IntroductionHereditary factor X deficiency is a rare bleeding disorder, with limited treatment options. This paper describes the approach to pre‐clinical development and characterization of a high‐purity plasma‐derived factor X concentrate, to achieve orphan drug marketing authorization for the treatment of hereditary factor X deficiency.MethodsA chromatographic process was developed, to purify factor X from human plasma for fractionation. The product was characterized using in vitro, in vivo and ex vivo tests for potency, purity, thrombogenicity, immunogenicity, toxicity and stability.ResultsThe production process complied with good pharmaceutical manufacturing practice. It achieved 6000‐fold purification and 100‐fold concentration of the factor X protein compared to human plasma. The factor X protein was 94%–96% pure. Other residual plasma proteins were well below levels in plasma, minimizing potential interference in hemostasis after therapeutic administration. Effective virus‐reduction during manufacture, and the absence of thrombogenicity, toxicity and immunogenic potential were confirmed, addressing the main safety concerns historically associated with plasma‐derived therapeutics. The freeze‐dried product remained stable between +2°C and +30°C for at least three years. After reconstitution with water for injections, the factor X activity was maintained for at least 48 h at +18°C to +22°C.ConclusionTargeted pre‐clinical development of the first highly‐purified concentrate to treat hereditary factor X deficiency is described. Following international guidelines for nonclinical safety testing, particular strategies were adopted for unmodified products derived from human blood plasma. This approach may also be relevant to the development of other ultra‐orphan medicinal products.
