Bioprocessing for Cell-Based Therapies

Che J. Connon

• Publisher: Wiley-Blackwell
• Year: 2016
• Print ISBN: 9781118743416
• eBook ISBN: 9781118743409
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Cell Biology
• Index: Biological Sciences

With contributions from leading, international academics and industrial practitioners, Bioprocessing for Cell-Based Therapies explores the very latest techniques and guidelines in bioprocess production to meet safety, regulatory and ethical requirements, for the production of therapeutic cells, including stem cells.

• An authoritative, cutting-edge handbook on bioprocessing for the production of therapeutic cells with extensive illustrations in full colour throughout
• An authoritative, cutting-edge handbook on bioprocessing for the production of therapeutic cells with extensive illustrations in full colour throughout
• In depth discussion of the application of cell therapy including methods used in the delivery of cells to the patient
• Includes contributions from experts in both academia and industry, combining a practical approach with cutting edge research
• The only handbook currently available to provide a state of the art guide to Bioprocessing covering the complete range of cell-based therapies, from experts in academia and industry

Chapter 1
Overview of the Cell Therapy Field

Michael Whitaker¹, Lucy Foley² and Stephen Ward³

¹Institute of Cell and Molecular Sciences,, Newcastle University, Newcastle upon Tyne, UK

²Centre for Process Innovation – Biologics, Darlington, UK

³Cell and Gene Therapy Catapult,, Guy's Hospital, London, UK

1.1 The Context of Cell Therapies and Their Manufacturing Challenges

Cell therapies are not new. The first cell therapy was the transplant of bone marrow stem cells for patients with leukaemia in the late 1970s (Thomas et al., 1975). Over the next 20 years bone marrow stem cell transplants were adapted and adopted for bone marrow cancers and extended into other clinical indications, for example, inherited immunodeficiency. Bone marrow stem cell transplantation is now a routine clinical procedure for multiple indications.

The example of bone marrow stem cell therapies illustrates several of the characteristics that define cellular therapies more broadly. They were developed for less prevalent indications. They are allogeneic (see Box 1.1) one donor-one recipient therapies that were developed wholly by clinicians in a hospital context. They require interventional clinical procedures for administration of the therapy. They led to widespread clinician-led adoption by the clinical community through global clinician networks. They defined an approach to the safety of cell therapies based on risk and benefit to patients. They encouraged the development of cell processing expertise within hospitals and in many ways provided a basis of skills and expertise for clinicians to facilitate the development of other cell therapies (Foley and Whitaker, 2012). Though led by clinicians, the development and widespread adoption of bone marrow stem cell therapies was facilitated by companies who provided high-value goods and services to help manufacture and deliver the therapies in a hospital context. Around the turn of the millennium, two cell therapy products developed by companies were the first cell-based therapies to be approved by the US Food and Drug Administration (FDA). Apligraf and Dermagraft were competing skin-equivalent products designed to improve the healing of wounds and burns (Kemp, 2006).

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Box 1.1 Cell Therapy Definitions

Autologous

The patient's cells are the cells used in the therapy. No immune response is expected.

Allogeneic

The cell source is different to the patient receiving the cell therapy. There is a possibility of an immune response.

One to one

The cells used in the therapeutic dose are only of sufficient quantity to treat one patient; these treatments can be autologous or allogeneic.

One to many

The cells used are amplified to a scale able to treat many patients; these treatments can only be allogeneic.

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These two therapies illustrate some of the characteristics of company-led approaches to cell therapies. They are allogeneic, one donor-many recipient cell therapy products that are manufactured at scale for prevalent indications. They do not require complex clinical procedures (Foley and Whitaker, 2012).

Apligraf and Dermagraft initially failed in the market (Lysaght and Hazlehurst, 2004). One key reason was cost of goods: the products were manufactured manually and had a short shelf life – two aspects of manufacture and distribution that are not well suited to prevalent indications. A contributing factor was cost relative to existing treatments, despite improved efficacy (see Box 1.2).

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Box 1.2 Dermagraft and Apligraf – a roller coaster of investment, manufacturing costs and reimbursement

In the 1990s, Advanced Tissue Sciences invested around $300m to develop Dermagraft and Transcyte for the treatment of diabetic foot ulcers. In 2000, ATS formed a marketing partnership with Smith and Nephew, a global leader in wound care products. Dermagraft was approved by the FDA in 2001. In 2002, ATS filed for bankruptcy. In 2003, Smith and Nephew purchased ATS from bankruptcy and continued with manufacturing and sales. Smith and Nephew ceased production in 2005. In 2006, Advanced Biohealing purchased the Smith and Nephew manufacturing assets for an undisclosed amount (Jones, 2011), presumably at a value destroying discount, and in 2007 resumed manufacture, with a sales/reimbursement model that led to $147m sales in 2010. In 2011, Shire bought ABH for $750m (Smith, 2014). In 2013, Dermagraft assets were declared at $683m on Shire's balance sheet and 9 month losses for Dermagraft were $324m (Reporter, 2014).

Organogenesis was the first to receive FDA approval for a living, allogeneic, cell-based product (Apligraf). They were successful in securing a marketing agreement with Novartis in 1996 (Connolly, 2002a). However, the cost of producing Apligraf was too high and in 2002 Organogenesis filed for bankruptcy and terminated its marketing agreement with Novartis. A short-term deal with Novartis and company restructure (Connolly, 2002b) today means that Organogenesis develops, manufactures and markets its own products.

In early 2014, Organogenesis acquired Dermagraft from Shire, with a promise of a $300m payment based on future sales, but without accepting liability for the ongoing Department of Justice investigation into ABH sales and marketing practices (GenEngNews, 2014). Later that year, Medicare altered reimbursement rules (Carroll, 2013), suggesting that the $1,500 cost of Dermagraft would be reimbursed at a maximum of $840. Dermagraft is a very effective treatment for diabetic ulcers, but costs and reimbursement routes may prevent it reaching patients.

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1.1.1 Regulation of Cell Therapies

Neither bone marrow stem cell transplantation nor the first two marketed cellular products were regulated as cell therapy products now are. A key question in the current regulatory landscape is whether cells are substantially manipulated before administration to the patient. Minimally manipulated cells, for example, using aseptic separation or enrichment, are governed by the same regulations that apply to any cell or tissue taken from a patient. Therapeutics that involve any more substantial manipulation including expanding cell numbers are now governed by different and more stringent rules akin to those used in the regulation of other medicinal products such as small molecule pharmaceuticals and biologics. These rules require that quality, safety and efficacy are demonstrated to the satisfaction of the regulators, both in order to undertake the clinical trials and for authorization as an approved medicinal product if the trials are successful. The rules include a requirement to show that the product has been manufactured according to Good Manufacturing Practice. So products similar to Apligraf and Dermagraft now require these new authorizations, while bone marrow stem cell transplantation with its minimal manipulation before administration does not and is overseen for Good Clinical Practice by organizations such as JACIE in Europe. In the US, the FDA oversees Good Clinical Practice for bone marrow transplantation, but this is separate from Biologics manufacture; in the US, the term “Biologics” encompasses cell therapies and the more traditional biopharmaceuticals (Oancea et al., 2012).

The uncertainties that preceded the introduction of the new regulations and the costs in time and money that were required for compliance with the new regulations led to a pause in the development of cell therapies, above all in the US and Europe. Nonetheless it is notable that both clinician- and company-led cell therapies have adapted to the regulatory change. As an example of the former, 12 of the 26 cell therapy manufacturing facilities in the UK are now accredited for Good Manufacturing Practice-compliant manufacture of cellular products (Foley et al., 2012). It should be acknowledged that the new regulations for cell therapies are very similar to those for biologics, and so are well understood by the pharmaceutical sector. They do however still pose a substantial manufacturing challenge, since it is the cells themselves, not a biotherapeutic product produced by cells, that are the medicinal product (the ATMP: Advanced Therapeutic Medicinal Product).

1.1.2 Manufacturing Challenges in Cell Therapy

The key raw material for cell therapy manufacture is a cell type obtained from a human source. A key distinction between cell therapies is whether the cell type or its differentiated or otherwise modified derivatives are destined for a single patient or for many patients. A second difference is whether the cells of origin are administered to the patient from whom they are taken. If they are, then they have the genetic identity of the patient and the therapy is autologous. If they are not, then the cells are genetically distinct from the patient recipient and the therapy is alloge...

Table of contents

• Cover
• Title Page
• Copyright
• Table of Contents
• List of Contributors
• Preface
• Chapter 1: Overview of the Cell Therapy Field
• Chapter 2: Structured Methodology for Process Development in Scalable Stirred Tank Bioreactors Platforms
• Chapter 3: The Effect of Scale-up on Cell Phenotype: Comparability Testing to Optimize Bioreactor Usage and Manufacturing Strategies
• Chapter 4: The Scale-up of Human Mesenchymal Stem Cell Expansion and Recovery
• Chapter 5: Challenges of Scale-up of Cell Separation and Purification Techniques
• Chapter 6: Fundamental Points to Consider in the Cryopreservation and Shipment of Cells for Human Application
• Chapter 7: Short-term Storage of Cells for Application in Cell-based Therapies
• Chapter 8: Cell Therapy in Practice
• Index
• End User License Agreement