pharmaceutical QBD has evolved with the issuance of:

ICH Q8 (R2)- Pharmaceutical Development Introduced by FDA in 2002

ICH Q9 – Quality Risk Management
ICH Q10- Pharmaceutical Quality System
QBD-GMP for the 21st century

Merck & Co’s Januvia (2006)- First FDA

Approved product

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 WHAT IS QUALITY BY DESIGN ?
QBD elements include the following:

1. QTPP( quality target product

profile) that identifies CQAs
(critical quality attributes)
of the drug product.
2. Product design and
understanding including
identification of CMAs
(critical material attributes)
3. Process design and
understanding including
identification of CPPs
(critical process material)*
4. Control strategy that includes
specifications for the drug substance,
excipients, and drug product as well as controls
for each step of the manufacturing process.
5. Process capability and continual improvement.
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 WHAT IS QUALITY BY DESIGN ?
QBD elements include the following: In a quality-by-design system:

1. QTPP( quality target product  Product is designed to

profile) that identifies CQAs meet patient requirements.
(critical quality attributes)  Process is designed to
of the drug product. consistently meet product
2. Product design and critical quality attributes.
understanding including  Impact of formulation
identification of CMAs components and process
(critical material attributes) parameters on product
3. Process design and quality is understood.
understanding including  Critical sources of process
identification of CPPs variability are identified
(critical process material)* and controlled.
4. Control strategy that includes  Process is continually
specifications for the drug substance, monitored and updated
excipients, and drug product as well as controls to assure consistent
for each step of the manufacturing process. quality over time.
5. Process capability and continual improvement.
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 QBD ELEMENTS
Quality Target Product Profile (QTPP): A prospective summary of
the quality characteristics of a drug product that ideally will be
achieved to ensure the desired quality, taking into account safety
and efficacy of the drug product.
Considers:
 Route of administration
 Strength
 Dosage form and delivery system
 Container closure system
 Attributes affecting pharmacokinetics characteristics, and drug
product quality criteria.

EXAMPLE:
QTPP for biotech liquid product
Clarity, pH, sterility, colour, sub-visible particulates, concentration,
etc
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 QBD ELEMENTS
Critical Quality Attribute (CQA): 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.
Identification of CQAs is done through risk assessment as per the
ICH guidance Q9.
Generally associated with the
 Drug substance
 Excipients
 Intermediates (in-process materials) and
 Drug product

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 QBD ELEMENTS
Critical Quality Attribute (CQA): 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.

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 IN QBD ELEMENTS
Material: Raw materials,
starting materials, reagents,
solvents, process aids,
intermediates, APIs and
packaging & labeling materials
Attributes: A physical,
chemical, biological or
microbiological property
or characteristic.

Critical Material Attributes (CMAs)

 Can be an excipient CQA, raw material CQA, starting material
CQA, drug substance CQA, etc.
 Can be quantified,
 Typically fixed,
 Sometimes be changed during further processing

EXAMPLE:
Impurity profile, Porosity, Specific volume, Moisture level, Sterility
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 QBD ELEMENTS
Critical Process Parameters (CPPs): 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.

CPPs have a direct impact on CQAs.

PP can be measured and controlled (adjusted).

EXAMPLE
Small molecule- temperature, addition rate, cooling rate, rotation
speed
Large molecule- temperature, pH, agitation, dissolved oxygen,
medium constituents, feed type and rate

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 QBD ELEMENTS
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.
Regularity flexibility- working within design space is not considered a
change.
Design space is proposed by the applicant and is 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) , linear and multiple-linear regression.
Scale-up correlations- Translate operating conditons between different
scales or pieces of equipment.
Risk analysis- determine significance of effects.
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Any combination of the above.
 QBD ELEMENTS
Control Strategy: A planned set of controls, derived from current
product and process understanding that ensures process
performance and product quality.

Control strategy can include the following elements:

 Procedural controls
 In-process controls
 Lot release testing
 Process monitoring
 Characterization testing
 Comparability testing
 Stability testing

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 QBD SCHEME

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 QBD CASE STUDY
ON ACE TABLETS

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 QBD CASE STUDY ON ACE TABLETS
Identify Risk
Control
Define QTPP CPPs and assessm
strategy
CMAs ents

Design Update
Outline
Define space risk
process
CQAs studies assessm
maps
(DOE) ent

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 Create the ‘ACE tablet’ drug profile
(using Lean QBD software)

…..Next is to extract QTPP,

CQA, CPP and CMA
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 Extract QTPP and CQAs
QTPP are patient and
clinical outcome metrics.

CQAs are drug product/

substance quality
metrics.

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 Extract QTPP & CQAs

…..Continue with process map to

extract process parameter
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 Process Map or Process Flow Diagram
Typical set of 6 unit operations for
tablets:
1. Blending
2. Dry granulation
3. Milling
4. Lubrication
5. Compression
6. Packaging

Critical steps are blending, dry granulation

And compression

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 Process Map or Process Flow Diagram
Excipients include MCC, lactose monohydrate
Croscarmellose sodium, magnesium
stearate and talc.

Manufacturing process
involves pre-blending step, roller
compaction of the acetriptan with MCC,
croscarmellose sodium, magnesium stearate
and lactose monohydrate.
Then milling to produce granules before
blending with magnesium stearate, and talc.
Followed by compression on a rotary tablet
press.

ACE tablets are white, biconvex, round

tablets containing 20 mg of acetriptan (ACE)
with “ACE” and “20” debossed on one side,
in cartons containing a blister pack of 6
tablets, or in polypropylene bottles
containing 10 tablets.
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 Process Map or Process Flow Diagram
1. BLENDING CPP

Uniformity- main quality attribute for the

blending process.

Cause and Effect or Fishbone Diagram

shows all of the process parameters and
variation sources for the blending process.

After initial risk assessment, 2 CPPs selected:

%CV and
Moving window size
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 Process Map or Process Flow Diagram
2. ROLLER COMPACTION CPP:

Ribbon density- main quality attribute

Dissolution- associated CQA

Process parameters from roller compaction

are: Feed rate, Roller pressure, Roll speed,
Gap size, Humidity,etc

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 Process Map or Process Flow Diagram
3. MILLING CPP:

CPP are mill speed and screen size

Granule Surface Area, Granule Moisture

Content, Granule Uniformity of Content are
in-process quality attributes.

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 Process Map or Process Flow Diagram
4. LUBRICATION CPP:

The milled granulation is blended with

extragranular excipients in a second blending
operation.
The granules are mixed with 0.25%
magnesium stearate (as lubricant) and5%
talc (as glidant).

Only 2 process parameters identified for

Lubrication:
Revolutions
Fill volume
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 Process Map or Process Flow Diagram
5. COMPRESSION CPP:

Compression process flow

Input-Process-Output diagram for the

Compression unit operation.
Process Parameters for the compression are:
Pre-compression force, Compression Force,
Press Speed, Die Fill Depth, Feeder Speed,
Ejection Force, and Height of Drop.

Parts geometry and tooling geometry are

pre-specified and should be a source of
31 variation.
 Process Map or Process Flow Diagram
6. PACKAGING CPP:

Main attribute- stability

10 tablets are packaged into 30cc HDPE

bottles containing cotton wadding and a
heat-induction seal, closed with
polypropylene caps and 6 tablets per blister
with push-through foil lidding.

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 Summarise CPPs and CMAs into the
Lean QBD table

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 Link
QTPP-CQA-CPP/CMA
through QBD risk
assessment

This assessment really

depends on the
capability
of the manufacturing
facility and the staff’s
knowledge.

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 ADVANTAGES OF QBD
Benefits for industry Additional opportunities
 More flexible
 Better regulatory
understanding of approaches
the process  More efficient
 Less batch failure technology transfer
to manufacturing
 More efficient and
effective control of  Risk-based approach
change and identification
 Continuous
improvements over
total product life
cycle
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 QBD TOOLS AND STUDIES
Includes:
Prior knowledge
Risk assessment
Mechanistic models.
Design of experiments (DoE)
Data analysis
Process analytical technology (PAT)

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 PAT (PROCESS ANALYTICAL
TECHNOLOGY)
DEFINITION GOALS
a system for designing,  understand and control
analysing, and controlling the manufacturing
process
manufacturing through
 design and develop
timely measurements of processes that can
critical quality and consistently ensure a
performance attributes of predefined quality at
raw and in-process the end of the
materials and processes. manufacturing process
 enhance process safety
 reduce variation in
processes
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 PAT (PROCESS ANALYTICAL
TECHNOLOGY)
FRAMEWORK FRAMEWORK
 Process understanding  PAT tools
 All critical sources of variability  Multivariate data acquisition and
are identified and explained. analysis tools
 Variability is managed by the  Modern process analysers
process.  Process and endpoint monitoring
 Product quality attributes can be and control tools
accurately and reliably predicted  Continuous improvement and
over the design space established knowledge management tools
for materials used, process
parameters, manufacturing,
environmental, and other
conditions
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 HOW PAT WORKS?

Design process
Selection of suitable Identification of
Selection of process -on-line test
PAT system CPP
-in-line test

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 TYPES OF PAT IMPLEMENTATION

INITIAL PHASE SCALE-UP TEMPORARY PERMANENT

PHASE PROCESS PROCESS

Process
optimization Comparing data Gaining process Actual process
information & monitoring &
understanding control
process

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 PAT (PROCESS ANALYTICAL
TECHNOLOGY)
WHY PAT ANALYSIS IS PROFILE OF A PAT
BETTER THAN LAB. SCIENTIST
ANALYSIS?  Technical
 Control environment  Interpersonal
 Speed effectiveness
 Operator error  Initiative
 Safety  Business focus
 Sample integrity  Learning
 Innovative
 Overall leadership

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 ADVANTAGES OF PAT
1. Reduces 5. Meets all kinds of 7. Prevents rejects
processing cost regulatory and re-
requirements processing
2. Improves quality
6. Increases 8. Controls
automation to variability
3. Provides product improve operator
uniformity safety and reduce
human errors 9. Continuous
improvement &
4. Reduces product knowledge
change-over time management

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 DISADVANTAGES OF PAT
1. Require efforts during design

2. Implementation and maintenance stages is high

3. Require specialised, expertise person

4. Costly

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 Thank You
For Your
Time And
Attention
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