Background: OPKO Biologics is a clinical-stage public company developing long-acting therapeutic proteins utilizing CTP technology. The technology involves fusion of the C-terminus peptide of human chorionic gonadotropin (hCG), a highly O-glycosylated peptide, to the target protein. CTP enabled the production of a long-acting human growth hormone (hGH) (MOD-4023) that supports a single-weekly injection in growth hormone-deficient patients. MOD-4023 is manufactured as a non-viscous liquid formulation.
Objective: Effective inactivation and/or removal of viruses in the downstream manufacturing process of MOD-4023 was validated as part of the regulatory requirement to demonstrate the safety of pharmaceutical products derived from a biological source.
Design and methods: The overall study design consists of a detergent-based virus inactivation step, a virus filtration step, and three chromatographic steps (anion exchange chromatography, mixed-mode chromatography, and cation exchange chromatography). Chromatography-based removal of four different viruses with distinct characteristics was evaluated with fresh resins and with used resins at the end of column lifetime. In addition, carry-over runs were conducted, in which the effectiveness of the regeneration/sanitization procedures was evaluated. In these studies, the removal of residual viruses potentially left on the column was demonstrated using non-virus-spiked runs.
Results: The viral validation study had demonstrated that the manufacturing process of MOD-4023 provides a total clearance of >20 log for lipid-enveloped viruses and >9 log for chemically resistant, non-enveloped small viruses. Moreover, the process consists of 2 to 5 robust removal steps for each of the viruses.
Conclusions: The manufacturing process of MOD-4023 provides a robust removal of viruses, with high virus reduction capabilities and high safety margins (>14 log). The study demonstrates a safe production process, in accordance with FDA and EMA requirements.