Abstract
Protein therapeutics have unique critical quality attributes (CQAs) that define their purity, potency, and safety. The analytical methods used to assess CQAs must be able to distinguish clinically meaningful differences in comparator products, and the most important CQAs should be evaluated with the most statistical rigor. High-risk CQA measurements assess the most important attributes that directly impact the clinical mechanism of action or have known implications for safety, while the moderate- to low-risk characteristics may have a lower direct impact and thereby may have a broader range to establish similarity. Statistical equivalence testing is applied for high-risk CQA measurements to establish the degree of similarity (e.g., highly similar fingerprint, highly similar, or similar) of selected attributes. Notably, some high-risk CQAs (e.g., primary sequence or disulfide bonding) are qualitative (e.g., the same as the originator or not the same) and therefore not amenable to equivalence testing. For biosimilars, an important step is the acquisition of a sufficient number of unique originator drug product lots to measure the variability in the originator drug manufacturing process and provide sufficient statistical power for the analytical data comparisons. Together, these analytical evaluations, along with PK/PD and safety data (immunogenicity), provide the data necessary to determine if the totality of the evidence warrants a designation of biosimilarity and subsequent licensure for marketing in the USA. In this paper, a case study approach is used to provide examples of analytical similarity exercises and the appropriateness of statistical approaches for the example data.
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Acknowledgments
We would also like to acknowledge the AAPS organization and the Biosimilars Focus Group for their support throughout this initiative.
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Glossary
- 2D-NMR
-
Two-dimensional nuclear magnetic resonance spectroscopy
- SEC-MALS
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Size exclusion chromatography-multiangle light scattering
- FFF
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Field flow fractionation
- RP-HPLC
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Reverse phase high-performance liquid chromatography
- SEC
-
Size exclusion chromatography
- CEX
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Cation exchange chromatography
- IEF
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Isoelectric focusing
- LC-MS
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Liquid chromatography-mass spectrometry
- SPR
-
Surface plasmon resonance
- ELISA
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Enzyme-linked immunosorbent assay
- HILIC
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Hydrophilic interaction chromatography
- PAGE
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Polyacrylamide gel electrophoresis
- FPLC
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Fast protein liquid chromatography
- DSC
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Differential scanning calorimetry
- AUC
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Analytical ultracentrifugation
- PCR
-
Polymerase chain reaction
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Burdick, R., Coffey, T., Gutka, H. et al. Statistical Approaches to Assess Biosimilarity from Analytical Data. AAPS J 19, 4–14 (2017). https://doi.org/10.1208/s12248-016-9968-0
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DOI: https://doi.org/10.1208/s12248-016-9968-0