GEN reporter Vivienne Raper, PhD, recently interviewed Mo Heidaran, PhD, vice president, technical, at Parexel Consulting. He spoke at PepTalk 2021 in January about the importance of comparability studies.

Why is it important to study how manufacturing changes affect product quality?

Heidaran: Gene therapies are complex, and the product is largely defined by the process, which means minor changes could potentially cause major changes in quality and efficacy.

Development timelines are also quite compressed. Whereas you might have a 10- to 15-year development program for a small molecule or biologic, you can get some advanced therapies approved in around five years. There’s also quite a bit of process change involved because you’re starting with small-scale academic manufacturing and switching to an internal facility or CMO [contract manufacturing organization] for commercial production.

In addition, cell and gene therapy developers are new to comparability studies, which means they’re less familiar with how to meet the requirements of the FDA [and other regulators].

What are your top tips for companies doing comparability studies?

Heidaran: You should identify all changes to the manufacturing process and prioritize which could affect product quality. That’s the first element of a good comparability study.

Next, look at which attributes could potentially be affected by those major changes. So, for example, with AAVs, you typically introduce missing genes, meaning transgene activity is a key quality attribute. You can also measure the percentage of full and empty capsids, and the presence of manufacturing impurities like residual DNA or proteins.

The third stage is doing a side-by-side comparison to make sure the new and the old process produce similar products. So, for CAR-T, for example, you can take samples from a healthy donor, or preferably patient material and split them to minimize donor-to-donor variability. If you perform one process using the old procedure and one using the new one, you should compare them under identical conditions, if feasible, for example, in the same facility with the same validated assays.

And what are the major challenges?

Heidaran: Critical quality attributes, such as potency, and their relationship with product quality and efficacy are not well understood for gene therapies, and the assays for measuring them aren’t necessarily validated or quantified either. Moreover, gene therapies are expensive to make, meaning batch sizes and sample sizes are small. As you have a limited number of samples available to compare, it’s harder to identify a suitable statistical model.

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