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

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



Methods comparable








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


Method

Proof of Concept



Methods comparable







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


Method

Proof of Concept



Methods comparable





Different Number/Profile


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

bridging methods for analysis of therapeutic vaccines: …€¦ · test methods. paired t-test:...

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