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

Virginie Bettonville,Alexandra Briquet,Chantal Lechanteur,Etienne Baudoux,Yves Beguin

doi:10.3390/cells10061320

Abstract

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.

Highlights

Cell-based therapy is a fast-growing field including various cell products and indications
While enforcing good manufacturing practice (GMP) standards on our mesenchymal stem or stromal cells (MSCs) banking activity, we introduced some changes in reagents and disposables that were not mandatory according to the regulation, but that we had found appropriate
Three large-scale clinical MSC cultures were initiated for validation of the GMP manufacturing process

Summary

Introduction

Cell-based therapy is a fast-growing field including various cell products and indications. The first success for cell-based therapies was bone marrow (BM) transplantation around 60 years ago. Mesenchymal stem or stromal cells (MSCs) are one of the most studied, with more than 1500 ongoing clinical trials (https://clinicaltrials.gov, accessed on 26 May 2021) investigating their regenerative properties and immunomodulatory potential. MSCs are evaluated in numerous indications, such as graft-versus-host disease (GVHD), autoimmune and inflammatory diseases (Crohn’s disease, etc.), heart failure, solid organ transplantation, liver or kidney failure, and bone diseases [1,2,3,4,5,6,7,8]. Most of them are phase I–II studies with only around

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