Acceleration of Translational Mesenchymal Stromal Cell Therapy Through Consistent Quality GMP Manufacturing

Abstract

Human mesenchymal stromal cell (hMSC) therapy has been gaining immense interest in regenerative medicine and quite recently for its immunomodulatory properties in COVID-19 treatment. Currently, the use of hMSCs for various diseases is being investigated in >900 clinical trials. Despite the huge effort, setting up consistent and robust scalable manufacturing to meet regulatory compliance across various global regions remains a nagging challenge. This is in part due to a lack of definitive consensus for quality control checkpoint assays starting from cell isolation to expansion and final release criterion of clinical grade hMSCs. In this review, we highlight the bottlenecks associated with hMSC-based therapies and propose solutions for consistent GMP manufacturing of hMSCs starting from raw materials selection, closed and modular systems of manufacturing, characterization, functional testing, quality control, and safety testing for release criteria. We also discuss the standard regulatory compliances adopted by current clinical trials to broaden our view on the expectations across different jurisdictions worldwide.

When Origin Matters: Properties of Mesenchymal Stromal Cells From Different Sources for Clinical Translation in Kidney Disease

“…For this reason, in the absence of proof of product comparability, regulatory authorities are prompted to require further re-validation, which in the worst-case scenario have resulted in pre-clinical data being invalidated and clinical trial approval requiring re-authorization. Thus, optimal manufacturing variables must be considered and identified during early stages of development, as changes in the bioprocess workflow later in the translational pathway may have a significant long-term impact on the success of the therapy with time and cost consequences but also a significant time-to-market delay ( 320 , 321 ). In addition, having full control of the process is crucial for ensuring consistent production and quality standards in terms of safety, identity, and potency, and this control can only be guaranteed by having in place systems of quality assurance (QA) and quality control (QC) across all stages of the bioprocess.…”

“…Due to the concerns mentioned above, the development of new xenogeneic-free, chemically defined formulations is urgently needed. Chemically defined media (CDM) are generally composed of basal media to which supplements of known composition (i.e., growth factors, hormones, attachment factors, binding proteins, and vitamins) are added ( 320 ). An ideal MSC media should contain chemically defined constituents preferably of recombinant human origin that support the isolation and culture expansion of human MSCs obtained from different tissue sources while maintaining MSC phenotypic characteristics, morphology, and mechanism of functional benefit.…”

“…Traditionally, scale-out of MSC manufacturing has been achieved using 2D monolayer cultures using multilayered flasks (Corning® CellSTACK and Nunc TM Cell Factory TM ) of 1 to 40 levels, and surfaces ranging from 636 cm to 25, 440 cm. However, this is not an optimal system for large-scale production of therapeutic doses, as it is labor-intense, requires significant manual handling, and is not cost-effective ( 320 , 364 ). These are also static systems, which lack real-time process monitoring of culture conditions, and are more susceptible to batch-to-batch variation due to a non-homogeneous environment within layers ( 320 ).…”

“…However, this is not an optimal system for large-scale production of therapeutic doses, as it is labor-intense, requires significant manual handling, and is not cost-effective ( 320 , 364 ). These are also static systems, which lack real-time process monitoring of culture conditions, and are more susceptible to batch-to-batch variation due to a non-homogeneous environment within layers ( 320 ). Alternatively, GMP-compliant, closed, automated, high-volume cell expansion systems offer great advantages, as they enable the real-time monitoring of process variables such as pH, pO 2 , pCO 2 , metabolite accumulation or presence of contaminants, and hence it guarantees a homogeneous distribution of culture environment and ensures a culture process under well-controlled and reproducible conditions and production of quality MSCs for clinical use.…”

“…A variety of bioreactors are available including stirred tank bioreactors with microcarriers ( 365 , 366 ), rocking motion ( 367 ), disposable fixed bed ( 368 ), and hollow fiber-based continuous perfusion bioreactors ( 369 , 370 ). The surface area from these bioreactors ranges from 21, 000 cm 2 /unit to up to 3, 750, 000 cm 2 /unit, and they all offer distinct advantages and limitations that must be considered ( 320 , 364 , 371 ). In our search, an overwhelming majority of clinical trials have used 2D culture conditions, with only 1 study considering a 3D bioreactor, the Quantum Cell Expansion System (Terumo BCT) (NEPHSTROM clinical trial, NCT02585622) ( Table 2 ).…”