Advanced therapies are reshaping the treatment landscape, offering curative potential for conditions once managed only symptomatically. Gene therapies, gene modified cell therapies, mRNA medicines, and DNA based vaccines are moving steadily toward broader clinical and commercial use. Yet as these modalities scale, it has become increasingly evident that their manufacturing processes are not built for sustainability.
Notably, it was estimated that the healthcare sector was responsible for 4% of global carbon dioxide (CO2 ) emissions in 2023, with projections suggesting a more than threefold increase by 2050 if no mitigative action is taken.1 This trajectory is incompatible with global climate goals and with the industry’s own commitments to environmental responsibility. While traditional biologics manufacturing has made progress through decades of process optimisation, advanced therapies which are still early in their industrial maturation, face steeper hurdles.
Advanced therapies also face an unprecedented scale challenge. AAV gene therapies delivered systemically may require doses as high as 1×10¹⁷ viral genomes per patient, a level that places extraordinary pressure on upstream DNA supply and manufacturing infrastructure. As more programs move toward late stage development, the resource intensity of producing these materials, particularly plasmid DNA (pDNA), becomes a defining constraint on both sustainability and commercial viability.
The Environmental Burden of Fermentation-Based DNA Production
Fermentation has been the backbone of plasmid DNA production for decades. Its scientific foundations are well established, but there are substantial environmental and operational drawbacks. For example, fermentation requires large bioreactors, extensive water use, and significant energy inputs. Cleaning in relies on bacterial hosts, pDNA can carry unwanted bacterial sequences, antibiotic-resistance markers, and endotoxins. These impurities must be removed, further adding to the resource burden, and underscoring both environmental and public-health concerns. Furthermore, fermentation struggles to scale efficiently, especially for complex plasmids containing high GC content, inverted terminal repeats, or unstable motifs. Yields vary widely, sometimes by orders of magnitude, which makes production unpredictable and resource intensive. Even with careful control of critical process parameters such as agitation, pH, and temperature, achieving high percentages of supercoiled DNA remains challenging. These limitations collectively increase the cost of goods, slow production timelines, and inflate environmental impact. As advanced therapies move toward commercial scale, fermentation’s inefficiencies become increasingly untenable. A further sustainability challenge lies in the inherent variability of fermentation yields. Plasmid productivity can fluctuate by one to two orders of magnitude depending on sequence complexity, meaning that facilities must routinely overallocate water, media, and energy to compensate for unpredictable output. This variability forces manufacturers to operate with excess capacity and safety margins, inflating the environmental place (CIP) operations alone consume vast quantities of water and chemicals. Even with the adoption of single use systems in some facilities, most pDNA is still produced in stainless steel reactors that demand intensive cleaning cycles.
