Scaleup will remain a challenge for the cell and gene therapy industry until developers adopt a more integrated approach that envisions manufacturing as a single process.
At least, that is according to researchers at the Manipal Academy of Higher Education in Karnataka, India, who argue in a new review that developers struggle because they treat manufacturing, analytics, and regulatory compliance as separate issues.
“Historically, the field has tackled these problems separately: one group focused on CAR T manufacturing, another on viral vector production, and another on logistics or regulatory strategy, rather than treating the whole product lifecycle as a single connected system.
“Our review argues that scalability must be built in from the start, using lifecycle-oriented tools that allow manufacturers to embed flexibility into the process from early development through commercial-scale production, rather than trying to bolt scalability on afterward, once problems appear,” study co-author Sachin Dattram Pawar, PhD, tells GEN.
The key, Pawar and colleagues suggest, is to treat all parts of CGT production as a single, unified process designed with scalability in mind.
“The idea is to stop treating early development, scale-up, and commercial manufacturing as separate problems and instead manage manufacturing knowledge continuously across the product’s lifecycle,” he says.
The lifecycle approach is also in keeping with trends in bioprocessing technology development, Pawar says, pointing to decentralized systems like the CliniMACS Prodigy or Lonza Cocoon platforms as examples.
“The approach would involve closed and automated manufacturing systems, real-time process monitoring, advanced analytics, digital tools, scalable cell and vector platforms, and robust cryopreservation and cold-chain infrastructure.
He adds, “Emerging approaches, such as digital twins, AI, allogeneic and iPSC-derived platforms, and improved vector production technologies, could further enhance scalability and consistency.”
In addition, treating manufacturing as a single process would also be a better reflection of the complex interactions that take place between unit operations, Pawar says, citing cell culture systems as an example.
“Switching from one to another can simultaneously alter product yield, purity, and even cell behavior, which in turn has knock-on effects on analytics and regulatory submissions.”
Regulations
A lifecycle-based view of manufacturing also fits with evolving regulations, according to Pawar, who points to the development of “concrete regulatory mechanisms” as evidence of growing support for the approach.
“ICH Q12 provides tools such as established conditions (ECs) and post-approval change management protocols (PACMPs) to help manufacturers manage process changes based on risk and accumulated knowledge.
“Likewise, the FDA’s flexible CMC approach for CGTs also supports greater flexibility during development, while the agency’s RMAT designation and the EMA’s PRIME scheme encourage early regulatory engagement. Overall, regulators are moving toward a more risk-based, lifecycle-oriented approach that supports innovation while maintaining product quality and patient safety,” he concludes.
