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Chapter 3: Approaches to the Characterisation of Biosimilars Biosimilars, Biogenerics and Follow-on Biologics words, non-inferiority is the minimum requirement. This approach is applicable to equivalence testing for a natural or rDNA-derived protein, where relevant clinical outcomes should stay within the equivalence interval. Biosimilars should be neither markedly superior nor markedly inferior to the reference product.3.2.9 Immunogenicity Many exogenously administered proteins produce an antibody response, but this usually causes few or no clinical problems. Because significant immune responses occur infrequently, clinical trials may not reveal them, and some type of market surveillance may be needed instead. Many factors affect the immunogenicity of protein therapeutics, including structural and chemical alterations, storage conditions, production/purification techniques, formulation, route of administration, dose and frequency of administration, and various patient characteristics. Immunogenicity may have no clinical impact, if the response is small or transient, or it may produce a spectrum of responses including hypersensitivity and neutralisation of biological effects. Neutralisation may also extend to endogenous proteins related to the therapeutic, as with the incidents of pure red cell aplasia among patients receiving recombinant erythropoeitin. Antibodies may also accelerate or retard clearance of the therapeutic protein. It is important to fully characterise an immune response using both immunoassays, which detect antibodies that bind to the drug, and biological assays, which detect neutralisation of biological effects by antibodies. Human immune responses cannot be predicted from animal testing.3.3 Analytical methods3.3.1 Introduction The ultimate structural characterisation of a protein can be achieved with either nuclear magnetic resonance (NMR) spectroscopy or X-ray crystallography. X-ray structures are the “gold standard” in protein biology because a map of every single atom in a protein can (in principle) be obtained, but X-ray studies take a long time to complete and cannot be done at all for many proteins. Hence we do not discuss it further in this Report. Although computationally intensive, NMR is probably the more practical of these two methods. A variety of other techniques are important in detecting amino acid sequence alterations, differential glycosylation, etc. Table 3.2 summarises the type of information contributed by the most widely used analytical procedures. In this section we review selected techniques in greater depth.3.3.2 Chromatography The general principle of chromatography relies on a matrix, for example consisting of dextran or silica beads, that chemically or physically binds and retains a molecule of interest; contaminating proteins and other impurities interact with the matrix less strongly (or not at all) and become separated in the solvent (also called the eluant). M