Evolution of Approaches to the Development, Life Cycle Control, and Interchangeability of Veterinary Biosimilars Based on Hemoproteins (with a Focus on Cytochrome C).

Abstract

<b>Background/Objectives:</b> Biosimilars are central to the modernization of veterinary pharmacology, improving access to complex biological therapies while maintaining quality, safety, and efficacy. Hemoproteins such as cytochrome c, used to support liver function and manage metabolic disorders in animals, are of particular interest. However, their structural complexity and species-specific pharmacology create significant analytical and regulatory challenges for biosimilar development and life-cycle management. Addressing these issues is critical for improving therapeutic outcomes and enabling the broader adoption of biosimilars in veterinary practice. <b>Methods:</b> This narrative review examines the scientific and regulatory principles underlying the development of veterinary biosimilars of hemoproteins, with cytochrome c as a representative model. Regulatory guidelines and relevant scientific literature were analyzed to identify key challenges, knowledge gaps, and required adaptations from human to veterinary medicine, with a focus on biosimilar assessment and life-cycle management. <b>Results:</b> Veterinary biosimilar frameworks are largely informed by EU and US regulatory pathways, emphasizing the stepwise demonstration of biosimilarity through extensive analytical and functional characterization. Long-term safety and efficacy depend on robust Pharmaceutical Quality Systems and effective life-cycle management to ensure manufacturing consistency. For cytochrome c, interchangeability may be acceptable when analytical similarity is exceptionally high. Critical Quality Attributes include polypeptide integrity, heme-protein interaction, iron redox state, and correct three-dimensional conformation. Quality by Design approaches are essential to control manufacturing variability. Despite regional regulatory differences, core scientific principles remain consistent. <b>Conclusions:</b> Hemoprotein biosimilars hold significant promise in veterinary medicine, provided their development is supported by rigorous analytical characterization, strong life-cycle management, and science-based regulatory approaches.