Developing Regulatory Strategies for Cell Line Changes Allison Wolf

Global Regulatory Affairs, CMC Biotechnology

Outline

• General Change Management Concerns

• Reasons to Change a Cell Line

• Assessing Risk of Cell Line Changes

• Examples

• Final Thoughts & Considerations

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Changes: Industry Reg Affairs Perspective

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Small Molecules Large Molecules

Manufacturing Site

Manufacturing Site

Manufacturing Scale

Manufacturing Scale

Purification

Cell Culture

Cell Line

Formulation Formulation

Purification / Final Crystallization

DS Process [Early Steps]

DS Process [Final Step]

Why Would You Ever Change a Cell Line

Compliance Drivers

• Remove animal sourced materials

• Ensure clonality

• Ensure compliance with ICH Q5D

Business Drivers

• Low titer/Not commercializable

• Align with corporate platform

• Intellectual property

Technical Drivers

• Improve control of quality attributes

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Potential Impact of Cell Line Changes

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Additional Round of Cloning

Select New Clone

New Host Cell

Risk will Determine Level of Studies Needed

CTs

Animal Testing

Analytical/in vitro Testing

Cell Line Change: Timing Considerations

Key Goals of Clinical Development

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Safety Dose

Definition Efficacy

Significant changes should be avoided once efficacy trials begin, so cell line changes should be made during early phase development CMC Development teams need to work closely with their broader development team to determine when to implement a cell line change. - risk assessments can inform this decision

Early Phase Challenges

• Data and experience is often limited

• Incomplete knowledge about a process

• Analytical methods may not be optimized to detect all potential problems

• Bioassay reflective of MoA may not be available

• Immunogenicity data is often limited

Early phase is the preferred time to implement complex changes, but it can be very difficult to assess risk and establish acceptance criteria with limited data

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Risk Assessment of Cell Line Change

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Quality Attribute or Modification

Identify Potential Impact

Criticality Assessment

Safety

Bioactivity

PK/PD

Leverage: 1. Molecule specific data 2. Platform knowledge 3. Literature or expert opinion

Outputs Inform Comparability Requirements

and Studies Needed

CTs

Animal Testing

Analytical/in vitro Testing

Detectability Needed

Example 1: New Host Cell

• Change Host Cell for IgG4 Monoclonal Antibody

Switch cell line from NS0 to CHO to align with manufacturing platform

Drug substance manufacturing site change

Purification process changes made

Independent viral clearance studies were performed for the NS0 and CHO processes

Change made after Ph1/chronic toxicology and before the start of Phase 2

Change in cell line supported with a comparative in vivo primate PK study

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Example 1: Comparability Protocol

• A risk assessment was performed to identify potential changes as well as expected changes (e.g., glycosylation)

• Pre-determined acceptance criteria were documented in a protocol and reviewed by a cross functional group of experts

• Protocol included details on batches to be evaluated as well as tests and acceptance criteria

• For attributes that were expected to change, the rationale for these changes was documented in the protocol

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Example 1: Comparability Assessment

• Four batches were used in assessment including some testing of retained samples from initial toxicology & clinical batches (NS0)

• Standard release, in-process, and stability testing

• Biological activity [cell based bioassay & binding affinity]

• Co-mixture analysis done with key methodologies

• Oligosaccharide profile characterized

• Peptide mapping

• Biophysical testing to confirm secondary and tertiary structure

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Example 1: Regulatory Submissions

• An amendment was filed to the US IND prior to start of Ph2

3.2.S.2.6 included the rationale for the change and complete comparability analysis

3.2.S.2.6 also including strategy for introducing the change

• Global Clinical Trial Applications (CTA) are study specific, so new CMC content was filed for the CHO process

Data for the historical NS0 material was included as well as the comparability analysis in 3.2.S.2.6

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Key Feedback from Health Authorities

• Clearly state which attributes are expected to change and rationale provided to justify the change (e.g., oligosaccharide profile, HCP)

• Explain the details of the derivation of the cell line comparing to previous (same expression construct?)

• Provide reports for safety evaluation of the new cell line

• Comparability should include assessment of DP attributes including endotoxin levels and particulates

• GMP batch data should be submitted prior to introduction of the material into clinical trials (DS & DP)

• Received several typical CTA questions not specific to the cell line change

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Country Specific Requests

• DS and DP dating

New cell line restarts shelf life

Several EU authorities would not allow for dating extensions without substantial amendments

• Full viral safety reports

Summaries were not sufficient for France & Germany

• Details about cell line generation and cell bank

Raw data for testing (France & Germany)

Detailed questions about animal sourced materials

• Redlined comparison copy of changes from previous CTA (France & Canada)

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Country Specific Requests (cont’d)

• Many “typical” CTA questions were received that were not directly related to the cell line change

• Control strategy questions [DS & DP]

Numerical limits requested for tests without limits

Additional method details requested

Tightening of limits requested for some attributes

Rationale for shelf life extrapolation

Prefiltration bioburden acceptance criterion

• Some forward looking comments to consider for future development

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Example 2: New Clone & Media

• Select New Clone for IgG4 Antibody

Existing cell bank has low titer (~1 g/L)

Expression of variant with reduced potency in cell based bioassay at levels ~25%

Ph1 enabling toxicology and Ph1 CTs used material from initial clone and media package

― Future work includes chronic toxicology studies and dose ranging clinical studies

―New clone & media should be implemented prior to start of dose ranging study

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Example 2: Risk Considerations

• MoA is not dependent on effector function

• Cell based bioassay reflective of MoA is available

• No findings in previous toxicology studies

• Phase 1 toxicology and GMP material available for testing (e.g., co-mixture analysis)

• Knowledge available for similar molecules in Phase 3

• Platform knowledge exists

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Example 2: Risk Considerations

• Consider the need to establish a new reference standard

Potentially different profile including quantity of variant with reduced potency

• Evaluate the HCP assay to confirm that it is still able detect population of HCPs from new cell line

• Safety evaluation of new cell bank needed as well as assessment of viral clearance data package

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Considerations for Cell Line Changes

• Use risk assessments when assessing cell line changes

• When possible, discuss these changes with health authorities prior to submission

• Introduction of “new” material should be made at the start of a new clinical study if possible

Provide transparency in regulatory submission

• Clinical Trial supplies should have a clean cutover from one cell line to another

• Changes made after key toxicology or PK studies will likely need bridging studies

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