Control strategy and validation

Control strategy and validation
Emanuela Lacana
PhD
Office of Biotechnology Products
CDER/FDA
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Disclaimer
The views and opinions expressed in this
presentation are those of the speaker and
should not be used in place of regulations,
published FDA guidances or discussions
with the Agency
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The history of control strategy
• Defined in several ICH guidances
• Evolved over a period of time
• Reproducibly provide high quality, safe
and efficacious medicinal products
– A shared goal of FDA and industry
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ICH Early Mentions
• Q6B (1999)
– Specifications are one element of a total control
strategy
– Other elements include:
•
•
•
•
product characterization
adherence to cGMPs
a validated manufacturing process
raw materials, in-process & stability testing, etc.
Adapted from Moheb Nasr and Steve Kozlowski
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ICH Early Mentions, cont.
• Q8 (2006) and Q10(2008)
– At minimum, pharmaceutical development
section should include the definition of control
strategy [and justification]
– Using enhanced product and process
understanding in combination with quality risk
management to establish an appropriate
control strategy
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Q8 and Q10 definition of Control
Strategy
– A planned set of controls
• derived from current product and process understanding
• that assures process performance and product quality
– The controls can include:
•
•
•
•
•
parameters and attributes
facility and equipment operating conditions,
in-process controls,
finished product specifications,
associated methods and frequency of monitoring and
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control
ICH Q11 Drug Substance (2012)
• A control strategy can include, but is not
limited to:
– Controls on drug substance (e.g., release testing)
– Controls on material attributes (including raw
materials…)
– In-process controls (including in-process tests and
process parameters)
– Controls implicit in the design of the
manufacturing process (e.g., sequence of
purification steps…)
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ICH Q11 Example 5a. Possible Control Strategy
Summary – Biotechnological Products
Drug
Substance
CQA
Contaminant
(Viral Safety)
Residual Host
Cell
Proteins
Specific
Glycoforms
Control Strategy for drug substance CQA
Section(s) in CTD where
detailed information is
located
Summaries of viral safety information for biologically-sourced materials
3.2.S.2.3
Detailed information including for materials of biological origin, testing at
appropriate stages of production and viral clearance studies
3.2.A.2
Design Space for an individual unit operation (e.g. see Example 3)
3.2.S.2.2
Target range for consistent removal assured by validation
3.2.S.2.5
Analytical procedures and their validation
3.2.S.4.2 , 3.2.S.4.3
Controls implicit in the design of the manufacturing process including a
summary of process control steps (e.g. cell culture conditions,
downstream purification, holding conditions etc.)
3.2.S.2.2
Characterisation to justify classification as CQA (cross reference to nonclinical/clinical sections if relevant)
3.2.S.3.1
Control of Critical Steps, Testing program and specifications
3.2.S.2.4, 3.2.S.4.1
Justification of specification
3.2.S.4.5
Stability
3.2.S.7
Control strategy in summary
Planned set of controls
Specifications
Process design
and development
Raw
Materials
That assures process
performance and
product quality
Monitoring
Control Strategy
Facilities and
equipment
Desired
Product
Parameters and
attributes
In-process
controls
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Control strategy is built upon
• Understanding of product and process
– Adequate process development and product
characterization
• “Know thy product”: quality attributes, how they may be
linked to process
• “Know thy process”: understand and control those variables
that impact process performance and product quality
• Validation of the process
– Exercise that scientifically establish that a process is
capable of consistently delivering a product that
meets the expected quality criteria
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– It is a state, not an event
Continued Process Verification
• Assure that the process is continually in a state
of control
– Monitoring and sampling, adjusted as needed based
on data collected
• Systems capable of detecting unplanned variations
– Evaluate sources of variability to control and reduce
variation
• Common cause variability
• Special cause variability
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Continued Process Verification
• Need an adequate program to collect and
analyze process data
– Trending in-process data
– Evaluation of in-process materials
– Evaluation of products
• Statistical trending of data
– Product related data
– Statistical process control
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Continued Process Verification
• Facilitate process optimization and
improvement
– May identify areas of improvement in the
process
• Changes needed to maintain product quality
• Need for additional process design and
qualification to optimize the process
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Continued Process Verification
• What’s new?
– Formalizes expectations for a “state of
control”
– Information gathering and review process is
dynamic and data-driven
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Examples of what is not CPV
• A substitute for inadequate process
development
– PAI during an original BLA review cycle
– Process changes made on almost daily basis to
adjust and tweak multiple unit operations
– As a result, the actual process was quite different
from the process submitted in the BLA to support the
license
– Justification: It is in the spirit of what FDA described in
the PV guidance…..
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Examples of what is not CPV
• Changes proposed without keeping the
product in the line of sight
– Change in a piece of equipment resulted in
increase in oxidation and loss of potency
– Proposed changes in specifications to “fit” the
current results
– Would result in changes in product quality
beyond clinical experience
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Element of a control strategy
• Adequate control on raw materials
• Well designed manufacturing process
–
–
–
–
–
Appropriate in-process controls
Critical and key parameters
Appropriate alert and action limits
Statistical process control
Appropriately qualified equipment
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Element of a control strategy,
cont.
• Cross-site evaluation of product to avoid
drift
• Risk assessment and management
• Robust PQS
• Clinically relevant specifications
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Changes to an approved
application
• Result from knowledge acquired post-approval
(CPV activities)
• Process, product, facilities
• Managed and executed in conformance with
cGMP
• Reported to the Agency per appropriate
regulation
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Regulatory Reporting Mechanisms
601.12 An applicant must inform the FDA about each change in the…
[conditions] established in the approved license application(s).
• PAS-- substantial potential to have an adverse
effect on the… product… safety or effectiveness
• CBE 30-- moderate potential [of] an adverse effect
• In certain circumstances… may be distributed
immediately upon receipt…
• AR-- minimal potential to have an adverse effect
• Protocols to reduce reporting categories
What changes are reported?
• Is everything in the BLA a commitment?
• Uncertainty on what is a commitment leads to:
– “If we do not submit that we will not need to report a
change”
– “My QA person told me that if I submit this SOP I will
need to submit a supplement every time I make a
change”
• Need for clarity on reportable changes
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Established conditions
• Description of the product, manufacturing process, facilities and
equipment, and elements of the associated control strategy, as
defined in an application, that assure process performance and
quality of an approved product.
• Not all that is submitted in an application is an established condition
• The guidance clarifies which elements of the control strategy
submitted in the application may be considered established
conditions
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Overall control strategy
Managed by PQS
Described to support product
and process
Reportable
Post approval
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Examples of established conditions
• Drug substance and product manufacturing processes:
–
–
–
–
Manufacturing and testing facilities
Description of manufacturing process
Source and specifications for biologics starting materials
Process, including in-process tests and sequence of operations,
equipment; and process parameters.
• Specifications, including tests, procedures and criteria
• Container closure system, components, and specs.
Examples of established
conditions, cont
• Specifications
– Analytical procedures
– Reference standards or materials
• Container closure system
• Protocols
• Drug product specific
– Excipient, batch formula, composition
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Generally not established
conditions
• Batch records
• Development data
• Characterization
• Validation data
• Batch analysis data
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Process
• Submitted by the Applicant (recommended
in module 2)
• Evaluated by the Agency
– Product and process understanding
– Risk assessment and mitigation strategies
• Finalized after negotiation at the time of
licensure
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Benefits of clearly defined
established conditions
• Reduce submission of unnecessary
supplements
– Effective post approval submission strategies
• Encourages continual process improvements
• Allows FDA to better regulate post approval
changes
– more flexibility
– Risk based principles
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Questions?
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