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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Issue Vol 4 Issue 11

Editorial

Critical considerations for allogeneic cell therapy scale up

Spotlight Article

Editorial

Sharon Grimster

Strategies for Scale-up & Scale-out

Sharon Grimster joined ReNeuron in 2013 and was subsequently appointed as General Manager of the Wales facility in September 2014. Sharon has significant experience in pharmaceutical development, and she has particular expertise in ATMPs, project management, biologics development and manufacturing. Prior to working at ReNeuron, Sharon held senior team roles at Celltech, Antisoma and F-star, and has had responsibility for a range of development functions, including project management, regulatory affairs, manufacturing, quality and general operations. Sharon qualified as a coach at the Henley Business School and has a BSc from the University of Leicester and a Diplomas in Immunology and in Management Studies. She is also a Fellow of the Royal Society of Biology and an active member of a number of significant industry committees.

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Interview

Biopharma scale-up lessons to learn for cell & gene therapy

Spotlight Article

Interview

Prof Nik Willoughby

Strategies for Scale-up & Scale-out

Prof Nik Willoughby is Professor of Bioprocessing and Deputy Director of the Institute of Biological Chemistry, Biophysics and Bioengineering at Heriot Watt University. Nik carried out his PhD at University College London in Biochemical Engineering, and his research interests focus on applying engineering principles to biological challenges. Primarily working in downstream processing, Nik has moved the focus of his research over the past 20 years from protein therapeutics to more complex cellular targets. His research group have worked with a wide range of cell types but primarily have focused on red blood cells, working with the NovoSang consortium – with the ultimate objective of developing passive, scalable, label-free solutions for separation of heterogeneous cell populations manufactured from multipotent and pluripotent cell sources.
Nik has spent time in both industry and academia, in the former managing the Protein Purification group at Metris Therapeutics as well as working for Lonza Biologics in cell culture development, and in the latter helping to establish the Innovative Manufacturing Research Centre for Bioprocessing at UCL before setting up the Cellular Bioprocessing Group at Heriot Watt.

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Towards commercial allogeneic cell therapy manufacturing

Spotlight Article

Interview

Maria Del Pilar Redondo

Strategies for Scale-up & Scale-out

MARIA DEl PILAR REDONDO holds an MsC in Pharmacy, specializing in Pharmaceutical technology and analysis and control of drugs. Although she began her career at Pfizer within the area of Quality, she later focused on Pharmaceutical Development. After incorporation into the Pharmamar group in 2005, she became in charge of pharmaceutical development and production of investigational medicines for the treatment of Alzheimer’s disease. Pilar joined Tigenix SAU in June 2013 as Senior Director of Technical Operations. Her responsibilities included the overview and management of activities in the areas of Pharmaceutical Development (CMC/Industrialization) and Manufacturing of the stem cell platform.

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Autologous T cell immunotherapy scale out manufacturing models – the biotech perspective

Spotlight Article

Interview

Dr Nina (Ekaterini) Kotsopoulou

Scale-Out and -Up Strategies

DR NINA (Ekaterini) KOTSOPOULOU is Vice President of Process Development at Autolus. She joined the UCL spin-out CAR-T company in 2015 and set-up the vector and CAR-T production process and analytics, including delivery of the first clinical patient batches. Nina has a BSc in Chemistry from the University of Athens and a DPhil in lentiviral vectors for gene therapy from Oxford University. Following her PhD, she briefly worked in her supervisors’ company, Oxford BioMedica, and went on to do 2 post-docs on haematopoietic stem cell biology, at Harvard Medical School and the University of Cambridge. She then joined GSK, where she initially led cell line development and associated process research for monoclonal antibodies and derivatives thereof. She then led Process Development for GSK’s Cell and Gene Therapy portfolio, including working with the inspirational team at TIGET, and completing the MAA submission for the first product, Strimvelis, for the treatment of ADA-SCID.

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Expert Insight

The long road to affordability: a cost of goods analysis for an autologous CAR-T process

Spotlight Article

Expert Insight

Katy Spink & Andrew Steinsapir

Strategies for Scale-up & Scale-out

With the 2017 FDA approvals and launches of the first gene-modified cell and pure-play gene therapy products to gain licensure in the United States, increasing attention has been paid to the high cost of this emerging class of therapies. Although currently approved therapies are for orphan indications, prices similar to those charged today will be unaffordable for products marketed for larger indications. Using public information, we constructed a cost of goods model for an autologous gene-modified cell therapy product, evaluated the relationship of estimated manufacturing costs to list prices of CAR-T products, and investigated the potential impact of various factors on manufacturing costs. Our findings highlight in particular the importance of maximizing employee productivity, leveraging automation and technology, and accurately forecasting capacity needs to achieve the manufacturing cost improvements that will likely be required to drive broad adoption of autologous gene-modified cell therapies.

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Back to the future: where are we taking lentiviral vector manufacturing?

Spotlight Article

Expert Insight

Hanna P Lesch

Separation & Expansion Technologies

From more than 200 clinical trials involving lentiviral vectors, only a handful of products have reached marketing approval. One reason for this may be the technical bottleneck in large-scale lentiviral vector manufacturing. Today there are several upstream and downstream technology solutions, which claim to support clinical manufacturing at large scale. These still have several limitations, such as a complex production methodology and the relatively high cost of the goods. The fragile nature of the vector further causes its own challenges. No one knows yet where the future will take us. This insight covers an overview of the current technology and discusses the possible future solutions for lentivirus manufacturing.

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Translating cell and gene therapies to the clinic

Spotlight Article

Expert Insight

Hema Dave, Devin Saunders, Nan Zhang & Patrick J Hanley

Strategies for Scale-up & Scale-out

The translation of cell and gene therapy products requires significant resources, knowledge, experience, and infrastructure. Even with vast resources, the path forward is often non-linear, confusing, and cumbersome. Here we review the process by which to take a cell or gene therapy product from discovery into a phase 1 clinical trial in the academic setting.

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Management of ‘out of specification’ commercial autologous CAR-T cell products

Expert Insight

Alexey Bersenev & Sven Kili

Strategies for Scale-up & Scale-out

2017 witnessed historic regulatory approvals of two chimeric antigen receptor T-cell (CAR-T) products – Kymriah® (Novartis) and Yescarta® (Kite Pharma/Gilead). One year later, these approvals have highlighted some specific post-marketing challenges for this new class of therapies. The purpose of this paper is to discuss ‘out of specification’ (OOS) CAR-T products as a unique post-marketing issue for commercial autologous cell therapies.

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Innovator Insight

Commercial Lessons for Clinical Success

Spotlight Article

Innovator Insight

Simon Ellison, Heidi Hagen and Christophe Suchet

Strategies for Scale-up & Scale-out

Advanced therapies require highly-sophisticated advance planning. For long-term success, transformative cell and gene therapies rely on a risk-based understanding of the supply chain, with all aspects mapped out early. Recent draft guidance from regulatory authorities stresses early end-to-end systems thinking and data management capabilities. A commercially-minded approach to each clinical phase will help create viable commercial supply chains and patient journeys from the beginning. This article provides valuable commercial-phase insights from industry veterans with deep commercialization experience, and discusses how these lessons can be applied to clinical-phase therapies to help drive advancement and success.

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Research Article

Scale-up of a perfusion-based dendritic cell generation process

Spotlight Article

Research Article

Andrew Kozbial, Hope Weinstein, Shashi K Murthy & Jennifer M Rossi

Strategies for Scale-up & Scale-out

Scale up of dendritic cell production is a critical challenge that is infeasible with current static culture systems such as well plates, T-flasks, and bags. We have developed a fully enclosed, sterile cell culture system, called EDEN, that allows for continuous perfusion of fresh differentiation medium into the cell culture cartridge and simultaneous removal of depleted medium. EDEN generated ca. 25 million immature dendritic cells (iDCs) per run with a yield, relative to seeded monocytes, of 20-30%. Immunophenotyping showed that EDEN generated iDCs were phenotypically similar to 6-well plate generated iDCs. Maturation of EDEN iDCs using a standard maturation cocktail was successful with upregulation of CD80/83/86 and downregulation of CD209. Computational fluid dynamics simulations aided the EDEN cartridge design to ensure proper differentiation medium perfusion. These results indicate that EDEN successfully generates clinically relevant numbers of iDCs in a single cell culture cartridge with fewer manual interventions compared to standard culture techniques.

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Methylcellulose as a scaffold in the culture of liver-organoids for the potential of treating acute liver failure

Research Article

Anil Chandrashekran, Ragai R Mitry, Tharindu Prema-chandra, Chris Starling, Sharon Lehec, Valeria Iansante, Emer Fitzpatrick, Celine Filippi, Maesha Deheragoda, David Hay & Anil Dhawan

Strategies for Scale-up & Scale-out

Much progress has been made in understanding the development of human organs through advanced cellular and molecular techniques. Acute liver failure (ALF) in children is a life-threatening condition that relies on liver or hepatocyte transplantation. The translation of novel regenerative medicine strategies for the treatment of ALF is however somewhat limited. Here, we show that in vitro liver-organoids derived from human umbilical cord derived mesenchymal stem cells and human cadaveric donor-derived hepatocytes, cultured in a clinically appropriate manner, exhibit liver function. We obtained organoids that varied in size and morphology which produced albumin, and detoxified ammonium chloride into urea. Immunohistochemistry of these organoids revealed hepatocyte specific, non-parenchymal markers and histological organisation. Our in vitro findings indicate that these organoids may be a useful bridge in ALF while awaiting liver recovery or transplant. The organoid culture system we have established here is also well suited to drug screening and disease modeling.

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