Although it is a known fact that biologics and biosimilars are significantly indifferent, there are some differences between the two drugs when it comes to the manufacturing. Biologic medicines are extremely complex when it comes to their structure. They are also very sensitive to manufacturing conditions and thus more difficult to characterize and produce in comparison to small molecule drugs. Biologics have the opportunity to be 200 to 1000 times the size of small molecule drugs. A biologic is an extremely large molecule, which is synthesized by different cellular systems using recombinant DNA technology. The slightest changes during the manufacturing may lead to significant changes in the cellular systems used for biologic production. Slight differences in the structure, stability, or other quality aspects of the end product may also cause significant changes. A change in these conditions has the potential to affect the tolerability and/or the efficacy of the drug and increases the risk of immune responses (4,14).
As noted before, Bevacizumab was subsequently produced by humanizing the A4.6.1 antibody in order for it to contain human constant region sequences (93%) and murine light and heavy chain Complementarity Determining Region sequences (7%). During the manufacturing of bevacizumab, the plasmid that is responsible for the encoding of bevacizumab is inserted into Chinese hamster ovary parental cells (CHO-cells). The final drug substance is obtained with the help of fermentation, purification and characterization. These processes are very complicated and require a lot of precision. During the fermentation, the cells that contain the plasmid undergo three types of trains during which the production of the cultures is initiated and has the ability the expand the cell population. With the help of centrifugation, the production culture fluid can be separated from cells and is captured in the harvested cell culture fluid (HCCF). After obtaining the secreted bevacizumab in the HCCF, it undergoes purification. The purification process consists of several complex steps wherein the HCCF, CHO-proteins, DNA and any potential viruses get reduced. It also ensures that any bevacizumab aggregates and the excipients used for purification are left behind. During the final step, characterization, any differences between a reference standard and the bevacizumab samples is observed. It is important that there are no significant differences among the samples (15).
Once the purified bevacizumab has been approved, it is ready to be used for the production of clinical material and will eventually be used as a basis for the final drug substance that is intended for the marketing (15).
Biosimilars are often mistakenly thought of as generic versions of biologically-derived or biotechnology-derived drugs. Generic drugs are chemically synthesized small molecular drugs which are the equivalent of an originator (biologic) and may only differ in the inactive ingredients(16). However, unlike generic drugs, biosimilars are, as their name states, similar but not identical to their originators. Minor differences among the active ingredients are allowed, as long as the differences are not significant (5).
The primary amino acid sequence of Mvasi® is identical to the sequence of Avastin® (10). However, the manufacturing processes for biologics are typically proprietary, which is why pharmaceutical companies without access to this information have to produce biosimilars using existing technologies. The process requires production and purification from living systems such as bacteria, yeast or mammalian cell lines. Since the scientific discussion of Mvasi® has yet to be made public, it is impossible to make a statement about the specific development of this biosimilar. Nevertheless, it can be noted that biosimilars are manufactured through a process of reverse engineering and have to undergo several steps in order to become a suitable biosimilar (5).