Bridging Methods for Analysis of Therapeutic Vaccines: …€¦ · test methods. Paired t-test:...
Transcript of Bridging Methods for Analysis of Therapeutic Vaccines: …€¦ · test methods. Paired t-test:...
Bridging Methods for Analysis of
Therapeutic Vaccines: Opportunities
and Challenges
CMC STRATEGY FORUM
Paul Dillon 27-Jan-2014.
Presentation Summary
Vaccines molecules: Opportunities and Challenges.
Analytical method lifecycle
Method comparability & equivalency requirements
Proof of concept study requirements.
Key considerations for method equivalency.
Example approach to equivalency testing.
Example statistical approach to equivalency testing.
Successfully bridged methods & challenges with bridging
methods.
Conclusion
Vaccines molecules: Opportunities and Challenges
Vaccine Molecules:
Stimulate production of antibodies
and provide immunity.
Challenging manufacturing processes
- continually advancing.
Large complex molecules requiring
sophisticated techniques for analysis.
Extended analytical characterisation
required for New/2nd generation
Vaccine Molecules.
Vaccine production and analysis is
continually evolving - Requirement to
move to Novel/ Advanced Analytical
Technologies.
Vaccines Molecules: Opportunities and Challenges
Analytical Challenges:
Identifying appropriate new/Improved technologies.
Demonstrating method equivalency.
Setting appropriate equivalency acceptance criteria.
Requirement to perform characterisation studies to compare
methods with different profiles as part of proof of concept.
Implementing replacement methods without equivalency data sets.
Developing data sets to support new specification limits (if required).
Bridging data sets of some product quality attributes difficult to
build.
i.e. Size distribution vs relative molar mass methodologies.
Regulatory requests for method improvements.
Analytical Drivers:
Technology advancements:
New technology introduction.
Technology to improve process understanding/characterisation.
Implementation of in-line/at-line technologies.
Business:
Improve method throughput – automation....
Precision/capability Improvements – TT, trending, stability.....
Regulatory:
Regulatory Commitments (FUMs).
Expectation to deliver more advanced analytical methods.
Vaccines Molecules: Opportunities and Challenges
Expectation to move
to more advanced
technologies
Analytical Method Lifecycle
Analytical
Method
Lifecycle
Continuous
Improvement
Quality
Control Use
Validation
and
Transfer Method
Development
Method
Design
Space
Integrated
Control
Strategy
Patient
And
Product
Needs
Method
Design
Requirements
Continuous method improvement/
replacement is an important
component of method lifecycle.
Proof of concept for alternative
methods must include an
understanding of any differences
and how these can be bridged.
Evaluate new/improved
Method
Proof of Concept
Characterise method differences.
Understand functional significance.
Methods comparable
Method Qualification/Validation
Comparability and Equivalency Study
Specification Change? Design Filing Strategy
Methods not comparable
Different number/profile
Method Comparability & Equivalency Requirements
Evaluate new/improved
Method
Proof of Concept
Characterise method differences.
Understand functional significance.
Methods comparable
Method Qualification/Validation
Comparability and Equivalency Study
Specification Change? Design Filing Strategy
Methods not comparable
Different number/profile
Method Comparability & Equivalency Requirements
Proof of Concept Study Requirements
Demonstrate feasibility of new/novel technology
Assess parameters that show differences between the two
methods:
Precision/Accuracy etc
Equivalent results:
Different number (i.e. bias)
Different profile (i.e. More peaks in HPLC method)
Different output (i.e. Size distribution vs Molar mass)
Difference between methods need to be fully understood:
Method characterisation required.
An understanding of the difference will enable completion of method
comparability and equivalency assessments.
Evaluate New/Improved
Method
Proof of Concept
Characterise method differences.
Understand functional significance.
Methods comparable
Method Qualification/Validation
Comparability and Equivalency Study
Specification Change? Design Filing Strategy
Methods not comparable
Different number/profile
Method Comparability & Equivalency Requirements
Method Comparability & Equivalency Requirements
Method Comparability: Evaluates similarities/differences of the entire
method profile – captured in Qualification/Validation exercise.
What about method Equivalency?
Method Equivalency: Equivalency is subset of comparability and demonstrates
the sameness of two analytical methods by comparison of a specific set of results.
Output of method qualification/
validation as per ICH:
Assesses overall performance
of method.
Assesses comparability with
two methods.
Key Considerations for Method Equivalency
Establishing appropriate acceptance criteria critical
Define what is unacceptable/acceptable difference (i.e. Expected vs
Practical vs Statistical)
Expectation that more capable methods will not be equivalent for
some parameters.
Scientifically sound justification required to move forward.
Proof of concept must characterise/understand change/difference.
Enable the design of equivalency study.
Design of equivalency study:
Include factors that influence method performance
Number of assays/sample size required statistically calculated
from method variability of two methods and acceptable difference.
Identify samples for study and select statistical approach.
Choice of samples critical.
Samples must be selected to ensure results cover a wide spectrum of
results
Comparing results from samples that yield a range of values will
provide the greatest assurance that methods are equivalent.
Representative commercial lots.
Commercial data across a number of batches (eg N = 30++)
used to assess specification range.
Demonstrate process capability and consistency.
Stability samples – within/beyond expiry periods.
Demonstrate stability indicating capability of method.
Build equivalency data across a range of expected commercial
results.
Example Approach to Equivalency Testing: Sample Selection
Edge of specification samples.
Confirm assay performance at edge of failure compared to old
assay.
Confirmation that new method can detect and provide same
results when close to specification.
Pilot scale or force degradation (aberrant) samples.
Understand how method performs for samples outside commercial
specification range.
Clinical samples.
Important to demonstrate clinical experience with method.
Example Approach to Equivalency Testing: Sample Selection
vs
Strong bridging data set required between methods........
The appropriate statistical approach is one designed to determine:
If differences between two methods are within acceptable limits.
Determined by the design to be practically relevant.
Identify appropriate statistical approach important:
Example: T-test approach can demonstrate equivalency of two
test methods.
Paired t-test: testing multiple samples once each with the different test
methods - offers potential to assess method equivalency over a wide
range of conditions - preference.
2-Sample t-test: testing same samples (e.g. an assay control) multiple
times with each test method.
Both approaches valid and the choice of which to use will depend
on the nature of the samples available.
Example Statistical Approach to Equivalency Testing
Evaluate New/Improved
Method
Proof of Concept
Characterise method differences.
Understand functional significance.
Methods comparable
Method Qualification/Validation
Comparability and Equivalency Study
Specification Change? Design Filing Strategy
Methods not comparable
Different number/profile
Method Comparability & Equivalency Requirements
Specification change may be required for implementation of
some methods.
Question: How is new specification range generated?
Understand if correlation exists between the two methods
to enable generation of new specification range.
Samples must be representative of entire specification range.
Equivalency results and data generated will enable
Specification range to be generated.
To support correlation, Clinical batches can be tested.
Specification Change
Evaluate New/Improved
Method
Proof of Concept
Characterise method differences.
Understand functional significance.
Methods comparable
Method Qualification/Validation
Comparability and Equivalency Study
Specification Change? Design Filing Strategy
Methods not comparable
Different Number/Profile
Method Comparability & Equivalency Requirements
Implementation of Bridged Methods
Commercial Implementation Strategy:
Filing strategy design important:
Complicated strategy if product approved in multiple countries
Filings can take a number of years to approve depending
on number of affiliates and filing required.
Staggered filing approach - Complicate product supply.
Robust filing plan should ensure that dual testing of old vs new
method is not required - dual testing requires additional
resources, cost etc.
Transfer method into Quality labs and complete all documentation.
Commence running method post approval.
Summary/Conclusion
Manufacture/testing process of vaccine products continually
evolving.
Improving analytical capability is a continual process for
therapeutic vaccines.
As long as there is method changes, there will be a desire to
compare the old and the new method.
Proof of concept studies must include method characterisation
to understand differences.
Equivalency assessment design and samples used critical in
demonstrating equivalency.
Changes in analytical methods may at times produce true changes
in the results that may not be equivalent between methods.
Change should proceed if:
There is sound scientific rationale for implementation.
New technology improves analytical capability.
Acknowledgements
Brian Fitzpatrick
Manufacturing Sciences and Technology Team
Thank You