Quality by Design approach in

Bioprocessing

BITS Pilani By Shivyam Rastogi

K K Birla Goa Campus
 Quality by Design – A brief
history
• Concept first outlined by quality expert J. Juran
in his publication Juran on Quality by Design
• Juran believed that quality could be planned,
and that most quality crises and problems relate
to the way in which quality was planned.
• Since then QbD principles have been used to
advance product and process quality in industry,
and the automotive industry, they have also
been adopted by the U.S. FDA for the discovery,
development, and manufacture of drugs
2
5/12/19 BITS Pilani, K K Birla Goa Campus
 Definition of Quality

The Juran Trilogy defines the word "quality" as having

two meanings:
• the presence of features that create customer
satisfaction
• the reliability of those features.
Juran's process seeks to create features in response
to understanding customer needs. These are
customer-driven features. The sum of all features is
the new product, service, or process.

3
5/12/19 BITS Pilani, K K Birla Goa Campus
 QbD Philosophy

4
5/12/19 BITS Pilani, K K Birla Goa Campus
 Conventional Approaches vs QbD
• Hit and trial approach
• Method performace
evaluated during
validation
• Limited understanding of
analytical variables
• No regulatory flexibility
• No space for further
improvement
5/12/19
• Well structured approach
• Focus on performance
through establishment
• Systematic evaluation of
individual variables and
interaction
• Working withing MODR is
not considered changed,
reduces post approval
changes
• Flexibility to improve
continuously
5
BITS Pilani, K K Birla Goa Campus
 Need for QbD? (1/2)

• The pharmaceutical market is valued at $774bn

and expected to reach $1.06tn by 2022.
• Biopharmaceuticals play an important role in this
increase and their contribution is set to increase
from 27% to 52% of world pharmaceutical sales.
• Compared to the 21 biologics approved by the US
Food and Drug Administration (FDA) in 2015, only
14 were approved in 2016, indicating a scarcity in
innovation and lack of progress in bioprocess
development strategies – mainly in early-stage
screening and manufacturability.
6
5/12/19 BITS Pilani, K K Birla Goa Campus
 Need for QbD? (2/2)

• Limited emphasis on process understanding, led

to manufacturing failures and consequently
increased product wastage.
• The need for Quality by Design (QbD) arose in
early 2000, as the traditional approach to
biopharmaceutical drug development was
primarily empirical.
• The costs involved in development and
production of biopharmaceutical entities are 1.5-
2.5 times higher than that of small molecule drugs
7
5/12/19 BITS Pilani, K K Birla Goa Campus
 Integrated QbD Approach

8
5/12/19 BITS Pilani, K K Birla Goa Campus
 Quality by Design

• Integration of patient needs, science and

quality requirements during the
development of a pharmaceutical product
and its manufacturing process
• Close collaboration between industry and
regulators to achieve a regulatory review
based on a scientific understanding of the
product and its manufacturing process

9
5/12/19 BITS Pilani, K K Birla Goa Campus
 Quality by Design

• Well known as standard of practice in other

industries (automotive/microchip/electronics/
chemical industries)
• QbD was introduced in bioprocessing
industry over 10 years ago however,
regulatory agencies are now in the process
of moving it from recommended (optional) to
mandatory in drug submissions and filings.

10
5/12/19 BITS Pilani, K K Birla Goa Campus
 QbD Principles

1. A clear line of sight from clinical to

product release and stability
• Clear understanding of product requirements and
performance
• QTPP should be defined and communicated to all
teams
• CQAs defined early in development process and
managed/developed thoughout product’s lifecycle

11
5/12/19 BITS Pilani, K K Birla Goa Campus
 2. QRM in every aspect of
development
• QRM is designed to ensure that drug CQAs are defined and
maintained from phase to phase during drug development
and manufacturing.
• It’s meant to secure that changes in drug product
formulation, definition, analytical methods, and associated
process changes are understood and managed to ensure
patient safety and drug efficacy

Two key QRM principles are as follows:

• Risk assessment should be based on scientific knowledge associated with product and
process understanding
• The level of effort and detail associated with risk assessment and management should
be commensurate with the level of risk being identified and evaluated.

12
5/12/19 BITS Pilani, K K Birla Goa Campus
 3. Enhanced product
understanding
• The three parts of product understanding
are system design, parameter design, and
tolerance design
 System design
Selection of a technology, chemistry, active pharmaceutical
ingredient, and materials
 Parameter design
Selection of key targets, set points, and concentrations.
 Tolerance design
The allowable range or limits for each parameter.

13
5/12/19 BITS Pilani, K K Birla Goa Campus
 4. Assay Understanding

• Care must be taken to properly select

analytical methods for measuring all CQAs.
• Each selected assay must be fit for use
and valid for the condition to be measured.

14
5/12/19 BITS Pilani, K K Birla Goa Campus
 5. Process Understanding and
Characterization
• Factors influencing a production process
and associated variations should be
understood.
• Process understanding has the same three
components as product understanding:
system, parameter, and tolerance design.
• Process understanding is a prerequisite to
stage 1 process validation.

15
5/12/19 BITS Pilani, K K Birla Goa Campus
 6. Generation of Transfer
Functions
• Manufacturers should understand how X
factors influence Y responses, where each
is in the form of an equation and either
reflect scientific knowledge or be
empirically derived from structured multiple
factor experimentation.
• Ultimately, knowledge should be expressed
in the form of an equation to be fully useful

16
5/12/19 BITS Pilani, K K Birla Goa Campus
 7. Improved Product Specification
Limits and Justification
• Specification limits must be a part of an
overall product control strategy.
• They should be linked to CQAs and the
QTPP (line of sight).
• These limits should be based on scientific
knowledge, transfer functions, and/or
statistical distributions.

17
5/12/19 BITS Pilani, K K Birla Goa Campus
 8. Robust Design Space and
Edge of Failure
• ICH defines design space as “The multidimensional
combination and interaction of input and process
parameters that have been demonstrated to provide
assurance of quality”
• Design space is a visualization of the average
performance at fixed set points.
• In truth, it often may misrepresent the edges of failure
and the actual process dynamics at play during
processing. This analysis ensure that the allowable
range of variation will cause no harm and will not
result in out-of-specification (OOS) conditions.
18
5/12/19 BITS Pilani, K K Birla Goa Campus
 9. Control Strategies

• Controls are defined to ensure potency,

purity, safety, and efficacy.
• The three parts of a control strategy are:
• in-process test and release
• postprocess test and release
• closed-loop process measurement and adjustment
during processing.

19
5/12/19 BITS Pilani, K K Birla Goa Campus
 10. Continuous improvement
and validation
• Tracking and trending have generally been
the method for monitoring drug products
and drug substances to assess lot
variation and process trends.
• Properly designed, such systems and
controls will lead to preventative action
rather than corrective action before OOS
events and lot failures.

20
5/12/19 BITS Pilani, K K Birla Goa Campus
 Principles Summarized (1/2)

• Product is designed to meet patient needs

and performance requirements
• Process is designed to consistently meet
product quality
• Impact of starting raw materials and
process parameters on product quality is
understood

21
5/12/19 BITS Pilani, K K Birla Goa Campus
 Principles Summarized (2/2)

• Critical sources of process variability are

identified and controlled
• The process is continually monitored and
updated to allow for consistent quality over
time

22
5/12/19 BITS Pilani, K K Birla Goa Campus
 Ongoing challenges

• Development of regulatory processes

• Need international harmonization and
collaborative efforts
• Need to build knowledge/experience
• Shift “wait and see” attitude to an active
participation attitude to an active
participation for both industry and
regulatory agencies

23
5/12/19 BITS Pilani, K K Birla Goa Campus
 Environment needed for
Successful adoption
• Regulatory flexibility to accommodate
quality by design submissions
• Common dossier accepted worldwide by
regulatory agencies
• Post-approval changes within pre-defined
design space can be implemented with
regulatory flexibility
• Laws and processes in place to protect
intellectual property (IP)
24
5/12/19 BITS Pilani, K K Birla Goa Campus
 References
• https://bioprocessintl.com/analytical/cell-line-development/essentials-in-quality
-by-design-350512
/

• https://bioprocessintl.com/analytical/qa-qc/an-industry-perspective-on-quality-b
y-design-328066
/

• https
://www.europeanpharmaceuticalreview.com/article/70588/rapid-bioprocess-devel
opment-strategies
/

• http
://www.ich.org/fileadmin/Public_Web_Site/Training/GCG_-_Endorsed_Trainin
g_Events/APEC_LSIF_workshop_Seoul__Korea_Sep_07/Day_2/Industry_perspecti
ve_-_
Elaine_Esber.pdf 25
5/12/19 BITS Pilani, K K Birla Goa Campus