Manufacturing Scale-up, Purification, and Analytical Method Development, Validation and Qualification for KC1003, Key Precursor for ErythroMer (RBC substitute)

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Project Summary/Abstract ErythroMer (EM) is a novel biosynthetic blood substitute developed to address the critically unmet need for emergency transfusion in situations where the use of banked red blood cells (RBCs) are inaccessible or undesirable. EM is a self-assembled lipid-peptidic hybrid nanoparticle with a high per particle payload of hemoglobin (Hb) that is specifically designed to rectify failures of previous hemoglobin-based oxygen carriers, which do not preserve key features of RBC physiology. The bio-inspired EM design surmounts previous obstacles by emulating RBC features: long term stability, precise dynamically-responsive allosteric effector control of Hb oxygen affinity, control of Hb interaction with nitric oxide (NO), preventing vasospasm, and mitigation of hemoglobin oxidation via payload antioxidants. EM is designed for sterile lyophilization enabling extended shelf life at ambient conditions and offers cost-effective production at scale. KaloCyte has developed a pragmatic yet robust stepwise goal-oriented development plan for GMP commercialization including the scale- up and cGMP manufacturing of ErythroMer and its key ingredients, customized lipid precursor, and hemoglobin. Previously completed studies on the synthesis and scale-up of the lipid precursor, and the purification of hemoglobin from red blood cells (RBCs) have been extremely promising. These studies provide strong evidence of the premise for and feasibility of this proposal and our commitment for the manufacturing scale-up, purification and analytical method development, validation, and qualification of the lipid precursor. The pre-IND stage preclinical studies require EM volumes larger than and at a quality that necessitates CDMO services. Successful completion of the scale-up and analytical work proposed in the current submission will provide KaloCyte the confidence in the manufacturing processes for KC1003, and that the components being used for the fabrication of EM are of the highest quality and fall within the acceptable specifications required by the regulatory agencies. The manufacturing scale-up of KC1003 will include scale specific optimization of key parameters for it manufacturing such as temperature, time, pressure, and reactant concentrations at each step of its manufacturing process. Analytical methods development, validation, and optimization for KC1003, shall be performed as per ICH guidelines recommended by the FDA. Statistical analysis of methods validation data shall be performed to demonstrate the validity of each method. Completion of these steps in the path to product commercialization, will help complete IND-enabling preclinical studies for EM under strict GLP guidelines. EM has the capability to dramatically transform care in life-threatening blood loss situations where stored red blood cells (RBCs) are unavailable (ambulances, military and austere environments, undeveloped countries), undesirable (situations in which risk of transfusion exceeds benefit), or in short supply (mass casualty events).