Cell and gene therapies (CGT), also known as advanced therapy medicinal products (ATMPs) in the EU, are a class of products based on genes, tissues or cells that can benefit patients with debilitating or life-shortening diseases. Most CGTs are “living” therapies, with highly complex manufacturing processes and unclear mechanisms of action. In addition, these therapies are characterised by variable starting materials, short shelf lives and small sample sizes. They may also pose unique risks such as immunogenicity, tumorigenicity, microbiological purity and variable efficacy.
Due to their unique qualities and risks, CGTs require specific regulatory requirements and guidelines. Additional, more targeted regulations are required for the subset of CGTs that harness replicating viral vectors, which carry potential transmission risks. These guidances are updated regularly to account for our evolving understanding of CGTs and CGT manufacturing. Several changes to two key regulatory guidance documents for CGTs were released by the U.S. Food and Drug Administration (FDA) in January 2020, and are summarised below.
Updated FDA guidance: Chemistry, Manufacturing and Control Information for Human Gene Therapy Investigational New Drugs
Updates to this guidance supersede the previous one published in 2008, and describe what information is required to assure product safety, quality and purity. It applies to human CGTs and therapeutics that contain a human gene therapy in combination with a drug or device. Key changes include:
- Expansion of required safety information regarding reagents used in manufacturing, specifically reagents of biological origin that increase the risk of introducing unintended agents in the final product.
- Recommendations on the characterisation of cell lines used in the manufacture of monoclonal antibodies and product testing requirements for antibodies, including those used as ancillary products.
- Updated recommendations for the derivation, testing and reporting of plasmids used as intermediates in the manufacturing of CGTs, specifically adeno-associated viruses and lentiviral vectors.
- Additional detail on the characterisation of product- and process-related drug substance impurities, and recommendations for manufacturing optimisations to minimise the level of impurities present in final CGT products.
Updated FDA guidance: Testing of Retroviral Vector-based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up
Vector-based human gene therapy products must undergo testing to ensure they exclude the potentially pathogenic replication competent retrovirus (RCR), historically referred to as the replication competent lentivirus (RCL). The 2020 guidance supersedes the guidance from 2006, and provides updated recommendations on testing for RCR during the manufacture, follow-up and monitoring of gene therapy products derived from the Retroviridae family of viruses. As per this guidance:
- Cells and the supernatant from the master cell bank production should still be tested for RCR. However, working cell banks, from a master cell bank that tested negative for RCR, no longer need to be tested.
- All transduced cells, which are modified through retrovirus or lentivirus transduction, should be tested for RCR, regardless of the time in culture. This is a change from the previous guidance, which recommended RCR testing only for transduced cells cultured longer than four days.
- Appropriate, accumulated manufacturing and clinical data of RCR-negative transduced cell products may be provided to the FDA to reduce or eliminate RCR testing. If the FDA supports the reduction or elimination of testing, the archival of cell products for future RCR testing is recommended.
- Testing 5 percent of the total production volume in the RCR assay is still recommended. While the prior guidance permitted an alternative testing volume of 300 mL for production volumes that exceed 6 L, this volume may be insufficient to detect one RCR per dose given current manufacturing practices. For production volumes that exceed 6 L, new guidance outlines how to conduct testing that will ensure a 95 percent probability of detecting one RCR per dose.
To date, 47 cell therapy and 23 gene therapy products have been approved. As knowledge of CGTs and CGT manufacturing increases, appropriate guidance from regulatory agencies will be critical to the continued growth of the industry. Therapeutic developers may benefit from working with a partner whose regulatory expertise with CGTs will help ensure that development programmes are optimal and compliant, despite evolving global and regional regulatory requirements.