Approaches to Gene Therapy Plasmid DNA Manufacture – Plasmid DNA is the core of viral and mRNA vector generation. It provides the coding sequences to gene-based advanced therapeutic medicinal products (ATMPs). This is why its manufacture is crucial for both supply and success of these products.
When you create viral vectors via transient transfection, the manufacture of plasmid DNA is crucial. This production method requires the creation of four plasmids. If production is not done properly, it may not be possible to produce a vector that can be used in human studies.
You may require Multiple plasmids for production routes. This puts additional pressure on plasmid manufacturing, which must also supply enough plasmids in order to support growth in ATMP markets. This is evident in the increase in products in development and in products that are in late clinical or commercial production. This growth will continue, and plasmid suppliers must modify their service offerings if they want to maintain it.
In that the market for plasmid DNA is unique, its customers, vector developers, have two slightly conflicting perspectives. These developers view plasmids as commodity products that can be purchased from many suppliers. Developers also acknowledge that plasmids present regulatory challenges as plasmid suppliers have their own manufacturing processes, and more importantly, their own quality and testing methods. These perspectives must be reflected upon by vector developers during production and procurement, as well as in the subsequent stages of clinical research.
Plasmid Production platforms
Each producer of plasmids has its own platform process for producing plasmid DNA. These processes can be used to make multiple plasmids, but they may not have been extensively optimized.
Plasmid Offering
These regulations and guidance documents have prompted plasmid producers to develop service offerings that are not part of the GMP plasmid production platform. These services are designed to fulfil regulatory requirements for “high-quality” plasmids. Plasmid producers have developed a phase-dependent strategy that addresses both production scale as well as quality assurance. Figure 2 outlines the approach. This shows that non-GMP and high quality (HQ) grades are made in 5g scales, primarily to support Phase I/II clinical trials. Most vector producers will switch to GMP grade for Phase III and commercial supply. The 2021 EMA guidelines include this key element.
The need to adopt (and justify) risk-based methods for plasmid manufacturing that are phase appropriate and quality management systems for vector production operations. While some might consider the use of GMP grade plasmid in vector production excessive, many people are using this approach, particularly for late-phase production. They believe this is the best way to manage the risks associated with lentiviral vector production.
Regulatory status
Quality assurance is another issue in plasmid production. Because plasmids are not final drug substances, it can be difficult to design a quality assurance system. Actually, plasmids can be many steps away from final drug substances.
There were no guidelines for the quality of vectors when they first began. Producers used very different methods. The European Medicines Agency (EMA), 2005, issued guidelines that required lentiviral vectors to be of high quality. However, producers used very different approaches. In 2018, the EMA updated its guidelines and designated plasmid as a starting material.
Conclusion
ATMPs are increasingly dependent on plasmid DNA production. Therefore, it is becoming more important that vector producers. and plasmid suppliers collaborate to ensure that plasmid supplies remain available. While maintaining the quality standards required for the commercialization of potentially life-saving drugs. If they are phase-dependent and risk-based, plasmid suppliers and vector producers can collaborate effectively on approaches.