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In developing a new gene therapy, working successfully with regulatory bodies is complicated and challenging. Chemistry, manufacturing, and controls (CMC), for instance, must provide extensive data. At an FDA gene therapy town hall on April 25, 2023, for example, the regulator noted: “The CMC information should describe the sponsor’s commitment to perform manufacturing and testing to ensure product safety, identity, quality, purity, and strength, including potency.”¹ Accomplishing all of that often requires working with a contract development and manufacturing organization (CDMO).

According to María Orío, Director of Regulatory Affairs CMC at Viralgen in San Sebastian, Spain, “We provide regulatory CMC support to help our clients to navigate the complex and constantly changing rules around gene therapy.” That support ranges from ensuring that a product is compliant with global regulations to preparing documentation for submissions and even support throughout the entire lifecycle of the product. “The main goal is to make sure that these therapies can move smoothly from development to approval while maintaining top quality,” Orío says.

AAV-based benefits and challenges

Viralgen develops and manufactures gene therapies based on adeno-associated viruses (AAVs). “One of the biggest benefits of using AAVs for gene therapy is that it’s really efficient at delivering genetic material to target cells,” Orío says. “AAV vectors are safe, nonpathogenic, and tend to cause minimal immune reactions, which is a huge advantage in treating genetic disorders.” In addition, one dose of an AAV-based gene therapy can provide long-lasting effects by maintaining stable gene expression over time. “These factors make AAV-based therapies promising options for both common and rare genetic diseases,” Orío explains.

Nonetheless, it can be difficult to meet regulatory expectations. “One of the main challenges is that there aren’t many specific regulatory guidelines that are tailored for gene therapy, especially for AAV-based therapies,” Orío says. “The requirements can sometimes be unclear or too general, which makes the approval process a bit uncertain.” Regulatory approval also requires consistent manufacturing across different batches of an AAV-based gene therapy. “Plus, there’s a need for precise methods to measure things like product quality, which adds extra layers of complexity to the process,” Orío says.

Addressing the obstacles

Viralgen helps customers address these challenges in several ways. For example, Viralgen “developed a streamlined platform for producing AAV vectors,” Orío explains. “This platform lets us use historical data from different batches, and by doing a statistical analysis on this data, we can meet regulatory expectations and reduce the risk of delays.” In addition, the historical data can be leveraged to develop acceptance criteria for different quality attributes when the number of batches for a certain program is limited. Perhaps most important, Viralgen’s platform provides the flexibility needed to develop gene therapies for multiple diseases—all with the same technology.

This flexibility also allows Viralgen to adapt to accommodate the growing regulatory requests for more accurate measurements. For example,Viralgen switched from quantitative PCR (qPCR) to droplet digital PCR (ddPCR). “The previous methods had a high variation rate,” Orío says. “By adopting ddPCR, we can provide much more precise and reliable data, which made a big difference in meeting regulatory requirements.”

As the use of gene therapies grows and extends to treating more diseases, the regulatory challenges will continue to evolve. Nonetheless, Orío points out that regulators around the world are “looking toward being more consistent with their requirements, and more alignment between global regulatory agencies will make it easier to get gene therapies approved across different regions.”

Accelerating the process of approving gene therapies will benefit companies and patients. As Orío says, “In many cases, a gene therapy is a patient’s only hope.”

Reference

1. U.S. Food and Drug Administration. OTP town hall: gene therapy chemistry, manufacturing, and controls. (2023).

For more information, see the white paper: “Enhancing CMC Regulatory Efficiency in Gene Therapy: Viralgen’s Perspective” or visit viralgenvc.com.