This blog is a summary of Chapter 4 of the Advanced Therapies Investment Report 2017 produced by Phacilitate & Biotech and Money. The report aims to equip investors with the basic knowledge required to understand the risks of investing in cell and gene-based technologies through contextualised and empirical experience, valuable insight from a series of leading industry stakeholders, and market research and analysis. You can get the full detailed report here.
Advanced therapies are characterised by a high degree of technical complexity and face substantial challenges for their scalable manufacture. The novel nature of cell-based therapies and an associated lack of precedence presents a particularly unique set of challenges; bioprocessing equipment options are limited, and many available platforms are imported and adapted from blood product processing, research-scale cell culture, or antibody production, and are therefore suboptimal for scalable manufacturing. Cell and gene vector bioprocessing can be divided by expansion phase into upstream and downstream halves, each involving a series of unit operation steps. The immaturity of the advanced therapy manufacturing ecosystem in combination with rapid growth means that raw materials are often in short supply. Securing backup suppliers is therefore a vital requirement in de-risking the supply chain.
Typical Stages of Advanced Therapy Manufacturing
Cell bioprocessing is generally segmented into a series of discrete unit function steps which may differ between cell types and according to the specific needs of the product.
Major Challenges in Advanced Therapy Manufacturing
Medicinal product manufacturing environments are globally subject to GMP protocols, regulatory mandates enforced by national level agencies but internationally harmonised that aim to ensure production of high quality products that pose no risk to the consumer or public. ATMP manufacturing in particular requires a stringent and carefully controlled bioprocess to control for the intrinsically complex and variable nature of cell therapy products.
Centralised and Decentralised Manufacturing Models
Advanced therapy supply chains must be intelligently designed to maximise product availability. Owing to long shelf lives and simple distribution needs, small molecules can be manufactured in a single manufacturing site and readily shipped across the world. For cell therapy developers, opting for single or multiple manufacturing centres will depend upon the preferred business model, regulatory, economic, and supply chain factors.73 Autologous therapies in particular may benefit from multicentre manufacturing solutions, particularly where bioprocessing can be confined to black-box systems installed within the healthcare setting. Multicentre manufacturing models are subject to substantial comparability requirements, where centres must demonstrate the precise replication of products between centres, but can offer logistical advantages. Different elements of the supply chain have various levels of associated risk (Figure 4) and this must be considered when designing a manufacturing model.
When to Invest in Manufacturing?
Deciding on the stage and degree of investment in manufacturing is a strategically important decision. We searched for press releases between 25/04/17 and 01/01/2016 announcing manufacturing decisions (Table 11), finding the most common manufacturing investment period was in preparation for phase II trials. Several companies also invested prior to pilot clinical trials, plus some expansions to manufacturing resources in anticipation of commercial launch. Press releases listed include both integrated infrastructural development and virtual model out-licensed manufacturing agreements.
Major Manufacturing Stakeholders
GE Healthcare
GE Healthcare are a subsidiary of General Electric and produce a significant range of medical equipment, predominantly imaging devices and other hospital services. The company have interest in cell-based drug screening through three core collaborations: a cell analysis research alliance with BGI (2012), a license to Cellular Dynamics’ drug screening platform (2012), and a license to CRISPR-Cas9 technology with the Broad Institute (2014).
Invetech
Invetech are a large manufacturing company with interest across a range of engineering exploits. Invetech specialise in automation, providing bespoke solutions to clients across medical, industrial and consumer markets. Through their Cell Therapies Group (established in 2004) Invetech have completed over 35 projects for more than 25 advanced therapy companies, including Argos Therapeutics (2014), Ceylad (2016), NanoCellect (2015), NeoStem (a Caladrius subsidiary) (2015) and Erytech (2017). They do not offer contract manufacturing services but work directly with technology developers or manufacturing organisations to integrate bespoke and often automated bioprocessing solutions.
PCT, A Hitachi Group Company
PCT, one of the most widely used CDMOs, having agreed manufacturing contracts with Orchard Therapeutics (2017), Adaptimmune (2016), TxCell (2016), Kiadis (2016), Kite Pharma (2015), IRX Therapeutics (2015), Immunocellular Therapeutics (2015), Medstar Georgetown University Hospital (2013), Hackensack University Medical Center (2013), Baxter (2012), and Sotio (2012). PCT also announced a collaboration agreement with supply chain management platform TrakCel and one with instrument developer Invetech, both in 2015. PCT has 55,000ft2 of development and manufacturing space across two separate US facilities (Allendale, New Jersey on the east coast, and Mountain View, California on the west coast), and announced in October 2016 a $17.5 million CDMO facility in Yokohoma, Japan, to be constructed by parent company Hitachi Chemical and to be fully operational by April 2018.
Lonza
Lonza offer manufacturing solutions across chemical, water processing, consumer, agricultural, pharmaceutical, and other industries. In the advanced therapy sector they manufacture a range of off-the-shelf bioprocessing solutions, but also engage directly with technology developers as a CMO. Lonza currently have two advanced therapy manufacturing facilities, a cell therapy suite in Walkersville, Maryland, and a 2,000L, 100,000ft2 viral therapeutics facility in Houston, Texas. In the advanced therapy sector Lonza have agreed manufacturing contracts with Selecta (2017), Renova (2016), bluebird bio (2016), Massachusetts Eye and Ear centre (2016), Benitec (2015), TiGenix (2015), Regneus (canine cell therapy) (2014), and Celladon (2014). Lonza were awarded a $9.5 million contract from the NIH to develop and manufacture clinical-grade iPSCs, plus the associated manufacturing infrastructure (2016), and are collaborating with Nikon to build a cell and gene therapy manufacturing facility in Japan (2015).
Other Manufacturing Organisations
Numerous contract development and manufacturing (CDMO) organisations exist globally, some of which with integrated product pipelines for their own therapeutics.
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