A Quality Risk Management Model Approach for Cell Therapy Manufacturing

Abstract

International regulatory authorities view risk management as an essential production need for the development of innovative, somatic cell-based therapies in regenerative medicine. The available risk management guidelines, however, provide little guidance on specific risk analysis approaches and procedures applicable in clinical cell therapy manufacturing. This raises a number of problems. Cell manufacturing is a poorly automated process, prone to operator-introduced variations, and affected by heterogeneity of the processed organs/tissues and lot-dependent variability of reagent (e.g., collagenase) efficiency. In this study, the principal challenges faced in a cell-based product manufacturing context (i.e., high dependence on human intervention and absence of reference standards for acceptable risk levels) are identified and addressed, and a risk management model approach applicable to manufacturing of cells for clinical use is described for the first time. The use of the heuristic and pseudo-quantitative failure mode and effect analysis/failure mode and critical effect analysis risk analysis technique associated with direct estimation of severity, occurrence, and detection is, in this specific context, as effective as, but more efficient than, the analytic hierarchy process. Moreover, a severity/occurrence matrix and Pareto analysis can be successfully adopted to identify priority failure modes on which to act to mitigate risks. The application of this approach to clinical cell therapy manufacturing in regenerative medicine is also discussed.

Use of the quality management system "JACIE" and outcome after hematopoietic stem cell transplantation

“…It has improved structures of health services' organizations and altered professionals' attitudes towards external and internal assessment. [9][10][11][12][13] Competent authorities, healthcare payers and hospitals devote increasing resources to quality management systems and to accreditation or certification of parts or all of their activities. Still, evidence of improved patients' outcome is scarce.…”

Bioprocess engineering strategies for autologous human MSC-based therapies: one size does not fit all

“…An example of adoption of a failure mode and effects analysis (FMEA) can be seen in Lopez et al [54] whereby risks were identified and prioritized and a severity/occurrence matrix was highlighted for the production of liver progenitor cells. In another study it was shown that the implementation of an FMEA/ FMECA method revealed the causality of human errors (either due to errors or inadequate training) and the subsequent introduction of 26 criticalities within GMP production of autologous chondrocyte implantation [55].…”

European Regulatory Framework for the Development of Cell-Based Medicines

“…c. Cell encapsulation [38,39]. f. Quality risk management approach [47]. e. Preclinical and clinical experience with mesenchymal stromal cells [44][45][46].…”