5/13/08
Quality by Design
Gail Burnett, Ph.D.
© 2005, Genentech
Agenda – Quality by Design
Slide 2
5/13/08
• Background on ICH Q8, Q9, and Q10
• Quality by Design (QbD) Definitions
• QbD Framework
The What, Why, and How of QbD
© 2005, Genentech
The New Paradigm of ICH Q8, Q9, Q10
Slide 3
5/13/08
Q10
Q9
Q8
The new
Paradigm
Documents available on ICH web site
www.ich.org
© 2005, Genentech
The Role of Process Understanding
Slide 4
5/13/08
A Process is well understood when…
• all critical sources of variability are identified
and explained;
• variability is managed by the process; and,
• product quality attributes can be accurately
and reliably predicted over the design space
© 2005, Genentech
ICH Q8 Summary
Slide 5
5/13/08
ICH Q8 Basic Guideline
• Defines what is the ‘minimum’ (Base Line)
• The role of Process Understanding
• Defines what is a Design Space
• Defines Regulatory Flexibility
ICH Q8(R1)
• Defines what is Quality by Design
• The role of a Systematic Approach
• Defines Critical Quality Attribute
• Examples of Design Space
• Defines Control Strategy
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ICH Q8(R) : Quality by Design
Slide 6
5/13/08
Important Elements:
Systematic approach
Predefined objectives (Target Product Profile)
Product and process understanding based on sound science
Quality risk management
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Q8 – General Concepts: What we get in return
Slide 7
5/13/08
This scientific understanding facilitates establishment of an
expanded design space. In these situations, opportunities exist to
develop more flexible regulatory approaches, for example, to
facilitate:
• risk-based regulatory decisions (reviews and inspections);
• manufacturing process improvements, within the approved
design space described in the dossier, without further regulatory
review;
• reduction of post-approval submissions;
• real-time quality control, leading to a reduction of end-product
release testing.
© 2005, Genentech
ICH Q9: Quality Risk Management
Slide 8
5/13/08
Initiate
Quality Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
ICH Q9
Team
approach
unacceptable
Risk Control
Risk Reduction
Risk Acceptance
Risk Management tools
Risk Commu nication
Risk Evaluation
Output / Result of the
Quality Risk Management Process
Risk Review
Review Events
© 2005, Genentech
ICH Q10 Pharmaceutical Quality Systems
Slide 9
5/13/08
Key aspects of the Pharmaceutical Quality System
Management Responsibility
Product Realization
Continual Improvement
– Product and Processes
– Quality System
© 2005, Genentech
QbD Definitions
Slide 10
5/13/08
Quality:
The suitability of either a drug substance or drug product for its
intended use. This term includes such attributes as the identity,
strength, and purity (from ICH Q6A Specifications: Test Procedures
and Acceptance Criteria for New Drug Substances and New Drug
Products: Chemical Substances). (ICH Q8)
• noun: an essential and distinguishing attribute of something or someone
• noun: a degree or grade of excellence or worth
• noun: a characteristic property that defines the apparent individual nature of
something
© 2005, Genentech
QbD Definitions
Slide 11
5/13/08
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. Working within the
design space is not considered as a change. Movement out of the
design space is considered to be a change and would normally
initiate a regulatory post approval change process. Design space is
proposed by the applicant and is subject to regulatory assessment
and approval. (ICH Q8)
Critical Quality Attribute (CQA):
A physical, chemical, biological or microbiological property or
characteristic that should be within an appropriate limit, range, or
distribution to ensure the desired product quality.
© 2005, Genentech
Quality by Design Framework
Slide 12
5/13/08
1. Create the Knowledge Space
2. Create the Design Space
3. Link to Quality Systems
© 2005, Genentech
QbD Framework
Slide 13
5/13/08
1. Create the Knowledge Space
• Identify the Critical Quality Attributes (CQAs)
• Apply QbD by Unit Operation, working
backwards from Drug Product
• Do a Risk Assessment on each Unit Operation
• Conduct Designed Experiments
© 2005, Genentech
QbD Framework
Slide 14
5/13/08
• Identify the Critical Quality Attributes of the new drug product
CQA assessment is an iterative process of evaluating the drug product and
drug substance attributes throughout development to determine which have
potential impact on the safety, efficacy, or potency of the drug.
• What do we know from research and pre-clinical development?
• Are there any surrogate measures for clinical safety and efficacy?
• Do we know what affects clearance or immunogenicity?
• Do we know what affects CDC or ADCC?
• What do we know from work with molecules of the same class?
• Consider how the clinical indication, mechanism of action, route of
administration, dosing frequency, patient population, etc. could
influence the selection of CQAs
© 2005, Genentech
CQA Assessment
Slide 15
5/13/08
Use CQA assessment to guide development plan
– Declare “non-critical” those attributes that are demonstrated through
product specific or platform knowledge to not impact safety, efficacy, or
potency across a broad range
– Focus product characterization and process development activities on
attributes that have potential of impact (presumptive or potential CQAs =
pCQAs)
– Discussion point: Is criticality of an attribute related to control?
– A product profile (e.g. chromatogram) can be a quality attribute.
– Should product attributes and process impurities be handled the same?
© 2005, Genentech
QbD Framework
Slide 16
5/13/08
Apply QbD by Unit Operation
• Work backwards from Drug Product
The purpose of each unit operation should guide evaluation of
critical attributes (pCQAs) at that step
• Define unit operations (process steps) by specific output required ‒
e.g. cell mass vs product titer
• The outputs of one unit operation may be the input variables for the
next step
• Consider the order of unit operations
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QbD Framework
Slide 17
5/13/08
Apply QbD by Unit Operation
• Start with a risk assessment (Q9) for each unit operation
• Consider and document all parameters that could affect output
(pCQAs)
• Which process parameters might affect the desired quality attributes
at the end of that step?
• Which input variables might affect the output quality?
• What is the severity and probability of negative impact?
© 2005, Genentech
QbD Framework
Slide 18
5/13/08
Apply QbD by unit operation
Example ‒ anion exchange column
• Purpose of step ‒ remove host protein
Therefore critical attribute (output) studied in experiments
should be host protein
• What are the input variables that could affect this step?
• What process parameters could affect quality?
e.g. load, flow rate, pH, conductivity
• Design of Experiments (DOE) should evaluate those input
variables along with process parameters that have been
assessed to have potential to impact host protein clearance.
© 2005, Genentech
QbD Framework
Slide 19
5/13/08
Design of Experiments
• How small can we make the experiments?
• Understand what design fits what need ‒ screen, uncover
interactions, refine
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• Plackett-Burman
• Etc.
• Make sure we are looking
at the right outputs
• Multiple outputs analyzed separately
• Consider where stability is an output
© 2005, Genentech
QbD Framework
Slide 20
5/13/08
Incorporating scale into design space
• Should scale be a variable or input factor in DOE?
• Can we identify surrogate factors that might vary with scale?
Time
Contact surface
Mixing
Heat transfer
• Approach will vary for batch or continuous process
© 2005, Genentech
QbD Framework
Slide 21
5/13/08
2. Create the Design Space
• Identify the Critical Steps
• Identify Critical Process Parameters
• Identify Critical Input Variables
© 2005, Genentech
QbD Framework
Slide 22
5/13/08
Definition unclear?
• Critical Process Parameter: A process parameter that must be controlled
within predetermined criteria to ensure the bulk drug substance meets its
specification/quality attributes. A process parameter is critical if the target
range (TR) is near the acceptable range (AR) or as determined by a
technical expert.
Industry not unanimous in regard
to importance or relevance of
ability to control the parameter.
Acceptable Range
Acceptable Range
© 2005, Genentech
QbD Framework
Slide 23
5/13/08
Selection of Critical Process Parameters
• What if there is no impact on Quality Attributes (e.g. Yield)?
• By expert opinion
• By risk assessment
• By lack of significant effect in robust DOE
• By six sigma
Critical Parameter
• By ratio to CpK
Acceptable Range
• ???
Non-Critical Parameter
Acceptable Range
© 2005, Genentech
QbD Framework
Slide 24
5/13/08
Selection of limits to test in DOE
• Do we need to test to failure?
• How far beyond control capability is far enough?
• Consider all sources of error
Critical Parameter
Acceptable Range
Non-Critical Parameter
Acceptable Range
© 2005, Genentech
QbD Framework
Slide 25
5/13/08
3. Link to Quality Systems (Q10)
– Documentation of Quality Attributes
– Approve Specifications
– Documentation of Manufacturing Process
(Parameters and Input Variables)
– Validation
– Change Control
– Deviations, Discrepancies, and Investigations
© 2005, Genentech
Specifications for Quality Attributes
Slide 26
5/13/08
• Should all CQAs have specifications?
• Must all “Specifications” be demonstrated for each batch on a
CoA?
• Should some CQAs just be used for comparability?
• If process is demonstrated (validated) to achieve the desired
level or range of a quality attribute, is a specification needed?
• What about removal of process impurities?
• What about viral clearance?
• Should specifications allow the full acceptable ranges of critical
quality attributes?
Attributes that we test for process consistency (not CQAs)
should have or action / alert limits
© 2005, Genentech
QbD Framework
Slide 27
5/13/08
Link to Quality Systems
– Manufacturing Documentation to reflect critical parameters and
input variables
– Validation should focus on CPPs
– Change Control allows change within design space
– Deviations, Discrepancies, and Investigations may be reduced
by better process knowledge
 QbD leads to identification of critical quality attributes, process
steps, and process parameters, which provides focus to
specifications, validation protocol, batch record and controls
© 2005, Genentech
Quality by Design Submissions
Slide 28
5/13/08
• CQAs must be defined before BLA/NDA filing and should include those
attributes that have been demonstrated to impact safety, efficacy, or
potency of the drug or have high potential to do so (but still unknown)
and are not easily controlled.
• QbD may be applied to entire process or to selected unit operations
• How should we describe Quality Attributes and Design Space in
Regulatory Filings?
 Better understanding of process and product can lead to better
science and risk-based regulation of individual products
Continue to work with Regulatory Agencies and Industry
groups to advance QbD.
© 2005, Genentech