control strategy for co-formulated biologics · 2018. 4. 2. · bms internal use only. 2. outline...
TRANSCRIPT
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
6
• 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
11
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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