The Basics

Biosimilars versus generics

There are important differences between biologics (or biopharmaceutical medicines) and “ordinary” or conventional medicines (that contain chemical active substances) and these, of course, also hold true for biosimilars and generic medicines.1

Key differences

Firstly, biologics are produced by living cell cultures (and hence there is always slight variability), whereas ordinary medicines are produced by chemical synthesis (the latter which yields a final structure that is always the same and easily verified). In addition, biologics consist of molecules that are much larger (with high molecular weights) than the smaller chemical active substances (with low molecular weights) found in conventional medicines.

The active molecules in biologics (and biosimilars) are proteins or polypeptides. Proteins are made from amino acids and a single protein can contain many such amino acids. Polypeptides are linear chains of amino acids. Apart from amino acids, sugars or carbohydrate groups may also be incorporated in such amino acid chains. Once the amino acids and other sugars or carbohydrates have been joined together, the protein will fold into a specific shape. This is important, because this 3-dimensional shape will determine how well the protein binds to its receptor on cell membranes or other surfaces. 1,2,3

Biologics in current clinical use differ widely in terms of the size and structural complexity of their proteins and may range from simple proteins like insulin or growth hormone to more complex proteins such as coagulation factors or monoclonal antibodies.3 Since all biopharmaceutical medicines, whether a biologic or a biosimilar, are produced by living cell cultures, the end product has to be purified (or separated) from the thousands of other proteins or molecules present in a living cell. The production process for a biosimilar is therefore much more complicated than for an ordinary generic medicine and requires sophisticated and validated technologies.1

Size and structure

From the below it can be seen that biologics have complex, heterogenous structures and manufacturing processes whereas orthodox medicines have well-defined structures and manufacturing processes.

Biologic/Biological Drug
  • Produced by living cell cultures
  • High molecular weight
  • Complex, heterogeneous structure and manufacturing process
  • Strongly process-dependent
  • Impossible to fully characterize molecular composition and heterogeneity
  • Unstable, sensitive to external conditions
Chemical/Small Molecule Drug
  • Produced by chemical synthesis
  • Low molecular weight
  • Well-defined structure and manufacturing process
  • Mostly process-independent
  • Completely characterized chemicals
  • Stable

The final quality, safety, and efficacy of a biologic strongly depends on the process, whereas it is mostly process-independent for small molecule chemicals. Given the complexities of high-molecular weight proteins, it is impossible to fully characterise the molecular composition and heterogeneity of a biopharmaceutical; however, the molecular composition of conventional medicines has been completely characterised. Lastly, biopharmaceuticals are unstable and sensitive to external conditions, whereas small molecule medicines are comparatively stable.2

Due to these striking differences in size and structure, the marketing approval or registration process (i.e., the process through which medicines are evaluated prior to being authorised for use in humans) for ordinary medicines and biosimilars are also fundamentally different. Whereas there is usually a fixed set of criteria governing the approval process of generic medicines, the evaluation process and comparability criteria may be defined for each biosimilar on a case-by-case basis, given the complexities of the substances involved.1,2

Biosimilars and generic medicines do, however, have one remarkable characteristic in common in that both biosimilars and generics have greatly improved access to affordable healthcare by stimulating competition.1,2,3