Recently in Washington, DC, two conferences were held on the topics of cell and gene therapy. The California Separation Science Society (CASSS, www.casss.org) hosted a Well-Characterized Biological Products (WCBP) Chemicals, Materials, and Controls (CMC) strategy forum on “Current Practices for Assessing the Comparability and Stability of Gene Therapy Products,” while blocks away, Phacilitate hosted the 2008 Cell and Gene Therapy forum.
At the WCBP CMC strategy forum, participants heard the US FDA–CBER perspective on the importance of comparability studies for gene therapy products. Denise Gavin discussed the available guidance and references for such products, then outlined in more detail the purpose and importance of comparability studies in the field along with methods for demonstrating comparability.
J. Fraser Wright, scientific director of the clinical vector core in the Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia, PA, presented a case study assessing comparability of a recombinant adenoassociated virus (AAV) gene therapy product during various phases of manufacturing process development. He presented the pros and cons of cell culture systems his team had considered and the ultimate conclusion of an ideal system using a helper-virus–free mammalian producer line. His team moved forward with a 13-step clinical manufacturing process. Following extensive product purity characteristic investigations and process optimization, the team refined that to an 11-step process.
Wright posed an interesting problem that pointed to the bigger picture. His process needed further refinement before it would be commercially acceptable. With the cell and gene therapy sector in its relative infancy, are there not lessons to be learned from significant advancements and shared research and lessons in the monoclonal antibody sector over the past two decades? Some involved in gene therapy argue that because the products are more complex than monoclonal antibodies, the lessons cannot be directly applied. However, there are some fundamental challenges for which scientists in gene therapy can look to their MAb colleagues for assistance: “What does comparability mean?” “How do I know if I’m using the right bioassay?” or “How do I conduct stability testing?”
There are some fundamental certainties cell and gene therapy companies can leverage from predecessor biotechnology sectors:
1. You will want to make changes to your production process in the future. Whether it’s to scale-up or out or down, enjoy cost efficiencies, use new technologies, tweak the product, respond to regulatory pressures, close systems and/or any of a plethora of other reasons, process change is part of biotechnology production and integral to commercial survival.
2. Obtaining regulatory approval for process changes will depend on your ability to demonstrate comparability. As Organogenesis has demonstrated with Apligraf, this is increasingly true as products progress through clinical trials, but is a certainty postapproval.
3. Your ability to demonstrate comparability will depend on product characterization data. The best data set comes from preclinical and clinical trial data. So a comprehensive characterization panel is best thought of early, even if such data are not required yet or considered to be critical to the eventual final product characterization and/or mechanism of action.
Here’s where some unique challenges of cell and gene therapy present themselves as a different scientific exercise than characterizing an antibody or protein. The same kind of molecular analysis simply cannot be used to characterize cell- or gene-based therapeutics. These are characterized at least in part by markers they express, their function(s), their mechanism of action, and/or the process used to produce them.
The FDA Office of Cells, Tissues, and Gene Therapies is comfortable with those differences in principle, but precisely what will be required to show comparability has yet to be tested. To what extent will functional assays be sufficient? Will current assay methods demonstrate what will be required — or will new assays have to be developed? Will mechanism-of-action be more important for these therapies than for other biologics or pharmaceuticals (e.g., was this a barrier to Dendreon’s BLA approval last year or a red herring)? Will cell tracking data (for which there has yet to be a proven clinical tool) be required for approval of some products? The conversation was lively, and a white paper based on it will be published in a future issue of BioProcess International.
Until we have a precedent, the strategies required to get to the end goal remain in question. We are all working collaboratively to develop answers, but the body of scientific, clinical, and regulatory evidence from predecessor biotechnology sectors does not entirely determine the required approach for these new therapies. The good news for cell and gene therapy companies is that several commercial partners and contract manufacturing organizations have learned lessons from monoclonal antibodies and can bridge the gap to help jump-start processes.