The clinical development of cell therapies is revealing that extracellular vesicles (EVs) may become very instrumental as subcellular therapeutic adjuncts in human medicine. EVs are released by various types of cells, grown in culture, such as mesenchymal stromal cells, or obtained from patients or allogeneic donors. Some EV populations (especially species of exosomes and shed microvesicles) exhibit inherent roles in cell-cell communication, thanks to their ca. 30∼1000-nm nanosize and the physiological expression of cell-specific markers on their lipid bilayer membranes. Biomedical engineers are now attempting to exploit this cellular crosstalk capacity to use EVs as smart drug delivery systems that display substantial benefits in targeting, safety, and pharmacokinetics compared to synthetic nanocarriers. In parallel, the development of a set of nano-instrumentation, biochemical tools, and preclinical assays needed for optimal characterization of both naïve and drug-loaded EVs is ongoing. Although many hurdles remain, owing to the complexity of EV populations, translation of this “subcellular therapy” platform into reality is at hand and may soon change the landscape of the therapeutic arsenal in place to treat human degenerative and metabolic pathologies as well as diseases like cancer. Researchers from Taipei Medical University and Eastern Virginia Medical School provide objective opinions, balanced between unrealistic hopes of the capacity of EVs to resolve multiple clinical issues and concrete hurdles that have to be overcome to ensure that EVs are not lost in the translation phase, so that EVs can fulfill their promise by becoming a reliable therapeutic modality.
Phase-by-phase proposed development of an industrial microvesicle (MV) project and main stakeholders (identified in boxes with a light-blue background).
After conducting pilot-scale design and validation of the MV production process at the research and development scale, the MV producer engages a contract manufacturing organization to produce MV batches for clinical trials under investigational new drug status, or equivalent, under supervision of a competent National Regulatory Authority (NRA). Once clinical data are conclusive, the MV producer hires an engineering company specializing in the biotechnology industry, which by closely following the user requirement specifications from the MV producer, can proceed with the conceptual, basic, and detailed design phases of the facility and select suitable equipment from qualified biotechnology industry suppliers. Next, the construction of the facility and the making of equipment go through the qualification phases: design qualification (DQ), installation qualification (IQ), factory acceptance tests (FAT), site acceptance tests (SATs), operational qualification (OQ), performance qualification (PQ), and production of consecutive MV validation batches meeting pre-established quality specifications. Following submission and approval of all the required validation and clinical documentation, the manufacturing site is licensed, and the MV product receives a marketing authorization by the relevant NRA. The MV producer operates the facility under good manufacturing practices (GMPs) and conducts quality audits of the suppliers of raw materials (eg, growth medium; fetal bovine serum, and buffer components) and excipients used during manufacture. The facility is operated under GMPs and is subjected to periodic NRA inspections to maintain manufacturing site license and MV marketing authorization. The MV product is subject to pharmacovigilance, in particular to monitor adverse reactions. Reprinted from of Trends Biotechnol. 37. Agrahari V, Agrahari V, Burnouf PA, Chew CH, Burnouf T. Extracellular microvesicles as new industrial therapeutic frontiers. 707–729. Copyright (2019)3. With permission from Elsevier.Abbreviation: QRM, quality risk management.