What the Cold Chain Cannot Reach
How a new manufacturing technology could change who makes biological medicines — and where
In a field hospital in an active conflict zone, a patient arrives with a severe bacterial infection. The hospital has the diagnostic equipment to identify the pathogen. What it does not have is the specific therapeutic protein — the monoclonal antibody, the recombinant enzyme, the vaccine dose — that the patient needs. The nearest manufacturing facility that could produce it is a continent away, behind a cold chain that has been disrupted, in a centralised facility that requires months of lead time to retool for a new product.
A cold chain is a temperature-controlled supply chain. It involves the logistical planning, thermal packaging, and continuous refrigeration required to transport and store temperature-sensitive goods such as fresh produce, frozen foods, pharmaceuticals, and vaccine, ensuring they remain safe, potent, and high-quality from production to the end consumer.
This is not an edge case. It describes, in concentrated form, the structural problem of biological medicine manufacturing: the gap between knowing what a patient needs and being able to produce it where the patient is. Most biological medicines are made by growing engineered living cells in large fermentation tanks, harvesting and purifying the protein they produce, and shipping it through refrigerated supply chains to the places where it is needed. The system works well in wealthy countries with stable logistics and well-capitalised health systems. It works considerably less well everywhere else.
Cell-free biomanufacturing is a different approach, and it is further along than most people know.
Biology outside the cell
Every living cell is a protein-making machine. The genetic instructions encoded in DNA are transcribed into messenger RNA, which is then translated by ribosomes into proteins. Cell-free protein synthesis, an active research area since at least the 1960s, captures that production machinery and runs it outside any living cell. The process begins by breaking open a batch of cells, typically engineered bacteria such as Escherichia coli, though yeast, plant, and mammalian cell extracts are also used, and extracting the ribosomes and associated enzymatic machinery. Add the genetic instructions for the protein you want; the machinery reads them and produces it. No fermentation tank. No living cell line. No months of retooling to switch to a new product.
The practical advantages over conventional biomanufacturing are specific. Because there is no living cell to maintain, proteins that would kill a conventional host cell line before producing useful quantities can be made cell-free without this constraint. Process development is faster: switching from producing one protein to another requires changing only the DNA or mRNA template, not engineering a new cell line and running the months of validation work that goes with it.
The property with the most direct implications for global health is lyophilisation. Cell-free reactions can be freeze-dried into a stable powder that requires no refrigeration. Researchers at the Jewett Laboratory, now at Stanford, have demonstrated conjugate vaccines produced this way at approximately $0.50 per dose, stable at 37 degrees Celsius — ambient temperature in much of the world without reliable cold chains — for up to four weeks. Separate work from the same group, funded by DARPA and published in Biotechnology and Bioengineering in 2025, demonstrated scalable cell-free production of T7 RNA polymerase — a critical enzyme in mRNA vaccine synthesis — achieving over 90% purity at one-litre scale.
Commercial applications are beginning to emerge. Sutro Biopharma uses a proprietary cell-free platform to produce antibody-drug conjugates and bispecific antibodies, with candidates in clinical trials. Ipsen Biopharm uses cell-free synthesis specifically because it minimises containment risk when producing highly toxic botulinum toxin — a case where the open system’s safety advantages are directly relevant to manufacturing practice. GreenLight Biosciences applied cell-free systems to RNA vaccine production before its 2023 acquisition, after which the platform was redirected to RNA-based agricultural biocontrol — a reminder that commercial priorities and public health priorities do not always point in the same direction.
What the technology cannot yet reach
Technology Readiness Level 5 is an honest assessment of where most cell-free biomanufacturing sits in 2026. The technology has been validated in laboratory settings and small-scale demonstrations. It has not yet been validated in the large-scale, regulated manufacturing environments that pharmaceutical products require before they can be administered to patients.
The most significant technical constraint is yield. Cell-free systems typically produce lower quantities of protein per unit volume than conventional cell-based fermentation at commercial scale. For high-value, low-volume applications — speciality biologics, antibody-drug conjugates, research reagents — this is manageable. For mass vaccine manufacturing at the scale of hundreds of millions of doses, the yield gap remains a real cost constraint.
Post-translational modifications present a related challenge. Many therapeutic proteins require specific chemical modifications after assembly — glycosylation being the most important, where sugar molecules are attached at specific positions and affect the protein’s stability, activity, and immunogenicity. Recent work from the Jewett group, published in ACS Synthetic Biology in 2025, achieved over 85% glycosylation efficiency and yields of up to 450mg per litre of glycoprotein in a two-step cell-free platform. Progress, but still an active engineering challenge rather than a solved problem.
Good Manufacturing Practice validation, the regulatory standard required before medicines can be produced for clinical use, has not yet been established for cell-free biomanufacturing systems. The mRNA vaccine precedent is informative in both directions: a sufficiently urgent need can accelerate regulatory development dramatically, and absent that urgency, the pathway tends to lag the science by years.
The $0.50 per dose figure for lyophilised conjugate vaccines is also derived from raw material costs at laboratory scale — a proof of concept, not a commercial cost estimate. At manufacturing scale, enzyme costs, lysate production, energy, and quality control all need to be incorporated. The expectation is that cell-free systems will be cost-competitive for certain product classes, particularly those requiring rapid product switching, but this has not yet been demonstrated in practice.
Who gets to make medicine
The current geography of biological medicine manufacturing is highly concentrated. The large fermentation-based facilities required to produce biologics at scale are predominantly located in the United States, Europe, and a small number of other high-income countries. The capital cost, typically in the range of hundreds of millions to over a billion dollars, and the technical expertise required to operate such a facility means that most low- and middle-income countries have no domestic biomanufacturing capacity for the medicines their populations need most.
The COVID-19 pandemic made this structural dependency visible in its most acute form. When mRNA vaccine production was concentrated in a handful of facilities, the question of who received vaccines first was not determined by medical need. It was determined by geography, procurement power, and the location of manufacturing capacity. Countries without domestic production capability were last in line, and in some cases, doses pledged through COVAX arrived too late to prevent the deaths they were intended to prevent.
Cell-free biomanufacturing addresses this problem directly. A cell-free system producing lyophilised vaccine components requires no fermentation infrastructure, no refrigeration during storage or transport, and significantly less technical overhead to operate than a conventional bioreactor facility. The direction the research points toward is distributed, decentralised manufacturing: regional production facilities, field hospital capabilities, in principle point-of-care production in the settings where patients need treatment.
The access implications extend beyond pandemic preparedness. Many neglected tropical diseases — conditions that cause enormous suffering in low-income countries but attract little pharmaceutical development investment because the affected populations cannot pay prices that support conventional manufacturing economics — could in principle be addressed by cell-free produced therapeutics if the manufacturing cost barrier were reduced. A vaccine against enterotoxigenic E. coli, one of the leading causes of diarrhoeal disease and child mortality in the developing world, was among the first demonstrated applications of low-cost lyophilised cell-free vaccine production. The connection between manufacturing economics and which diseases receive medicines is direct.
The test that matters most is whether the technology is deployed where the access gap is sharpest, rather than where the regulatory environment is most familiar. A reduction in the capital and manufacturing threshold changes little if the pathway to GMP certification, WHO prequalification, and COVAX procurement simply replicates the infrastructure requirements of conventional manufacturing. Regulatory agencies in low-income countries, COVAX procurement frameworks, and WHO prequalification processes will all need to develop explicit pathways for cell-free produced biologics. The geographic promise of the technology does not translate into geographic reality without that work.
The field hospital in the conflict zone, the outbreak in the region without cold chain infrastructure, the neglected disease in the country without manufacturing capacity — these are not hypothetical future scenarios. They are the current state of biological medicine access for a substantial portion of the world’s population.
Cell-free biomanufacturing does not yet solve those problems. It is an early-stage technology with real constraints and a significant gap between laboratory demonstration and clinical deployment. It is, however, the first credible technical approach to a problem that has always been treated as structural and immovable: that making biological medicines requires the kind of industrial infrastructure that is simply not available in most of the world.
The geography of manufacturing is the geography of access. The question the science cannot answer on its own is who will fund the work to change it.
My Opinion
You’re reading The Next Evolution by Neil Catton, articles that explore the human world and the intersection of technology, they try and ask difficult questions - not to scare - but to inform. If someone forwarded this to you, you can subscribe free at neilcatton.substack.com.
Neil Catton is the author of The Next Evolution, The Cognitive Crucible and The Shadow System - available on Amazon, and writes at the intersection of technology, ethics, and human purpose.