This blog post is the second in a series on accelerating the development and manufacturing of cell-based cancer therapies. In the last post, we outlined the promise and potential of immune cell therapies to treat cancer along with an overview of the central challenges that impede their broad accessibility. In this article, we take a closer look at key considerations for establishing a reliable supply chain of quality materials to ensure a robust and reproducible workflow.
As immune cell therapies advance through the development pipeline, the need for an optimal scaling strategy becomes more apparent. Much of the deliberation centers around cell expansion approaches to attain clinically relevant cell numbers and features such as automation and process control to ensure high-quality cell products. Yet there are many more decisions to be made that can to a large degree determine the ultimate success or failure of a large-scale immune cell therapy manufacturing process, such as which starting materials to use and which suppliers to partner with. At clinical stages, cell expansion, viability, and efficacy depend on the timely arrival of high-quality GMP raw materials and reagents, and any disruption in supply can lead to variability or delays in the process and product. And while assured supply of source material has always been appreciated, disruptions due to COVID-19 highlighted how imperative it is to establish resilient and flexible supply chains from the start. Failure to mitigate disruptions can result in costly time delays and ultimately grave consequences for the patient. Therefore, when choosing starting materials, both quality and assured supply of resources must be evaluated for successful scale-up.
The Importance of High-Quality Raw Materials
While cells are often thought of as the key material in a final immune cell therapy product, many other materials contribute to the making of a quality therapy. Raw materials, which in the context of immune cell therapy are defined as components that come in contact with the cells but may or may not be present in the final drug product, can include cell culture media, viral vectors, and even product contact materials like disposable bags.1
Even with excellent starting cells, the quality of a cell product is only as good as the medium in which it is grown. Culture media formulations that include human or animal-origin sera have high lot-to-lot variability, can be limited in supply, and are expensive. Optimized, serum-free media, specifically designed for cell expansion, is an attractive alternative for more consistent long-term manufacturing and scale-up. Use of optimized culture media is key to successful expansion of desired T-cell subpopulations. Developers often screen different media formulations design of experiments (DOE)-based optimization protocols and characterize expansion using output measurements such as cell viability, cell yield, the distribution of cell phenotypes, cell health, cytokine profiles, cell purity, activation and CAR transduction, and donor compatibility.
Sterility is a primary concern when choosing raw materials and ultimately delivering safe products to patients. To this end, the industry has shifted to using single-use technologies, such as bags, to process and store cells and media. While these consumables solve many issues pertaining to contamination of immune cell therapies, they also come with their own set of challenges to consider. Single-use plastics pose risks of leachables and extractables, which are chemical compounds that migrate from the plastic into the cellular or raw material it is containing. Different bags can contribute these chemical contaminants to varying degrees, leading to cell-growth inhibition, batch failures, and lot-to-lot variability, and can ultimately impact the final drug product’s safety, stability, and efficacy. Therefore, identifying suppliers that can deliver consistent, high-quality single-use consumables is an essential part of building a robust cell therapy platform.
Derisking the Supply Chain
Given the importance of securing high-quality raw materials, partnership with reliable suppliers is critical. To ensure a robust manufacturing process with minimal disruptions, early strategic selection of vendors knowledgeable about the immune cell therapy workflow is prudent. The right supplier can provide precise equipment, a steady supply of high-quality single-use plastics and consumables, or QC testing capabilities.2 Furthermore, it is critical that each link in the supply chain is secured to avoid disruptions. For example, a vendor that supplies bags should guarantee that their supplies of resins and films are also assured. Ultimately, a supply chain strategy and risk assessment plan can be invaluable to ensure pipeline success. Risk assessment and development activities that include careful examination of cell expansion, harvesting, downstream processing, and formulation, as well as the effects of scaling on these processes, serve to mitigate product change and batch failure risk down the road.3 4
For example, as processes scale up, the need for large volumes of consistent media increases. Additionally, as therapies enter clinical trials, increased regulatory requirements necessitate the use of chemically defined, GMP-grade media. If a preferred lot of media becomes unavailable at larger scale or is not GMP-compliant, testing new lots from alternative suppliers will invariably lead to increased labor costs, introduce variability, and can delay time-to-market. Further, this may create regulatory vulnerabilities and increase documentation requirements. Thus, from the outset, it is important to consider the ability of a business to provide continuous supply of GMP-grade media and consumables commensurate with clinically relevant volume requirements.
Additionally, the supply of viral vectors is especially susceptible to shortages of production capacity and reinforces the need for a strong supply chain. Efforts are underway to circumvent some of these challenges through the development of non-viral vector technologies.
When considering equipment, regulatory requirements can influence purchase decision. For example, regular equipment maintenance must be performed and documented under strict guidelines. If a part or consumable is not on hand or backordered, then the manufacturing operation is at risk of a shutdown. Therefore, it is critical to partner with a vendor who can anticipate manufacturing needs and assure supply of their components to prevent additional risk to the pipeline.
Another aspect of supply chain strategy that is particularly relevant for allogeneic therapies involves the coordination of immune cell therapy transport between the manufacturing and administration sites. Process developers may need to consider the location, product profile, and transportation to maintain the product's safety and quality, along with an audit trail for source material.5
Regulatory agencies also require that staff be trained to use standardized materials and methods across sites for collecting, cryopreserving, and shipping cells as well as performing QC and stability studies. There is always the option to engage a contract development and manufacturing organization (CDMO) to take advantage of economies of scale and access to expert knowledge and to equipment. However, this option won’t eliminate all disruptions and may offer less process control or ownership for the developer.
Conclusion
Establishing and protecting the supply chains needed to support scale-out and scale-up of cell-based therapies demands attention and foresight. The logistics of how to orchestrate this level of production requires consideration of media and viral vectors, along with the consumables used for production, including plasticware and bags. Another challenge facing the industry is the ability to recruit the talented and knowledgeable workforce it takes to scale a production facility.6
Undoubtedly, the success of advanced modalities such as cell therapy is highly dependent on the consistent and timely supply of high-quality raw materials and consumables. Developers and manufacturers of these therapies should proactively evaluate options for their raw materials and supply networks to mitigate risk, maintain accelerated timelines, and address the needs of patients.
1 Rathore, A.S., et al. (2018). Role of raw materials in biopharmaceutical manufacturing: risk analysis and fingerprinting. Current Opinion in Biotechnology. 53: 99-105. https://doi.org/10.1016/j.copbio.2017.12.022.
2 Pereira Chilima, TD, et al. (2018) Impact of allogeneic stem cell manufacturing decisions on cost of goods, process robustness and reimbursement. Biochemical Engineering Journal. 137:132-51. https://doi.org/10.1016/j.bej.2018.04.017.
3 Heathman, T. (2016, February 26). Scalability in cell-based therapy manufacture. Technology Networks. https://www.technologynetworks.com/biopharma/news/scalability-in-cellbased-therapy-manufacture-mind-the-gap-208461
4 Masri M., et al. (2017). Challenges and advances in scale-up of label-free downstream processing for allogeneic cell therapies. Cell Gene Therapy Insights 3(6), 447-467. DOI: 10.18609/cgti.2017.041
5 Reed C. (2019, February 25).Recalibrating the Supply Chain For Allogeneic Cell Therapies. Cell & Gene. https://www.cellandgene.com/doc/recalibrating-the-supply-chain-for-allogeneic-cell-therapies-0001
6 Lemicke M. (2019, June).Manufacturing Cures: Infrastructure Challenges Facing Cell and Gene Therapy Developers. Alliance for Regenerative Medicine. https://alliancerm.org/wp-content/uploads/2019/06/Manufacturing-Cures-In-Vivo-PDF.pdf