GMP‐Compliant Process for the Manufacturing of an Extracellular Vesicles‐Enriched Secretome Product Derived From Cardiovascular Progenitor Cells Suitable for a Phase I Clinical Trial

Abstract

Extracellular vesicle (EV)-enriched secretomes are emerging as a new and innovative therapeutic option in the field of regenerative medicine. The clinical use of EV-enriched secretome-based products requires manufacturing processes and quality control (QC) testing that comply with current good manufacturing practice (GMP). The goal of this work was to develop a robust and reproducible large-scale GMP-compliant process for the production of an EV-enriched secretome derived from cardiovascular progenitor cells (CPC), including the vesiculation of CPC, purification and concentration of the product; and sterilising filtration. QC strategies for in-process and release testing of an investigational medicinal product (IMP) were developed to guarantee quantity, safety, purity and identity. The IMP showed biological activity and was non-immunogenic in vitro, and showed no signs of toxicity or tumour development in vivo. The IMP was approved for use in a single-centre Phase I clinical trial by the French National Agency for Medicines and Health (ANSM) for the treatment of heart failure. The IMP is stored between -65°C and -85°C and can be easily diluted by the hospital pharmacy for infusion to the patient. This work represents a major advance for the use of CPC derived EV-enriched secretomes as a biological drug for cardiac clinical applications. Trial Registration: ClinicalTrials.gov identifier: NCT05774509.