Allogeneic cell therapy bioprocess economics and optimization: downstream processing decisions

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From: Regenerative Medicine(Vol. 10, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 7,505 words
Lexile Measure: 1680L

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Author(s): Sally Hassan aff1 , Ana S Simaria aff1 , Hemanthram Varadaraju aff2 aff3 , Siddharth Gupta aff2 , Kim Warren aff2 , Suzanne S Farid [*] aff1

Keywords:

allogeneic cell therapy manufacture; bioprocess economics; centrifugation; downstream processing; filling; tangential flow filtration

Allogeneic stem cells are showing clinical promise in several therapeutic indications, with regional approvals for graft-versus-host disease (GvHD; Prochymal® , Osiris) and osteoarthritis (Cartistem® , Medipost). Advantages of allogeneic cell therapies include being sourced from a healthy donor, which makes it more possible to scale-up rather than scale-out and cryopreserve the cell-based product for short-term storage and multidosing [1 ]. Hence it is possible to envisage allogeneic therapies following a product-driven, off-the-shelf business model. Yet, several cell therapy products have experienced manufacturing challenges upon scale-up leading to processes with high cost of goods (COG) and high process variability [ 2-4 ]. This has triggered increasing interest in estimating manufacturing costs and identifying opportunities for cost reduction. Simaria et al . present a detailed process economics analysis for cell expansion that predicted dose-demand combinations when planar technologies would cease to be feasible, as well as target performance capabilities of microcarrier-based systems for the industry to be sustainable for high-demand, high-dose (10 9 cells/dose) scenarios [5 ]. The commercial feasibility of cell therapies for large commercial lot sizes (e.g., 1012 cells/lot) will depend not only on the technology capabilities for expansion but also on commercially available technologies for downstream processing that are capable of handling this high cell load. This article presents a decisional tool to investigate the impact of commercial doses, demands and lot sizes on the cost-effectiveness of scalable, single-use downstream processing and fill finish technologies for cell therapies.

Figure 1 illustrates a typical cell therapy process flowsheet for allogeneic cell therapies. Cell expansion is performed using either planar technologies such as T-flasks or multi-layer stacked vessels (e.g., Cell Factories [Nunc, ThermoFischer Scientific, MA, USA], Cell-STACKs or HYPERstacks [Corning Incorporated Life Sciences, MA, USA]) or via 3D microcarrier-based culture in single-use bioreactors. Following enzymatic treatment (e.g., trypsinization) to release the adherent cells, the downstream processing (DSP) stages comprise microcarrier removal, where relevant, and volume reduction (VR) for concentration and washing of the cells. This is followed by formulation into the cryopreservation buffer, vial filling and cryopreservation.

Some cell therapy manufacturing processes include downstream processing and fill finish technologies that are not amenable to scale-up such as benchtop centrifuges for volume reduction and manual filling in laminar air flow cabinets. However, this quickly becomes impractical for large commercial lot sizes for some high dose, large commercial demand indications. There are a limited number of DSP technologies that have been purpose-designed to meet the specific needs of allogeneic cell therapy manufacturing at large scale. These requirements include minimal processing time, achieving high concentration factors while preserving high cell viabilities, integrating volume reduction and washing to reduce impurity levels to [less than]1 ppm [ 6 ] and providing a low-shear processing environment. Furthermore, technologies need to be closed, automated, scalable and employ single-use components; the latter of which...

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Gale Document Number: GALE|A424015176