Quality by Design ( QbD )

Department of Pharmaceutics, KCP, CBE-32 1Monday, July 23, 2019

CONTENTS
INTRODUCTION
ICH GUIDELINE Q8
REGULATORY AND INDUSTRY VIEW
ON QBD
2Department of Pharmaceutics, KCP, CBE-32Monday, July 23, 2019

QbD
Introduction:
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.

QbD Will Enhance
4Department of Pharmaceutics, KCP, CBE-32
SAFE
EFFECTIVE
Mfg QUALITY
Monday, July 23, 2019

QbD
Design a Quality
Product
Quality of Mfg
Process
Product should meet
patients needs
Product development
may vary between
products
AIM of QbD

QbD
APPROCHES
Empirical
method
Systematic
method
Combination
of Both

QbD
A more systematic approach to development
(also defined as QUALITY BY DESIGN)
for example,
– incorporation of prior knowledge,
– results of studies using design of experiments,
– use of quality risk management,
– use of knowledge management (ICH Q10)
throughout the lifecycle of the product.

QbD

Steps in QbD
CLINICALDEVELOPMENT
• Preclinical study
• Nonclinical
study
• Clinical Study
• Scale up
• Submission for
market Approval
MANUFACTURING
• Design Space
• Process
Analytical
Technology
(PAT)
• Real time
Quality Control
CONTROLSTRATEGY
• Risk based
decision
• Continuous
Improvement
•
• Product
performance

Elements For Pharmaceutical Development
ELEMENTS OF PHARMACEUTICAL DEVELOPMENT
The section that follows elaborates on possible approaches to
gaining a more systematic, enhanced understanding of the product
and process under development.
 Quality Target Product Profile (QTPP)
 Critical Quality Attributes (CQA)
 Risk Assessment
 Design Space
• Selection of Variables
• Describing a Design Space in a Submission
• Unit Operation Design Space(s)
• Relationship of Design Space to Scale and Equipment
• Design Space Versus Proven Acceptable Ranges
• Design Space and Edge of Failure
 Control Strategy
 Product Lifecycle Management and Continual Improvement

Quality Target Product Profile (QTPP)
The quality target product profile forms the basis of design for the
development of the product. (it mainly focus on the safety and
efficacy. )
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 (e.g., sterility, purity, stability and drug
release) appropriate for the intended marketed product.

Benefits in the Quality Target Product Profile
 Identifies risks and best approaches to manage.
 Uses tools/enablers in an optimized fashion (such as
integration of QbD and biopharmaceutics)
 Generates and enables knowledge sharing.
 An iterative, learning, life-cycle process for optimizing decision
making and the therapeutic outcomes for the patient benefit.
 A drug product designed, developed and manufactured
according to Quality Target Product Profile with specification
(such as dissolution/release acceptance criteria) consistent
with the desired in vivo performance of the product.

Critical Quality Attributes (CQA)
A CQA is a physical, chemical, biological, or
microbiological property that should be within an
appropriate limit, range, or distribution to ensure the
desired product quality.
CQAs are generally associated with the drug
substance, excipients, intermediates (in-process
materials) and drug product.

CQAs of solid oral dosage forms are typically those
aspects affecting
• product purity, strength,
• drug release and stability.
CQAs for other delivery systems can additionally include
more product specific aspects,
• such as aerodynamic properties for inhaled products,
• sterility for parenterals,
• adhesion properties for transdermal patches.
CQAs For drug substances, raw materials and
intermediates,
• It include the particle size distribution, bulk density

Risk assessment
Risk assessment is a valuable science-based process
used in quality risk management that can aid in
identifying which material attributes and process
parameters potentially have an effect on product
CQAs.
Risk assessment is typically performed early in the
pharmaceutical development process and is
repeated as more information becomes available and
greater knowledge is obtained.

Cont..,
They can overcome by Once the significant
parameters are identified, they can be further
studied (e.g., through a combination of design of
experiments, mathematical models, or studies that
lead to mechanistic understanding) to achieve a
higher level of process understanding.

Examples
Use of a risk assessment tool.
For example, a cross-functional team of experts
could work together to develop an Ishikawa
(fishbone) diagram that identifies potential
variables which can have an impact on the desired
quality attribute.

Ishikawa Diagram for Tablets

The relationship between the
1. (Material attributes and process
parameters)
&
2.
Can Be Described In The Design Space

SELECTION OF VARIABLES
The risk assessment and process development
experiments can lead to an understanding of the
linkage and effect of process parameters and
material attributes on product CQAs, and also help
identify the variables and their ranges within which
consistent quality can be achieved.

Example
Design space determined from the common region
of successful operating ranges for multiple CQAs.
The relations of two CQAs, i.e., tablet friability and
dissolution, to two process parameters of a
granulation operation.

Contour plot of dissolution as a function of Parameters 1 & 2.

Contour plot of friability as a function of Parameters 1 & 2.

Proposed design space, comprised of the overlap region of ranges for friability and or
dissolution.

CONTROL STRATEGY
A control strategy can include,
 Control of input material attributes (e.g., drug substance,
excipients, primary packaging materials) based on an understanding
of their impact on processability or product quality;
 Product specification(s)
 Controls for unit operations that have an impact on downstream
processing or product quality (e.g., the impact of drying on
degradation, particle size distribution of the granulate on
dissolution);
 In-process or real-time release testing in lieu of end-product testing
(e.g. measurement and control of CQAs during processing);
 A monitoring program (e.g., full product testing at regular intervals)
for verifying multivariate prediction models.

REGULATORY VIEWS ON QBD
As defined by an FDA official (Woodcock, 2004),
“The QbD concept represents product and process
performance characteristics scientifically designed to
meet specific objectives, not merely empirically derived
from performance of test batches.”
“Another FDA representative (Shah, 2009) states that
introduction of the QbD concept can lead to cost savings
and efficiency improvements for both industry and
regulators.”

QBD facilitate
• enhance opportunities for first cycle approval,
• streamline post approval changes and regulatory processes,
• enable more focused inspections,
• provide opportunities for continual improvement (Shah, 2009).
• innovation,
• increase manufacturing efficiency,
• reduce cost/product rejects,
• minimize/eliminate potential compliance actions,

EMA representatives (Korakianiti, 2009) point out that it
is preferable for a design space to be complemented by
an appropriate control strategy.
The review of variations regulations and the revised
Variations Classifications Guideline (2008) has taken into
account QbD submissions, to enable easier updates of
the registration dossier.
EMA templates and guidance documents used for the
assessment of any new drug application in the
centralized procedure include the possibility of design
space appointment (e.g. Day 80 Quality AR Template).

EMA, FDA, and ICH working groups have appointed
the ICH quality implementation working group
(Q-IWG), which prepared various templates,
workshop training materials, questions and answers,
as well as a points- to-consider document (issued in
2011) that covers ICH Q8(R2), ICH Q9, and ICH Q10
guidelines.
This document provides an interesting overview on
the use of different modeling techniques in QbD.

 There were several EMA marketing authorization applications
(MAA) with QbD and PAT elements
 for the following products: Avamys®, Torisel® , Tyverb® , Norvir® ,
Exjade® , Revolade® , Votrient® , etc.).
 Up to 2011, there was a total of 26 QbD submissions to EMA (for
the new chemical entities)
 18 of them were initial MAAs (4 including the realtime release),
 6 of them were concerning post- authorization, and 2 were
scientific advice requests.
 An additional two MAAs were submitted for biological products,
but none of the submissions were related to the generics industry
 Up to 2011, there were approximately 50 QbD related applications
to the FDA (Miksinski, 2011). FDA authorities state that QbD is to be
fully implemented by January 2013 (Miksinski, 2011).

INDUSTRY VIEWS ON QBD
 Pfizer was one of the first companies to implement
QbD and PAT concepts.
 Through these concepts, the company gained
enhanced process understanding, higher process
capability, better product quality, and increased
flexibility to implement continuous improvement
change.

QbD for industry and regulatory bodies
Industry Regulatory agency
Development of scientific understanding
of critical process and product attributes.
Scientifically based assessment of product
and manufacturing process design and
development.
Controls and testing are designed based
on limits of scientific understanding at
development stage.
Evaluation and approval of product
quality specifications in light of
established standards (e.g. purity,
stability, content uniformity, etc.).
Utilization of knowledge gained over the
product’s lifecycle for continuous
improvement.
Evaluation of post- approval changes
based on risk and science.

References
 Jelena Djuris Computer-aided applications in
pharmaceutical technology 2013 (1 to 7)
 PHARMACEUTICAL DEVELOPMENT – ANNEX. ICH
Harmonised Tripartite Guideline. 2013 (9 to 14)
 Nishendu P. Nadpara, Rakshit V. Thumar, Vidhi N.
Kalola, Parula B. Patel. Quality By Design (Qbd) : A
Complete Review, International Journal of
Pharmaceutical Sciences Review and Research. ISSN
0976 – 044X. 2012 (20 to 28).

Thank You

Quality by Design ( QbD )

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