EXCERPT:
A Nature Medicine study found manufacturing plasmid sequences and incomplete helper virus genomes in liver tissue from a patient who developed acute liver failure after AAV therapy. The implications for process development and residual testing are significant.
CONTENT:
A study published in Nature Medicine has put AAV manufacturing quality back in the spotlight, and not in a good way. Researchers found manufacturing plasmid sequences and incomplete genomes of helper viruses in liver biopsies from a patient who developed acute liver failure shortly after receiving an AAV-based gene therapy.
This isn’t just a safety signal — it’s a process development and analytical gap. The contaminating sequences likely originated from the upstream manufacturing process, where plasmid DNA and helper virus components are used to produce the AAV vector. If residual clearance isn’t adequately characterized and validated, these materials can make it into the final product.
For CROs and CDMOs supporting gene therapy programs, this study underscores the need for robust residual DNA and adventitious agent testing strategies earlier in development. Sponsors filing INDs and BLAs will increasingly face questions about how manufacturing-derived impurities are identified, controlled, and justified. This is an unmet need the industry needs to address systematically, not reactively.