Quality by Design Approaches
to Analytical Methods
-- FDA Perspective
Yubing Tang, Ph.D.
FDA/CDER/ONDQA
AAPS, Washington DC
October 25, 2011
Outline
What is Quality by Design (QbD)
Role of Analytical Methods Under QbD
Paradigm
Applying QbD Approach to Analytical
Methods
Current status
Regulatory considerations
Concluding Remarks
2
What is Quality by Design?
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), Step 2
3
What is Quality and Quality by Design?
Quality
Good pharmaceutical quality represents an
acceptably low risk of failing to achieve the
desired clinical attributes.
Quality by Design (QbD)
Means that product and process performance
characteristics are scientifically designed to
meet specific objectives, not merely empirically
derived from performance of test batches.
--Janet Woodcock (2004)
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Role of Analytical Methods
under QbD Paradigm
Provide information about process understanding,
process control and product quality
Product
profile
CQAs
Risk
assessme
nt
Design
space
Control
strategy
Lifecycle
Managemen
t
Product
Design
Prior knowledge used in initial risk assessment
Material quality assessment
Process
Perform in-process testing for timely process control
Understanding decision
-- adjust process before failures occur
Confirm product quality
-- quality is not determined solely by product specification
Lifecycle
Management
Provide data to better understand the process and
for continual improvement
Confirm success of process changes
--can use non-traditional methods
Analytical Method
and Risk Management
Risk Factor = Severity x Occurrence x Detectability
Severity = Effect on Patient
Related to safety or efficacy (CQAs)
Different than impact of a manufacturing failure
Likelihood of Occurrence = Chance of Failure
Related to product and process knowledge and controls
Includes uncertainty for new processes or process changes
Detectability = Ability to Detect a Failure
Appropriateness and capability of analytical method
Sampling considerations
6
Analytical Method
and Control Strategy
Control Strategy Includes:
Process parameters and material attributes
related to drug substance and drug product
manufacturing
Components, facility and equipment
operating conditions
In-process controls, finished product
specification, and the associated methods
and frequency of monitoring and control
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Use of Analytical Methods
in Control Strategy
Raw Material
Testing
Specification based on product QTPP and CQA
Effect of variability, including supplier variations, on
process is understood
In process
Testing
Real time (at-, on-, or in-line) measurements
Active control of process to minimize product variation
Criteria based on multivariate process understanding
Release
Testing
Quality attributes predictable from process inputs (Design
Space)
Specification is only part of the quality control strategy
Specification based on patient needs (quality, safety,
efficacy, performance)
Stability
Testing
Predictive models at release minimize stability failures
Specification set on desired product performance w/time8
Role of Process Analytical
Technology (PAT)
Provide real time information (at-, on- and in-line
testing) for process control and improvement
Non-traditional analytical techniques (e.g. NIR)
have been used in these areas:
identification, drying, blending, assay, and content
uniformity
Need reliable reference information to establish
calibration models
Need to maintain calibration models
Sampling effect on model calibration and validation
Analytical Method and Continual
Process Improvement
Routine analysis
Provides data for tracking and trending
Quantitative results are more useful than PASS/FAIL
Non-routine analysis
Evaluation of product quality on periodic basis for
higher quality assurance
Reassessment of process or product upon process
changes
Can use non-traditional analytical techniques that are
not typically applied to routine release testing
Performed under firms quality system
10
QbD Approach for Analytical Methods
ICHQ8(R2) doesnt explicitly discuss analytical
method development.
However, concepts apply:
Application of Science and Risk based
methodology
Systematic approach that includes: risk
assessment, defining a design space, control
strategy and continual improvement to increases
method robustness and understanding
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QbD Approach to Analytical Methods
Target
Measurement
Select
Technique
Risk
assessment
Method
Develop/ Val
Control
strategy
Continual
Improvement
Determine what to measure and where/when to measure it. Develop
measurement requirements based on product QTPP and CQA.
Select appropriate analytical technique for desired
measurement. Define method performance criteria.
Assess risks of method operating parameters and sample
variation. Can use risk assessment tools (e.g. FMEA)
Examine potential multi-variate interactions (DoE and design
space). Understand method robustness and ruggedness
Define control space and system suitability, meet method
performance criteria
Monitor method performance; update as needed as process and
analytical technology evolves
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Co
Imp ntin
rov ual
em
ent
Co
Str ntrol
ate
gy
M
De etho
d
vel
op/
val
Ass Risk
es s
me
nt
Se
Tec lect
hni
que
Me Targe
asu t
rem
ent
QbD Approach to Analytical Methods
Allow continual feedback and feed-forward
interactions among all steps.
Meet and maintain method performance
criteria
13
Variation of Analytical Method
Many Factors can affect analytical results.
e.g. variations in instrument, sample, method, choice of model
Sample
Characteristics
Method
Parameters
Instrument
Settings
Calibration
Model
Analytical Results
14
Analytical Method Understanding
Understand how variation in input parameters
affects analytical results
Examine multivariate relationships
Across instrument, laboratory, analyst, sample and
method parameters
Employ mechanistic understanding
Based on chemical, biochemical and physical
characteristics
Incorporate prior knowledge of techniques and
methods
15
Analytical Method Design Space
A science and risk based and multi-variate approach to
evaluate effects of various factors on method
performance
Typically DoE* (Design of Experiment) is used to find
ranges for instrument operating parameters, to
understand sample preparation variations and
variations of method precision.
* Example terminology for design space: MODR (method
operable design range)
Method performance criteria are response factors
Can be conducted together with method validation
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Benefits of Application of QbD
Approach to Analytical Methods
Development of a robust method
Applicable throughout the life cycle of the product
Regulatory flexibility
Movements within Design Space are not considered a
change in method
17
Current Status
FDA has approved some NDA applications
applying QbD approach to analytical methods
(e.g. HPLC and UV)
Regulatory flexibility has been granted for
movements within the defined analytical
method Design Space
18
Regulatory Considerations
Define intended use of the analytical method (e.g. RTRT
(real time release testing) or endpoint testing)
Not all analytical techniques are inter-changeable
Example: from HPLC to NIR
Require additional development and validation efforts
Submission of comparability protocols is recommended
Need sufficient statistical power to support analytical
Design Space
Applicants need to clearly define terminologies
Proposal for regulatory flexibility should consider
potential risk to product quality
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Concluding Remarks
Analytical techniques and methods play an essential role
in QbD paradigm
Real time release testing and non-traditional testing
techniques provide valuable information for in-process
control and improvement
Regulatory flexibility is achievable by applying QbD
approach, but requires
High degree of process, product and analytical method
understanding
Robust quality systems
Applicants are encouraged to discuss novel QbD
implementation approaches with the agency prior to
submission
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Thank You!
Questions?
NewDrugCMC@[Link]
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