# Biosimilar Medicines: From Development Process to Marketing Authorization by the EMA and the FDA
## 2 Overview of Biosimilar Medicines
### Biosimilar Medicines  
So far, there is no agreement among regulatory authorities on a universal definition for biosimilar medicine; however, they all emphasize that the main characteristic of these products is their high similarity to a certain previously approved biological product that served as a reference. Table 1 presents the definition of biosimilar medicine according to two of the main regulatory authorities, the EMA and the FDA. As the name implies, biosimilars are not an exact copy of their reference medicine, but they have a high degree of similarity in terms of physicochemical properties, safety and efficacy profile [13; 14]. When the API is a protein, the biosimilar medicine must contain exactly the same amino acid sequence and the same protein folding (3D structure) as the reference medicine [2]. However, considering that these products are made by living organisms that can carry some intrinsic degree of variability due to post-translational structural modifications they may be subjected to, this variability must be within acceptable limits to guarantee the safety and efficacy of the product [6]. The quality of these products depends mainly on their manufacturing process. The process used to produce the biological medicine is privately owned by the pharmaceutical company that developed it, so the biosimilar producer must develop its own manufacturing process. Given that each manufacturer uses a unique cell line, with a different growth medium and culture conditions to produce the biosimilar, some differences can be observed in comparison to its reference product [15]. These small differences can lead to unexpected adverse reactions, so the manufacturer must guarantee that the biosimilar meets the same requirements of safety, efficacy and quality that the reference product [2]. In relation to the final product, the biosimilar must have the same geology and route of administration of the reference medicine [14]. There may be some differences in the formulation (e.g., excipients), presentation (e.g., powder to be reconstituted/solution ready for injection) and administration device (e.g., type of delivery pen); however, they cannot affect the safety and efficacy of the final product [2]. The development of biosimilar medicines is quite different from the reference biological medicine, as shown in Figure 2. To develop a biological medicine, an extensive research and development (R&D) phase is required to find a molecule with the ideal characteristics. Non-clinical studies and phase I, II and III clinical studies are mandatory to guarantee the safety and efficacy of the new medicine. From discovery to phase III clinical studies, the process takes approximately twelve years. In the case of biosimilar medicines, they are approved by a shortened process since they are copies of products already on the market and with well-established characteristics so there is no need to carry out the research phase and initial efficacy studies (phase II clinical studies), which reduces the process time to approximately eight years and the development costs by 10-20% [16]. As a result, these medicines reach the market faster and at a more affordable price compared to the reference product. This improves patient access to these treatments and may lead to a reduction in the price of the reference biological medicine, due to the competition between the off-patent biological products and biosimilar medicines market [5]. \begin{table}
\begin{tabular}{p{113.8 pt} p{113.8 pt}} \hline \hline
**Regulatory Authority** & **Biosimilar Medicine Definition** \\ \hline EMA & “Biological medicine highly similar to another biological medicine already approved in the EU” [2]. \\ FDA & “Biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product” [12]. \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Definition of biosimilar medicine by the EMA and the FDA.