Finally, the recover phase is characterized by regained functionality, for example by reducing the protect and response measures that limit system functionality, such as production lockdown. Ultimately, this can result in an increased overall system functionality at the end of a resilience cycle and before the start of the next “iteration” . For example, a system such as society can be better prepared for a pandemic situation due to increased pharmaceutical production capacity or platforms like plants. From our perspective, the production of recombinant proteins in plants could support the engineering of increased resilience primarily during the prepare and respond stages and, to a lesser extent, during the prevent and recover stages . During the prepare stage, it is important to build sufficient global production capacity for recombinant proteins to mount a rapid and scalable response to a pandemic. These capacities can then be used during the response stage to produce appropriate quantities of recombinant protein for diagnostic , prophylactic , or therapeutic purposes as discussed above. The speed of the plant system will reduce the time taken to launch the response and recovery stages, and the higher the production capacity, the more system functionality can be maintained. The same capacities can also be used for the large-scale production of vaccines in transgenic plants if the corresponding pathogen has conserved antigens. This would support the prevent stage by ensuring a large portion of the global population can be supplied with safe and low-cost vaccines, for example, to avoid recurrent outbreaks of the disease.
Similarly,square pot existing agricultural capacities may be re-directed to pharmaceutical production as recently discussed . There will be indirect benefits during the recover phase because the speed of plant-based production systems will allow the earlier implementation of measures that bring system functionality back to normal, or at least to a “new or next normal.” Therefore, we conclude that plant-based production systems can contribute substantially to the resilience of public healthcare systems in the context of an emergency pandemic.The cost of pharmaceuticals is increasing in the United States at the global rate of inflation, and a large part of the world’s population cannot afford the cost of medicines produced in developed nations23 . Technical advances that reduce the costs of production and help to ensure that medicines remain accessible, especially to developing nations, are, therefore, welcome. Healthcare in the developing world is tied directly to social and political will, or the extent of government engagement in the execution of healthcare agendas and policies . Specifically, community-based bodies are the primary enforcers of government programs and policies to improve the health of the local population . Planning for the expansion of a bio-pharmaceutical manufacturing program to ensure that sufficient product will be available to satisfy the projected market demand should ideally begin during the early stages of product development. Efficient planning facilitates reductions in the cost and time of the overall development process to shorten the time to market, enabling faster recouping of the R&D investment and subsequent profitability.
In addition to the cost of the API, the final product form , the length and complexity of the clinical program for any given indication , and the course of therapy have a major impact on cost. The cost of a pharmaceutical product, therefore, depends on multiple economic factors that ultimately shape how a product’s sales price is determined .Plant-based systems offer several options in terms of equipment and the scheduling of upstream production and DSP, including their integration and synchronization . Early process analysis is necessary to translate R&D methods into manufacturing processes . The efficiency of this translation has a substantial impact on costs, particularly if processes are frozen during early clinical development and must be changed at a subsequent stage. Process-dependent costs begin with production of the API. The manufacturing costs for PMPs are determined by upstream production and downstream recovery and purification costs. The cost of bio-pharmaceutical manufacturing depends mostly on protein accumulation levels, the overall process yield, and the production scale. Techno-economic assessment models for the manufacture of bio-pharmaceuticals are rarely presented in detail, but analysis of the small number of available PMP studies has shown that the production of bio-pharmaceuticals in plants can be economically more attractive than in other platforms . A simplified TEA model was recently proposed for the manufacture of mAbs using different systems, and this can be applied to any production platform, at least in principle, by focusing on the universal factors that determine the cost and efficiency of bulk drug manufacturing .
Minimal processing may be sufficient for oral vaccines and some environmental detection applications and can thus help to limit process development time and production costs . However, most APIs produced in plants are subject to the same stringent regulation as other biologics, even in an emergency pandemic scenario . It is, therefore, important to balance production costs with potential delays in approval that can result from the use of certain process steps or techniques. For example, flocculants can reduce consumables costs during clarification by 50% , but the flocculants that have been tested are not yet approved for use in pharmaceutical manufacturing. Similarly, elastin-like peptides and other fusion tags can reduce the number of unit operations in a purification process, streamlining development and production, but only a few are approved for clinical applications . At an early pandemic response stage, speed is likely to be more important than cost, and production will, therefore, rely on well characterized unit operations that avoid the need for process additives such as flocculants. Single-use equipment is also likely to be favored under these circumstances, because although more expensive than permanent stainless-steel equipment, it is also more flexible and there is no need for cleaning or cleaning validation between batches or campaigns, allowing rapid switching to new product variants if required. As the situation matures , a shift toward cost-saving operations and multi-use equipment would be more beneficial.An important question is whether current countermeasure production capacity is sufficient to meet the needs for COVID-19 therapeutics, vaccines, and diagnostics. For example, a recent report from the Duke Margolis Center for Health Policy24 estimated that ~22 million doses of therapeutic mAbs would be required to meet demand in the United States alone ,square plastic planter assuming one dose per patient and using rates of infection estimated in June 2020. The current demand for non-COVID-19 mAbs in the United States is >50 million doses per year27, so COVID-19 has triggered a 44% increase in demand in terms of doses. Although the mAb doses required for pre-exposure and post-exposure COVID-19 treatment will not be known until the completion of clinical trials, it is likely to be 1–10 g per patient based on the dose ranges being tested and experience from other disease outbreaks such as Ebola . Accordingly, 22–222 tons of mAb would be needed per year, just in the United States. The population of the United States represents ~4.25% of the world’s population, suggesting that 500–5,200 tons of mAb would be needed to meet global demand. The combined capacity of mammalian cell bioreactors is ~6 million liters27, and even assuming mAb titers of 2.2 g L−1, which is the mean titer for well-optimized large scale commercial bioreactors , a 13-day fed-batch culture cycle , and a 30% loss in downstream recovery, the entirety of global mammalian cell bioreactor capacity could only provide ~259 tons of mAb per year. In other words, if the mammalian cell bioreactors all over the world were repurposed for COVID-19 mAb production, it would be enough to provide treatments for 50% of the global population if low doses were effective but only 5% if high doses were required. This illustrates the importance of identifying mAbs that are effective at the lowest dose possible, production systems that can achieve high titers and efficient downstream recovery, and the need for additional production platforms that can be mobilized quickly and that do not rely on bioreactor capacity. Furthermore, it is not clear how much of the existing bioreactor capacity can be repurposed quickly to satisfy pandemic needs, considering that ~78% of that capacity is dedicated to in-house products, many to treat cancer and other life-threatening diseases . The demand-on-capacity for vaccines will fare better, given the amount of protein per dose is 1 × 104 to 1 × 106 times lower than a therapeutic mAb.
Even so, most of the global population may need to be vaccinated against SARS-CoV-2 over the next 2–3 years to eradicate the disease, and it is unclear whether sufficient quantities of vaccine can be made available, even if using adjuvants to reduce immunogen dose levels and/or the number of administrations required to induce protection. Even if an effective vaccine or therapeutic is identified, it may be challenging to manufacture and distribute this product at the scale required to immunize or treat most of the world’s population . In addition, booster immunizations, viral antigen drift necessitating immunogen revision/optimization, adjuvant availability, and standard losses during storage, transport, and deployment may still make it difficult to close the supply gap. Regardless of the product, the supply of recombinant proteins is challenging during emergency situations due to the simultaneous requirements for rapid manufacturing and extremely high numbers of doses. The realities we must address include: the projected demand exceeds the entire manufacturing capacity of today’s pharmaceutical industry ; there is a shortage of delivery devices and the means to fill them; there is insufficient lyophilization capacity to produce dry powder for distribution; and distribution, including transportation and vaccination itself, will be problematic on such a large scale without radical changes in the public health systems of most countries. Vaccines developed by a given country will almost certainly be distributed within that country and to its allies/neighbors first and, thereafter, to countries willing to pay for priority. One solution to the product access challenge is to decentralize the production of countermeasures, and in fact one of the advantages of plant-based manufacturing is that it decouples developing countries from their reliance on the pharmaceutical infrastructure. Hence, local production facilities could be set up based on greenhouses linked to portable clean rooms housing disposable DSP equipment. In this scenario, the availability of multiple technology platforms, including plant-based production, can only be beneficial.Several approaches can be used to manage potential IP conflicts in public health emergencies that require the rapid production of urgently needed products. Licensing of key IP to ensure freedom to operate is preferred because such agreements are cooperative rather than competitive. Likewise, cooperative agreements to jointly develop products with mutually beneficial exit points offer another avenue for productive exploitation. These arrangements allow collaborating institutions to work toward a greater good. Licensing has been practiced in past emergencies when PMP products were developed and produced using technologies owned by multiple parties. In the authors’ experience, the ZMapp cocktail was subject to IP ownership by multiple parties covering the compositions, the gene expression system, manufacturing process technology/knowhow, and product end-use. Stakeholders included the Public Health Agency of Canada’s National Microbiology Laboratory, the United States Army Medical Research Institute of Infectious Diseases , Mapp Bio-pharmaceutical, Icon Genetics, and Kentucky Bioprocessing, among others. Kentucky Bio-processing is also involved in a more recent collaboration to develop a SARS-CoV-2 vaccine candidate, aiming to produce 1–3 million doses of the antigen, with other stakeholders invited to take on the tasks of largescale antigen conjugation to the viral delivery vector, product fill, and clinical development.25 Collaboration and pooling of resources and knowhow among big pharma/bio-pharma companies raises concerns over antitrust violations, which could lead to price fixing and other unfair business practices. With assistance from the United States Department of Justice , this hurdle has been temporarily overcome by permitting several biopharma companies to share knowhow around manufacturing facilities and other information that could accelerate the manufacturing of COVID-19 mAb products.26 Genentech , Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, and AbCellera Biologics will share information about manufacturing facilities, capacity, raw materials, and supplies in order to accelerate the production of mAbs even before the products gain regulatory approval. This is driven by the realization that none of these companies can satisfy more than a small fraction of projected demands by acting alone.