Understanding the latest FDA guidance on investigational new drugs for cell and gene therapy
On the 28th January 2020 we saw the FDA update its guidance for industry regarding chemistry, manufacturing, and control (CMC) on the application of (INDs) for cell and gene therapy, including assurance of clonality and stable cell line development.
Innovation driving gene therapy
Within this document the FDA provides guidance to the industry and to future sponsors developing INDs, ensuring the safety of future patient cohorts. The FDA recognises gene therapy is a developing field driven by innovation to cure previously untreatable patients. As such, details on process control may evolve over time. The document is timely as we transition into a new decade where the number of gene therapy trials is rapidly expanding, and the supply of viral-based drug products is becoming a bottleneck.
The FDA classifies gene therapy as: ‘human gene therapy products to include all products that mediate their effects by transcription or translation of transferred genetic material or by specifically altering host (human) genetic sequences’. The guidance covers the manufacture of investigational new drugs including viral-based vectors, autologous and allogeneic cell therapies. It is interesting to note that the guidance falls in line with that provided for biologics, and similarities can be drawn.
Key learnings and recommendations
The FDA’s guidance is driven by patient safety and the ability to create a reproducible manufacturing process to protect future continued supply of bio-based drugs. Of course, this can be challenging regarding the use of cell factories. With the decades of experience gained in biologics, the FDA and sponsors can cross-pollinate and identify areas of concern.
The use of animal-derived reagents in IND development is highlighted as undesirable and should be reduced or avoided where possible. By reducing the use of animal-derived reagents, IND sponsors can minimise the risk of adventitious agents, other impurities or lot-to-lot variation that may impact the reproducibility of the manufacturing process. For instance, if reagents are used from bovine origin, there is still a concern of transmissible spongiform encephalopathy. Thus requiring the statement ‘If serum is used, we recommend that it be y-irradiated to reduce the risk of adventitious agents. This information may be included on the COA and COO provided from the supplier.’ Some parts of the process traditionally use serum, so processes in banking and single cell isolation should be assessed with non-animal derived reagents.
Cell banks & transient production
The recommendations for banking of cells are covered in detail to ensure control and consistency of the product over the useable lifetime. The stability and purity of cell banks is an important area for consideration. Assurance of clonality can be a way to control the population of cells and limit the generation of future heterogeneous populations that may impact the quality of the viral-based product being produced. The FDA references “Q5D Quality of Biotechnology/Biological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnology/Biological Products”, which covers assurance of clonality in much greater detail.
For transient-based production that is reliant on starting material such as plasmid DNA being manufactured in a bacterial host, a master cell bank should be established for the transformed bacteria and quality assurance on the cell bank should be performed to protect the manufacturing process. When it comes to the use of packaging cell lines that are tumour derived or have tumourigenic phenotypes (e.g., HeLa, HEK293), they may give rise to concerns and the limitation of specific residual cellular DNA should be addressed to assure product safety. With some vectors, including AAV, these risks are heightened. For instance, AAV can package non-viral DNA (cellular DNA or plasmid DNA). Process parameters should be optimised to reduce this risk on product quality. The movement from transient production to stable cell line production may reduce the exposure to this risk and provide greater stability in the generation of future products as they scale for larger patient cohorts.
Autologous & allogeneic cell therapies
When considering autologous or allogeneic cell therapies recommendations touch on the source of cells and the nature of the cells. One seeming extension to the responsibility of the manufacturer is providing sufficient information on the source of cells or tissue for autologous or allogeneic therapy. This can extend to the devices, reagents, and consumables used at the bedside for collection. Suitable definition is provided for donor screening between autologous cells and allogeneic cells, with the latter commanding higher rigour in testing. The ex vivo genetic modification of cell-based gene therapies needs to be well described, from the vector containing the transgene, summary of any genome editing, and include the expected major and minor cell populations. As the efficiency of genome editing improves with new technology, the minor populations may become less problematic.
For those groups requiring in-process staining of cells to select desired populations, these products (secondary monoclonal antibodies or stains) that come into contact with the cells should be tested according to the previously described FDA guidance “Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use”. It may be necessary to provide another regulatory submission for this material. This could provide a need for offline testing or non-staining methods to identified desired populations.
Solentim has taken steps to support its customers developing stable vector producing cell lines in gene therapy, including the deployment of the Cell Metric and VIPS products to support clonality assurance, and availability of unique growth supplements that support HEK293 growth and expansion with its InstiGRO HEK product line. Additionally, Solentim’s partner, ATUM, provides “Leap-in” transposon technology that can introduce transgene cargo into stable locations within mammalian cells with inherent high expression and stability.
It is an exciting time for the field of gene therapy, and guidelines such as this on investigational new drug application are essential to ensure high-quality outcomes. However, all researchers in this field should be mindful of not just creating an efficacious therapy, but also consider the manufacturability of the therapy as patient numbers increase for a marketed drug.
Author: Mark Stockdale, Amalgamator of Business and Biology, Solentim