In this unit, Drs. Angelica Meyer and Steven Gray explore why gene therapy manufacturing matters, why quality checks are an essential part of the development timeline, and the challenges faced with large-scale production. This content was developed in partnership with the Bespoke Gene Therapy Consortium.
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Listen to Quick Takes from experts in the community on the following questions (Time: 20:29 min):
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What is a plasmid, and how does it help in making a gene therapy?
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Why are quality checks so critical when making gene therapies, and what kinds of things do scientists look for to make sure the therapy is safe and works as intended?
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Why is it hard to make enough gene therapy for everyone who needs it?
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How long does it usually take to make a batch of AAV vectors, and why?
Key Takeaways
What is a plasmid?
Plasmids are small, double-stranded circular DNA molecules naturally found in bacteria. They can carry genetic information and replicate independently. Scientists engineer plasmids to include the genetic instructions needed to produce AAVs for gene therapy. Bacteria can rapidly produce large amounts of plasmids, making them a scalable tool for generating raw genetic material for gene therapy manufacturing.
Why are quality checks so critical when making gene therapies and what kinds of things do scientists look for to make sure the therapy is safe and works as intended?
Gene therapies are complex biological drugs involving engineered viruses and synthetic DNA. Quality checks ensure that correct DNA sequences are used, there is no cross-contamination between batches, and there is product consistency and safety across batches. Rigorous testing reduces risk of adverse reactions and ensures data from trials is reliable and attributable to the drug not due to contamination.
Why is it hard to make enough gene therapy for everyone who needs it?
Diseases like muscular dystrophy or neurological disorders require high doses due to their systemic nature. Scaling from treating 10 to 1,000 patients demands exponentially more raw material, time, and manufacturing space. Manufacturing processes are still evolving. They are specialized, expensive, and time intensive. Current systems are not yet optimized for mass production, making gene therapies limited in supply and costly.
How long does it usually take to make a batch of AAV vectors, and why?
The production of AAV gene therapies is complex and takes longer than expected. This is not due to the length of time taken to produce but rather the needed time to test and document each required step for ensuring safety and consistency.
For example, the actual production of plasmids takes about two weeks, but the overall timeline is significantly longer due to quality testing, documentation, traceability of materials, and strict compliance with Good Manufacturing Practices (GMP). These steps can extend the process to three to six months. For AAV vector production, growing the necessary cells and producing the virus itself typically takes around one month. However, additional time is required for pre-production testing and small-scale pilot runs to minimize the risk of failure. After production, another two to three months are often needed for post-production testing and documentation to ensure the product is safe and effective for use in humans. Additionally, manufacturing facilities often have long queues, which can add several more months before production can even begin.
Altogether, from initial preparation to final release, manufacturing a single batch of AAV can take anywhere from six to twelve months or more. These manufacturing timelines affect how quickly a gene therapy can move through clinical trials. Delays in production or release testing can hold up the trial, even if all other elements are functioning as they should. While the process is lengthy and complex, these built-in safeguards are essential to ensuring safe practices for in-human testing.
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