Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) may deliver therapeutic effects that are comparable to their parental cells. MSC-EVs are promising agents for the treatment of a variety of diseases. To reach the intermediate goal of clinically testing safety and efficacy of EVs, strategies should strive for efficient translation of current EV research.
On the basis of their in vitro an in vivo findings regarding the biological actions of EVs and their experience in manufacturing biological stem cell therapeutics for routine use and clinical testing, researchers at Paracelsus Medical University discuss strategies of manufacturing and quality control of umbilical cord-derived MSC-EVs. The researchers introduce guidelines of good manufacturing practice and their practicability along the path from the laboratory to the patient. They present aspects of manufacturing and final product quality testing and highlight the principle of “The process is the product.” The approach presented in this perspective article may facilitate translational research during the development of complex biological EV-based therapeutics in a very early stage of manufacturing as well as during early clinical safety and proof-of-concept testing.
Manufacturing of UC-MSC-EV potential therapeutics
The manufacturing scheme of UC-MSC-EV–based putative therapeutics depicts the main steps covering the upstream processing phase and the downstream technologies until filling and storage established in compliance with GMP. Growth-supporting additives such as human- or animal-derived sera should be depleted of endogenous extracellular vesicles before use in cell expansion to prevent contamination of the source cell–derived EVs, which are isolated from conditioned medium. EV purification is performed using tangential flow filtration (TFF) combined with a short ultracentrifugation (UC) step. A consistent quality control (QC) strategy for the final product testing is needed to fulfill regulatory requirements and to achieve the approval for clinical testing of the putative novel drug. In a very early stage of clinical testing of biological investigational medicinal products (IMPs)/investigational new drugs (INDs), the principle of “the process is the product” can be applied. It helps to bridge the initial phase of lacking knowledge regarding the active substance and the MoA responsible for a specific therapeutic activity until proof of mechanisms and therapeutic activity are identified and a clinical trial (CT) initiated.
Rohde E, Pachler K, Gimona M. (2019) Manufacturing and characterization of extracellular vesicles from umbilical cord-derived mesenchymal stromal cells for clinical testing
[Epub ahead of print]. [article