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Moving Beyond “Grande-Sized” Manufacturing for Gene Therapies

3 coffee cups, Small, Medium, and Large. Small cup says 'Small-Scale Batch', Medium cup says 'Mid-Level Batch', and Large cup says 'Large-Scale Manufacturing'.CBER Director Peter Marks compared the current state of manufacturing for individualized gene therapies to the drink sizes at a coffee shop in his introduction to the public workshop, Facilitating End-to-End Development of Individualized Therapeutics, held March 3 at the U.S. FDA headquarters in Silver Spring, Md.

“We are still making vectors much the same way we made them at the turn of the millennium, and we really need to figure out how to move that forward,” he said.

“Right now, we have one sweet spot, which is the ‘grande’ size.” (For those unfamiliar with the “grande” size used at one of the world’s largest coffeeshops, it is ironically the “medium” of the three sizes offered.)

According to Marks, manufacturers of individualized gene therapies are currently capable of producing between 100 and 10,000 batches a year, equated to mid-level manufacturing. To achieve large-scale manufacturing, they need to produce more than 10,000 batches. Unfortunately, he noted, “the technology is simply not there.”

During a session dedicated to manufacturing issues, two leading experts in the field of individualized gene therapies offered their insights, including potential solutions to the challenges they face.

Guangping Gao, PhD, University of Massachusetts Medical School, explored the manufacturing of adeno-associated viral (AAV) vectors in his talk, “Challenges and Opportunities in Development and Manufacturing of Individualized Therapeutics with AAV Vector-Based Gene Therapies.” Dr. Gao is one of the leading researchers studying the potential for AAV vectors to cure patients suffering from the genetic, degenerative neurological disorder Canavan’s disease. This rare disorder commonly affects infants, who lose their motor abilities over time and, most often, do not live past childhood.

When it comes to manufacturing, the number one hurdle is getting the therapy to patients.

“I do not think we have enough vectors to treat patients for a commercial drug,” Gao said. A need for vectors with high enough potency to develop an effective treatment remains problematic. While advancements have been made at the clinical level, commercial-scale is still a high bar for these therapies.

As for a solution, high-throughput sequencing is one way that additional vectors are being located.

“We still have room to improve our vectors,” he emphasized.

Current AAV manufacturing platforms generally rely on two different approaches: transfection-based and infection-based. Transfection-based approaches, which involves inserting genetic material directly into a cell, have proven quite popular. Infection-based approaches, as indicated by the nomenclature, involve infecting a line of cells with an adenovirus. Gao showed data indicating that certain infection-based approaches using baculoviruses and HELA cells are gaining in popularity.

Other major manufacturing challenges for AAVs include the gap between producibility and need, scaling up bioreactor-size versus yield-per-cell, technology transfer, costs and storage and distribution.

Jason J. Gill, PhD, Associate Professor, Bacteriophage Biology and Microbiology, Texas A&M University, spoke about some of the challenges associated with manufacturing phage therapy. In “Development of Phage Therapy: Personalized Medicine and Individualized Therapeutics,” he began with an overview. Phage therapies involve using bacteriophages (or “phages”) to treat infections. Generally a type of virus, phages were studied through the 1940s as a potential treatment for bacterial infections. The development of antibiotics put an end to those studies, until recently.

Manufacturing phage products requires understanding their biology, he explained. Phages are millions of years old and quite hardy, easily adapting to their hosts, making them very specific. Phages also have a diverse set of genomes. In fact, different phages from the same host can have unique genetic codes. This makes scaling up from small, clinical batches to large-scale commercial manufacturing difficult.

Gill sees the development of a phage library as one potential way to offset this challenge. Manufacturers could then “take that through some sort of regulatory process and it [the product] could be widely available and even mass-produced.”

At the same time, intellectual property (IP) concerns from companies developing phage therapies would need to be resolved.

“IP protection would help get more investment in the field,” he said.

From Individualized Therapies to Individualized Inspections

Next, Roger Plaut, PhD, Research Microbiologist and Reviewer, CBER, FDA, and Anita Richardson, Associate Director for Policy, CBER, FDA, joined Gao and Gill for a Q&A session open to the audience.

During the Q&A, one audience member asked Gao about the potential for creating a cell line that produces high enough titers to avoid having to perform transfection, as this would improve manufacturing capacity.

Gao replied that there are two major issues with this approach. One, the regulatory protein (the protein that influences DNA molecules) used for AAVs is highly cytotoxic. The second is a lack of knowledge regarding the factors that can improve gene therapy vector production. He thinks a tighter system that reduces protein expression could address both challenges.

Another question was posed about FDA’s strategy for inspecting facilities producing individualized gene therapies, particularly if they are made at various different hospitals.

Richardson replied that CBER is currently taking an individualized approach, much like the products and processes being inspected.

“I think that we are looking at those types of facilities on a case-by-case basis, taking all the facts and circumstances and the product into consideration, and also the flexibility needed in this field,” she said.

As individualized gene therapies grow in the marketplace, manufacturing will continue to face unique challenges. The Facilitating End-to-End Development of Individualized Therapeutics showed that CBER continues to look at progress in this area.

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