By: Bernard Massie, Pierre Bourassa and Sonia Thomson
Biomanufacturing
Photos: PnuVax SL Bio’s Montréal plant; Final formulation
Canadian Biomanufacturing: Opportunity for Pride and Prosperity
I
t’s no secret that Canadian biotechs can design and develop cutting edge biotherapeutics and vaccines. For example, Calgary-based Oncolytics’s Reolysin is among the first wave of oncolytic viruses edging its way to market,1 while Vancouverbased Zymeworks successfully developed a best-in-class, bi-specific antibody design platform that attracted the attention of giants like Merck, Eli Lilly, Celgene and GSK.2 Along the preclinical development pathway, Canadian universities, research and technology organizations, consultants, and contract research organizations support the country’s biopharma developers in their quest to reach clinical trials. When it comes time to select a Good Manufacturing Practices (GMP) manufacturer for clinical trial batches however, Canadian biologics developers are likely to go south of the border, especially if their products rely on mammalian expression systems. Yet Canada’s biopharmaceutical manufacturing sector is gaining steam. Microbial fermentation, biotech’s tried and true protein factory, is well represented nationally, with players like Apotex Fermentation, BioVectra, Viventia, Microbix and KABS leading the way. Chemical synthesis remains a foolproof, rapid method for producing smaller biologics such as peptides and RNA. Firms in this space include Dalton, Patheon, Piramal, Omega, and Paraza. Egg-based platforms continue to be used by the country’s influenza vaccine producers, multinationals GSK and Sanofi, while groups around the world work to develop mammalian and plant alternatives. In terms of alternatives, plant production has certainly made a bold entry on the scene: Medicago built their success manufacturing influenza VLPs in plants and will be using plant systems to produce anti-Ebola antibodies for the Public Health Agency of Canada.3 They received nearly $75 million in financing
in 20154 that will go toward the construction of a new$245 million facility in Québec City, where 200 new high-skilled jobs will be created by 2019.5 Another player harnessing the trend is Plantform, who recently announced they will be manufacturing an anti-nerve agent enzyme in plants, as well as producing monoclonal antibodies against Ebola and HIV/AIDS and developing a biosimilar version of Herceptin.6 And finally, a few biomanufacturers with mammalian capacity are emerging to greet the spring: Therapure is expanding its business beyond plasma products to optimize mammalian expression systems and produce antibodies in CHO cells, and just announced in November that they have filed a preliminary prospectus with securities regulatory authorities in Canada in connection with a proposed initial public offering.7, 8 Meanwhile, PnuVax SL Bio acquired DSM’s former Montréal facility in 2012 and is working with the Bill and Melinda Gates Foundation to produce a low-cost pneumococcal conjugate vaccine (PCV-13) for the developing world.9 Up and coming mammalian manufacturers are just in time to meet the increasing cGMP production needs that Canadian biotechs have. The nation has a rich pipeline: about 110 firms, 90 per cent of whom are small or medium sized biotechs, are developing over 325 promising biologics – the majority of which require mammalian production in CHO or HEK293 cells.10 What’s more, about 75 per cent of these products are at the preclinical stage or earlier, and their production is not yet committed to a contract manufacturing facility abroad. As production accounts for roughly 20 per cent of the final product value (10 per cent production cost and 10 per cent profit for the manufacturer), there is a tremendous opportunity for the Canadian biomanufacturing sector to capitalize on
6 BIOTECHNOLOGY FOCUS December 2015/January 2016
Canada’s investments in biopharmaceutical development.11 Growing Canada’s mammalian biomanufacturing capacity makes sense globally as well. International trends demonstrate that CHO cells have become the workhorse of the biopharma industry. Six of the ten top selling biologics in 2014 were produced in CHO cells: Humira, Enbrel, Rituximab, Avastin, Herceptin, and Avonex.12 With annual sales ranging from US$3 billion to $12.5 billion per product for these blockbusters, profits from manufacturing each one of them may represent $300 million to $1.25 billion per year. Biologics are a successful business, and most are produced in CHO cells, so it follows that the number of facilities working with these cell lines is growing as well. A snapshot of global biomanufacturing facilities in 2007 versus 2014 reveals that mammalian producers increased their share from 41 to 55 per cent, while microbial facilities dropped from 34 to 24 per cent, yeast installations downsized from 16 to 12 per cent, and insect cell production declined from seven to four per cent. The only other segment besides mammalian production that grew or remained stable was plants, which checked in at two per cent in both 2007 and 2014.13 And what about producing biosimilars – or subsequent entry biologics (SEBs), as Health Canada calls them? Though few are presently approved in Canada compared to Europe and the U.S., the cost savings they offer over originator biologics will be difficult for regulators to ignore. As highlighted in the October/November 2015 issue of Biotechnology Focus, Merck Canada sees a major opportunity to bring these products to the Canadian market, and has partnered with Samsung Bioepis in Korea, who will take care of biosimilar process development,
