Development of biosimilars.

Objective: To provide an overview of the underlying scientific principles and standards for developing a biosimilar product.

Methods: An Internet-based literature search through June 2015 was performed for information related to biosimilar manufacturing and development, including a review of regulatory guidelines and requirements.

Results: Biologics, both biosimilars and their corresponding reference products, are complex molecules produced by biotechnology in living systems. The development of biologics involves multiple levels of intricate, highly controlled manufacturing processes, combined with pre-clinical structural, functional, and biological assessments, as well as clinical efficacy and safety, including immunogenicity, analyses. In addition, to ensure a high degree of similarity, a biosimilar must undergo a comparability exercise at every step of its development, as outlined by regulatory agencies, to demonstrate that potential differences from the reference product are not clinically meaningful with regard to quality, safety, and efficacy [European Medicines Agency (EMA)] or safety, purity, and potency [US Food and Drug Administration (FDA)]. At the foundation of the biosimilar development process lays the establishment of a high degree of structural similarity with its reference product. State-of-the-art technologies must be employed to demonstrate a high degree of structural and functional similarity. Finally, clinical pharmacokinetic and pharmacodynamic as well as clinical efficacy and safety similarity must be confirmed between biosimilar and originator. Regulators, including the FDA and the EMA consider the totality of the evidence from this comprehensive step-wise comparative similarity exercise in its determination of biosimilarity for licensing.

Conclusions: The rigorous and highly regulated processes required to develop a biosimilar have been designed as such to establish a high degree of biosimilarity with a reference product in terms of the structural, functional, biological, and clinical attributes.