P221: Physicochemical Characteristics of the Iron-Carbohydrate Complexes, Venofer and an Approved Iron Sucrose Generic
Global Lead Non-Biological Complex Drugs
Vifor Pharma Switzerland
The full spectrum of critical quality attributes Iron-carbohydrate complexes has not been established. The purpose of this study was to characterize the physicochemical characteristics of the reference listed drug (RLD) Venofer with an iron sucrose generic approved for clinical use in Canada.
A large battery of validated analytical tests were performed on two batches of pms-iron sucrose (Pharmascience, Canada) and compared to batch standards for Venofer (Vifor Pharma, LTD, Switzerland) in accordance with USP requirements as well as additional techniques validated for iron nanoparticles.
The following tests were performed in accordance with USP specifications; molecular weight, specific gravity, alkalinity, osmolarity, pH, turbidity, presence of particulate matter and reduction potential. All test results met USP specifications for both the RLD and iron sucrose similar. Additional validated tests for nanoparticle preparations were also performed including; 13C nuclear magnetic resonance (NMR), dynamic light scattering, polydispersity index (PDI), zeta potential, labile iron release, in vitro release kinetics (T75), molecular weight (Mw/Mn) and polarography. For 13C-NMR, both pms-IS preparations were within the mean (range) baseline range for Venofer (0.92 (0.82-1.01 µ_eff^2/35)), however, the two pms-iron sucrose batches were lower compared to Venofer (0.264 and 0.262, respectively). Particle size (nm) measured by DLS (reported a Z-average) for the two pms-IS batches was smaller (10.17 and 11.02) compared to mean (SD) values for Venofer (11.43 (11.02 – 11.84)). The polydispersity index also differed for the pms-IS batches (0.094 and 0.095) compared to the baseline range reported for Venofer (0.128 (0.097 – 0.158). All other test results were comparable between pms-IS and Venofer.
Physicochemical characterization is a key step in comparing follow-on copy to an RLD of a drug product. While this approach is well-established for small molecule drugs where the critical quality attributes can be easily established, many research gaps remain with regard to establishing CQAs for nanomedicines. Iron-carbohydrate nanomedicines are particularly complex and results from analytical testing may vary based on laboratory equipment utilized as well as sample preparation techniques. The entire iron-carbohydrate complex dictates the pharmacokinetic (PK) and pharmacodynamic profile (PD) and ultimately tissue biodistribution after which iron becomes bioavailable and can be metabolically utilized by target tissues. Thus, even small differences in physicochemical characteristics may result in different PK/PD profiles. This underscores the need for further research to better understand fully how the physicochemical characteristics affect the in vivo fate of these complex drugs. Until CQAs are fully established, additional data submissions (e.g. pre-clinical biodistribution and/or clinical efficacy studies) should be required to supplement follow on copy applications to regulatory agencies. This study was performed to compare physicochemical characteristics of these two approved products. Further studies are needed to establish details of any clinical differences of these products.