The document provides an overview of Quality by Design (QbD) in the pharmaceutical industry. It discusses key concepts like defining objectives, determining critical quality attributes, risk assessment, experimental design, control strategies, and continuous improvement. A case study is presented on developing naproxen enteric-coated pellets using a QbD approach including failure mode and effects analysis, Plackett-Burman design, and Box-Behnken design to establish a design space meeting quality criteria. The document serves to introduce QbD principles and how they were applied in a specific drug development example.

1. M. Pharm Sem-I Presentations
QUALITY BY DESIGN
IN THE SUBJECT
Pharmaceutical Quality Management System
IN THE FACULTY OF SCIENCE AND TECHNOLOGY
Bhujbal Knowledge City,
MET’s Institute of Pharmacy,
Adgaon, Nashik, 422003.
Maharashtra, India
1
Presented By
Shweta Sonawane (14)
Krishna khamkar (8)
Guided By
Dr. Sapna Ahirrao

2. INDEX
2
Sr.
No.
CONTENT Page No.
1 Introduction 2-3
2 Concept and Background of QbD 4
3 Objectives of QbD 5
4 Advantages of QbD 6
5 Regulatory aspects to QbD 7-10
6 Elements of Qbd 10-20
7 Reference 21

3. What is Quality by Design (QbD)?
Quality :
It is defined as totality of characteristics of an entity that bears on its ability to
satisfy stated and implied needs.
Quality By Design :
It is defined as 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
3

4. Concept and Background of QbD
4
 Quality by design is a concept first outlined by Joseph M. Juran in various
publications.
 He supposed that quality could be planned.
The concept of QBD was mention in ICH Q8 guidelines, which states that, ‘To identify
quality can not be tested i products, i.e. Quality should be build in to product by
design.’

5. Objectives of QbD
5
1. To encourage pharmaceutical companies to develope sufficient understanding of
their product and manufacturing processes.
2. To ensure that their processes are robust.
3. To demonstrate this enhanced understanding to the pharmaceutical regulatory
agencies.

6. Advantages of QbD
6
• Patient safety and product efficacy are focused.
• Scientific understanding of pharmaceutical process and methods is done.
• It involves product design and process development.
• Science based risk assessment is carried.
• Critical quality attributes are identified and their effect on final quality of product
is analysed.
• It offers robust method or process.
• Business benefits are also driving force to adopt QbD.

7. Regulatory aspects to QbD
7
1. FDA perspective
• FDA’s view of QbD is ‘‘QbD is a systematic approach to product and process
design and development’’.
• This concept was accepted by FDA in 2004 and detailed description was given in
‘pharmaceutical cGMPs for 21st century – a risk based approach’.

8. 8
1. Product quality and performance can be assured by designing efficient
manufacturing processes.
2. Product and process specifications are based on a scientific understanding of how
process factors affect product performance.
3. Risk-based regulatory approaches are for scientific understanding and control
related process for product quality and performance

9. 2. ICH Guidelines and QbD
9
• Q8- Pharmaceutical Development
• Q9- Quality Risk Management
• Q10- Pharmaceutical Quality System
• Q11- Development and Manufacture of Drug Substances

10. 3. Regulatory challenges and inspection
10
• Traditionally, inspections have been conducted using the FDA system-based
approach and in accordance with CDER’s Compliance Program ‘‘Inspection of
Licensed Bio-logical Therapeutic Drug Products’’.
• The inspection will evaluate the quality system and its effectiveness regarding
consistent product quality, change in control procedures, process improvements,
deviation management, and knowledge and risk management during the product
lifecycle.
• Inspection of facility and equipment qualification and maintenance as well as raw
material screening and supplier management will be same as it was performed
previously.

11. Elements of pharmaceutical
development
11
Different elements of pharmaceutical development include,
• Defining an objective
• Determination of critical quality attributes (CQA)
• Risk assessment
• Development of experimental design
• Designing and implementing control strategy
• Continuous improvement

12. 1. Define an objective
12
Quality target profile (QTP) forms the basis of QbD
As per ICH guideline Q8 R2 the Quality Target Product Profile forms the basis for
design and the development of the product. Considerations for the Quality Target
Product Profile could include:
• Intended use in clinical setting, route of administration, dosage form, delivery Systems.
• Dosage strength(s), Container closure system.
• Therapeutic moiety release or delivery and attributes affecting, Pharmacokinetic
characteristics (e.g., dissolution, aerodynamic performance).
• Drug product quality criteria like sterility, purity, stability and drug release as
appropriate for dosage form the intended for marketing.

13. 13
• QbD requires a Target Product Profile; it may be called as Quality Target Product
Profile (QTPP) which defines the expectations in final product. In case of analytical
method development it is called as analytical target profile (ATP), it is also called as
Target Product Profile (TPP).
• The TPP will help to identify critical quality attributes such as potency, purity,
bioavailability or Pharmacokinetic profile, shelf-life, and sensory properties

14. 2. Determination of critical quality attributes.(CQA)
14
• According to ICH Q8 R2 ‘‘A CQA is 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’’.
• CQAs are generally linked with the drug substance, excipients, intermediates
(inprocess materials) and drug product.
• It is stated in ICH Q9 that in case of Potential drug substance CQAs are used to
guide process development.
• Inclusion and exclusion in list of potential CQAs can be done as knowledge drug
substance and process understanding increases.
• A quality attribute that must be controlled within predefined limits to ensure that
the product meets its intended safety, efficacy, stability and performance. It means
all the factors which affect final quality and safety should be controlled.

15. 3. Risk assessment
15
• It is commonly understood that risk is defined as the combination of the probability
of occurrence of harm and the severity of that harm.
• Risk assessment helps to increase quality of method or process. Also it is
determinant for effect of input variable on method or processes.
• From risk assessment one can recognize critical attributes that are going to affect
final quality of product.
• Principles of quality risk management are:
1. Scientific knowledge based evaluation of the risk to quality which eventually links
to the protection of the patient.
2. Adequate effort should be taken; formality and documentation of the quality risk
management process should be done with the level of risk involved.

16. Methods of risk assessment:
16
Some methods of risk assessment are mentioned in ICH guideline Q9 as follows:
• Failure Mode Effets Analysis (FMEA);
• Failure Mode, Effects and Criticality Analysis (FMECA);
• Fault Tree Analysis (FTA);
• Hazard Analysis and Critical Control Points (HACCP);
• Hazard Operability Analysis (HAZOP);
• Preliminary Hazard Analysis (PHA);
• Risk ranking and filtering;
• Supporting statistical tools.

17. 4. Development of experimental design
17
• Experimental design is the multidimensional combination and interaction of input
variables (e.g., material attributes) and process parameters that have been
demonstrated to provide assurance of quality.
• Pharmaceutical development scientists have began making use of computer-aided
process design (CAPD) and process simulation to support process development and
optimization of manufacturing.
• Design space is proposed by the applicant and is subject to regulatory assessment
and approval of ICH Q8 (R2).
• Different mathematical models are available for design of experiment like Placket–
Burman, Box Behnken, Taguchi, Surface Design, Full and fractional factorial
designs.

18. 5. Designing and implementing control strategy
18
• Control strategy is required to ensure that material and process are within the
expected lower and upper limits.
• Parameter and material are routinely controlled during production in order to assure
reproducibility.
• During scale up processes parameters may differ but attributes which affect quality
remain the same hence control strategy is required.
• QbD gives trace on reproducibility and robustness. Process capability index
expresses reproducibility of process.
• Process capability index (CpK) =
upper limit of specification - lower limit of specification
standard deviation

19. Design Space
19
• Control space should be within the design space, it is an upper and lower limit for
raw material or a process within which parameter and material are regularly
controlled which assures quality of product.
• Design space cover control space, If control space is smaller than design space it is
considered as robust.
Control
Space
Figure 1 Control space within the design space.

20. 6. Continuous improvement throughout product life
cycle
20
• Product quality can be improved throughout the product lifecycle; companies have
opportunities to opt inventive approaches to improve quality.
• The QbD approach avails the continuous improvement throughout products’ life
cycle this is distinguishing point from the conventional method which is much
frozen process.

21. Case study
• The study aims to prepare naproxen enteric-coated pellets (NAP-ECPs) by fluid-bed coating
using QbD principle. Risk assessment was firstly performed by using failure mode and effect
analysis (FMEA) methodology.
• A Plackett–Burman design was then used for assessment of the most important variables
affecting enteric-coated pellets characteristics.
• A Box-Behnken design was subsequently used for investigating the main, interactive, and
quadratic effects of these variables on the response. By FMEA we discovered that eight
factors should be considered to be high/important risk variables as compared with others.
• The responses of acid resistance and cumulative drug release were taken as critical quality
attributes (CQAs). Pareto ranking analyses indicated that the coating weight gain (X7),
triethyl citrate percentage (X1) and glycerol monostearate percentage (X2) were the most
significant factors affecting the selected responses out of the eight high-risk variables.
• Optimization with response surface method (RSM) further fully clarified the relationship
between X7, X1, X2 and CQAs, and design space was established based on the constraints set
on the responses.
• Due to the extreme coincidence of the predicted value generated by model with the observed
value, the accuracy and robustness of the model were confirmed.
• It could be concluded that a promising NAP-ECPs was successfully designed using QbD
approach in a laboratory scale.

22. Reference
1. Jaiprakash N. Sangshetti, Zahir zapper, ‘Quality by Design in Pharmaceutical’s’,
unique publication, 1st edition, page no.
2. Om M. Bagade, QA (for sppu), Career Publication 1st edition, page.no.
3. “A Quality by Design (QbD) case study on enteric-coated pellets: Screening of
critical variables and establishment of design space at laboratory scale”,
August 2014, Asian Journal of Pharmaceutical Science.
4. Japrakash N.sangshetty, Mrinmayee Deshpande. “Quality by Design
approach:regulatory need” Arabian journal of chemistry,2014