Pandemic Response Strains Global Biopharmaceutical Reactor Capacity
Executive Summary
Distress grows as manufacturers wait for suppliers to boost production. One idea: stretch inventories by qualifying single-use bioreactors for reuse.
The supply of plastic bioreactor systems used in manufacturing a wide range of vaccines, monoclonal antibodies and cell and gene therapies has tightened so much during the COVID-19 pandemic that some manufacturers are considering desperate measures to maintain production.
Normally, manufacturers go through enough of these systems, which are designed to be used once and discarded, to produce 5 billion doses of vaccines per year, industry experts say. However, the SARS-CoV-2 pandemic increased overall vaccine demand nearly three-fold to more than 14 billion doses.
Driven by biotech demand, the industry was growing 15% to 18% per year before the pandemic, Kevin Ott, executive director of the Bio-Process Systems Alliance, told the Pink Sheet. While post-pandemic growth has not yet been surveyed, Ott said, “I’m sure it’s through the roof.”
A Dangerous Period
The US government is using tools like Defense Production Act rated orders to give COVID-19 vaccine makers top priority for the single-use systems they need. That leaves developers and manufacturers of other biopharmaceuticals scrambling for the remainder.
Single-use systems suppliers realized they would need to add manufacturing capacity to accommodate the pandemic response. But it will take time to build it, time that some manufacturers may not be able to afford.
Demand for single-use systems already was increasing before COVID-19 hit, driven by a surge in cell and gene therapy development on top of continuing growth in manufacturing of monoclonal antibody drug products.
“We’re probably entering the most dangerous period,” said Bob Brooks of BioPhorum, an organization based in London that helps the global biopharmaceutical industry collaborate on best practices, “because not all of this new capacity is yet online.”
Waves Of Impacts
The pandemic hit biopharmaceutical supply chains in waves.
Matthew Muldoon who leads sourcing and supplier management for Allogene Therapeutics Inc., told the recent BIO Digital annual meeting that it started with supplies like gloves and pipette tips, “things you wouldn’t necessarily consider to be your most critical materials.” Then there were challenges obtaining raw materials and equipment, followed by a tightening of the market for contract manufacturing services and then constraints on cold chain transport and logistics.
Today, Muldoon said, “we have the COVID-19 volumes still straining our supply chain, as well as projects that were put on hold in early 2020 now coming back to life.”
Demand for single-use systems already was increasing before COVID-19 hit, driven by a surge in cell and gene therapy development on top of continuing growth in manufacturing of monoclonal antibody drug products.
Before the pandemic, manufacturers were not ordering single-use systems until three to six months before they needed to use them. This made it difficult for suppliers to anticipate changes in demand, Brooks told the Pink Sheet. “The level of visibility was really poor in the industry.”
As manufacturers began producing COVID-19 vaccines, Ott said lead times went from weeks to months: “I’m talking double digit months.”
Brooks said lead times for single-use systems procurement soon increased to 18 months, with many customers issuing purchase orders 18 to 24 months in advance. In one case, a customer booked supplies 48 months in advance.
Horror Stories
Brooks has heard horror stories from companies worried about their dwindling inventories of single-use systems.
“People are starting to seriously consider questions about reusing,” he said, even though single use “is the whole premise of it.”
There has been talk as well of shifting to perfusion manufacturing, in which larger batches are staged through bioreactors, which could extend their life.
Companies are even looking at returning to stainless steel bioreactors, which are steam cleaned between batches. But not everyone has access to such reactors – or products with enough market demand to be made profitably in such vessels.
Finding Flexibility
Plastic gradually replaced steel over the past decade, initially for development, later for commercial production. Size increased over time, topping out at 20,000 liters.
The new approach provided flexibility: rather than scaling up to meet demand with larger bioreactors, manufacturers could scale out with additional single-use systems operated side by side, avoiding the need for scale-up studies. Rather than work in fixed clean rooms, manufacturers could operate in so-called ballroom facilities that could accommodate a flexible array of single-use systems.
The single-use approach has reduced barriers to entry for biopharmaceutical start-ups, particularly for the emerging cell and gene therapy sector with its personalized, even individualized products.
But the need to vaccinate the world against a pandemic has strained the system to the breaking point, challenging it to attain an even greater degree of flexibility.
Better Demand Forecasting
A forecast demand planning group that BioPhorum established before the pandemic had been encouraging manufacturers to share information with single-use-system suppliers at least 18 to 24 months out.
Without such information, it is difficult for suppliers to justify the multimillion-dollar expense of building new cleanroom facilities to increase production, Brooks said. “If you’re not getting any concrete signals from your end-user community beyond three to six months, who’s going to write that check?”
Although suppliers finally had decided to invest in expanding capacity based on belated signals of pre-COVID-19 demand growth by the time the pandemic hit in early 2020, it quickly became apparent that additional expansion would become necessary.
Training, Automation And Standards
Training is another big challenge, because many people will need to be trained to operate the new facilities, as the manufacture and use of single-use systems is highly manual, Brooks noted.
Thomas Page, VP for engineering and asset development at FUJIFILM Diosynth Biotechnologies, suggested at the BIO meeting that these processes need to be automated to keep up. “If you go to these single-use production sites, it's very labor intensive,” Page said. “I think the role of innovation there is to automate bioreactor bag manufacturing and tube set manufacturing.”
The supply of single-use systems also is challenged by a lack of industry standards. One supplier’s single-use system cannot be swapped for another’s, nor can components be mixed because of the way they are customized. If they were all built to an industry standard, customers could establish alternate sources.
Pharmaceutical companies have unsuccessfully pressed suppliers for such standards, which could turn their products into commodities.
From Gamma Rays To X-Rays
Another factor of concern is the question of how single-use-system suppliers sterilize their products.
The conventional method of gamma sterilization relies on gamma rays from the radioactive decay of cobalt-60.
Cobalt is not one of the four metals regulated as conflict minerals, but much of it is mined in the country targeted by conflict minerals regulations, the Democratic Republic of the Congo.
In any case, there is some concern that demand for gamma sterilization, which also is used in the medical device sector, may exceed capacity.
The industry is beginning a transition to X-Ray sterilization, the supply of which would not be limited by nuclear materials. An added advantage is the lower energy level of X-Rays compared to gamma rays is easier on plastics. However, an X-Ray standard has not been developed yet.
Yet another challenge is a lack of single-use-systems production facilities in Asia.
Suppliers recognize that manufacturing is concentrated in the US and Europe and are working to expand production capacity in China, India and other Asian countries. This is occurring even as the pharmaceutical industry is retreating from overreliance on China and India for the manufacture of drug products, active pharmaceutical ingredients and key starting materials.
Capacity Is Expanding Though Demand Is Uncertain
In recent months, single-use-systems suppliers have been announcing manufacturing expansions.
Cytiva on 21 December said it retrofitted a plant in Shrewsbury, MA, to manufacture single-use stirred-tank bioreactors, freeing up space to add manufacturing lines for complementary single-use technologies at its Westborough, MA, plant. Cytiva completed that project in just five months with partial funding support from the US government’s Biomedical Advanced Research and Development Authority.
Thermo Fisher Scientific on 10 March said it was expanding capacity to manufacture single-use technologies at sites in Logan, UT, Millersburg, PA, Cramlington, UK, Singapore, and Suzhou, China.
Avantor, Radnor, PA, on 26 April said it plans to boost global production of single-use technologies by doubling clean room space in the US and Europe. Expansions were already completed in Morrisville, NC, and underway in Devens, MA, and a second European facility was going up in Hillegom, the Netherlands.
There remains uncertainty about likely demand for COVID-19 vaccines as SARS-CoV-2 variants emerge that could be more transmissible or more able to escape existing vaccines. The timing of an expected transition from pandemic to endemic and the possible need for booster shots that may have to target new variants are unknowns that will affect demand for single-use systems and other COVID-19 vaccine manufacturing elements.
Another uncertainty is the timing and extent of pent-up demand for non-COVID treatments that fell during the pandemic as people avoided the risk of coronavirus infection that they associated with visiting health care providers.
Given the challenges of demand forecasting, some suppliers may take a cautious approach to capacity expansion, Ott said. “You don't want to get stuck with a few empty clean rooms in the year 2026, when this is all over.”