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QUALITY by DESIGN:
From Theory to Practice

Soula Kyriacos, PhD

Research & Development Manager
PHARMALINE

HEALTH INSIGHT, June 2011

 What is Quality by Design (QbD)?
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 (ICH Q8(R))

QbD means designing and developing formulations and

manufacturing processes to ensure predefined product quality.
– Understanding and controlling formulation and manufacturing process
variables affecting the quality of a drug product.
– Dependence of consistent quality product on risk assessment, based
on process understanding.

⇒ Best solution but also major challenge to the Pharmaceutical

industry whose processes are fixed in time, despite inherent process
and material variability.
What is Quality by Design (QbD)?

Moheb Nasr
 What is Quality by Design (QbD)?

Moheb Nasr

QbD GOAL: develop a process that can accommodate the range of

acceptable variability for maintaining product quality .
⇒ MANUFACTURING FLEXIBILITY
 QbD is Product and Process

• Product Knowledge– mechanistic understanding of how

variability impacts product
– Material variability -PSD, surface area, moisture content, etc.
– Process variability -granulation, tableting conditions, etc.

• Product Specification
– to provide continued assurance of clinical performance

• Product Performance
– ensuring product quality as dissolution links/relates product
attributes to clinical performance

Moheb Nasr
 Benefit for pharmaceutical industry
Improved efficiency and flexibility whilst
maintaining high quality standards.

• Rapid introduction of state-of-the art science and technology

• Encouraged continuous manufacturing process improvements
• Real-time quality control →reduced end-product release
testing
• Fewer lost batches
• Fewer manufacturing deviations, saving costly investigative
hours
• Reduced out-of-specification results, reducing rework

From a “Reactive” to a “Proactive” Decision System for

Pharmaceutical Quality
 Components of a QbD Program
• Statistical Analysis/ Modeling
e.g. Statistically designed experiments (DOEs)
Efficient method for determining impact of multiple parameters and
their interactions.

• Design Space
The multidimensional combination and interaction of input
variables (e.g., material attributes) and process parameters
that have been demonstrated to provide assurance of quality.
– Translation –what combination(s) of input settings will meet the
specifications for the output(s)?
Working within the design space is not considered as a
change.
⇒ REGULATORY FLEXIBIBLITY
 Components of a QbD Program
• Process Analytical Technology (FDA PAT Guidance,
2004)
– A system for designing, analyzing, and controlling
manufacturing through
• TIMELY measurements (i.e., during processing) of
CRITICAL quality and performance ATTRIBUTES
of raw and in-process materials and processes
with the goal of ensuring final product quality.

= “Continuous Quality Assurance” paradigm that can

improve our ability to ensure quality was “built-in” or was
“by design” - ultimate realization of the true spirit of
cGMP!
 Components of a QbD Program
WHY PAT?
– Greater insight and understanding of processes
– At/On/In-line measurement of “performance” attributes
– Real-time or rapid feedback controls
– Potential for significant reduction in production and development
cycle time
– Minimize risks of poor process quality and reduce (regulatory)
concerns

PAT Tools
• Near Infra Red technology for RM identification, moisture
measurement, blend uniformity, CU of tablets.
• Torque sensor for endpoint granulation
• Focused Beam Reflectance Measurement (FBRM) for PS
measurements
• Imaging systems for process controls and process monitoring in
various applications.
 Example QbD Approach - Q8(R1)
• Target the quality product profile (QTPP)
• Determine critical quality attributes (CQAs)
• Link raw material attributes and process parameters to CQAs
and perform risk assessment
– application of common risk management tools (e.g. Failure Mode
and Effects Analysis (FMEA) )
• Develop a design space = understand the relative impact of
input variables (process steps, process parameters, and raw
materials) on CQAs.
• Design and implement a control strategy
• Manage product lifecycle, including continual improvement
 QbD - Risk Based Development
• Use sound scientific principles
in the design of the product and
Process
• Identify the critical attributes
(CAs) for the raw materials
• Identify the process critical
control points for the processes
(PCCPs)
• Employ the proper analyses and
PAT concepts for process
understanding and control
• Were the principles appropriately
applied?
• How were the CA’s identified and
the formula designed?
• Ditto for the PCCP’s
• What were the bases for analyses
selection?
• What are the supporting data for
all of the above?

• Tie it all together with the • Product Development History

appropriate informatics to feed the
information forward and
backwards for QbD and Ken Morris
continuous improvement and
innovation = reduced risk
 QbD - Risk Based Development
(1) Choose experimental (2) Conduct randomized experiment
design Experiment Factor Factor Factor C
(i.e., full factorial) A B
1 + - -
2 - + -
3 + + +

(3) Analyze data (4) Create multidimensional

surface model (for optimization or
control)
 How do you know when you have
understood the process?

• All critical sources of variability are identified and

explained
– Can you explain the variability from batch to batch?
• Product quality attributes can be accurately and reliably
predicted
– Can you predict a good run from a bad run?
⇒ The ability to predict reflects a high degree of
process understanding.
• Variability is managed by the process

Process Understanding inversely proportional to risk

FDA PAT GUIDANCE
 Generics QbD Principles
Target product quality
profile
well defined such as
dissolution, purity,
uniformity, and stability

Extensive formulation
and manufacturing OBJECTIVE:
experience for many
generic manufacturers understand attributes of the
formulation and
Biopharmaceutical properties manufacturing process that
have the potential to change
of drugs already known
the bioavailability of a
such as polymorphism, particular active ingredient.
absorption, and pharmacokinetics
information
 Generics QbD Principles

• API • Process
– Polymorphism – Compression ranges
– Particle size – Physical
– Stability characteristics
– Blend uniformity
• Excipients
– Polymers to control • Finished product
release (proper – Formulation
selection) Optimization
– Compatibility to API – Stability
– Flow – Drug Release
– Compression – Packaging
characteristics
 Quality by Design for ANDAs: An
Example for Immediate-Release Dosage
Forms

Pharmaceutical Development Report

Example QbD for IR Generic Drugs
Draft April 26, 2011

How to move toward implementation of quality by design

 QbD for ANDAs: An Example for IR DF
Product development outline:
• Analysis of the reference listed drug (RLD) product
• Defining Quality Target Product Profile (QTPP)
• Identification of Critical Quality Attributes (CQAs) for the drug product
(DP)
• Identification and prioritization of potential risks for each unit operation
(Risk assessment)
• Screening and optimization of formulation (DOE for high risk
components) including a development PK study
• Development of a robust process (DOE for high risk parameters)
– Blending / Roller compaction / Lubrication/ Compression
• Scale up and manufacture of the exhibit batch
•Establishment of control strategies
– Input material
– Unit operations - process controls and monitoring, design spaces
around individual or multiple unit operations
• Blending/ Roller compaction and milling/ Lubrication/ Tablet compression
– Finished product specifications
 QbD for ANDAs: An Example for IR DF

CONTROL STRATEGY
A risk matrix table for the blending operation demonstrates that the identified risk to
the quality Attributes = control of API, lactose and MCC particle size and monitorin
of blend uniformity.
Blending
Attribute or Parameter Range Type of Control

Mixing Speed 8 rpm Operating range

Number of Revolutions 128-256 PAR

Online NIR monitoring

Blend Uniformity NMT 6.5% In-process control

A near IR online tool for monitoring the blend uniformity was developed and
is used to terminate the blending when sufficient uniformity is reached
 WHERE DOES INDUSTRY STAND?
Level of maturity and drug type of examined companies
Fully lack of belief
Group Novice Pilot Rollout implemented Total in the
business case
New Rx 22% 33% 22% 22% 100

Gx 40% 20% 40% --- 100 lack of

technology to
Biologics17% 67% 17% --- 100 execute

Novice: Company is skeptical about the value QbD can bring. Utilizes conventional
development.
Pilot: Company is trying QbD, but still on the fence about the potential value. Tends to
apply QbD to a small subset of projects and processes and has implemented limited.
Rollout: Company is convinced about impact of QbD and is beginning to see some of
the benefits. Uses QbD techniques regularly, but not universally. May engage in some
lifecycle management with integrated platform and network strategy.
Fully implemented: Company is completely convinced about the positive impact of
QbD and is realizing the benefits. Uses QbD in almost every development program and
almost every production step. Additionally, has a systematic, comprehensive review and
re-design of in-line products.
FDA, December 2009
 Obstacles to Implementing QbD
• Internal misalignment within a company around if and how to
implement is a key adoption challenge and can take several forms.

1. Misalignment horizontally across the organization. (i.e.,

Disconnect between cross functional areas, e.g., R&D and
manufacturing or quality and regulatory)
Potential for confusion: How could R&D define attributes outside of its
domain and area of practice, that were critical to quality?
2. Disconnect between leadership and middle management.
Clearly state the specific benefits the organization wants to get
from QbD and how those benefits will be realized.
3. Culture of conservatism.
4. Amount of change required within company is not feasible.
Many companies will have to redesign certain aspects of their
operating model.
5. For some, QbD remains low on the priority list.
 Obstacles to Implementing QbD
• Lack of belief in the business case.
– $$$ for more extensive characterization and development
– Financial payback is over the lifetime of the product, but requires
investment early in development

Moheb Nasr
 Obstacles to Implementing QbD
• Lack of technology to execute (e.g., Difficulty managing data,
limited understanding of Critical Quality Attribute (CQA) implications)
– new experimental techniques, new types of measurements
– need to develop new skill sets and get new technology to execute data
gathering and analysis. “Huge volume of information” need to be
continuously managed and maintained.
• Companies identified the need for “more statisticians with different skill sets
and more education to be able to handle all this data.”

• Alignment with 3rd parties. (i.e., How to implement QbD with

increasing reliance on suppliers and contract manufacturers?)

• Inconsistency of reviews and degree of internal alignment

• Misalignment of international regulatory bodies

 CONCLUSION
• Application of QbD principles facilitate development of quality products
and their assessment throughout their lifecycle, and ultimately, result
in greater patient benefit.

• QbD readiness assessment

– Clearly define the strategic objective
– Assessment of organization and culture
• QbD is relatively new: will require original thinking,
organizational re-training/hiring and learning
• Process goals must be communicated across all business units
“Right-first-time” culture, where quality means continuously
creating more value
– Operational assessment

• Process development : Individual unit operations/entire

manufacturing process.

• Challenges to Regulatory agencies

"The World According to Peter Drucker“:

“In my view, he said, the future has already

happened. The task we must take up is to look at all
that has already happened, but has yet to have an
impact. “

THANK YOU.