Cell Therapy Product Development: Main Hurdles to Regulatory Approval

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As of today, there are over 8,600 ongoing trials related to cell therapy listed on clinicaltrials.gov, most of which are in phase 2 (~4,000) or phase 1 (~2,500), with more than 1,000 in phase 3, although only a handful of products have reached the clinical approval stage.

The primary reasons why the maturation of cell therapy trials to commercial stage is slow, and why only a very small fraction of trials reach clinical approval, are thought to be, broadly, the following:

  • Product development and characterization. Cell therapies are complex: different cell types, various tissue sources and treatment type (allogeneic vs autologous) introduce significant levels of complexity to the development of CT products. This also includes raw material sourcing.
  • Manufacturing and scale up. Manufacturing and scale-up to clinical stages is marred with difficulties for reasons which include the need to tightly ensure reproducibility, consistent potency, a control of manufacturing costs, process and environmental controls (e.g. closed systems, batch-to-batch variations etc.)
  • Regulatory landscape. Not fully defined regulatory guidelines.

Regulatory landscapes are, moreover, set up differently in different markets: the Japanese regulatory landscape follows different regulations than doesthe FDA in the USA. For that reason, some US companies are engaged in trials in foreign markets (for example, Japan), due to more favorable approval hurdles than those in the USA.

As far as product development is concerned, process controls start with raw material sourcing. The cellular starting material is an integral part of the living, functional cells that constitute the active drug substance of cell therapy products. It is for that reason that tight controls must be in place to ensure traceability and quality control of raw material for cell therapy products. Moreover, special considerations in starting material qualification for patient-specific products (autologous or allogeneic) vs. off-the-shelf allogeneic products (multipotent or pluripotent stem cell-derived) are of significant importance too.

Manufacturing considerations also relate to closed systems (cell therapy products cannot be manipulated after manufacturing and must thus ensure aseptic processing during the manufacturing and formulation stages), environmental controls and scaleability.

Finally, logistics in relation to transport, shipping and storage during these steps is critical in ensuring integrity of the product is maintained by the time the cell therapy product reaches the end user facility (usually the hospital). Cryopreservation strategies must not only ensure the product is fully potent by the time of administration (usually stored in the frozen state), but the time from thawing to administration must also be accounted for (during which the product is stored at temperatures far above freezing).

All of this must be done while ensuring cGMP compliance, which is related to the maintenance of tightly controlled production, process and personnel flow documentation.

We have previously discussed efforts aimed at improving standardization for cell therapy product development across various markets, and the gaps that currently exist in harmonizing various guidelines, including the key organizations operating in that space.

If you have particular comments/thoughts in relation to what you consider the most important considerations to be with regards to cell therapy product development, we would love to hear them. This is part of a concerted effort to understand the developer and market sentiments that align with bringing more clarity to issues that will ultimately help cell therapy products find more favorable paths to market.

Feel free to share them in the comments or email us at info@akronbiotech.com.

 

 

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