Cell and gene therapy makers need fit-for-purpose chemistry, manufacturing, and controls (CMC) standards, according to the Alliance for Regenerative Medicine (ARM), which says the current guidelines lack clarity.
Therapeutic candidates only become products if their developers can prove they are made in consistent manner, in line with quality requirements. Such issues are covered in the CMC section of dossiers filed for review.
For therapeutic proteins and monoclonal antibody-based ((mAb) medicines, CMC requirements are well established. And more importantly developers know what reviewers look for and, to a greater or lesser extent, manufacturing methods are standardized.
Cell and gene therapy developers also have CMC guidelines. For example, in 2020 the FDA published information for gene therapy developers.
However, the challenge is understanding how to interpret these guidelines says Stephen Majors, director of public affairs at the Washington, DC-headquartered ARM.
“Industry and regulators are grappling with the fact that we don’t yet have fit-for-purpose CMC standards for cell and gene therapy, notes Majors. “We can’t just apply the standards that are in place for earlier therapies, even complex biologics.”
Risk-based CMC reviews
The ARM says there is a “lack of clarity on what regulators are looking for with potency assays” in the current CMC guidelines that is a challenge for cell and gene therapy developers.
However, the main issue is that experience of commercial-scale cell and gene therapy production is limited, according to Majors, who points out that “We have been advocating for regulatory clarity and flexibility with the US FDA, and specifically for a risk-based, iterative approach to CMC review.”
But industry can also help itself by trying to build production quality into process development, which was the aim of a recent project carried out by ARM and researchers at the National Institute for Innovation in Manufacturing Biopharmaceuticals.
“ARM along with sector partners just released Project A-Gene, a case study that applies quality by design principles to the manufacture of an AAV vector. The goal is to help standardize the manufacturing process and to assist with sector workforce development. A similar project that focuses on manufacturing a CAR-T cell therapy is underway,” Majors says.
The lack of clear CMC requirements is not the only manufacturing challenge for the cell and gene therapy sector, according to Majors, who notes that there is ongoing debate about whether to keep production in-house or to outsource.
“Manufacturing capacity has certainly been a challenge, particularly during the COVID-19 pandemic, but this may just be temporary. And capacity issues are part of the calculation as the sector navigates the ‘make vs. buy’ question,” he continues.
“There are clear advantages to owning–and having control over–your own manufacturing capabilities, but if you encounter a program delay your expensive assets may be sitting idle for a while.”