Abstract
Background: The selection of assays suitable for testing the potency of clinical grade multipotent mesenchymal stromal cell (MSC)-based products and its interpretation is a challenge for both developers and regulators. Here, we present a bioprocess design for the production of Wharton’s jelly (WJ)-derived MSCs and a validated immunopotency assay approved by the competent regulatory authority for batch release together with the study of failure modes in the bioprocess with potential impact on critical quality attributes (CQA) of the final product. Methods: The lymphocyte proliferation assay was used for determining the immunopotency of WJ-MSCs and validated under good manufacturing practices (GMP). Moreover, failure mode effects analysis (FMEA) was used to identify and quantify the potential impact of different unexpected situations on the CQA. Results: A production process based on a two-tiered cell banking strategy resulted in batches with sufficient numbers of cells for clinical use in compliance with approved specifications including MSC identity (expressing CD73, CD90, CD105, but not CD31, CD45, or HLA-DR). Remarkably, all batches showed high capacity to inhibit the proliferation of activated lymphocytes. Moreover, implementation of risk management tools led to an in-depth understanding of the manufacturing process as well as the identification of weak points to be reinforced. Conclusions: The bioprocess design showed here together with detailed risk management and the use of a robust method for immunomodulation potency testing allowed for the robust production of clinical-grade WJ-MSCs under pharmaceutical standards.
Highlights
Cell-based medicinal products hold the promise to bring therapeutic alternatives to address unmet medical needs [1,2,3]
According to quality risk management, we studied in detail potential failure risks in critical steps involved in the production process using failure mode and effects analysis (FMEA) [9] and identified parameters that may lead to potential out-of-specification (OOS) of any of the critical quality attributes (CQA) of the final Wharton jelly (WJ) mesenchymal stromal cell (MSC)-based product, with special attention being given to the immunopotency assay currently used for batch release
Further expansion was performed after thawing for the generation of either working cell bank (WCB) or drug product (DP) directly using expansion medium composed of Dulbecco’s modified Eagle’s medium (DMEM) containing 2 mmol/L glutamine and supplemented with 10% hSerB
Summary
Solid data on efficacy are jeopardized by poor translation of preclinical results that may have been interpreted too optimistically [5,6] In this sense, a huge effort is currently being made to define specific target conditions that could be realistically treated with such therapies, which requires robust methods of production and suitable potency assays directly related to the mechanism of action [7]. A huge effort is currently being made to define specific target conditions that could be realistically treated with such therapies, which requires robust methods of production and suitable potency assays directly related to the mechanism of action [7] This is a major challenge for both developers and regulators, since the pharmacological activity of MSCs is poorly understood, and the choice of an appropriate potency assay needs to be agreed with the competent regulatory authority. Conclusions: The bioprocess design showed here together with detailed risk management and the use of a robust method for immunomodulation potency testing allowed for the robust production of clinical-grade WJ-MSCs under pharmaceutical standards
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