UWE GUDAT
Head of Safety, Biosimilars
Merck Biosimilars
Aubonne , Switzerland

Abstract

Biologics have revolutionised medical practice. They have improved the outcomes, the length and quality of life of patients in the diverse fields of endocrinology, haematology, oncology, and inflammatory disorders. As the patents for some of the ground-breaking monoclonal antibodies expire, the door opens for corresponding copies.
The distinctive feature of a biologic medicinal product (BMP) is that it is manufactured using living cells. The complexity of these molecules is such that they cannot be synthesized using conventional chemical methods. Recombinant technology makes it possible to selectively introduce specific genetic material into suitable host cells. Under appropriate conditions the genetically modified cells replicate, transcribe and translate the introduced genetic material to synthesise the desired BMP. The BMP is subsequently isolated and purified from the cells and culture medium.

The science
The genetic material introduced into the host cell sets the amino acid sequence and the primary structure of the synthesised molecule. This describes only in part of what occurs. Most peptides and proteins are further processed, e.g. in the endoplasmic reticulum and Golgi apparatus. These refinements are referred to as post-translational modifications (PTM) as they occur after the synthesis of the primary amino-acid chain. PTM are influenced by environmental conditions such as enzyme activities, availability of substrates, temperature etc. Aside from miss-incorporation that is essentially an error in the translation, almost all the heterogeneity in a given biologic is attributable to PTM (1, 2). In sum the PTM can influence the spatial organisation of a BMP, its functional properties and clinical behaviour (3). It is therefore, that much attention is given to process details as these influence the nature and extent of PTM during manufacturing and thus a product’s characteristics, i.e. its quality attributes (4).
Most small molecular therapeutics generally contain only one unique active component. In contrast, the active ingredient ...