Application of a Mass Spectrometry Based Multi-Attribute-Method (MAM) for QC Release and Stability Testing of Protein Therapeutics Tamer Eris, Principal Scientist Process Development Amgen, Thousand Oaks, CA CASSS CMC Strategy Forum July 18 th , 2016
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Application of a Mass Spectrometry Based Multi-Attribute-Method (MAM) for QC Release and Stability Testing of Protein Therapeutics
Tamer Eris, Principal Scientist Process DevelopmentAmgen, Thousand Oaks, CACASSS CMC Strategy Forum July 18th, 2016
For Internal Use Only. Amgen Confidential. 2
Key Drivers for a Multi Attribute Method (MAM)
• MAM allows for direct monitoring of relevant product quality attributes rather than indirect measurement by conventional methods
• MAM has capability for new peak detection
Attribute focused Process Development
and Quality Control
• MAM has potential for reduced number of assays for process development, product disposition, and improving cycle time
• Potential for modality independent , platform based method
Reduce Cost of Development and
Quality Control
• Application of MAM method to process development and characterization embraces QBD principles
Quality-By-Design (QBD)
For Internal Use Only. Amgen Confidential. 3
Identification and Selection of the Critical Quality Attributes is Key for Application of MAM
The QTPP guides product quality characteristics prospectively
Definition: A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product
The quality target product profile forms the basis of design for the development of the product.
Considerations for the Quality Target Product Profile (QTPP) could include:
• Intended Use in Clinical Setting, Route of Administration, Dosage Form, Delivery Systems
• Dosage Strength(s)
• Container Closure System
• Therapeutic Moiety Release or Delivery and Attributes affecting Pharmacokinetic Characteristics Appropriate to the Drug Product Dosage Form being Developed
• Drug Product Quality Criteria (e.g. sterility, purity, stability, and drug release) Appropriate for the Intended Marketed Product
Drug Substance and Dug Product are in Scope of QTPP
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QTPP: PQA Ranges can be designed into the Product during Development
Category DS Attributes Target Range Ranges Achieved
Relative levels of Clips by MAM (H9DP + H18DP clips) and reduced CE-SDS (LMW + MMW species) are in agreement
MAM has potential to Replace Several Non-attribute Specific Assays
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Purpose Current DS Release Method Strategy
Purity - Clips rCE-SDS
Multi-Attribute Method
Purity – Charge Variants CEX-HPLC
Glycans Glycan Map
Identity Immunoassay
Process Impurities Protein-A-ELISA
VH
CH1VL
CL
CH2
CH3
Glycosylation
C-Terminal LysPro Amidation
Oxidation
Oxidation
Disulf ide variants
Deamidation
Truncation
Isomerization Cleavage
MS BasedPeptide Map
toQuantifySpecificCQAs
Multi Attribute Method has the potential to replace several Methods and Provide more Detailed Information
QUALIFICATION/VALIDATION OF MAM
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Advancing Highly Sensitive Analytical Technology
When utilizing highly sensitive methods, one has to assure that you have extensive knowledge of method capability:
• Reproducibility/Ruggedness• System Suitability• Robustness
• Sample prep conditions• Chromatography conditions• MS conditions
• Factors that Affect Results• Sensitivity, Interference, Critical method parameters
• Identification of Species• Data Interpretation• Relationship to other Methods
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Qualification Design Aligned with ICH Guidelines for Purity Methods
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Benefits of the Single Multi Attribute Method for Release:
• Automated quantification combining Orbitrap mass spectrometry technology and dedicated software for routine application in QC environment
• Science-based• Provides direct measurements of attributes of criticality captured in the QTPP • Scientifically superior to current methods (CE-SDS, CEX-HPLC, UV based
Peptide Maps). • Reduces number of release tests with the benefit of more detailed
product information
• Flexibility• Method allows for continuous input resulting from increased knowledge of the
drug attributes during process development and better understanding of their criticality from clinical experience
• Modality independent Universal Method
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PacifiChem 2015, Technical Program #242 25
Acknowledgements• Jette Wypych• Izydor Apostol• Rohini Deshpande• Sabrina Benchaar• Da Ren• Quanzhou Luo• Wenzhou Luo• Robert Hung• Helen Chung• Le Zhang• Zhongqi Zhang• Pavel Bondarenko• Suminda Hapuarachchi• Greg Flynn• Janet Cheetham• Richard Wu
• Tony Mire-Sluis• Mike Abernathy• Jason Hampson• Wendy Laderach• Armineh Stone• Rich Rogers• Nancy Nightlinger• Amanda Miller• Alain Balland• Bob Bailey• Catherine Eakin• Dean Pettit• Brent Kendrick• Amol Prakash• Scott Peterman• Jenifer Sutton• Christoph Nickel• Ryo Komatsuzaki