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Contract partners must help innovators, especially smaller and virtual companies, consider manufacturability as early as possible in development. This requires focusing on technical and operational performance, as well as cost.
The cell and gene therapy industry is at a major inflection point, as therapies move out of clinical trials and into the commercial market. As more therapies are commercialized and become established, demand for cell and gene therapies will grow, leading to vast changes in patient care.
Currently, dozens of products are already in Phase III, including second-generation cell and gene therapies such as CAR-T (chimeric antigen receptor T cells). Over the next 5–10 years, more than 70 cell and gene therapies are expected to be commercialized and available to patients.
Small and virtual biotechs are driving innovation in this sector, and make up over 85% of cell and gene therapy developers. Without the infrastructure of larger pharma & biotech companies, these smaller innovators face unique challenges in manufacturing these advanced therapies and ultimately bringing them to the market (1). The question for the industry and the contract development and manufacturing organizations (CDMOs) that support them is: “How do we robustly produce, ensure quality, and deliver these transformative and life-saving products to patients around the world safely?”
As patient numbers addressable by cell and gene therapies grow, new technologies will be needed to meet manufacturing demands. Standardized and robust manufacturing platforms will need to be established, and a global network of facilities will be required to serve the main cell and gene therapy development hubs across the globe.
CDMOs are responsible not only for manufacturing drugs safely and robustly to meet customer demands, but also for supporting innovation from these small biotechs. This requires facilitating the delivery of therapies to the market under the right conditions, while accelerating an increase in overall capacity, and the infrastructure required to meet increased demand for these therapies at scale. For example, Lonza has been working with a small biotech that is innovating within the oncology and immune tolerance space. As their CDMO, we are committed to leverage our experience and expertise to de-risk their product’s pathway from lab to market and maximizing the product safety by industrializing its manufacturing process.
For any manufacturer, successful industrialization requires focus on the “cubic effect,” a concept to be discussed later in this article, which includes technical and operational development, as well as cost.
First, consider that cell and gene therapy is an ever evolving and complex science dealing with autologous and allogeneic cell therapies as well as viral vector gene therapies. There are variations in approaches to manufacturing between different therapies, and in the critical steps that surround streamlining and ensuring good process development.
However, when it comes to the regulatory pathway to scaling up processes and ensuring consistency, success depends on the manufacturing process and associated critical quality attributes. A fully optimized and robust process is needed, one that can be “mass customized” (i.e., for autologous therapies, for example, the process must be scaleable, reproducible, commercially viable, and customized for every single patient at a large scale). This is where CDMO experience and capabilities are most critical for customers who have been focusing on the safety and the efficacy of their therapy and now face an accelerated path to commercialization.
Reflecting on the difficulties of optimizing the process to ensure its scalability is the trouble that some innovators are currently experiencing in commercializing therapies. The importance of good process development is illustrated by the difficulty some therapies are encountering when moving to the commercial phase. Once approved, cell and gene therapies must comply with more stringent characteristics defined by regulatory bodies. Getting the process and the manufacturing approach right from the start can facilitate scale-up and reduce the risk of quality and consistency issues, which often result in delays due to the need to tweak processes at the critical commercialization point.
Regulatory agencies are offering increased support to help advance the growth of innovative therapies that aim to meet unmet medical needs. Given the levels of efficacy that some cell and gene therapies have shown, FDA and other global regulators have created accelerated approval pathways and allowed unprecedented small-scale clinical trials for these therapies. Regulators are also supporting technologies that can advance manufacturing and shorten the timeline between clinical trials and commercial scale-up.
At this crucial point in the development of cell and gene therapies, developers need to constantly reassess the demand forecast and scale their production accordingly to ensure the right investments are made into CAPEX (capital expenditure) and OPEX (operating expense). Overestimating the figure will result in overcapacity in five or 10 years. This is particularly true since some of these therapies are curative and only administered to patients once, unlike treatments for chronic conditions, which require multiple doses or treatments over time. Once the current prevalent patient population is treated, the therapies would only be needed for newly diagnosed patients.
The need for industrialization is not new for the life-sciences industry. In fact, with cell and gene therapies, we are seeing history repeating similar patterns that were seen in the past, when the first monoclonal antibodies (mAbs) and recombinant proteins were industrialized. While cell and gene therapy is much more complex, with autologous, viral, allogenic or in-vivo modalities, we would not be where we are today without the technological advancements of the past 30 years.
Estimating infrastructure needs and achieving scale are not the only hurdles that cell and gene therapy developers now face. Success will also depend on reducing the cost of material goods for products, and maintaining consistent quality standards for the delivery of live biologic material within the stringent profile characteristics required for commercialization.
At this point, cell and gene therapy is still mainly driven by manual processes. Innovators will need to shift to a mindset based on mass customization. Every patient in the future will be different and will need to be treated in a different way. However, developers will have to produce a single, customized product with the same efficiency and quality used to mass-produce product.
Having standardized processes in place will be a competitive differentiator for CDMOs that operate in the cell and gene therapy space. For example, autologous therapies will require disruptive solutions necessary to deliver on the promise of personalized medicines and move the industry from the standard of “one batch for many” to “one batch per patient.” For allogeneic therapies, CDMOs will look to leverage the expertise and experience acquired in large-scale manufacturing of biologics to drive the commercialization of these therapies, making them in a scalable manner so they can be available to large patient populations.
In order to achieve these results, the industry as a whole must work together in a three dimensional “cubic effect” to drive improvements across:
Although technology is important, improvements will be needed on the operational side. In order to deliver and treat patients in a more robust, safe, and cost-effective way, innovators and their contract partners will need to define and improve the way that they approach the following, in the cell and gene therapy space:
This shift in focus has already occurred in other aspects of life sciences, so we know that it can be applied to cell and gene therapy. Consider, for example, the fact that it used to cost more than $30,000 to manufacture just one gram of a standard mAb. Within two decades, CDMOs, working with innovators within the framework of the cubic effect, brought that cost down to under $10.
In short, cell and gene therapy innovators and their contract partners need to focus on manufacturability and process industrialization as early in the development cycle as they can, to avoid a technical development bottleneck. Developers can greatly benefit from working with CDMOs, not only for traditional capacity but also to de-risk their path to commercial launch and to help them manage the unpredictability of demand associated with the curative nature of cell and gene therapies. Focusing on technical developments and the cubic effect must guide CDMOs as they work with smaller biotechs, who are at the heart of what the industry is trying to accomplish with meeting unmet medical needs.
1. IQVIA Institute, “Emerging Biopharma’s Controbituion to Innovation: Assessing the Impact,” p. 13, June 2019.
Supplement: Partnering for Bio/Pharma Successâ¨
When referring to this article, please cite it as A. Santagostino, "Using the 'Cubic Effect' to Drive Cell and Gene Therapy Commercialization," Pharmaceutical Technology Supplement: Partnering for Bio/Pharma Success, February 2020.