During the Ebola crisis in 2014, I was asked to help coordinate efforts to quickly scale up manufacturing of the then-experimental ZMapp antibody cocktail.
By that point, I had 30 years of experience at Genentech, Immunex and Amgen, working with teams that figured out how to scale up manufacturing of a number of biologically complex molecules to meet global demand. During the Ebola outbreak, the world was urgently looking to biotech for solutions. People were terrified that this highly lethal virus would spread from West Africa to the rest of the planet with essentially no therapeutic defense.
Fortunately, this did not happen. But it was clear from our efforts that the world was not ready to rapidly respond to a global pandemic.
We’ve made significant progress in the five years since that crisis, but we’re still a long way from being ready to “rapidly” respond to such viral threats. We can self-isolate and practice social distancing to limit the impact, as was done with the 1918 flu pandemic, but pandemics in general, like COVID-19, will continue to extract an enormous human and economic toll unless we find effective global solutions in the form of rapidly developed and mass-produced therapeutics and vaccines.
The scientific and medical communities are collaborating and working hard to discover and develop new therapeutic approaches to battle the current pandemic. Safely manufacturing and distributing these therapies to a global community is not trivial, and the need to accelerate our efforts to bring meaningful manufacturing solutions forward adds complexity.
Vaccines – our best long-term hope
A variety of approaches are being tried for vaccines like inoculating people with genetic material (mRNA or DNA) coding for viral antigens to educate the immune system on specifically what to attack, making classic vaccinations with live-attenuated or killed virus particles, or using subunits (parts) of the virus as vaccines to raise specific and potent antibodies against conserved regions of the virus that are incapable of causing the actual illness.
The objective is the same for each variation; pre-condition the immune system by exposing it to a highly immunogenic vaccine that drives formation of specific antibodies to the virus. The immune system then places these antibodies into “memory,” in preparation for a real infection if it occurs. Vaccines are our best long-term hope for protection from SARS-CoV-2 and other viruses with pandemic potential.
Therapeutic antibodies as strategic near-term tools
Therapeutic antibodies offer another potential solution for addressing infectious disease if used strategically. An infected patient can be treated with a therapeutic antibody before their adaptive immune system has time to respond with their own endogenous antibodies to the virus. The patient’s family, friends and those who have come into contact with the infected person can also be given the therapeutic antibody as a prophylactic treatment to build up their antibody defenses.
This sort of treatment approach could be practical for people at the greatest risk of acquiring an infection – doctors, nurses, EMTs, firefighters and police. If an antibody has a half-life of a month, they could reasonably receive repeat dosing to keep their defenses up to stay on the job.
This approach has great potential to limit the severity and spread of infections when combined with rapid testing. Several companies and organizations are sorting through millions of antibodies from patients who’ve survived SARS-CoV-2 infections, to find the best ones with broad ability to neutralize various forms of the virus. Once found, the DNA that codes for the most effective antibodies can then be engineered into living cells for production in a consistent, scalable manufacturing process.
Meeting global demand for biologics against SARS-CoV-2
As we sort through the efficacy and safety of the different vaccine approaches, we must critically evaluate the potential manufacture and vaccination of billions of people. If conventional approaches are contemplated seriously, like the production of viruses in eggs, capacity limitations in light of current demand for seasonal flu and other vaccines should be carefully considered.
The current system for making traditional flu vaccines can’t be nimbly adjusted for a new strain in mid-season, at least not at global scale. Even if we know exactly what virus we want to use in these traditional systems, supply could be constrained. If one dose of seasonal flu corresponds to the inoculation of one or two eggs, do we really have the excess capacity to add in a new COVID-19 vaccine with the potential requirement for billions of doses while also keeping up with the global demand to produce flu vaccine?
Manufacturing and scale-up of vaccines will be as varied as the vaccine approaches themselves. The capacity for manufacturing mRNA and DNA-based vaccines, because this is currently a nascent technology, is still rather limited compared to recombinant therapeutics and vaccines. Theoretically, they aren’t limited by some of the traditional manufacturing constraints, but this is a hypothesis that hasn’t been put to the true test of a pandemic with billion-dose demand, such as this one.
Vaccines, of every kind, are quite challenging to initially develop. Traditionally, regulators have required very large, randomized controlled trials to demonstrate efficacy, and long-term follow-up to establish a safety profile. This work is time-consuming and expensive. Companies usually don’t invest billions of dollars in global manufacturing capability until they’ve cleared a lot of those hurdles. But once developed, only a small amount of antigen is usually needed to mount an immune response, perhaps 10’s to 100’s of micrograms per dose.
Even if immunization can’t be done in a single shot, and requires multiple doses over a period of time, the actual mass of drug substance and ultimate drug product needed per patient is low. Global scale manufacturing is possible under these circumstances. A straightforward path for meeting global capacity demand could be through the use of recombinant subunit vaccines that use genetically engineered living cells for production. This approach is now being applied to several vaccines, and could piggyback off of technological advances and perhaps capacity resident today in the biopharma industry for the manufacture of other recombinant biologics.
The greatest challenge for manufacturing therapeutic antibodies will be the effective dose needed for treatment. Therapeutic antibodies will require >100 times more of the active ingredient than vaccines. This will place significant pressure on meeting both capacity and cost demands if large patient populations are considered.
Fortunately, substantial knowhow for manufacturing antibody therapeutics exists in the biopharma industry. Many drugs on the market today and literally hundreds that are in the current pipelines of biopharma companies are antibodies or antibody-like therapeutics.
New antibody therapeutics directed at SARS-CoV-2 and other infectious disease threats will exert pressure on existing capacity and force companies to make difficult choices, like choosing between dedicating their manufacturing runs to a promising cancer therapeutic or one directed toward this infectious disease threat. The former kind of product is normally priced much higher than the latter, making the choice even more challenging.
There simply isn’t a lot of slack in the world’s capacity for biologics manufacturing, based on our interactions with large drug makers around the world. While a few companies may have capacity that can be diverted to SARS-CoV-2 therapeutics, there are recent reports (i.e., BioProcess International, Nov. 2019) that suggest overall industry demand for biologics manufacturing capacity is growing faster than it can be created. There are several hundred novel, biosimilar and bio-better molecules currently in the clinic and moving toward commercial products today. Almost 100 novel biologics have been approved for the market in the US during the last decade and 26 biosimilar products. The total combined number of novel biologics and biosimilars approved as commercial products in the last three years alone in the US totals 66 (BioWorld, January, 2020).
With biologics representing the fastest growing segment of the global pharmaceutical industry, it’s not hard to imagine that COVID-19 could add significant stress on current biologics manufacturing capacity.
It is critically important to create greater access to manufacturing capacity that supports a variety of therapeutic approaches, including vaccines, to be truly successful battling pandemics like COVID-19.
The future of biologics manufacturing
We need new approaches for manufacturing biologics to aggressively meet the challenges we currently face. A list of some desired attributes for future facilities might be:
- Relatively simple and fast construction
- Flexible capacity–can produce a few kilograms or multiple metric tons of product
- Flexible operation–capable of efficiently running a variety of processes
- Minimum capital investment–shift costs from fixed to variable
- Fully regulatory compliant for commercial manufacturing of multiple products
- Deployable–can be easily constructed in different geographies
A manufacturing plant with these attributes can be constructed if we connect the design of the molecule, process and manufacturing plant into a single integrated platform. Antibodies can be optimized for improved manufacturing in high yielding processes, producing kilograms per day from relatively small-scale continuous processes, several times greater productivity than just a few years ago. The high productivity of the manufacturing process can allow operation with relatively small single-use technologies placed inside autonomous cleanrooms – as opposed to massive stainless-steel facilities with fixed infrastructure from the past costing up to a billion dollars to construct, millions more to maintain, and years to build.
The new, lean style of biologics manufacturing will dramatically reduce the overall space required for manufacturing and increases flexibility from making one product to the next, because the cleanroom space can be reconfigured to run a variety of process formats. Our team is doing this already in a facility being built in Redmond, Washington in collaboration with Merck. We know the underlying processes and design will work, and believe the principles can be applied more broadly to help meet global capacity demands.
These cleanrooms or manufacturing units can be placed inside a relatively inexpensive building or outer shell. The facility of the future can be a simple warehouse built while process equipment and manufacturing units (clean rooms) are fabricated in parallel by vendors. To expand capacity, additional manufacturing units can be added to “scale out” with modular units running the same process, without the technical risk of “scaling up” in a way that might alter the underlying process and fundamentally alter the ultimate product. Capital costs for building a warehouse are relatively low, so extra “shell space” can be factored into the design or another warehouse can be built to expand capacity. One can even contemplate converting existing warehouse space into a low-cost, flexible biologics manufacturing facility.
This flexible, modular and relatively low-cost approach lends itself to different strategic scenarios for creating future manufacturing capacity for biologics; both therapeutic antibodies and recombinant vaccines. Response time for expanding capacity needs to be dramatically reduced with thoughtful, strategic investments that can be gated and triggered by real demand needs. If staged properly, additional capacity can be added quickly, in a matter of months.
We are still behind the curve in responding to COVID-19. We need to play catch up through wise strategic choices, both in the therapeutics we choose to move forward and in the way we manufacture them for a global community. Hopefully our choices in this present crisis will lay a foundation for more nimble, scalable biologics manufacturing that will better prepare us for the next pandemic.