A regulatory Perspective on Novel Approaches to Demonstrate

Comparability

Frances Namuswe, Ph.D.Office of Biotechnology Products

OPQ/CDER/FDA

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The views and opinions expressed here should not be used in place of regulations,

published FDA guidances, or discussions with the Agency

www.fda.gov

DISCLAIMER

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• Common manufacturing changes

• ICH Q5E and phase appropriate comparability

• Case studies: Late development and post-approval

• New regulatory guidances and comparability protocols

www.fda.gov

Outline

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Reasons for Manufacturing Changes

• Manufacturing site and scale changes

• Changes to raw materials, critical intermediates, equipment

• Improve product safety and/or stability

• Process improvements and new technologies

• Regulatory expectations/requirements

• Business decisions

Risk assessment used to assess the potential impact of changes on product quality as it relates to safety and efficacy

Examples

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Comparability

• Needed to demonstrate that pre- and post-change products are comparable and no adverse impact of changes on the quality, safety and efficacy of the product

• Demonstration of comparability (ICH Q5E)

— Quality attributes of pre-change and post-change product are *highly similar not identical (per ICH Q5E)

— Existing knowledge is sufficient to ensure that differences in quality attributes have no adverse impact on safety or efficacy of the product

*Highly similar as defined in ICH Q5E

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Comparability StudiesAnalytical• Structure • Function • Impurity Profile • Molecular Heterogeneity • Stability

Non-clinical• Toxicity• PK/PD• Tissue Cross Reactivity

Clinical• PK/PD• S&E• ImmunogenicitySe

nsiti

vity

to d

etec

t diff

eren

ces

lower

higher

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Analytical comparability Product comparability may include

• Release testing

• Extended characterization*

• Stability (real-time, accelerated, stressed*)

Comparative stressed stability studies

• Relevant if change has potential to impact product quality

• Should be designed to provide meaningful information

• Include conditions that result in incremental changes over time

• Include stability indicating assays

*May be limited during early development

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Outcome of Analytical Comparability (ICH Q5E)

Comparable• *Highly similar, no adverse impact

on safety or efficacy foreseen

• Quality attributes appear *highly similar. Some differences observed but no adverse impact on safety or efficacy is expected

Additional studies needed• Quality attributes appear *highly similar

but analytical procedures used are not sufficient to discern relevant differences that can impact safety or efficacy

• Additional analytical testing, nonclinical and/or clinical studies

Non-clinical/Clinical studies needed• Quality attributes appear *highly

similar but differences observed and possible adverse impact on safety or efficacy cannot be excluded

• Additional analytical data unlikely to assist in determining comparability

Not comparable• Products are not *highly similar. Out

of scope of ICH Q5E

*Highly similar as defined in ICH Q5E

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Role of Technology Improvements

Product Knowledge– Structure/Function– Formulation/Stability– Quality attribute/

Clinical performance

Analytical Methodology – Glycan analysis– HOS (NMR, H/D MS)– Particulate matter analysis– PAT– MAM

Advancement in product and process knowledge +improvement in technology and analytical methodology

=Better product characterization and risk assessment, more meaningful comparability assessment, less uncertainty

Process understanding

– Platform technology– Process parameters

/ Quality attributes

Examples

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Phase Appropriate Analytical Comparability

Non-clinical(Toxicology)

Phase I / II(Safety)

Phase III(Safety/ Efficacy)

Approval Phase IV Post marketing

Expectations for level of characterization are commensurate with stage in lifecycle, extent of change, potential impact of change on safety and efficacy, product & process knowledge, QTPP, suitability of available analytical methods, availability and characterization of pre- change material

Comparability milestones

Pivotal to commercial

Post-approvalTox/FIH Early clinical

to pivotal

• Make major changes during development before pivotal studies

• Save pre-change material, clinical/reserve samples, well characterized RS. Store samples under appropriate conditions

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• Emphasis is on safety– Product and process related impurities– Viral clearance– Uncontrolled product degradation

• Typically fewer lots available– 1 tox and 1 clinical lot typically acceptable for new FIH IND– # of lots used in phase 1 and phase 2 comparability studies varies

• Analytical methods– Methods are suitable for intended use (usually not validated)– Numerical acceptance criteria for purity assesses instead of “report results” are

important

• Data – Lot release testing, some stability, limited characterization– Raw data for purity assays (e.g. gels and chromatograms) important

Expectations during Early Clinical Development

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• New or higher levels of impurities in post-change material (e.g. clinical lot vs tox lot)

• Small scale viral clearance model of pre-change process not adequately representative of post-change process and no new studies conducted

• Increased rate of degradation of post-change material

• Differences in potency between pre- and post-change (especially with a narrow therapeutic window)

Examples of potential hold issues

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• Safety and efficacy

• Recommend making major manufacturing changes prior to initiation of pivotal clinical studies

• Comprehensive comparability package expected (release testing, additional characterization, stability)

• # of Lots– 1 lot not sufficient; 3 pre-change and 3- post-change lots typical

– Comparison to historical pre-change data and trend analysis (e.g. for release and real time stability) provides more comprehensive evaluation

– Side-by-side testing for extended characterization, stressed stability– Avoid cherry picking

• Analytical methods– Changes to analytical methods typical and bridging to earlier methods and pre-

change material sometimes necessary

Later Clinical Development and Post Approval

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Case studiesLate development and post-approval

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Case Study 1: Post phase 3

• DS scale up and other process modifications

• Post change DS has ~20 – 40% reduced potency

• Root cause for change in potency not identified

• Non-clinical studies suggest the change may not impact clinical efficacy; however questions about the correlation remain

• FDA requested additional investigation into root cause to ensure potency could be controlled

• Additional clinical studies were requested

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Case Study 2: Post Phase 3

• Major changes to upstream and downstream DS manufacturing process of glycosylated product

• Glycosylation important for biological activity

• Available data suggested possible differences in critical glycans

• No historical data for pre-change lots for trend analysis of critical glycans due to inadequate release testing – Critical glycan structure analysis was part of extended characterization not

release testing

• Reference material changed multiple times and linkage to original clinical material lost

• No retained samplesJoslyn Brunelle

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Case Study 2: Cont’d

• Analytical comparability could not be demonstrated

• Clinical comparability (PK) study conducted. Differences observed.

• Additional efficacy study needed for approval

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Case Study 3: Post approval

• Changes to upstream DS manufacture with no changes downstream.

• Proposed comparability exercise includes:– Upstream process performance evaluation (PPQ) at full scale

– Product comparability:• Release, extended characterization and forced degradation• Post-change DS lots includes:

– Full scale DS (manufactured using full scale upstream + full scale downstream processes)

– Small scale DS ( manufactured using full scale upstream + small scale downstream processes)

– Real time and accelerated stability data for full scale DS

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Case Study 3: Cont’d

• Proposal reasonable provided: – No changes to downstream process– Upstream changes that could impact downstream performance

are evaluated and addressed– Small scale model is representative of downstream commercial

scale

• Sponsor asked to provide DP manufactured from full scale post-change DS

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Case Study 4: BLA Review• Transfer of DP manufacturing site pre-licensure for breakthrough product

• Comparability conducted with one PPQ and one engineering (ENG) lot from new site

• Stability data available for one ENG lot from new site

• Approved with comparability protocol for concurrent validation and release of DP from new site. Data for other PPQ lots to be submitted in CBE-30s.

Considerations• Available data suggested comparable post-change & clinical material

• Benefit to patients justifies risk

• Risk associated with change in this case was low and detectable

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New guidances and comparability protocols

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New regulatory guidances

• Draft Guidance for Industry: Comparability protocols for Human Drugs and Biologics (April 2016)

• ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (under development)

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Comparability Protocols (CP)• 21 CFR 601.12 (e) and 21 CFR 314.70 (e)

• Typically used post-approval with extensive process and product knowledge

• Can be used for a specific change, multiple related changes, or multiple products

• Frequently approved for manufacture of new WCB, RS, resin &membrane reuse

• Used to introduce new products into DS/DP manufacturing sites; additional of new DS/DP manufacturing sites

• CP submitted as PAS; typically reduced reporting category (CBE) for implemented changes

• Benefits: expedited product distribution, flexibility and planning in managing drug supply

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CP Common Review Challenges• Acceptance criteria

• Setting appropriate comparability acceptance criteria. Meeting release acceptance criteria typically not enough

• Lack of data to support proposed comparability acceptance criteria

• Agreeing to changes sight unseen• Hard to predict the synergistic impact of multiple attributes on product

performance

• Comparative stability studies not included or properly designed

• Request to downgrade subsequent submission that cannot be downgraded e.g. inspection requirements

• Insufficient information to address additional requirements for process changes e.g. validation

• WCB qualification protocols: lack of comparability assessment of full scale DS manufactured with current and new WCB

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2016 Draft Guidance on CP- What’s new?

• Replaced previous (2003) draft guidance

• The expectations for assuring safe and efficacious product following manufacturing changes did not change

• Includes regulatory concepts in ICH Q8 – Q11

• Provision for reporting some changes to approved CPs in CBE-30 —Changes to a CP are typically reported in a PAS

—For specific situations e.g. modification with same or increased level of rigor

• Provision to use additional supporting information and analysis to potentially lower the reporting category

—Requires a considerable amount of product and process understanding to justify that the information lowers the risk

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ICH Q12: Lifecycle Management

- Final Concept Paper; Q12: Technical and Regulatory Considerations for PharmaceuticalProduct Lifecycle Management; dated 28 July 2014

- Ashley B. Boam, CASSS CMC Strategy Forum, July 2016

• PACMP/CPs

• Risk based categorization of changes

• Established conditions

• PQS and CMS

• Applying Q12 to currently marketed products

Tools proposed for inclusion in ICH Q12

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Need for Global Harmonization: An example

“A pre-license comparability study resulted in 3 distinct regulatory decisions from 3 regions:

• One region only approved the small scale process based on differences in the API

• One region only approved a large scale process based on differences in impurities

• One region approved both”

From Barry Cherney – WCBP, Washington DC 2010

Same change, 3 different regulatory decisions

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• Comparability studies should be guided by risk assessment of the potential impact of changes on safety and efficacy of the product

• Consider making major changes before pivotal studies

• It is important to retain pre-change and clinical samples and well characterized reference standards. Store under appropriate conditions

• Comparability protocols have benefits and challenges

• New guidances have the potential to improve management of comparability

www.fda.gov

Summary

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Acknowledgement• OBP

– Susan Kirshner– Maria Teresa Gutierrez-Lugo– Juhong Liu– Sarah Kennett– Cecilia Tami– Emanuela Lacana– Joslyn Brunelle– Willie Wilson– Marjorie Shapiro– Antonina Aydanian– Michele Dougherty

• Ingrid Markovic• Stephen Moore

Thank you!