MSC Manufacturing for Academic Clinical Trials: From a Clinical-Grade to a Full GMP-Compliant Process

Following European regulation 1394/2007, mesenchymal stromal cell (MSCs) have become
an advanced therapy medicinal product (ATMP) that must be produced following the good
manufacturing practice (GMP) standards. We describe the upgrade of our existing clinical-grade
MSC manufacturing process to obtain GMP certification. Staff organization, premises/equipment
qualification and monitoring, raw materials management, starting materials, technical manufacturing
processes, quality controls, and the release, thawing and infusion were substantially reorganized.
Numerous studies have been carried out to validate cultures and demonstrate the short-term stability
of fresh or thawed products, as well their stability during long-term storage. Detailed results of media
simulation tests, validation runs and early MSC batches are presented. We also report the validation
of a new variant of the process aiming to prepare fresh MSCs for the treatment of specific lesions
of Crohn’s disease by local injection. In conclusion, we have successfully ensured the adaptation of
our clinical-grade MSC production process to the GMP requirements. The GMP manufacturing of
MSC products is feasible in the academic setting for a limited number of batches with a significant
cost increase, but moving to large-scale production necessary for phase III trials would require the
involvement of industrial partners.