Lentiviral vector bioprocess economics for cell and gene therapy commercialization

Ruxandra-Maria Comisel,Bo Kara,Frederick H Fiesser,Suzanne S Farid

doi:10.1016/j.bej.2020.107868

Abstract

• Decisional tool presented for identifying cost-effective lentiviral vector processes. • Scalable bioreactors can achieve ∼90 % COG LV /dose savings over traditional routes. • Suspension STR is the most cost-effective technology across indications. • For adherent cell culture, fixed bed bioreactor is the most cost-effective option. • Target harvest titre values were identified to drive down lentiviral vector costs. Traditional viral vector processes rely on lab-scale methods that need to be industrialised so as to avoid viral vector supply shortages during commercialisation of cell and gene therapies such as CAR T-cell and HSC gene therapies. This paper describes the application of a decisional tool to identify the most cost-effective scalable cell culture technologies used in the manufacture of lentiviral vectors (LVs) across a range of products. The tool consists of a whole bioprocess economics model linked to an optimisation algorithm and analyses the cost of goods (COG) associated with adherent (e.g. 10-layer vessels (CF10)) and suspension (e.g. single-use stirred tank bioreactor (SUB)) cell culture technologies. The SUB was the most cost-effective technology across most scenarios when a suspension-adapted cell line was available, while the fixed bed bioreactor (FB) was the most cost-effective when adherent cell culture was preferred instead. At large scale, the COG reduction achieved by switching from CF10 to SUB or FB was at least 90 %. The SUB capacity limits were highlighted for high dose and high demand scenarios. The cost drivers were explored and the target harvest titre required to drive down LV cost contributions to cell therapy costs was identified. Finally, the tool highlighted the impact of increasing the specific productivity in the FB on COG LV /dose for transient transfection and stable producer cell line scenarios.

Highlights

With the advent of chimeric antigen receptors (CAR) T-cell and T-cell receptors (TCR) gene-modified cell therapies, as well as other such as CD34+ haematopoietic stem cell gene therapies, lentiviral vectors (LVs) have become of great interest
A deterministic cost of goods (COG) analysis of processes utilising five different cell culture technologies was run for a hypothetical base case CAR T/TCR LV product with a dose size of 2 × 109 trans ducing units (TU) across a range of demands
The results showed that the suspension stirred-tank bioreactor was the most optimal technology across demands, followed by the fixed bed bioreactor, achieving cost savings between 94–97 % when compared to the tradi tional 10-layer process at large demands

Summary

Introduction

With the advent of CAR T-cell and TCR gene-modified cell therapies, as well as other such as CD34+ haematopoietic stem cell gene therapies, lentiviral vectors (LVs) have become of great interest. Two gene-modified cell therapy products utilising LV as the gene delivery method were approved to date: Kymriah (Novartis, Basel, Switzerland) for blood cancers and Zynteglo (bluebird bio, Mas sachusetts, USA) for beta-thalassemia [3,4,5]. These therapies are considered expensive, with list prices of 475,000 USD for Kymriah, 373, 000 USD for Yescarta (a gammaretroviral gene-modified cell therapy product for blood cancers) and an announced likely price of 1.8 M USD for Zynteglo; this can be partly attributed to the high manufacturing costs of these complex therapies [5,6] and the high cost of development [7]. This article presents the development of a decisional tool aimed at investigating the costs of LV manufacturing using different technologies as well as the target process performance required to lower LV-associated costs down to critical threshold levels

Methods

Results

Conclusion