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Quality by Design and Optimization
Quality by Design and Optimization
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 .
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
• 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
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…
Formulation Optimization
Objectives
• Defining optimization
• Steps to optimize a formulation
• How to use a software (Design Expert) for
optimization
–Optimization
» Traditional
» Modern
11/20/2018 Optimization Techniques 33
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
• 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
• 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)
• 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
11/20/2018 Optimization Techniques 46
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
11/20/2018
» 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
11/20/2018 Optimization Techniques 48
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
11/20/2018 51
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
• 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
54
11/20/2018
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
Model graphs
– 2D and 3D
– See the software
• Numerical
– Desirability function
– ..
• Graphical
– Overlay plot
– ….
Numerical
– Desirability function (0 to 1)
» 0.956