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Background/Objectives: For several decades, protein drugs (biologics) made in cell cultures have been delivered as sterile injections, decreasing their affordability and patient preference. Angiotensin Converting Enzyme 2 (ACE2) gum is the first engineered human blood protein expressed in plant cells approved by the FDA without the need for purification and is a cold-chain and noninvasive drug delivery. This biologic is currently being evaluated in human clinical studies to debulk SARS-CoV-2 in the oral cavity to reduce coronavirus infection/transmission (NCT00543318). Methods: Chemistry, manufacturing, and control (CMC) studies for the ACE2/Ang(1-7) drug substances (DSs) and ACE2 gum drug product (DP) were conducted following USP guidelines. GLP-compliant toxicology studies were conducted on Sprague Dawley rats ( n = 120; 15/sex/group) in four groups-placebo, low (1.6/1.0 mg), medium (3.2/2.0 mg), and high (8.3/5.0 mg) doses IP/kg/day. Oral gavage was performed twice daily for 14 days (the dosing phase) followed by the recovery phase (35 days). Plasma samples ( n = 216) were analyzed for the product Ang(1-7) by ELISA. Results: The ACE2 protein was stable in the gum for at least up to 78 weeks. The toxicology study revealed the dose-related drug delivery to the plasma and increases in the AUC (56.6%) and Cmax (52.9%) after 28 high-dose gavages (95% C.I.), although this quantitation excludes exogenously delivered membrane-associated ACE2/Ang(1-7). Vital biomarkers and organs were not adversely affected despite the 10-fold higher absorption in the tissues, demonstrating the safety for the first in-human clinical trials of ACE2/Ang(1-7). The NOAEL observed in the rats was 2.5-7.5-fold higher than that of the anticipated efficacious therapeutic dose in humans for the treatment of cardiopulmonary disorders, and it was 314-fold higher than the NOAEL for topical delivery via chewing gum. Conclusions: This report lays the foundation for the regulatory process approval for noninvasive and affordable human biologic drugs bioencapsulated in plant cells.