control strategy for co-formulated biologics · 2018. 4. 2. · bms internal use only. 2. outline...

1BMS Internal Use Only

Control Strategy for Co-formulated Biologics

Amit Katiyar, Tapan Das, and Reb RussellBristol-Myers Squibb, NJ

CASSS, CMC Europe, May 2017

2BMS Internal Use Only

Outline

• Introduction: Control Strategy for Co-formulated Biologics• Analytical Separation Methods Workflow• Case Study: Overlapping Profiles for CE-SDS-NR• Case Study: Method Bridging and Method Correlation• Analytical Challenges for Co-formulated Biologics Products with

Wider Ratios• Summary

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Co-formulated Biologics

DS #1

DS #2

Co-formulated DP

Drug Substance Control Strategy

Drug Product Control Strategy

Release and stability methods for combination product

Product Understanding: Characterization, CQA assessment

Process Understanding: In-Process Control

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Analytical Separation Methods Workflow

4

mAb-1

mAb-2

Combination Product

CQA Assessment

CQA Assessment

Analytical Methods Monitor and Control CQAs for Combination Product

Removal of Analytical Methods

Upgrading of Analytical Methods

Method Bridging

Method Correlation to Support Specifications

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Analytical Separation Methods

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Attributes Methods Co-elution/Separation Purity/Fragments CE-SDS Co-elutionAggregates SEC Co-elutionCharge Heterogeneity iCIEF Complete separationCombination Ratio RP Complete separation

CE-SDS-R

SEC

RP

iCIEF

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Case Study: Overlapping Profiles for CE-SDS-NR

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• Partial separation of mAb-1 and mAb-2 • Lack of accurate quantitation of product

related impurities from mAb-2

Monotherapy degradation pathways are well understood and controlled during DS release and stability

Extended Characterization for combination product on multiple lots were similar to monotherapies

Interaction study shows no significant evidence of protein-protein interactions.

SEC and CE-SDS-reduced method as a purity method on combination product

LTSS data for mAb-1 and mAb-2 showed minimal changes in the non reduced purity levels

Product Understanding and Control Strategy

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CE-SDS-R Method for Co-formulated Biologics

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Case Study: Method Bridging and Method Correlation

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Method Correlation

mAb-1 (iCIEF)Method Bridging and Method Correlation

mAb-2 (CEX)Final Method

Combination Product (iCIEF)

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Method Bridging: CEX to iCIEF

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• Isolation and characterization of acidic and main species from CEX method resulted in similar profile in iCIEF

• Differences in basic species were related to the presence of N-terminus pyroglutamate

• Stability indicating acidic species are captured in both methods

• Method Correlation needs to be established to support the specification for combination product

Abso

rban

ce

0.00

0.10

0.20

0.30

0.40

0.50

pI8.70 8.80 8.90 9.00 9.10 9.20 9.30 9.40

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Correlation between CEX and iCIEF for Specification Support

10

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Analytical Challenges for Co-formulated Biologics with Wider Ratios

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Charge Heterogeneity• Quantitation of stability

indicating peaks cannot be achieved for wider ratios

• Is it important to quantitate post translation modifications that are below method quantitation limit?

Abs

orba

nce

0.00

0.05

Abs

orba

nce

0.00

0.05

0.10

Abs

orba

nce

0.00

0.05

0.10

Abs

orba

nce

0.00

0.05

0.10

0.15

Abs

orba

nce

0.00

0.05

0.10

0.15

Abs

orba

nce

0.00

0.05

0.10

0.15

Minutes6.80 6.90 7.00 7.10 7.20 7.30 7.40 7.50 7.60 7.70 7.80 7.90 8.00 8.10 8.20 8.30 8.40 8.50 8.60 8.70 8.80

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• Overlapping profiles • Accurate quantitation of stability indicating peaks is challenging

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Charge HeterogeneityAb

sorb

ance

-0.02

0.00

0.02

0.04

0.06

0.08

0.10

0.12

Minutes6.90 7.00 7.10 7.20 7.30 7.40 7.50 7.60 7.70 7.80 7.90 8.00 8.10 8.20 8.30 8.40 8.50 8.60 8.70 8.80

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Size Heterogeneity• Monomers from mAb-1 and mAb-2

are not co-eluting• Quantitation of monomer is

challenging for minor component • Presence of HMW species well

below quantitation limit does not pose the immunogenicity concern

mAb-1

mAb-2

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Summary• Control strategy to support co-formulated biologics is driven by:

• Monotherapy control strategy• Interaction Study• Combination product control strategy

• Analytical method panel can be modified based for the co-formulated product ratio with suitable justification to provide comprehensive control strategy

• Method bridging and method correlation provide support to justify specifications for co-formulated product

• Approach for reporting certain CQAs might differ from conventional mAbs due to sensitivity limitations associated with certain analytical methods for a given ratio