The market for the supply of plasmid DNA is a unique and fast expanding one, with suppliers are having to develop their service offerings to reflect changing needs.
Whilst there are plasmid therapies and vaccines including COVID-19 vaccines in development, much of the market is for the production of plasmids for the transient production of viral vectors, and more recently RNA based therapies, where it provides genetic templates for the production of these therapies.
From a regulatory perspective plasmid DNA is regarded as critical starting material, with regulators now expecting plasmid DNA for late phase and commercial products to be supported by comparable documentation to drug substance submissions. However, from a manufacturing perspective it is also seen as a “commodity” in that end users will source plasmid from multiple vendors using different manufacturing processes to produce clinical and commercial products.
Consequently, at present, the market is driven by the needs of the viral vector market, which saw record investments in 2020 in the region of $20bn, so we can expect strong demand for plasmid products going forward. However, within this market we are also seeing a change in approach by developers; moving away from “proof of principle” to one where patient safety and therapeutic efficiency is becoming increasingly important. We are also seeing significant increases in production scales especially for AAV vectors with several manufacturers scaling up to 2000L production platforms and AAV vectors being produced at up to 1000L to support early phase clinical studies.
The production of vectors via transient plasmid transfection at large scale is challenging and plasmid costs are a significant proportion of the overall production costs. Whilst drug developers are progressing alternative approaches such as producer cell lines, currently plasmid transfection remains the most common approach to vector production. However, the emergence of these alternative approaches increases the need for plasmid producers to decrease production costs and improve supply chains especially during the pandemic.
Phase Dependent Response
Plasmid DNA manufacturers need to recognize this changing market, and develop a service offering to provide a phase dependent response to support customer pipelines. A key element of this is being able to supply material that is representative in terms of purity of material that will be used for commercial supply at all stages of development, so that vector generated for pre-clinical or early clinical needs is fully representative of the final commercial material.
The first change in the market is that there is an increasing desire to improve vector targeting and the efficiency of vector delivery especially for AAV vectors, with the need to enhanced safety by reducing dose levels and in doing so reducing costs. This is particularly important for treatments requiring vector doses >1E14/kg which is creating a need for plasmid DNA to support pre-clinical evaluations for vector and candidate selection for new therapies. To support customer programs in this market requires rapid response, low-cost and high throughputs, where quality oversight is less critical.
High Quality DNA
Once developers move towards clinical development, then there is a step change in both the amounts of material, and quality systems, required. To support rapid clinical evaluation of early-stage vectors, many developers are using High Quality (HQ) rather than GMP materials; where plasmid DNA is produced with high levels of traceability and operational control, outside of a GMP umbrella. Cobra Biologics, a Charles River company, like many plasmid manufacturers, is investing significantly in expanding capabilities in this area. Here the requirements are around having robust, high throughput platforms which can supply up to 1g of plasmid DNA.
As products move into late clinical phase again there is not only a significant increase in material requirements, full GMP compliance is required for plasmid DNA production. There is an essential need to provide robust supply chains to support late phase and commercial supplies, with a critical eye on as procurement is on a gram rather than batch basis. Some suppliers requiring >100g of multiple plasmid DNA per annum to support clinical studies. To achieve this, production scales need to be increased, productivities enhanced, and facility throughput raised. In recognition of these demands, Cobra is investing in a large scale production facility at its site in Matfors, Sweden.
Going forward, whilst there is increasing pressure on plasmid DNA suppliers with regards to cost and supply chains, significant opportunities still exist within this market for growth and expansion of plasmid manufacturing services.
Author: Tony Hitchcock, Technical Director, Cobra Biologics: A Charles River Company
Photo: Facility expansion at Cobra Biologics, Matfors