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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
Tie it all together with the
appropriate informatics to feed the
information forward and
backwards for QbD and
continuous improvement and
innovation = reduced risk
Were the principles appropriately
applied?
How were the CAs identified and
the formula designed?
Ditto for the PCCPs
What were the bases for analyses
selection?
What are the supporting data for
all of the above?
Product Development History
Ken Morris
QbD - Risk Based Development
(1) Choose experimental
design
(i.e., full factorial)
Experiment Factor
A
Factor
B
Factor C
1 + - -
2 - + -
3 + + +
(3) Analyze data
(4) Create multidimensional
surface model (for optimization or
control)
(2) Conduct randomized experiment
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
experience for many
generic manufacturers
Biopharmaceutical properties
of drugs already known
such as polymorphism,
absorption, and pharmacokinetics
information
OBJECTIVE:
understand attributes of the
formulation and
manufacturing process that
have the potential to change
the bioavailability of a
particular active ingredient.
Generics QbD Principles
API
Polymorphism
Particle size
Stability
Excipients
Polymers to control
release (proper
selection)
Compatibility to API
Flow
Compression
characteristics
Process
Compression ranges
Physical
characteristics
Blend uniformity
Finished product
Formulation
Optimization
Stability
Drug Release
Packaging
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
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
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.
WHERE DOES INDUSTRY STAND?
Level of maturity and drug type of examined companies
Fully
Group Novice Pilot Rollout implemented Total
New Rx 22% 33% 22% 22% 100
Gx 40% 20% 40% --- 100
Biologics17% 67% 17% --- 100
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
lack of belief
in the
business case
lack of
technology to
execute
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.