Thanks in part to lessons learned and trends accelerated by COVID-19, there have been many significant developments in cell and gene therapy (CGT) manufacturing. Clinical activity ramped up, and the industry is poised for rapid growth. However, there are long-standing and new challenges to overcome that can hinder this progress. The following three trends will help to address current and future issues, accelerate transformations in CGT and propel the industry forward.
1. Transition from serum-containing to serum-free media
Many innovative approaches for treating cancer employ Chimeric Antigen Receptor (CAR) T-cell therapy in their development. These therapies involve the isolation of T cells from patients through apheresis and process-specific cell selection. The patient-specific T cells are then genetically engineered ex vivo to express the artificial protein receptor that can bind to specific cancer cell antigens and activate T cell functions. Finally, the cells are expanded via a cell culture medium and subsequently infused back into the patient to recognize and eliminate target cancer cells.
The cell expansion medium is essential to the health and effectiveness of the cells used during the CAR T manufacturing process and after gene transfer. Serum-containing media are most commonly used in these processes. However, serum has an undefined composition with high batch-to-batch variability. As a result, it may contain toxic substances, pathogens, or impurities that are difficult and costly to screen for and remove, and potentially harmful to patients. Furthermore, with regulatory requirements becoming more stringent over time, there is an increasing demand for defined culture conditions.
Serum-free media offers a solution to the challenges, limitations and costs associated with serum-containing media. By nature of being chemically defined, serum-free media provide a higher level of control, reduce lot-to-lot variability, and increase reproducibility in the CAR T production process. Serum-free media can use proteins purified from human plasma, which is safer than materials derived from cattle. The purification process also eliminates many contaminants found in serum and minimizes the introduction of adventitious agents. Serum-free media are a more reliable, flexible and versatile alternative for facilitating the CAR T expansion process and can support large-scale and regulatory compliant processes to quickly and safely produce CAR T.
2. Increased focus on in vivo (vs. ex vivo) CGT technologies
CGT can be applied by either ex vivo or in vivo methods. CAR T is an example of an ex vivo CGT that involves genetic modification of patients’ cells outside the body to produce CGT products that are subsequently transplanted back into the patient. Ex vivo CGT is often used in blood-related disorders, including some cancers and genetic disorders. Ex vivo CGTs enable scientists to control the entire process and verify the health of the material before using it. However, they are time-consuming and difficult to manufacture, and less effective at targeting specific organs.
In vivo CGTs involve creating new genetic materials in a lab and then transplanting the material directly into the patient’s blood or a specific organ. In vivo therapies can be allogeneic, meaning the treatment is not patient specific and can be offered “off the shelf.”
Whereas Car T (ex vivo) generally targets blood cancers by harnessing the power of the immune system ex vivo treatments can target cancer in numerous ways, such as by expressing genes to make the cancer more visible to the immune system, inducing apoptosis to kill the cancer cells or converting prodrugs into their active form by introducing an enzyme.
3. Changing approach to CDMOs and the supply chain
COVID-19 illustrated the fragility of the global supply chain. Executing a vaccination campaign proved to be more complicated than expected due to the limitations of cold storage capacity for mRNA vaccines. Just-in-time manufacturing fell apart very quickly, mainly due to the non-availability of critical raw materials and single-use components. One dose of a typical CGT requires significant quantities of raw materials and components. Each item has different supply chain challenges, including long lead time to manufacture, transportation and shelf life. The pandemic-related issues with the supply chain were exacerbated by the rapid growth of the CGT industry.
The reality of the current situation with the supply chain requires a new approach. This includes treating vendors and CDMOs as true partners and involving them in the process at an early stage. Your CDMO can analyze your supply needs and make recommendations to streamline manufacturing and reduce cycle time and costs.
For example, a CDMO may recommend alternate supplies (e.g., reagents, single-use components) that have been tried and tested or validated for similar applications. The data required for GMP compliance may already be available. This information can help consolidate demand for materials, allowing them to be procured more economically with greater predictability. It allows the supply chain functions at the CDMO to have efficiency in their internal and external procurement processes, thus increasing efficiency across the manufacturing value chain.
A closer and more transparent relationship with CDMOs and vendors enables a better understanding of the overall supply chain risks. This will help avoid the shortages of critical raw materials and supplies as proactive measures, such as negotiating and maintaining safety stocks and having pre-set reorder points, may be used. The result will be stability in the supply chain and more consistent manufacturing, a reduction in cycle times, and delivery within timelines and budgets for CGT therapies.
Contact us to learn more about how our supply chain expertise can help in the manufacturing of your CGT.