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1. QUALITY- BY-DESIGN IN
PHARMACEUTICAL DEVELOPMENT
Presented by,
Pratiksha C
Chandragirivar
M pharma 2nd sem
Dept. of pharmaceutics
HSK COP Bagalkot
Facilitated to,
Dr. Laxman Vijapur
Assistant professor
Dept. of
pharmaceutics
HSK COP Bagalkot
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2. Contents:
1.Introduction
2.ICH Q8 guidelines
3.Applications
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3. INTRODUCTION:
ØThe pharmaceutical market has been considered as one of the
highly regulated sectors, which has been continuously providing
quality drug products for human use to provide desired
pharmacotherapeutic effects for the treatment of diverse
ailments.
ØFrom the past few decades, however, the pharmaceutical
industry has been continuously facing challenges in delivering
quality drug products.
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4. ØAs per the news article published in The Wall Street Journal on
September 2002, it was reported that “although pharmaceutical
industry has a little secret as it invents futuristic new drugs, yet its
manufacturing standards are lag far behind the potato chips and
laundry soap makers.”
ØThe major issues pertaining to the poor quality of drug products
could be attributed to more than one reasons such as variable
starting materials, lack of manufacturing process automation and
control, and improper understanding on the product and process
parameters.
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5. This figure shows the key sources of variability associated with the
development of pharmaceutical products, which are responsible for
product recall in a major manner.
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6. ØDue to the poor pharmaceutical product quality, the first initiative was
a step forward by the United States Food and Drug Administration
(USFDA)for inculcation of quality paradigms into pharmaceutical
development and regulatory practice.
ØIn this regard, a concept paper was published in 2004, which
highlighted the vision of agency for revolutionizing the quality
paradigm in the form of “Pharmaceutical cGMP for 21stCentury”.
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7. ØAfter this initiative, the International Conference on Harmonization
(ICH) instituted various regulatory guidances (Q8, Q9, and Q10) and
set forth the concept of quality by design (QbD) as a holistic
approach, which delivers high-quality robust drug products.
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8. EVOLUTION OF QbD:
ØQbD is not a new concept for the world.
ØThe concept was formulated by J.M. Juran, an American
Engineer, in the early 1970s through his famous book “Juran on
Quality by Design”, which was later adopted by several
technology-driven areas like, telecommunication, automobile,
and aviation industries engaged in the development of high-
quality products and services.
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9. The concept was later adopted by health-care industries, and
especially utilized by medical device manufacturers in the 1990s.
QbD into the pharmaceutical industry entered quite late in 2004,
when USFDA took initiative for improving the standards of
pharmaceutical manufacturing.
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10. DEFINITION, CONCEPT AND PRINCIPLE:
Definition:
The pharmaceutical Quality by Design ( QbD ) is 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.
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11. ØThe fundamental premise behind QbD is that quality can be
designed in processes through systematic implementation of an
optimization strategy to establish through understanding of the
response of the system quality to given variables , and the use of
control strategies to continuously ensure quality.
ØIn order to describe Quality by Design, We must know what is mean
by quality .
ØQuality in manufacturing is a measure of excellence or a state of
being free from defects, deficiencies, and significant variation .
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12. Principle:
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14. ICH Q8 GUIDELINES:
Q1A - Q1F Stability
Q2 Analytical Validation
Q3A - Q3D Impurities
Q4 - Q4B Pharmacopoeias
Q5A - Q5E Quality of Biotechnological Products
Q6A- Q6B Specifications
Q7 Good Manufacturing Practice
Q8 (R2) Pharmaceutical Development
Q9 Quality Risk Management
Q10 Pharmaceutical Quality System
Q11 Development and Manufacture of Drug Substances
Q12 Lifecycle Management
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15. ICH – Q8
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16. Part 1: Pharmaceutical development:
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17. Aim:
The aim of pharmaceutical development is to design a quality product
and its manufacturing process to consistently deliver the intended
performance of the product.
1.Components of the product that considered for quality check :
a. Drug substances
b. Excipients
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18. Drug substances:
ØThe physicochemical and biological properties of the drug substance
that can influence the performance of the drug product and its
manufacturability, or were specifically designed into the drug
substance (e.g., solid state properties), should be identified and
discussed.
ØTo evaluate the potential effect of drug substance physicochemical
properties on the performance of the drug product, studies on drug
product might be warranted.
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19. Excipients:
ØThe excipients chosen, their concentration, and the
characteristics that can influence the drug product performance
(e.g., stability, bioavailability) or manufacturability should be
discussed relative to the respective function of each excipient.
ØCompatibility of excipients with other excipients, where relevant
(for example, combination of preservatives in a dual preservative
system), should be established.
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20. ØThe ability of excipients (e.g., antioxidants, penetration enhancers,
disintegrants, release controlling agents) to provide their intended
functionality, and to perform throughout the intended drug product
shelf life, should also be demonstrated.
ØThe information on excipient performance can be used, as
appropriate, to justify the choice and quality attributes of the
excipient, and to support the justification of the drug product
specification.
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21. 2. Drug product:
a. Formulation Development
 A summary should be provided describing the
development of the formulation, including identification
of those attributes that are critical to the quality of the
drug product, taking into consideration intended usage
and route of administration.
 Information from formal experimental designs can be
useful in identifying critical or interacting variables that
might be important to ensure the quality of the drug
product.
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22. ØThe summary should highlight the evolution of the formulation design
from initial concept up to the final design.
ØThis summary should also take into consideration the choice of drug
product components (e.g., the properties of the drug substance,
excipients, container closure system, any relevant dosing device),
the manufacturing process, and, if appropriate, knowledge gained
from the development of similar drug product(s).
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23. b. overages:
In general, use of an overage of a drug substance to compensate for
degradation during manufacture or a product’s shelf life, or to extend
shelf life, is discouraged.
Any overages in the manufacture of the drug product, whether they
appear in the final formulated product or not, should be justified
considering the safety and efficacy of the product.
Information should be provided on the 1) amount of overage, 2) reason
for the overage (e.g., to compensate for expected and documented
manufacturing losses), and 3) justification for the amount of overage.
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24. c. Physicochemical and biological properties
ØThe physicochemical and biological properties relevant to the
safety, performance or manufacturability of the drug product
should be identified and discussed.
ØThis includes the physiological implications of drug substance
and formulation attributes.
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25. 3. Manufacturing process development
ØThe selection, the control, and any improvement of the
manufacturing process described in (i.e., intended for
commercial production batches) should be explained.
ØIt is important to consider the critical formulation attributes,
together with the available manufacturing process options, in
order to address the selection of the manufacturing process and
confirm the appropriateness of the components.
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26. ØAppropriateness of the equipment used for the intended products
should be discussed.
Ø Process development studies should provide the basis for process
improvement, process validation, continuous process verification*
(where applicable), and any process control requirements.
ØWhere appropriate, such studies should address microbiological as
well as physical and chemical attributes.
ØThe knowledge gained from process development studies can be
used, as appropriate, to justify the drug product specification.
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27. 4.Container closure system
The choice and rationale for selection of the container
closure system for the commercial product should be
discussed.
Consideration should be given to the intended use of the
drug product and the suitability of the container closure
system for storage and transportation (shipping), including
the storage and shipping container for bulk drug product,
where appropriate.
5. Microbiological attributes
For sterile product microbiological attributes are
considered and studied.
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28. Part 2. Annex to the pharmaceutical development
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29. ELEMENTS OF PHARMACEUTICAL
DEVELOPMENT
QUALITY TARGET PRODUCT PROFILE(QTTP):
The quality target product profile forms the basis of design for 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;
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30. Therapeutic moiety release or delivery and attributes affecting
pharmacokinetic characteristics (e.g., dissolution, aerodynamic
performance) appropriate to the drug product dosage form being
developed;
• Drug product quality criteria (e.g., sterility, purity, stability and drug
release) appropriate for the intended marketed product.
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31. Critical Quality Attributes
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.
ØCQAs are generally associated with the drug substance, excipients,
intermediates (in-process materials) and drug product.
ØCQAs of solid oral dosage forms are typically those aspects affecting
product purity, strength, drug release and stability.
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32. ØCQAs for other delivery systems can additionally include more
product specific aspects, such as aerodynamic properties for inhaled
products, sterility for parenterals, and adhesion properties for
transdermal patches.
ØFor drug substances, raw materials and intermediates, the CQAs
can additionally include those properties (e.g., particle size
distribution, bulk density) that affect drug product CQAs.
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33. Risk Assessment:
ØRisk assessment is typically performed early in the pharmaceutical
development process and is repeated as more information becomes
available and greater knowledge is obtained.
ØRisk assessment tools can be used to identify and rank parameters
(e.g., process, equipment, input materials) with potential to have an
impact on product quality, based on prior knowledge and initial
experimental data.
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34. Design Space:
The relationship between the process inputs (material attributes and
process parameters) and the critical quality attributes can be described
in the design space
I.Selection of Variables
II.Describing a Design Space in a Submission
III.Unit Operation Design Space(s)
IV.Relationship of Design Space to Scale and Equipment
V.Design Space Versus Proven Acceptable Ranges
VI.Design Space and Edge of Failure
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35. Control Strategy
A control strategy is designed to ensure that a product of required quality
will be produced consistently.
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36. Product Lifecycle Management and Continual
Improvement
ØThroughout the product life cycle, companies have opportunities to
evaluate innovative approaches to improve product quality (see ICH
Q10).
ØProcess performance can be monitored to ensure that it is working
as anticipated to deliver product quality attributes as predicted by the
design space.
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37. Scientifically based QbD - applications
Case study 1:
Application of Pharmaceutical Qbd for Enhancement
of the Solubility and Dissolution of Class II BCS Drug
Using Polymeric Surfactants and Crystallization
Inhibitors:
Development of Controlled - Release Tablets:
The aim of this research was to develop a Felodipine
Solid Mixture [FSM] containing hydrophilic carriers and/or
polymeric surfactants. Felodipine was chosen as the BCS
Class-II drug.
The material attributes of excipients used for preparation
of FSMs were identified.
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38. §For these effect of different hydrophilic carriers and polymeric
surfactants on solution of felodipine was studied. The screening of
the inhibitory effects of different hydrophilic carriers and polymeric
surfactants on crystallization of Felodipine from supersaturated
solution was done.
§The FSMs were prepared using Box-Behnken Design which helped
in obtaining results in fewer runs than Central Composite Design.
§The FSMs prepared were than evaluated. It was observed that there
was no proposed design space if pluronic content was below 45.1
mg. On the other hand, mixture of pluronic and HPMC showed dual
action which helped in development of design space.
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39. Experimental Design used was Box Behnken Experimental Design.
The software used was Design Expert Software.
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40. Case study 2:
A QbD Approach on Starch-Based Nanocapsules: A Promising
Platform for Topical Drug Delivery:
The aim of research was to develop novel Starch based
Nanoparticulate Carrier System [StNC] for topical delivery of lipophilic
bioactive molecules.
The method used was emulsification-solvent evaporation method.
Capric/ Caprylic triglycerides were dissolved in cationic surfactant
ethanol solution.
It was added to aqueous phase containing Tween 80 and hydrated
polymer.
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41. Constant magnetic stirring was done.
Coumarin-6 was incorporated [for the purpose of identification and
localization of drug in compound] and the probe was added
simultaneously to the lipid component.
Particle size analysis and zeta potential measurements were done.
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42. The QTPP element were defined in the beginning as
follows:
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43. References:
I.PHARMACEUTICAL QUALITY BY DESIGN Principles and
Applications edited by SARWAR BEG MD SAQUIB
HASNAIN,2019 edition, Academic Press is an imprint of
Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1650, San Diego, CA 92101, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United
States The Boulevard, Langford Lane, Kidlington, Oxford OX5
1GB, United Kingdom, Page number: 1 – 2.
II.https://www.ich.org/page/quality-guidelines
III.https://ijpsr.com/bft-article/application-of-quality-by-design-to-different-aspects-of-pharmaceutical-technologies/?view=fulltext

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