Canadian Biomanufacturing

Photos: PnuVax SL Bio’s Montréal plant; Final formulation

Canadian BiomanufaCturing:

OPPORTUniTy FOR PRide And PROsPeRiTy

It’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 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,

characterization, manufacturing and regulatory filings while Merck will handle their commercialization in Canada. Once these big players open the doors to SEB approvals in Canada, it’s quite conceivable that other firms will want to develop and produce biosimilars in the country, especially if mammalian manufacturers can secure a foothold.

With the robust growth of mammalian production facilities worldwide, what is hampering their expansion in Canada? Firstly, developing biologics is a high risk endeavour, and most companies are afraid to compound it by working with emerging manufacturers that cannot yet boast a long track record. To attract this crucial round of early customers, governments and venture capitalists could consider investing in pilot projects between Canadian biologics developers and emerging Canadian CMOs. Governments could also contract these facilities to produce biologics and vaccines in the case of pandemics and other health emergencies, projects that would enable these producers to gain further experience and contribute to their revenue stream in the early years.

Secondly, cities, provinces and the federal government could work together to remove financial obstacles to the growth of these enterprises. Manufacturers have the potential to create long term, high quality employment in their communities. Once a plant has been selected and certified for the production of a given biopharmaceutical by the FDA or Health Canada, production of that biologic is likely to remain at the facility for the duration of its patent life.

The National Research Council of Canada (NRC) offers two programs that contribute to growing Canada’s biomanufacturing capacity in mammalian cells. The first is the Industrial Research Assistance Program (IRAP), which can help emerging biomanufacturers make connections with investors and provide advice about growing the business. IRAP supports the development of new technologies and business networks at the most crucial time in an SME’s evolution: when they are experiencing high levels of risk and uncertainty.

The other is NRC’s Human Health Therapeutics portfolio, a strategic R&D arm that helps Canadian SMEs develop biologics and vaccines. NRC is co-developing a pipeline of biologics with Canadian firms, helping them not only advance the product, but also develop and scale up the process for the biologic’s production in CHO cells. Biologics manufacturing is R&D intensive, and the production parameters selected have a direct impact on the product’s composition and quality, a phenomenon often summarized by the concept “the product is the process.”

The NRC has been developing and optimizing its expression systems since 1987, the most recent of which, CHOBRI, is named in honour of NRC’s former Biotechnology Research Institute. The cell line’s parental genome has been fully sequenced, and can be customized for the production of Canadian SMEs’ lead candidates, with fully scalable, stable CHO clones obtained in four months. Once the most productive cell line has been selected, the production, purification and analytical processes can be scaled up, first in the lab and then inside NRC’s Cell Culture Pilot Plant – up to a capacity of 500 L.

Once all the parameters have been optimized, NRC encourages SME developers to select Canadian manufacturers for Good Laboratory Practice (GLP) toxicology batch and clinical batch production using CHOBRI. Transferring NRC’s expression systems and know how to Canadian CMOs reduces risk for the developer and helps stimulate a healthy biomanufacturing sector in the country.

Canada’s venture capital climate appears to be rebounding from 2008, and has shown solid growth in life science deals since 2013.14 Clinical trial providers have made considerable efforts and investments to ensure Canada remains an attractive location for commercializing new medicines. It’s time to leverage the nation’s strengths in large molecule research and roll out the red carpet for biomanufacturers, to propel Canadian developers past the hurdle of clinical batch production toward major investments and promising alliances. Let’s harness this incredible opportunity with an ounce of pride, and generate a pound of prosperity!

References:

1. http://www.onclive.com/web-exclusives/FDA-Grants-Reolysin-Orphan-

Drug-Designation-for-Ovarian-Cancer 2. http://www.forbes.com/sites/luketimmerman/2015/01/21/celgene-biotechsace-dealmaker-bets-on-canadas-zymeworks/ 3. http://www.medicago.com/English/

News-Releases/News-ReleaseDetails/2015/Medicago-engaged-by-the-

Canadian-Government-to-develop-Ebola-monoclonal-antibodies/default.aspx 4. http://s1.q4cdn.com/816223360/files/ documents_news/2015/Joint-News-

Release-Medicago-19052015-FINAL.pdf 5. http://s1.q4cdn.com/816223360/files/ documents_news/2015/EXPANSION-

MDG-EN.pdf 6. http://www.plantformcorp.com/products.aspx 7. http://www.therapurebio.com/CDMO/ upstream-process 8. http://seoprrank.com/admin001/mtherapurebio/corp/investors 9. http://www.gatesfoundation.org/

How-We-Work/Quick-Links/Grants-

Database#q/k=pnuvax 10. https://www.ic.gc.ca/eic/site/lsg-pdsv. nsf/eng/h_hn01728.html 11. VIE-Tech Consultants, 2014 12. http://cellculturedish.com/2015/03/10biologics-on-best-selling-drugs-listfor-2014/ 13. http://bioplanassociates.com/ publications/11th per cent20Annual per cent20ReportBiomfg per cent20Table per cent20of per cent20Contents.pdf 14. https://www.ic.gc.ca/eic/site/lsg-pdsv. nsf/eng/h_hn01776.html

Bernard Massie is the leader of the Biologics and Biomanufacturing program at NRC’s Human Health Therapeutics portfolio. He manages the development and transfer of NRC’s cell lines, production processes, analytics and quality assurance to biopharmaceutical developers and manufacturers. Pierre Bourassa is an Industrial Technology Advisor with NRC’s Industrial Research Assistance Program. A member of IRAP’s Biomedical Sector Team, he leads IRAP’s Biomanufacturing Initiative, which supports Canadian biologics and vaccine development through financial aid and advice.

Sonia Thomson is a Communications Officer with NRC’s Human Health Therapeutics portfolio, working to get the word out about Canada’s best kept secret in biologics development.

To see this story online visit www.biotechnologyfocus.ca/ canadian-biomanufacturingopportunity-for-pride-andprosperity/