For as long as nucleic acid medicine has existed, developers have structured their programs around a bottleneck that everyone in the field has understood and just accepted – plasmid manufacturing. When a genetic medicine program has missed or delayed its development or clinical timeline, there can be many reasons for that - the science wasn’t ready for primetime or they didn’t have the right team, but the reason can actually be far more simple than that - the plasmid starting material wasn’t available on time.
I’ve personally lived this conundrum. The science and technology was ready, the team was ready, the development pathway was clear, and what held us back was a plasmid supplier whose bacteria did not cooperate with the sequence. That kind of delay is not an anomaly. It is a completely standard feature of how nucleic acid medicine programs have been built for decades, and everyone in the field absorbs that risk and structures their timelines to account for it.
What has changed is that there is now a mature alternative, and I think the moment to take it seriously has arrived.
The use of cell-free synthetic DNA manufacturing enables the complete removal of bacterial fermentation from the production chain. At Artis, our proprietary process is enzymatic rather than biological, which means turnaround time is completely independent of whether a bacterial strain cooperates with a given sequence on a given run. Synthetic DNA manufacturing is sequence-agnostic. For development programs, where timing is a clinical consideration, such as personalized cancer vaccines or outbreak response, moving from multiple weeks or months down to days is not a logistics preference; it is imperative.
Taking bacterial fermentation completely out of the production flow also removes the need for an antibiotic resistance gene and the inevitable endotoxin profile that is associated with plasmid production. The synthetic DNA product is therefore purer and cleaner and the regulatory review reflects that. Regulators who have spent years working through concerns related to antibiotic resistance gene safety submissions find the synthetic DNA profile more straightforward to handle, and the review conversation shifts from defending a known limitation to simply presenting a better starting material.
At Artis, our synthetic DNA can go a step further than just replacing plasmid DNA. With our proprietary adapter technology, the ends of the synthetic DNA molecule - outside of the gene or sequence of interest- can be engineered for the specific downstream application. Examples of this could be improving polymerase processivity for in vitro transcription or enhancing nuclear translocation for DNA vaccine programs. The starting material is not just a cleaner and faster version of what plasmid historically provided. For many downstream applications, Artis’ synthetic DNA works better.
The three questions I hear consistently are cost, scale, and fidelity. On cost, our approach has been specifically built to have cost parity to plasmid. I feel strongly that the barrier to converting a developer from plasmid to something better should never be cost. On scale, we can support programs from small research in vitro and in vivo quantities through large scale GMP and commercial manufacturing, with production redundancy in the United States and Europe.
Fidelity gets a direct answer. Bacteria are very good at copying DNA accurately, and our synthetic process currently operates at approximately one error per ten million base pairs compared to roughly one per billion for bacterial copying. That gap is real and I say so with every client. The standard mitigation is sequencing as a release criterion, which is already common practice for clinical material, and we are working on enzyme engineering to narrow that gap further. I cannot say exactly where that work will land. What I can say is that the risk is understood, the mitigation is in place, and the full picture of the other advantages makes this a reasonable and considered position for programs where time is what matters most.
The base case for converting to synthetic DNA from plasmid DNA is not only about what synthetic DNA enables from a product perspective. It is also about what is happening to the plasmid infrastructure that developers are currently depending on. Major GMP plasmid manufacturers are leaving the market and the sparse capacity that remains is under real pressure. Countries without domestic plasmid fermentation infrastructure or companies without internal manufacturing capabilities are carrying real strategic exposure from their reliance on a small number of Western or Chinese CDMOs.
For developers still continuing to build programs around bacterial plasmid, the question goes beyond whether the alternative – synthetic DNA - is good enough. Will the infrastructure they are counting on still be there, at the scale and timeline they need, when they need it. For a lot of programs, that calculation is shifting.
Artis BioSolutions partners with advanced therapy developers across process development, analytical development, GMP manufacturing, and IND-enabling CMC support. Our integrated team draws on deep drug development expertise across process development, analytical science, quality, and regulatory affairs, working as a true extension of your organization at every stage of the program.
If your program is in cell therapy, gene therapy, viral vector, or complex cell system development, we would welcome the conversation about whether the framework in this series, applied to our team, our facility, and our scientific depth, supports your program's needs.
Synthetic DNA removes bacterial fermentation from the production chain entirely. Here is what that changes for timelines, purity, regulatory review, and supply.
Bacterial removalSynthetic DNA completely removes bacterial fermentation from the production chain. Turnaround times become entirely sequence-agnostic and compress from weeks or months to days for time-critical programs.
Purity and regulationRemoving the use of plasmid entirely removes the need for an antibiotic resistance gene and the inevitable endotoxin profile. The product is cleaner, purer and the regulatory review is simpler.
Functional tailoringAdapter technology at Artis allows synthetic DNA to be engineered for the specific downstream application, improving functional performance beyond what a standard plasmid can offer.
Scale and parityPricing is at parity with plasmid and manufacturing is available from research-grade through commercial GMP, with production redundancy in the United States and Europe.
Transparent fidelityOur synthetic process operates at approximately one error per ten million. Sequencing as a release criterion is standard practice.
Contracting infrastructureThe plasmid supply picture is contracting as major manufacturers exit the market under pressure from synthetic DNA. Planning future programs around synthetic DNA is the stronger position.
The questions developers bring to us most often about moving from plasmid to synthetic DNA.
Why do nucleic acid programs miss their development windows?More often than people expect, the reason is not the science or the team. It is the plasmid starting material. Bacterial fermentation is variable in ways that are difficult to manage or predict, and if the bacteria do not cooperate with a given sequence there is no way to force it to go faster. Programs account for this by building extended lead times into their planning, because they have learnt that they must. Major health crises in the form of infectious disease outbreaks put the cost of those lead times under a global magnifying glass.
Is plasmid supply a one-off problem or something the whole field deals with?The concern around plasmid availability and supply is entirely universal. Anyone who has spent time in nucleic acid medicine has had the call from a supplier where a plasmid was promised in two months but shows up four months later because the sequence was difficult or the bacterial strain did not perform. Programs have been absorbing that risk for decades without much comment, because until recently there was no alternative. That situation is now different.
What does synthetic DNA change beyond speed?Synthetic DNA is a paradigm shift over plasmid DNA, and the speed benefits tend to crowd out all the other positive aspects. Completely removing bacterial fermentation from your production chain removes the need for an antibiotic resistance gene entirely, and removes the inevitable endotoxin concerns that come as standard with plasmid production.
I have had many regulatory meetings during my career accounting for the limitations of plasmid DNA and justifying why they were manageable. That aspect of the regulatory discussion is completely removed with synthetic DNA. Artis' Adapter engineering also allows our synthetic DNA to be tailored for specific downstream applications, whether improving polymerase processivity for in vitro transcription or enhancing nuclear translocation for DNA vaccines, so you are not just removing a problem but replacing it with something better suited to your product.
What are the three questions developers ask most often?Cost, scale, and fidelity, almost always in that order regardless of the modality or stage of the program. Pricing is at parity with plasmid; that is central to our mission. Our scale covers small research and discovery quantities through large scale GMP and commercial manufacturing, with production redundancy in the United States and Europe. Fidelity is covered below.
What is the fidelity readout of synthetic DNA?It is a real consideration, and I raise it with every client rather than waiting for them to ask, because that is the only way to have a credible conversation about a new technology. Bacteria copy DNA at roughly one error per billion base pairs. Our synthetic process currently operates at approximately one error per ten million.
The standard mitigation is sequencing as a release criterion, which is already standard practice for any clinical material. In parallel, we are working on enzyme engineering to improve that further. The limitation is known, the mitigation is in place, and when you look at the full picture the trade-off is reasonable.
What is the regulatory environment for synthetic DNA?More favorable than it has ever been, and continuing to build strongly. Trials using synthetic DNA as the starting material are running in Australia and Europe, and regulators who have spent years working through antibiotic resistance gene submissions find the cleaner synthetic DNA profile considerably more straightforward.
What is happening to the plasmid supply picture?The historical plasmid production business is contracting, at least in part because of the growth of synthetic DNA. Major GMP plasmid manufacturers have left the market, and the infrastructure the genetic medicines industry has previously depended on is shrinking while demand for nucleic acid medicines is growing.
Countries without domestic fermentation capacity are entirely dependent on a small number of Western and Chinese CDMOs, and we see many of those countries now treating bringing synthetic DNA on shore as an industrial policy priority.
What would you say to a developer still planning around plasmid?I would ask them to look honestly at the full risk picture they are already carrying. That includes not just the lead time risk everyone in this field knows personally, but also availability risk given how the supply picture is changing, purity considerations, and the regulatory cost of not being able to move away from a known limitation. For time-critical programs, the cost of delay is not just a competitive problem.
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