Anti-COVID-19

Anti-COVID-19 Biologics – Using the BioPhorum Standard MAb Process to Estimate Required Manufacturing Infrastructure, Investment and Resulting Drug Cost

The biopharmaceutical industry is investigating various biologics as treatments for COVID-19. This blog looks at the scale of global manufacturing that may be required and the associated cost of goods of these drug products for COVID-19. Vaccine manufacturing will be discussed in a separate blog.

What manufacturing capacity might be required for COVID-19 treatments? Anti-interleukin treatments such as tocilizumab require 400-1600mg per treatment (1), with a neutralizing antibody treatment requiring 1.5g (e.g. Regen-EB3 during Ebola trials, ref 2). For our analysis we assumed one patient requires 1.5g. The demand for a biologic could vary depending on whether the treatment is used for mild-severe or severe disease states. Hydroxychloroquine was proposed as a treatment for mild-severe cases constituting 156 million patients (2% of population, ref 3). Remdesivir, for more severe cases only, is undergoing manufacturing for >1 million treatments by the end of the year (4), but Gilead Sciences Inc. is also making extensive additional manufacturing arrangements (5). A biologics-based treatment would follow the latter path – short-term requirement (months) for 1-2 million treatments – 2-3 metric tons – with follow-on capacity in place for at least 10 metric tons.

What would it take to rapidly manufacture 3 metric tonnes and then 10 metric tonnes of a mAb? Optimised product development procedures to speed up the transition of a discovered mAb into clinic and into commercialisation have been discussed in an excellent article by Brian Kelley (6). What about subsequent commercial manufacturing capacity? According to Ecker and Seymour (Jan 2020, ref 5), 23 metric tons of approved biologics were produced in 2018, with 65% of that capacity controlled by 10 companies. Squeezing an extra 10% of the global capacity out of the network seems achievable, particularly if these top 10 companies are involved. We used Biosolve Process to estimate the current manufacturing capacity and timeframes for production of these products. The mammalian cell-based mAb manufacturing process established at the BioPhorum Technology Roadmap Group – a group composed of manufacturers, suppliers, and service providers – was used for the present estimation (7). Using a 6 x 12,500L bioreactor system could generate up to 1.3 million treatments within 6 months of campaign start, if the standard mAb production conditions are able to be followed. The cost of production for bulk drug would be in the range of $50/g, which includes capital depreciation, but not drug product vial filling. Supply security would require a spread of manufacturing sites and it is interesting to see this scale of capacity already being secured – e.g. FujiFilm DB (Hillerod capacity of 6 x 20kL) agreement with Gates Foundation (8).

A 10 ton increase in demand would require substantial collaboration and prioiritisation amongst manufacturers. The timing of this 10-ton manufacturing capacity is important. Lockdown restrictions are being lifted now and population immunity is lower than required for further outbreaks to occur (9). The requirement for therapeutics, vaccines, contact tracing and testing will be increased to prevent further widespread lockdowns and further compounded economic consequences. So, the capacity is needed as soon as possible. To maintain existing production of approved biologics, new capacity will need to be built and/or repurposed. New stainless-steel facilities can take 3 years to add capacity, so a faster and more flexible approach to meet unknown demand is to build modular facilities based on single-use processing technology. Using the standard mAb, BioPhorum process assumptions in BioSolve Process, two cases were evaluated:

  1. Fed batch bioreactors combined with N-1 Perfusion (high density seed) giving a titre of 8 g/L at 2000L scale – 6 bioreactors + downstream steps per modular facility
  2. Perfusion 60 day with a high productivity cell line at 3 g/l at 500L scale – 2 bioreactors + downstream steps per modular facility

Case 1 – 1 metric ton per facility per year – $100M per facility (10 facilities, 1 billion USD in total). Estimated installation time – 1.5 years

Case 2 – 0.5 metric ton per facility per year – $40M per facility (19 facilities in total, $0.75 billion). Estimated installation time, 1 year.

The drug product manufacturing cost for each scenario is calculated as $52/g – $62/g respectively. The goal is to improve on delivery of capacity by the standardisation of design and the use of prefabricated modules, such as GCONs POD (10); employing these innovations in intensive process technology to ensure that facilities can easily be repurposed and respond to changing demand.

This simple evaluation does not include many other demand variables – a combination of biologics may be required (neutralizing antibodies and immunomodulators, for instance) – vaccinations may be successful or may not be successful at reducing severity of disease. Despite the variables, the conclusion is that preparation is needed to address the bulk biologics drug manufacturing capacity now; its needs significant capital input of more than 1 billion USD. The modular approach allows for deployment of manufacturing into the regions that need it securing the supply chain.

The infrastructure needs to be responsive and flexible allowing the same infrastructure to be utilised for the manufacture of different biologics and vaccines, which will be a discussion in our next blog.

BioSolve Process modelling software was used for this process, capacity, and output costs analysis. It allows the user to quickly analyse and evaluate options informing decision making. We are happy to discuss any comments or requirements you have.

 

References

  1. Xu, Xiaoling, Mingfeng Han, Tiantian Li, Wei Sun, Dongsheng Wang, Binqing Fu, Yonggang Zhou, et al. “Effective Treatment of Severe COVID-19 Patients with Tocilizumab.” Proceedings of the National Academy of Sciences, April 29, 2020, 202005615. https://doi.org/10.1073/pnas.2005615117.
  2. Mulangu, Sabue, Lori E. Dodd, Richard T. Davey, Olivier Tshiani Mbaya, Michael Proschan, Daniel Mukadi, Mariano Lusakibanza Manzo, et al. “A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.” New England Journal of Medicine 381, no. 24 (December 12, 2019): 2293–2303. https://doi.org/10.1056/NEJMoa1910993.
  3. Zhang, Tony Y., and Boyu Zhong. “Meeting the Potential Emergency Global Drug Supply Challenge of Hydroxychloroquine for COVID-19.” Medicine in Drug Discovery 5 (March 1, 2020): 100036. https://doi.org/10.1016/j.medidd.2020.100036.
  4. Gilead Sciences Investor Presentation – Q1 2020 Earnings Results. http://investors.gilead.com/static-files/af4599eb-4fb8-4cf7-96a1-38caf477e9b4.
  5. Gilead Press Release – “Voluntary Licensing Agreements for Remdesivir” –https://www.gilead.com/purpose/advancing-global-health/covid-19/voluntary-licensing-agreements-for-remdesivir
  6. Kelley, Brian. “Developing Therapeutic Monoclonal Antibodies at Pandemic Pace.” Nature Biotechnology, April 21, 2020, 1–6. https://doi.org/10.1038/s41587-020-0512-5.
  7. https://biopharmservices.com/industry-roadmap/ https://www.biophorum.com/phorum/technology-roadmapping/
  8. FUJIFILM Diosynth Biotechnologies. “FUJIFILM Diosynth Biotechnologies Teams with COVID-19 Therapeutics Accelerator to Reserve Manufacturing Capacity and Provide Technical Expertise to Deliver Future COVID-19 Therapies.” Accessed May 12, 2020. https://fujifilmdiosynth.com/about-us/press-releases/fujifilm-diosynth-biotechnologies-teams-with-covid-19-therapeutics-accelerator/.
  9. Salje, Henrik, Cécile Tran Kiem, Noémie Lefrancq, Noémie Courtejoie, Paolo Bosetti, Juliette Paireau, Alessio Andronico, et al. “Estimating the Burden of SARS-CoV-2 in France.” Science, May 13, 2020, eabc3517. https://doi.org/10.1126/science.abc3517.
  10. “Flexible Production Platforms for Pharma – and Biopharmaceutical Manufacturing” – White Paper, G-CON Manufacturing. https://youtu.be/Iz5CF4AP5Wk
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