4.10 Purity

Understanding biosimilarity

potential biological relevance; this product may not qualify as a biosimilar product. • Ensuring high similarity with no analytical difference between all CQAs which could impact ef cacy, immunogenicity, and safety. • Ensuring high similarity with no analytical differences for all

CQAs and a statistically rigorous pattern match for all other quantitative attributes relative to that of the reference product lots.

The factors that can potentially impact the ability to demonstrate that the biosimilar product is highly similar to the reference product may include, for example, the ages of the biosimilar product and reference product lots tested; optimizing assays and prespecifying the criteria under which wider similarity acceptance criteria for a particular assay would be considered appropriate. As more advanced and reproducible methods become available to characterize molecules, new possibilities have arisen to make the orthogonal testing an excellent tool to remove any residual uncertainty. Since these testings may require novel methods, the regulatory agencies do not need the test procedures used for analytical and functional similarities to be fully validated, just proven suitable. However, any method used to release the product must be validated as is required for all testing.

This element of the biosimilarity tetrahedron includes impurities that are related to the product, as well as the process; for example, a genetic mutation producing an excess of the acetylated product beyond the accepted purity pro le will be a signi cant event. These variations are related to the structure of the recombinant cell line and are very dif cult to modulate. However, some binding characteristics and glycan patterns are dependent on process conditions and where possible need to be optimized. More speci cally, the impurities may come from the following: • The majority molecular form and its variants and isoforms, each carrying an intrinsic biological activity close to the majority molecular form’s biological activity (for instance, erythropoietin [EPO] and its isoforms and three distinct forms present in etanercept) • The impurities that are linked to the product but which practically carry no biological activity; these may come from degradation as well • The impurities linked to the production process or to the puri cation scheme

175