The Next Frontier: Industrializing Cell Therapy Manufacturing

Overview: In this Q&A, Cell Process Development Scientist at AGC Biologics Cell and Gene Center of Excellence Sara Morlacchi, provides her expert analysis on the current state of the cell therapy space, the growth of the industry, and barriers for cost and accessibility. Sara and the team at the site recently helped a developer reach commercial approval with the FDA for their cell therapy product – Orchard Therapuetics’ Lenmeldy™.

Q: Cell therapies use a variety of immune and stem cells and are either autologous or allogeneic. Is there a common platform process for manufacturing that can be optimized to reflect the different starting points and sets of overarching challenges?

A: Cell therapy drug products offer a proven therapeutic approach with the potential to treat many life-threatening diseases through powerful modes of action. Those currently in clinical trials or with commercial approval have each been created individually through stem cell- or non-stem cell- based models and autologous or allogeneic methods, and each cell therapy product has complex characteristics unique to their individual classifications and applications. However, the manufacturing processes rely on a common modular platform that is then adaptable to multiple different cell types and to specific therapeutics’ needs.

Some of the most common steps and processes to consider when optimizing production and manufacturing include:

• Starting material processing: according to the specific final Drug Product (DP), a fresh or cryopreserved biological cellular source can be used. For autologous products, each batch is manufactured from patient-specific cellular starting material. By contrast, for allogenic products, multiple DP batches can be manufactured starting from a single healthy donor. The starting material can be then used as is or following selection of specific cellular sub-populations.
• Cell activation.
• Genetic modification: The main approaches for genetically modifying cells are gene replacement (the delivery of a functional gene to replace a non-working gene), gene silencing (inactivation of a mutated gene that has become toxic to cells), gene addition (over expression of a “foreign” or exogenous gene to impact cellular function) and gene editing (a permanent manipulation of a gene in a patient’s genome).
• Cell expansion at varying scale.
• Drug product formulation and fill & finish operation.

Starting from a flexible common workflow, these steps have the option to be adapted depending on the specific process design to support very different manufacturing requirements and therapeutic demands.

Q: What new tools or technologies need to be developed and implemented to address the challenges associated with cell therapy manufacturing?

A: Current manufacturing processes for cell and gene therapies, particularly in earlier stages of product development, are comprised of many open handling steps that can be error-prone and labor-intensive. Moving to a closed automated system can help address these problems, leading to a significant reduction of the risk of contamination, costs and timelines, improving the process’s reproducibility.

The market already offers several effective automated systems specific for Cell & Gene applications. Some of them represent a “one solution” automated platform that can perform all the cell manufacturing steps in a fully closed system. Other instruments are, instead, designed to perform only pre-defined steps and to work as a modular platform in combination with other instruments.

While these technologies are very promising, some constraints still need to be overcome to ensure their reliability for every cellular process workflow. In general, these devices lose accuracy when working with small volumes and, on the other hand, in case of allogeneic productions, the greatest challenge moving toward fully automated manufacturing is to guarantee production scalability. Moreover, some technologies lack flexibility and are not user friendly. Finally, for newer devices that are starting to be utilized in cell therapy production, compliance with requirements for cGMP production needs to be implemented.

Q: What are the prominent cell therapy trends you think will be most important over the next 3-5 years?

A: For sure, one of the most prominent cell and gene therapy trends over the next years will be represented by allogeneic therapies. These therapies utilize a single source of healthy donors’ cells by application of large-scale production of material to treat multiple patients. The strengths of allogeneic platforms are represented by the immediate availability of cells to treat patients, which is crucial when urgent care is needed. Allogeneic platforms are also more cost-effective, considering that a single batch could potentially cover the treatment of tens or hundreds of patients.

A second point of interest, in which AGC Biologics has been a pioneer, is automation. The employment and mass adoption of closed automated systems will be a key factor for successfully transitioning towards the mass production and commercialization of these treatments so they can reach as many people as possible.

Another trend of significant importance to the cell therapy industry is the adoption of gene editing systems. This has emerged as a powerful tool to introduce gene modification, and thanks to recent advances in technologies, an exponential increase in their application for therapeutic purposes will be expected over the next several years.

Finally, MSC-derived exosomes are also an emerging technology that our teams are focused on at AGC Biologics. Exosomes are thought to serve as paracrine mediators between MSCs and their target cells. MSC-derived exosomes can recapitulate the biological potential of MSCs and enable cell-free therapy. MSC-derived exosomes can provide significant advantages like enhanced safety due to their nanoscale size by efficiently decreasing unfavorable adverse effects, such as infusion-related toxicities.

Q: What work are you and the team at AGC Biologics currently focused on?

A: Cell therapy processes are highly variable in terms of cell type, length, volumes, reagents, equipment and testing, for both autologous and allogenic settings and processes for cell modification or cell expansion alone. To accommodate the customer’s requirements, AGC Biologics is focused on creating flexible service at each level – pre-clinical through commercial – including specialized technical capabilities, equipment availability, facility design and analytical platforms that can support every stage of the product’s journey. We offer two sites globally to support cell therapy products, our Milan Cell and Gene Center of Excellence and our Longmont Campus in Colorado, USA. We also recently announced a new cell therapy location in Yokohama, Japan with services beginning in 2025.

One of the things that makes our scientists stand out is our core teams’ strong expertise with both open and closed processes, including the use of a wide range of equipment and a proven expertise in Lenti and Retroviral transduction. We are also focused on continuing to undertake and implement the latest technology, such as genome editing using CRISPR-Cas9 systems (CRISPR/Cas9).

Our proprietary cell therapy platform processes include flexible processes based on different cell types such as HSCs, T-cells, NK and MSCs either in smaller scales for autologous production or in larger scales for allogeneic batches. Moreover, to ensure a fast turnaround and an all-in-one solution, all our PD processes are performed with a GMP-like approach to de-risk the transfer phase in GMP. Not least, our offer includes more than 160 in-house analytical tests to characterize a cell therapy product through its life cycle and to follow all development phases required for the establishment of a manufacturing platform.

Q: Where does cell therapy go next and how can developers prepare for the next phase of the industry?

A: The cell therapy market is expected to consistently grow over the next several years due to the increasing incidence of chronic pathologies and oncologic diseases. Strong scientific competence, technical expertise and flexible manufacturing platforms will be the key factors to successfully meet this challenging and complex demand. One of the most urgent trends that must be addressed will be the reduction of the prohibitive costs associated with cell therapies, which are expected to be a factor that will hinder market growth.

At AGC Biologics, we believe by finding ways to make processes more standardized and by investing in allogeneic methods, we can help ensure that production and manufacturing of cell therapies for a greater number of patients is possible, which in turn will help make them more affordable to produce and more accessible for patients that need them. In addition, with commercial expertise in manufacturing of cell therapies and viral vectors, we are uniquely positioned to help Developers navigate technical and regulatory hurdles at each stage of a product’s journey to bring these treatments to patients.

Want to learn more about regulatory strategies that open the path to FDA/EMA approval for gene therapy products? Register for AGC Biologics’ free webinar broadcasting on June 13th at 8:00AM PT.