The Switch to Cell-Free DNA: Streamlining Advanced Therapy Manufacturing
The landscape of advanced therapies is rapidly evolving, and so is the way we make them. Manufacturing changes are a natural part of a therapy’s lifecycle, from development through to commercial supply.
Why Manufacturing Changes Are Inevitable
These changes can be triggered by issues such as resolving manufacturing or contamination problems, addressing a shortage or unavailability of a key reagent or material. Issuing changes can also be a strategic decision, such as the desire to improve product quality based on new scientific and efficient methods, increase production scale, enhance product stability or comply with regulatory requirements.
For many advanced therapies, these adjustments aren’t just operational, they are an opportunity to innovate and improve quality of these therapies. A key innovation is the adoption of synthetic DNA as a starting material. It serves as an alternative to plasmid DNA (pDNA) in many applications, such as cell and gene therapies, mRNA vaccines, gene editing.
Cell-Free Synthetic DNA: A modern solution to pDNA
Traditional plasmid DNA manufacturing presents several challenges:
Long manufacturing timelines and difficulty to scale
Maintaining sequence integrity for long or complex sequences such as polyA tails, ITRs/LTRs.
Bacterial fermentation introduces increased risk of endotoxins, host-cell DNA and residual antibiotic resistance genes.
Due to the limitations of pDNA there is a growing demand for alternatives that offer a safer and more reliable DNA starting material. Synthetic DNA is produced through an enzymatic process which completely avoids bacterial fermentation. It allows for:
Faster production timelines and flexible batch sizes
Improved safety profile as no bacterial sequences are amplified during the manufacturing process
Complex sequences are maintained throughout the process, ensuring consistency of final DNA product
In short, cell-free synthetic DNA offers a modern and efficient alternative that meets the demand of today’s advanced therapies.
Demonstrating Regulatory Comparability
Switching to an alternative DNA source can be done at any stage of your drug development journey. When such a manufacturing process change is initiated, the manufacturer is required to conduct comparability studies to demonstrate that the post-change product is highly similar in quality, safety and potency to the pre-change product. This ensures the regulators that the change does not adversely affect the products’ clinical performance.
Comparability relies on a combination of analytical testing and biological assays and in only certain scenarios non-clinical and clinical data. The depth of the testing depends on the stage of clinical and product development. If a manufacturer can provide sufficient assurance of comparability through analytical studies alone, subsequent non-clinical and clinical studies using the post-change product are not necessary.
Download our full guide on making the switch and discover the steps to demonstrating comparability.
Submission Requirements and Reporting
Typically, a comparability report should follow a detailed structure to help facilitate agency review.
A robust comparability report should include:
Change description and background information
Risk assessment and chosen methodology
Lot selection and sample plan
Analytical methods, validation status, and acceptance criteria
Any triggers for additional non-clinical or clinical studies
Partnering for Success
Companies like 4basebio play a critical role in enabling innovators to make the switch to cell-free DNA with confidence. By providing highly pure, enzymatically produced synthetic DNA, 4basebio helps address many of the historical pain points associated with plasmid-derived material, including impurity profiles, scalability constraints, and batch-to-batch variability. 4basebio’s synthetic DNA and technical expertise reduce manufacturing burdens, control costs, and mitigate risk at every stage of development.
Conclusion
In advanced therapy manufacturing, process changes remain complex, therefore making well-planned comparability studies essential for a smooth and successful transition. Close collaboration with the FDA, supported by clear documentation, strong data, and proactive engagement, helps ensure regulatory confidence. By embracing innovation and partnering with industry partners such as 4basebio, manufacturers can confidently advance their therapies from development to patients.
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