Single-use technologies and CDMO expansions have resolved some of the issues in the cell and gene therapy space but analytical and supply chain challenges still exist, says Spark Therapeutics.

Spark Therapeutics is one of a handful of companies to achieve regulatory success with an advanced therapy, specifically its gene therapy for inherited vision loss Luxturna (voretigene neparvovec) which received US approval in December 2017.

Speaking as part of a panel discussion at the BPI Theater at BIO in Philadelphia last month, Diane Blumenthal, head of Technical Operations at Spark, spoke about how her firm overcame some of the hurdles of bringing its therapy to the market.

Many hurdles of gene therapy manufacturing have been cleared but challenges still exist, says Spark Therautics. Image: iStock/amanalang

From a manufacturing point of view, “every time a new modality comes to fruition, we face some similar challenges,” she said, before talking about translating technology from academic environments to scalable and commercial functions.

“There are difficulties, certainly, in getting enough capacity in the early stages of development of those modalities.” This led to the question of whether to commercialize products internally or externally but “back in 2014 when we were faced with this decision… it was very difficult to find well-established, late-stage and commercial capacity.”

Since then, the industry has responded to the high demands for cell and gene therapy services, with numerous investments in capacity, including from Lonza, WuXi, Brammer Bio (now Thermo Fisher) and others.

There is now a “very experienced and established” third-party sector, Blumenthal said, but with demand remaining so high “that capacity is still limited and there is still quite a bit of competition for that capacity.”

However, this has been alleviated somewhat by advances in and integration of technologies, specifically “the incorporation of single-use technology [and] modular facilities that allow us to stand-up facilities much more rapidly.”

Supply chain challenges

The imbalance in supply and demand aside, Blumenthal told the Theater challenges still focus on scaling-up processes, such as ultracentrifugation and adherence cell culture. But other problems still exist in throughout the supply chain.

“We still have challenges in our raw materials. Certainly in an AV [adenovirus] manufacturing where plasmas are a large part of our raw materials and the need for large quantities of those raw materials.”

She added: “In the early days, finding cGMP capability to manufacture plasmas was very, very difficult,” but was happy to report that there are now several companies which have advanced their capabilities of manufacturing in that area.

And from a logistics front, the need for products to remain frozen has disrupted the distribution process with a lot of distribution facilities incapable of dealing with temperatures of minus 80 degrees. “In addition, labeling frozen product at minus 80 is very, very challenging.”

Analytical technology

Industry is still continuing to advance its development in understanding the structure function of these molecules, she continued.

“As processes are advancing and expanding, we are moving technology away from adherent to suspension. We are moving our technology out of ultracentrifugation and into column chromatography. As we transition these processes through different development arenas, we need to better understand how our products are developed in the sense of understanding structure function, developing our analytical toolbox, bringing these academic methodologies – particularly in the area of potency assays – moving them into a QC laboratory and making them QC-able.

“There is a very, very large lift here and because we are not in a place where we understand structure function as well as we should, moving through comparability strategies and moving through the regulatory pathways are very, very challenging.”