Development and Regulatory Evaluation of Biosimilars

Biologics are large molecules—hormones, cytokines, monoclonal antibodies, vaccines—created by the process of recombinant DNA technology in living cells. These products have greatly contributed to therapeutic breakthroughs in oncology and inflammatory disorders among others.

As patents for many of these biologics begin to expire in the next few years, opportunities arise for developing generic versions of original biological products with similar biological activities (termed “biosimilars”). In this post, we will discuss the basic knowledge, current status, and technical challenges in the development and regulation of biosimilars.

Challenges in manufacturing biosimilars

Unlike small molecular drugs—which generally have robust production processes—biologics are large protein molecules produced by genetically engineered organisms through a complex series of steps: selection of host systems (bacteria, yeast, insect cells, or mammalian and human cell lines), cloning tools and expression systems, and purification processes.

Producing copy versions of biologics directly inherits these layers of complexity. In addition to possessing a similar primary amino acid sequence, the produced biosimilar should retain proper post-translational modifications and be a stable, appropriately folded, biologically active soluble biological product that is highly similar to the original biologic.

Comparability studies essential for validating biosimilars

Based on the FDA guidance documents and the EU regulatory framework for biosimilars (refer to the FDA and EU websites), the development of biosimilars is highly regulated owing to their complex nature, and biosimilars would be authorized only if they are demonstrated to be highly similar to the original biologics from a physiochemical and clinical perspective.

Using the first generation biologic as a reference product, it is essential to ensure close resemblance of the biosimilar to the reference product in the aspects of the drug target, mechanism of action, primary structure, physiochemical properties, efficacy, and safety. We summarize here the major characterizations that need to be carried out when conducting comparability studies:

Physiochemical properties

The first step of the comparability exercise requires extensive examination of both the biosimilar and the reference product to provide similarities and potential differences in structure (including secondary, tertiary and quaternary structures), physiochemical properties (e.g., aggregation, precipitation, cellular impurities), and manufacturing quality (e.g., batch-to-batch variability). If the differences detected exceed the variability limit of the reference product, “similarity” might not be justified.


Most of the clinical immunogenicity issues observed are connected to host-produced neutralizing antibodies. Effects from the formation of antidrug antibodies responding to a given biologic therapy not only compromise its bioavailability but also potentially cause serious adverse events. Given that small differences—such as glycosylation status—might have immunogenic consequences, immunogenicity studies along with pharmacokinetic/pharmacodynamic data should be included in comparability studies.

Biological activity and clinical performance

Sensitive bioassays and clinical endpoints should be employed to compare the reference product to the biosimilar in parallel at the same dose and route of administration. If biochemical, biophysical, and biological data can demonstrate that they are highly similar so that equivalence in clinical performance (pharmacokinetics/pharmacodynamics) can be assured, minimal clinical studies may be sufficient.

Approval of biosimilars in the EU and US

In 2005, the European Medicines Agency (EMA) was the first agency to issue scientific and regulatory guidelines for a path toward developing and marketing biosimilars. Since then, the EMA has approved 14 biosimilars including the first monoclonal antibody (Inflectra, a biosimilar of infliximab) in 2013. Under the Biologic Price Competition and Innovation (BPCI) Act, the US FDA was recently poised to approve the first biosimilar version for Neupogen (filgrastim), an immune-boosting drug for people undergoing cancer treatment originally made by Amgen.

In closing, the development of biosimilars is important because they are expected to meet worldwide demand and patients may have a greater chance to access potentially valuable therapeutics at a lower cost. Since biosimilars are not precisely identical, they are required to undergo many tests to ensure similar biological activity, physiochemical characteristics, efficacy, and safety by using sensitive and validated analytical tools.

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Categories: Inflammatory diseases, Oncology


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