Quality by Design and

Optimization
By Z
Outline
• Part-I
– QbD

• Part-II
– Formulation optimization
 Part-I
Quality by Design (QbD)
Outline
• Introduction
• Components of QbD
• Tools for QbD
Introduction
• Quality
– the degree to which a commodity meets the
requirements of the customer

• Pharmaceutical Quality
– The suitability of either a drug substance or drug
product for its intended use.
• This term includes such attributes as the identity, strength,
and purity.
– ICH Q6A, 2000
= f {drug substance, excipients, manufacturing..}
Introduction…
• In the traditional QbT approach,
– pharmaceutical quality is defined as
• the product meeting the pre-specified quality and
regulatory specification .

• QbT framework typically encompasses

– Raw material testing,
– In-process testing, and
– End product testing
 QbT
Quality Controlled by
Inspection and Testing of
Finished Product

QbD
Quality Built into Finished Product
(No Reliance on End Testing)
QbT vs QbD
Introduction…
• Quality by Design (QbD)
– is a concept first outlined by quality expert Joseph
M. Juran

– He defines the word "Quality" as having two

meanings:
• First
– the presence of features that create customer satisfaction;
• Second
– the reliability of those features.
Introduction…
– Failures in features create dissatisfactions,
• so removing failures is the purpose of quality
improvement, while creating features is the purpose of
quality by design.
– Juran's process seeks to create features in
response to understanding customer needs.
• These are customer-driven features.
– The sum of all features is the new product,
service, or process
• 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
Components of QbD
• Quality target product profile (QTPP)
– Critical quality attributes (CQA)
• Material attribute and process parameter (MA & PP)
– Critical material attribute and process parameter (CMA &
CPP)
• Quality risk management (QRM)

• Design space

• Control Strategies
Components of QbD…
• Quality target product profile (QTPP)
– FDA defines QTPP as the quality attributes
related to safety and efficacy of the product.

– It may include
• route of administration, dosage form, delivery
systems, dosage strength(s), container closure
system, pharmacokinetic consideration and drug
product quality criteria (e.g., sterility, purity, stability,
and drug release).
Components of QbD…
• Critical quality attributes (CQA)
– Once QTPP has been identified, the next step is to
identify the relevant CQAs.

– A CQA is defined as
• “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”
• This indicates that CQAs are subsets of QTPP that has a
potential to be altered by the change in formulation or
process variables.
Components of QbD…
• Identification of CQA can be performed based on
– Prior knowledge and/or
• literature review, manufacturing experience, technology
transfer, stability reports, raw material testing data, adverse
event report and recalls
– Quality risk management (QRM).
• Using various tools to identify and prioritize potential CQA

CMA
QTPP
CQA
Appearance, Dissolution,
color, size, RA DT, Assay,
friability, assay, CU
dissolution,
CU, DT CPP
Components of QbD…
• Material attribute and Process Parameter
– Material Attribute (MA)
• is any physical, chemical, biological or microbiological
property of materials, such as:
– Polymer type, drug to polymer ratio, moisture level, binder
concentration

– Process Parameter (PP)

• is any input operating parameter of a process, such as:
– Mixing speed, stirring speed, temperature, time
Components of QbD…
CMAs & CPPs CMA
CPP
• When will a MA or PP become a
CMA or CPP? MA
– When they have an impact on CQAs PP

MA
• Critical Material Attributes (CMAs) PP
– are MAs that need to be controlled and
cause a significant change on the CQAs.
• Critical Process Parameters (CPPs)
– are PPs that need to be controlled and
cause a significant change on the CQAs.

MAs
CMAs
and RA-2 and
PPs DoE CPPs
Components of QbD…

Quality risk management (QRM)

• FDA defines QRM as
– a systematic process for the assessment, control,
communication and review of risks to the quality of
the drug product across the product lifecycle.

• The goal of QRM is therefore to

– identify risks within a process or event,
– analyzing the significance of these risks, and
– take appropriate measures to mitigate such risks if
deemed unacceptable
Components of QbD…
• QRM helps in identifying the extent of the
impact of
– critical material attributes (CMA) and
– critical process parameter (CPP) on CQAs,
• FDA suggest various tools that can be applied
for QRM, like
– Failure mode effects analysis (FMEA)
– Fault tree analysis (FTA)
– Hazard analysis and critical control points
(HACCP)
Components of QbD…
Design space
• A design space is a multidimensional combination of
– input variables (material attributes),
– process parameters and
– their interactions that have been demonstrated to provide
assurance of quality

• A design space may be constructed for

– a single unit operation,
– multiple unit operations, or
– for the entire process.
Components of QbD…
• In this regards, one can apply
– one-factor-at-time (OFAT) approach,
• which vary only one factor or variable at a time while
keeping others constant.

– design of experiment (DoE) approach

• that vary several input variables simultaneously are
more efficient when studying two or more factors
Control strategy
• ICH Q10 defines a control strategy as
– “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 and drug product materials and components,
– facility and equipment operating conditions,
– in process controls,
– finished product specifications and the associated methods and
frequency of monitoring and control.”

• A control strategy ensures that the process is maintained

within the boundaries described by design space.
Components of QbD…
• Tools of quality by design
– DoE
– Process Analytical Technology (PAT)
Tools of quality by design…
• Design of experiments (DOE)
– is a structured and organized method to
determine the relationship among factors that
influence outputs of a process.
Tools of quality by design
• Process Analytical Technology (PAT)
– PAT is defined as
• Tools and systems that utilize real-time measurements,
during processing, of evolving quality and performance
attributes of in-process materials to provide
information to ensure optimal processing to produce
final product that consistently conforms to established
quality and performance standards
Advantage of implementing QbD
• The ability to design products and processes and bring fewer
setbacks at critical stages such as scale-up, validation, and transfer.

• Since the operation is working in a well-defined design space, it

allows greater flexibility of adjusting variables within such space.

• Greater regulatory flexibility based on a science-based approach to

risk management.

• Ability to continue to optimize and improve the manufacturing

operation without facing additional regulatory filings or scrutiny.

• Faster time to market and reduced rework, resulting in reduced

costs and increased revenues.
 Part-II

Formulation Optimization
Objectives
• Defining optimization
• Steps to optimize a formulation
• How to use a software (Design Expert) for
optimization

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Outline
• Introduction
• Terminology
• Formulation Optimization
– Defining target product profile
– Factor studies
– Selecting an experimental design for optimization
– Formulation and evaluation
– Data analysis and Model selection
– Searching for optimization
Simultaneous optimization
– Validation/ confirmation
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Introduction
• Drug product formulation involves handling a
plethora of drugs, polymers, excipients, and
processes
– may have different combinations to give responses.
finding the combination (from all feasible ones) that gives
best response/solution

–Optimization
» Traditional

» Modern
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Introduction… Traditional approach
• The traditional approach of optimizing a formulation or
process essentially entails studying the influence of factor
variables on a response by
– Changing One Single (or Separate) variable or factor at a Time
(COST), while keeping others as constant

– It can be called also as

 OVAT (i.e., One Variable at a Time) or
 OFAT (i.e., One Factor at a Time)

• During these COST studies, the other variables will be fixed

at a favorable values, and one variable is examined until no
further improvement is attained in the response variable.
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Introduction… Traditional approach…
• This approach can some how achieve the solution
of a specific problematic property, but attainment
of the true optimum composition or process is
never guaranteed.
– It may be due to the presence of interactions—i.e., the
influence of one or more variable (s) on others.

• In addition, it has a number of drawbacks

– The most important of these are enumerated below
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 Introduction… Traditional approach…

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 Introduction… Modern approach

• Involves systematic Design of Experiments (DoE)

• It encompasses use of
– Experimental designs and
– Generation of mathematical equations and graphic
outcomes,
thus depicting a complete picture of variation of the
product/process response(s) as a function of the input
variable(s).

 Simultaneous study of the influence factors on

response

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Introduction… Modern approach …
• Employing various rational combinations of
formulation variables,
– DoE fits experimental data into statistical equations, uses
these as models to predict formulation performance, and
optimizes the critical responses.

• In direct contrast to the COST approach,

– DoE optimization
Offers an organized methodology that connects various experiments
in a rational manner,
Gives more precise information from fewer experiments
Demonstrates how the system works as a whole
It enables the experimenter to optimize all the critical responses and
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Optimization Techniques 38
 Introduction… Modern approach …

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Terminology
• Variables
– Design and development of any drug formulation or
pharmaceutical process always involves several variables

– Independent variables (factors)

Controllable (signal factors)
– Quantitative
» eg. Concentration, time, temperature
– Qualitative
» eg. Polymer type
Uncontrollable (noise factors)

– Dependent variables (responses)

The effect to evaluate
– Eg. Disintegration time, drug release
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Terminology…

Independent variables Dependent variables

(Factors) (Responses)

Compression force Hardness

Disintegrant level Dissolution

Binder level Friability

Lubricant level Weight uniformity

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Terminology…
• Levels:
– the values or designations assigned to the factor.
Eg. Low, center (medium) , high
K # of factors 3three factors
x # of levels  2two levels,i.e low and high  23
 8 runs
• Effect
– The magnitude of the change in response caused by varying
the factor levels
 Main effect
– The effect of each factor
 Interaction effect
– The effect of combination of factors

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 Terminology…
• Interaction
– Occurs when there is lack of additivity of the factor
effects
Antagonism
Synergism

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Terminology…

• Coding/normalization
– The transforming a natural variable into a non-
dimensional variable, so that the central value of the
exp’tal domain is zero
Eg. Levels of factors (low, center, & high) can be coded as -1,
0, +1, respectively
Factor Low level Medium level High level
A 20 40 60
B 3 6 9

Factor Low level Medium level High level

A -1 0 +1
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Terminology…

• Experimental Domain
– The dimensional space defined by the variables is known
as factor space
Eg. Factor A (20-60)
– The part of the factor space, investigated experimentally
for optimization, is the experimental domain (the region
of interest)
Eg. Factor A (25-55)

Factor Low level High level

A 20 60
B 3 9
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Terminology…
• Experimental design
– is the statistical strategy for organizing the experiments in such a
manner that the required information is obtained as efficiently and
precisely as possible.
 Eg. Factorial design, CCD, …

• Runs or trials
– are the experiments conducted according to the selected experimental
design
 Eg. FD (3 factors at two levels), 23 = 8 runs (experiments)

• Response surface
– Graphical depiction of the mathematical relationship between the
independent variables and dependent variables
 3D, 2D
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Terminology…
• Mathematical model
– is an algebraic expression defining the dependence of a
response variable on the independent variable(s).
Linear, 2FI, quadratic, cubic

– The symbols
» Y= response
» Xi = represent the value of the factors, and
» βo = intercept
» βi, = coefficients of first-order
» βii, = coefficients of second-order
» βij = coefficients of interaction terms
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» ε = pure errorOptimization Techniques 47
Formulation Optimization
DoE Methodology
• DoE optimization of formulation comprises several
phases/steps
– Defining target product profile
– Factor studies
– Selecting an experimental design for optimization
– Formulation and evaluation
– Data analysis and Model selection
– Searching for optimization
Simultaneous optimization
– Validation/ confirmation
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Formulation Optimization…
1. Target product profile (what type of formulation that
you are going to formulate)
DF, strength, dosage design (MR/IR), release, …
Quality attributes of the product

2. Factor studies
Material and process attributes
– Screening of significant factors using screening designs
» Critical material and process attributes

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 Formulation Optimization…
Experimental designs
• Factorial Designs
• Fractional Factorial Designs
• Plackett–Burman Designs
• Star Designs
• Central Composite Designs
• Box–Behnken Designs
• Center of Gravity Designs
• Equiradial Designs
• Mixture Designs
• Taguchi Designs
• Optimal Designs
• Rechtschaffner Designs
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Application of Important
Experimental Designs
depending upon the
nature of Factor, Models,
and Strategies

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Formulation Optimization…
• Example:
– Objective:- To screen out critical processing parameters
of high shear wet granulation process.
Factors (variables) Level of factors
-1 +1
A Binder addition time (min) 1 2
B Impeller-mixed speed (RPM) 50 100
C Chopper-granulator speed (RPM) 1000 3000
D Kneading time (min) 3 5

Reponses (effects) Goals for individual responses

R1 % Fines To achieve fines after granulation, i.e. NMT 10%
R2 % Agglomerates To achieve agglomerates after granulation, i.e. NMT 10%
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Formulation Optimization…

– Choose an experimental design for screening

Example
– 2 level fractional factorial design

– Practice on Design expert software

Look over the ANOVA

Factors (variables) Level of factors

-1 +1
B Impeller-mixed speed (RPM) 50 100
C Chopper-granulator speed (RPM) 1000 3000
D Kneading time (min) 3 5

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 Formulation Optimization…
3. Selecting an experimental design for optimization
Based on the number of factors and its suitability

Objective: - To Optimize CPPs of Tablet Compression Process

Factors (Variables) Levels of factors
-1 +1
A Compression force (kN) 2 6
B Compression speed (RPM) 10 40

• Example
– CCD (Central Composite Design) So, the # of experiments
 Studies at five levels having two factors will be
N = 2n+2n + nc
N = (2n+2n + nc) N = 22 + 2*2 + 5
– n = # of factors = 4+4+5
– nc = center points (5 for 2 factors) = 13
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Formulation Optimization…
So, at five levels, we will have the following levels for each factor
Factors (Variables) Levels of factors
- -1 0 +1 +
A Compression force (kN) 1.17 2 4 6 6.83
B Compression speed (RPM) 3.79 10 25 40 46.21

Responses (Effects) Goal for individual responses

Y1 Friability (%) To achieve tablet friability NMT 0.2 %

Y2 Dissolution Drug release should NLT 90 % in 30 minutes

Y3 Content uniformity Variation should NMT 5%

Fill it in the software

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Formulation Optimization…
4. Formulation and evaluation
The prepared formulations will be suitably evaluated for
corresponding performance parameters and response variables

5. Data analysis and Modeling selection

Transformation
Fit summary
Model selection
– Diagnosis of model (Model adequacy checking)
» ANOVA
» Different plots
» Comparison of adjusted R2 and predicted R2
• Their difference should not be > 0.2
» Value of adequate precision (signal/noise ratio)
• It should be > 4
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Formulation Optimization…
Mathematical regression models in terms of coded factors

Friability = 0.17 - 0.06A + 0.02B

Drug dissolved in 30 min = 97.20 - 8.37A + 0.16B - 1.75AB - 5.73A2 - 1.48B2

Content uniformity = 4.15 - 0.090A + 1.45B - 0.075AB + 0.13A2 + 0.73B2

Model graphs
– 2D and 3D
– See the software

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Formulation Optimization…
6. Searching for optimization

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Formulation Optimization…

• Numerical
– Desirability function
– ..
• Graphical
– Overlay plot
– ….

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Formulation Optimization…

Numerical
– Desirability function (0 to 1)
» 0.956

Factors (Variables) Optimized values

A Compression force (kN) 3
B Compression speed (RPM) 18.96

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Formulation Optimization…
Graphical
–Overlay plot

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 Formulation Optimization…
7. Validation/Confirmation test
– Predicted value Vs Actual value
– To experimentally confirm the validity of obtained optimal
points, confirmation experiments will be carried out in
triplicate at the optimal combinations of the factors
(CF = 3kN, CS = 18.96)
To say, the optimized formulations are agreed with the predicted
values
– The percentage error should fall within 5%

Response Predicted Experimental % Error

value value
Friability (%) 0.19
Drug release in 30 min (%) 99.30
Content uniformity (%) 3.75
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