Gene Therapy CMC and Manufacturing Approaches Are Maturing

By Tonia Becker, Life Sciences Editor, Macon Raine

The gene therapy sector is maturing and the industry is poised to be able to produce products in more consistent and scalable ways. Although the COVID-19 pandemic caused some delays, on the whole, projects are moving forward as planned.

I had the opportunity to speak with Kirsten Pier, Senior Consultant for Technical Operations at BioTechLogic. She currently supports gene therapy CMC functions, and she shared a bit about her experiences working through the pandemic and her outlook on the overall state of gene therapies.

How has the pandemic impacted your clients’ progress and your work with them?

Kirsten: For the most part, projects are moving forward as planned, although it’s been a challenge to work through the lack of hands-on oversight we can provide right now. For example, in April, one of my overseas clients had a critical run using new equipment, which I had planned to observe and assist with in person. Obviously, with travel restrictions, and from a personal precaution perspective, traveling out of the country was not possible.

Nevertheless, we worked it out—I made myself available during working hours in their time zone and made sure that we had frequent communication. We were able to handle nearly everything with teleconferences or simple phone calls.

Nothing has officially been delayed, but the CMO we’re working with is actively participating in their country’s response to developing a vaccine for COVID-19. Some of the GMP documentation and the reports that we needed to finalize prior to our run were delayed.

We encountered some last-minute documentation headaches, probably due to the significant attention being directed toward the COVID-19 vaccine effort. In addition, a shift to people working from home probably also contributed to things moving somewhat slower than normal.

While development processes will be slowed as products move to the clinic, the CMC, tech transfer, and manufacturing aspects we support are, for the most part, on track.

The pandemic aside, gene therapy CMC isn’t nearly as mature as it is for more traditional biopharmaceutical products. Where is the industry in terms of more mature approaches for gene therapy CMC?

Kirsten: I think we will see the industry turn a corner in the next couple of years. The common use of transient transfection is a major roadblock standing in the way of progress toward more consistent manufacturing processes for gene therapies. Currently, transient transfection is more of an art than a science. I’ve seen product quality change just because a company’s particular manufacturing operator, who had always done this process, happened to take a vacation—and some other operator completed the process for a round.

However, I’m starting to see companies focus on developing stable cell lines, which should alleviate a significant number of inconsistent transient transfection outcomes. By using a stable cell line, one should not have to change processes much. Impurity profiles and overall product quality should be quite comparable, round to round.

Also, gene therapy companies themselves are maturing and are more frequently being acquired by larger players. The people who founded gene therapy companies, and those who work for them, are extremely smart people, but they tend to understand predominantly the R&D side of gene therapy. They’re often not highly experienced with GMP or formal CMC.

Many gene therapy companies are recruiting experienced professionals from more traditional biopharmaceutical organizations to help them move products through the later stages of development because they are adept at issues like CMC, quality, and regulatory compliance. Because they are hiring this talent, the industry is getting better at moving products out of academic labs to facilities that can accommodate later-stage development and manufacturing.

Gene therapy CMO capacity is scarce. How are you advising your clients to navigate this scarcity?

Kirsten: As the industry matures, select gene therapy companies are building out their own manufacturing facilities. However, most are using CMOs. I advise my clients to have one or more backup CMOs so that when you file, you are not relying on getting on the schedule of only one CMO.

As a sponsor, you want to secure your supply chain. Filing and tech transfer are much easier as part of phase three work; I don’t advise waiting for approval to secure the supply chain.

Is the gene therapy sector still going through a steep learning curve to handle tech transfer and the other challenges that come with advancing products through the development process?

Kirsten: Yes, and I think a lot of the product maturation challenges have to do with the inconsistencies of transient transfection. These inconsistencies mean we have scalability issues as products move into the large-scale manufacturing, suspension type, and cell culture processes. Actually, I have yet to see much success with a truly scalable pilot—for example, a pilot for full-scale production from a 50-liter process to 200 liters. So far, productivity decreases pretty significantly as we scale up. However, I’m hopeful that we will be able to achieve larger scales as stable cell lines are established.

 

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