Standardization and characterization of ATIR cell therapy product: applying QbD to both process and assay development

Kiadis Pharma is developing ATIR, a T-cell immunotherapy based on a donor lymphocyte preparation selectively depleted of host alloreactive T-cells to reduce risks and improve outcomes of haploidentical stem cell transplantation for blood cancer patients. Laboratory evaluations of ATIR have shown photodepletion of recipient-reactive cells and immune reactivity retention. ATIR product demonstrated favorable anti-infection and anti-leukemia properties without causing severe graft-versus-host disease in a Phase I clinical trial. In 2011, the company terminated a next-phase clinical trial, because the product did not resemble ATIR, but contained dead and apoptotic cells. A root cause failure investigation confirmed that the process should be re-engineered. A Quality-by-Design (QbD) approach was taken towards both process and assay development, aiming at (i) development of a standardized manufacturing process for a phase II clinical study, and (ii) development of new cellular potency assays that accurately measure critical process and product attributes. Experiments were designed to test single modifications in full ATIR runs. Ultimately, comparability of the new process/product to the original process/ product was demonstrated in a head-to-head comparison, using the fixed and qualified assays, currently used for release testing in ongoing clinical study CRAIR-007. This approach has resulted in a set of qualified assays fulfilling predefined requirements, enabling methodical process characterization during development. The knowledge gained about critical process parameters will be highly valuable during next phase development steps. The standardized, robust and transferable process resulting from the QbD approach is currently used for manufacturing ATIR at CMO’s in North America and Europe for ongoing clinical studies.