This document discusses Quality by Design (QbD), a systematic approach to pharmaceutical development that emphasizes product and process understanding based on sound science and quality risk management. It outlines the key elements of QbD including quality target product profiles, critical quality attributes, critical material attributes, critical process parameters, design space, control strategy, and product lifecycle management. Risk assessment tools and process analytical technology are also described as important tools that can be utilized in a QbD approach.

1. Quality by Design
CONTENTS:
 Introduction
 Aim
 Benefits
 Drawbacks
 Steps to implement QbD
 Elements of QbD
 Tools of QbD
 Applications of QbD

2. INTRODUCTION:
Defined as a systematic approach to development that begins with predefined objectives emphasizes
product and process understanding and process control, based on sound science and quality risk
management.
The concept of Quality by Design (QbD) was first mentioned by J.M. Juran, an American Engineer in
his book on "Juran on Quality by Design.“
Januvia ~ 1st drug to be developed based on QbD by Merck and company
The concept was first adopted to automobiles, telecommunication, aviation industries, by 1990s adapted
to medical device manufacturers and by 20004 the concept entered pharmaceutical industry

3. AIMS OF QbD:
To acheive predetermined or targeted product quality specifications.
To reduce the defects and failure of the end product by understanding product design and controls.
To Enhance process and product development efficiencies.
To Manage the root cause analysis and post-approval management

4. BENEFITS OF QbD:
Better process understanding.
Eliminate the batch failure.
Ensure better design.
Empowerment of technical staff.
Continuous improvement.
Organizational learning.
Avoid regulatory problems.
Increases the manufacturing efficiency.

5. STEPS INVOLVED IN IMPLEMENTING QbD

6. ELEMENTS
QUALITY TARGET
PRODUCT PROFILE
CRITICAL QUALITY
ATTRIBUTES
QUALITY
RISK
MANAGEMEnT
DESIGN SPACE
CONTROL
STRATEGY
LIFECYCLE
MANAGEMENT AND
CONTINUAL
IMPROVEMENT

7. 1) QUALITY TARGET PRODUCT PROFILE {QTPP}:
The QTPP is an essential component of a QbD strategy, which forms the basis for product design.
QTPP is a prospective review of drug product quality, which is to be achieved, taking into account drug product
safety and efficacy.
The QTPP discusses how the quality, safety, and efficiency of a given drug product for the patient can be
ensured.
For Abbreviated New Drug Applications (ANDAs), a target should be defined at an early stage in development
based on the
Drug substance's properties,
Reference Listed Drug (RLD) product characterization,
RLD label consideration
Target patient profile

8. QTPP may include the following
Intended use in a clinical setting.
Route of administration.
Dosage form.
Dosage strength(s)
Container closure system.
Therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics (eg .
dissolution, aerodynamic performance);
Drug product quality criteria (eg. sterility, purity, stability, and drug release)
When new information is collected during the development process, the QTPP can either modified or
changed at different stages of its growth.

9. 2) CRITICAL QUALITY ATTRIBUTES {CQA} ~ CMA & CPP
After the identification of QTPP, the next step is to identify the relevant CQAs.
 CQAs including physical, chemical, biological, or microbiological properties or characteristics of an output
material (finished drug products) which should be in prescribed limits for the quality performance of the product.
CQA includes
Impact of attribute is based on the degree of harm to patient if pdt. limit exceeds the limit
Identity Microbial limits
Test Color
Content uniformity Odor
Product degradability Shape
Residual solvents Morphology
Drug release Friability
Moisture content Score

10. a) CRITICAL MATERIAL ATTRIBUTES {CMA}:
For developing a robust drug product with intended CQAs, consideration of the physical chemical, and biological
CMAs of the drug substance and inactive ingredients is crucial.
CMA includes
PHYSICAL PROPERTIES particle size, shape, surface area, volume, density, solid-state,
polymorphic form, melting point, hygroscopicity,
intrinsic/aqueous solubility, and stability
CHEMICAL PROPERTIES pKa, reactivity, hydrolytic, oxidative and photolytic stability.
BIOLOGICAL PROPERTIES partition coefficient, permeability, bioavailability, and toxicity

11. EXAMPLE 0F CMA
If the product is an immediate-release formulation, one must have to concentrate on the drug substance material
attribute such as size, shape, and polymorphic forms.
These attributes have a significant impact on the quality attribute 'dissolution' as less particle size has more
dissolution and vice versa.
 In solids forms, the amorphous form has more solubility and less melting point than that of crystalline
structure. However, crystalline solids are more preferred due to their stability.
ICH Q8 recommends drug-excipient compatibility during the early phases of drug development for improved
stability. and hence shelf-life of the product.

12. b)CRITICAL PROCESS PARAMETERS:
Critical process parameters (CPP) are defined as "parameters whose variability have an impact on a CQA and
therefore should be monitered / collected to ensure the process and to produce the desired quality.
Process robustness is defined as the ability of a process to demonstrate acceptable quality and performance and
tolerate variability in its of the same time.
To demonstrate the reproducibility and consistency of a process, process capability should be studied.
Process capability is a statistical measure of the inherent process variability for a given characteristics.
Process capability index (CpK) = Upper Limit - Lower Limit
6 σ standard Deviation

13. A pharmaceutical production process usually involves several unit operations to produce the necessary products
with quality.
Operations in batch mode or a continuous production process may be performed.
The process involves physical or chemical changes such as milling, mixing, granulation, drying, compression,
and coating.
The manufacturing process improvement plan should define any critical process parameters which need to be
checked or managed to ensure the output is of the required qualities.
A process is generally considered well-understood when the critical sources of variability are identified,
managed, and controlled.
The input operational parameters (eg. speed and flow rate) or the process state variables (eg, temperature and
pressure) of a unit operation are referred to as process parameters.

14. Steps to establish CPP and CMA
Identify all possible known material attributes and process parameters that could impact the performance of
the product and process.
Use risk assessment and scientific knowledge to identify potentially high-risk material attributes and process
parameters.
Establish levels or ranges of these potentially high-risk material attributes and process parameters.
Using DoE, Design and conduct experiments.
Analyze the experimental data. Link CMAS and CPP to CQAs when possible.
Develop a control strategy.

15. 3)QUALITY RISK MANAGEMENT {QRM}:
As there are many CMAs and CPPs that may impact the CQAs of the intermediate and finished drug material
Formulation scientist can't examine all the content characteristics described in the formulation optimization studies.
QRM help identify the significant attributes and parameters to study further.
 The exam will depend on existing scientific expertise and the abilities of the formulator

16. QRM is defined as the systematic process for the assessment, control, communication, and review of risks to
the quality of the drug product across the product lifecycle.
-ICH guidelines Q8
QRM helps in identifying the extent of the impact of CMAS and CPPs on CQAs; therefore, it is an integral
part of QbD.
The initial list of potential parameters which can affect CQAs can be quite extensive but can be reduced and
prioritized by quality risk management(QRM).

17. 4) DESIGN SPACE :
After screening and justifying different quality attributes using QRM, the evaluation of boundaries in newly
designed and operational space
should be specified
to predict the probability of failure of any factor concerning quality objectives for the final products.
When such analyzes take place in carefully planned experimental studies, an integrated connection between the
material attributes CMA, process parameters CPP, and product attributes can be more readily established.
Design space is defined as the multidimensional combination and interaction of input variables (eg. material
attributes) and process parameters that have been demonstrated to assure quality.
-ICH guideline Q8

18. EXAMPLE 0F DESIGN SPACE:
A tablet preparation consists of the unit operations of milling, mixing, granulation, drying, and compression.
In this instance, the scientists have the choice of creating separate design spaces for one or more operations or a
single, multi-operative design.
Although a different design space is often more comfortable to develop for each unit operation individually, a
design space that spans the entire product life cycle may offer greater operational versatility.
Design space is proposed by the applicant and is subject to regulatory assessment and approval.
The movement out of the design space is considered to be a change and that would normally initiate the
regulatory post approval change process.
METHODS TO PRESENT: Graphs , Linear combination of parameters, equations, parameters

19. 5)CONTROL STRATEGY:
Controlled strategy is defined as the planned set of controls derived from the current product and process
understanding that assures process performance and product quality.
- ICH guidelines Q10
To keep producing the product of the required quality consistently, a control strategy is designed.
It is necessary to describe and clarify how
raw materials (APIs and excipients) relate to the final product quality and
intermediates (in-process materials) controls
package closure processes
drug components

20. Control strategy includes,
Control of input material attributes (eg. drug substance, excipients, primary packaging materials
 Product specification
 Controls for unit operations that have an impact on product quality (eg. the impact of drying on
degradation, the particle size distribution of the granulate on dissolution0
In-process or real-time release testing instead of end-product testing (eg. measurement and control of
CQAs during processing)
A monitoring program

21. 6) PRODUCT LIFECYCLE MANAGEMENT
Using the product lifecycle, manufacturers may analyze novel strategies to maximize product quality
The product performance can be tracked and ensured its working according to the design space to generate
characteristics of product quality
This tracking could include trend analysis of the production process
A set of tasks performed by the applicant to enhance production capacity to meet criteria is continuous
improvement which may include
defining the problem & project goals,
measuring the critical aspects of the process,
analyze the data to establish the cause & relationship
further improvement/ optimization of the current process
control over the deviation from the target

22. TOOLS OF QUALITY by DESIGN:
1. Risk management methodology
Steps:
i. Risk assessment
ii. Risk control
iii. Risk review
2. Process analytical technology

23. 1.QUALITY MANAGEMENT METHODOLOGY:
QRM definition as per ICH Q8.
Risk assessment tools can be used to identify and level parameters (eg. process, equipment, input material) with
potential to have an impact on product quality based on prior knowledge and primary experimental data.
Steps of Risk Management:
a) Risk assessment
b) Risk control
c) Risk Review

24. a) Risk assessment:
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.
 It is the first step of quality risk management process
COMPONENTS:
Risk identification
Risk analysis
Risk evaluation

25. 1.RISK IDENTIFICATION:
The systematic use of information to identify potential sources hazards that are referring to the risk question or
problem description, which can includes of historical data, theoretical analysis, informed opinions, and the
concerns of stakeholders.
2. RISK ANALYSIS:
The estimation of the risk associated with the identified hazards.
3 RISK EVALUATION:
The comparison of the estimated ride to given risk criteria using quantitative or qualitative scale to determine the
significance of the risk.

26. RISK ASSESSMENT TOOLS:
The pharmaceutical industry and regulators can evaluate and manage risks by using well-known risk management
tools viz,
a. Basic risk management facilitation methods
b. Failure mode effects analysis
c. Failure mode, effects and criticality analysis
d. Fault tree analysis
e. Hazard analysis and critical control points
f. Preliminary hazard analysis
g. Risk ranking and filtering
h. Supporting statistical tools

27. a) Basic risk management facilitation method
Flow charts, check sheets, process mapping, case and effect diagrams, etc., are the most commonly used
and simple method for RA and management.
 Process mapping is a technique which relates critical process parameters and/or critical material
attributes and critical product quality to a response surface derived from an experimental data.
Cause effect diagram or also called Ishikawa diagram or Fishbone diagram.
The diagram will be having
horizontal line, the end - product quality.
diagonal lines-Major influencing factors
sub lines for the diagonal lines – Influence of critical process parameters & critical
material attributes
Examples of basic fish bone diagram.

29. b) Failure mode effects analysis
This tool can be used to identify any inadequacies in the development of the product.
The method systematically identifies, prioritizes, and estimates the risk and prevents failure.
The risk involved in changing a process can also be limited using failure mode effects analysis (FMEA)
c)Failure mode, Effects and Criticality analysis
Failure mode, effects, and criticality analysis mode and associated with manufacturing processes. This
criticality analysis probability of failure modes
This, criticality analysis is used to chart the probability of failure modes against the severity of their
consequences

30. d)Fault tree analysis
Fault tree analysis (FTA) is a structured, graphical, quantitative assessment tool which makes modeling of
complex system easy.
It is an excellent tool for evaluating multiple factors affecting product quality.
 It is used for both RA and monitoring
Software can be used to calculate failure probabilities from fault trees.
e)Hazard analysis and critical control points
Hazard analysis and critical control points (ACCI) was approach for assuring product quality, reliability, and
safety as means of prevention rather than finished product inspection
 HACCP can be used to identify and manage risk associated with physical, chemical, and biological hazards.
HACCP is best utilized when product and process understanding is sufficiently comprehensive.

31. f) preliminary hazard analysis
This can be used in the early stages of product development when there is little information on design details
or operating procedures.
Hazards identified in the preliminary hazard analysis (PHA) are usually further assessed with some other RA
tools.
g)Risk Ranking and Filtering :
It is used for comparing and ranking risks. For each risk, multiple diverse quantitative and qualitative factors
are evaluated.
 This is useful to prioritize manufacturing sites for inspection/audit by regulators or industry
h)Supporting Statistical Tools:
These are used for effective data assessment, determining the significance of the data, and decision making.
It includes control charts (acceptance control charts, control charts with arithmetic average and warning
limits, cumulative sum charts, Shewhart control charts, weighted moving average, etc.), design of
experiments, histograms, Pareto charts etc.

32. b)RISK CONTROL
Control includes decision making to reduce and / or accept risks.
The purpose of the risk control is to reduce the risk to an acceptable limit
C) RISK REVIEW
At the final stage , the output / results of the risk management process should be reviewed to take into account
new Knowledge and experience

34. 2) PROCESS ANALYTICAL TECHNOLOGY (PAT):
PAT is defined as the system for designing, analyzing, and controlling manufacturing process through
timely measurements of critical quality and performance attributes of raw and in-process materials and
processes with the goal of ensuring final product quality.
~ FDA
The process involves the identification of scientific and engineering principles and variables that affect
product quality.
PAT is useful in the reduction of cycle times, prevention of reject product and waste, real-time product
release, greater use of automation and facilitation of continuous processing.

35. TOOLS FOR PROCESS ANALYRICAL TECHNOLOGY:
# Multi variate tools for design, data acquisition, analysis
# Process analyzers
# Process control tools
MULTI VARIATE TOOLS FOR DESIGN , DATAACQUISITION,ANALYSIS:
Management systems results in scientific understanding of the relevant multifactorial relationships. Design of
experiments, response surface methodologies, process simulation; and pattern, recognition tools can be used a
multivariate mathematical approaches
PROCESS ANALYSERS:
Process analyzers are able to provide much data. Real-time control and quality assurance during
manufacturing are possible with modern process analyzers. It involves at-line, on-line, or un-line
measurements
PROCESS CONTROL TOOLS:
According to PAT. a process end point is the achievement of desired material attribute rather than a
time-defined and point. Process control tools ant used to ensure effective control of all products CQA.
It also measures the ability and liability of process analyzers to measure critical attributes

36. Design of Experiments (DoE)
Design of experiments (DoE) is a structured and organized method to determine the relationship among
factors that influence outputs of a process.
With the help of DoE maximum information can be obtained from a minimum number of experiments
in a fraction of the time.
It is a valuable tool for choosing experiments efficiently and systematically to give reliable and coherent
information.
Moreover DoE can be used for comparative experiments, screening experiments, response surface
modeling, and regression modeling