US FDA Recommends Use Of Pre-Built Facilities To Ease Scale-Up Process For Cell And Gene Therapies
Executive Summary
As applications for expedited review of cell and gene therapies soar, it is important for their sponsors to take certain steps to enhance prospects for smooth commercial scale-up, the director of US FDA’s center for biologics suggests.
Cell and gene therapy ventures may be able to avoid the so-called valley of death between pilot- and commercial-scale manufacturing by investing in scalable pre-built biotechnology centers and partially automated facilities, Peter Marks, director of FDA’s Center for Biologics Evaluation and Research, recently asserted.
Both firms that have so far won FDA approval for chimeric antigen receptor T-cell therapies –Yescarta (axicabtagene ciloleucel) manufacturer Gilead Sciences and Kymriah (tisagenlecleucel) manufacturer Novartis AG, ran into challenges with commercial manufacturing, Marks said Oct. 23 at a Parenteral Drug Association meeting on cell and gene therapies in Bethesda, Md.
“The clinical data was pretty impressive, and it did not take an army of statisticians to contemplate the clinical effectiveness,” Marks said. “But the manufacturing had some real challenges.”
Growing Interest In Developing Cell Therapies
Marks said that approvals of the two CAR-T therapies “have driven a tremendous amount of venture capital” into cell and gene therapy product development. The growing number of these therapies in clinical development and under expedited approval reflect this interest.
As of Oct. 1, FDA has received 83 requests for Regenerative Medicine Advanced Therapy (RMAT) designations. Of those, 27 were granted, three were withdrawn, 43 denied and 10 remain pending. This is a substantial increase since June 1, when FDA had received 64 requests for RMAT designations, granted 20 and denied 33 with eight pending.
(Also see "RMAT Designation Requests May Rise Or Fall On Manufacturing Changes, Clinical Data Breadth" - Pink Sheet, 27 Jun, 2018.)
Created by the 21st Century Cures Act, the RMAT programs is an expedited regulatory pathway for sponsors developing cell therapies, therapeutic tissue engineering products and human cell and tissue products that are intended to treat, modify, reverse or cure a serious condition for which preliminary clinical evidence shows the product has the potential to address unmet medical needs.
There is also a growing number of investigational new drug applications for gene therapy, a 30% increase since the year before, and FDA expects to receive 150 applications for INDs for gene therapy products by the end of the year.
Difficulties in Manufacturing Products
Yet despite this growing interest, Marks said that manufacturing these products is difficult, and is more complex compared to small molecule products.
Marks said that in the small molecule world, drugs can be easily characterized by mass spectrometry and high-performance liquid chromatography and “we actually know what we have at the end of the day with the product.” Yet with cell and gene therapies, “you are dealing with something that is orders of magnitude more complex.’
Market Therapeutics Inc. CEO Peter Hoang concurred. “With cell therapies, the cells are very unpredictable, so when you make a very simple process change, such as going to a slightly higher glucose level, this can affect the cell’s activity and change the end product.”
Scale-Up Challenges
A major challenge is scaling up a clinical process to a commercial process when early results show promise, which is often the case for these products.
Marks said that “for a lot of these therapies the efficacy will be demonstrable in a Phase 1 trial. … The promise of a product will be seen very early on in a definitive way. For gene therapies, for a person that is not making red blood cells and they are now making red blood products, the endpoints are pretty clean.”
However, processes that worked well at pilot-scale for clinical trials may encounter problems with insufficient expression or increased cell deaths, for example, upon commercial scale-up, he said.
Manufacturers are making a mistake if they build a facility to accommodate manufacturing at a larger scale if they can’t ensure that the process will scale up sufficiently. They risk spending the money on a process that may fail in the end, he said.
Marks said that “in this competitive environment where it can take you two or three years to fix these problems, that can also be the equivalent of the valley of death. You will burn through your capital and be out of business. If you can’t get out of those manufacturing issues, this can be a real problem, but even more so it is a shame for the patients who are deprived of a potential therapy that might have shown promise.”
Marks Recommends Pre-Built Centers
Marks advised manufacturers to use scalable pre-built biotechnology centers. These centers, which fit “like Lego bricks” on top of each other, give manufacturers time to decide whether to invest in building commercial-scale facilities on the basis of promising Phase 1 data.
He said that these facilities are “really quite cool. … That may be a help because people may start with a small facility and if something works out they can build out … instead of building a large facility with a lot of capital.”
Use Automation To Lock In Process
To avoid scale-up problems, Marks also advised firms to use partially automated closed manufacturing systems. This enables firms to lock in the process early on.
Many cell and gene therapy products are made in academic centers and if they are transferred to another center, there is always the temptation to change the process, which can make scale-up problematic.
“One of the problems in the academic world is that people always want to reinvent how drugs are manufactured. If this system is used, the process is already locked in and cannot be changed,” he explained.
From the editors of The Gold Sheet.