After analytical characterization and non-clinical studies, originator approval relies on proof of clinical benefit vs. standard care. For biosimilars, the development
phases’ importance is opposite to the originator’s: analytical assessment provides the strongest proof of similarity. In humans, a pharmacokinetic study has to be
performed, and efficacy is evaluated in one main indication. EMA’s guideline13 on monoclonal antibody development describes parameters that need to be
controlled regarding process, e.g., cell line stability, continuous capability to produce the desired product quality; impurities, viruses, function operational
units, e.g., validation purification column, aseptic filling, column loads, pH, and temperature. Parameters regarding structure are identity, molecular weight,
isoform pattern, extinction coefficient, electrophoretic profiles, chromatographic and spectroscopic profiles, antibody class, subclass, light-chain
composition, primary structure e.g., peptide mapping, amino acid sequencing, and mass spectrometry analysis, N- and C-terminal amino acids e.g.,
C-terminal lysine(s), free sulfydryl groups, disulfide bridge integrity/mismatch, carbohydrate content, oligosaccharide pattern (neutral sugars, amino sugars,
and sialic acids), N-glycosylation on heavy chains, other glycosylation site(s), glycan structures, mannosylation, galactosylation, fucosylation, sialylation, main
glycan structure distribution (e.g., G0, G1, and G2). Regarding function, tests should reflect the clinic e.g., binding and neutralizing. Effector functions (also
when not part of mechanism): ADCC, cytotoxic properties, complement binding and activation, C1q binding, Fc gamma- and neonatal receptor binding
(cell-based assays preferred); antibody antigen affinity, avidity, and immunoreactivity; crossreactivity with immunohistochemistry; complementary
determining regions; target epitope, e.g., protein, oligosaccharide, glycoprotein, glycolipid, amino acid sequence, and carbohydrate structure. Parameters
regarding product are charge variants (quantitatively and qualitatively); chromatography/electrophoresis to detect truncation, dissociation, and
polymerization, impurities: protein A, host cell proteins, DNA, culture or purification residues, downstream residues; C-terminal lysine processing, N-terminal
pyroglutamate, deamidation, oxidation, isomerization, fragmentation, disulfide bond mismatch, N-linked oligosaccharide, and glycation (orthogonal
methods). General tests involve drug quantity, appearance, solubility, pH, osmolality, extractable volume, sterility, bacterial endotoxins, and visible and sub-
visible particulate matter on batch release and for stability.
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