Why Do So Few Cell Therapies Make The Leap From Lab To GMP?

By Tatiana Golovina

Adoptive cell therapy (ACT) has shown its often-outstanding efficacy against otherwise untreatable cancers. There are multiple ACT types, such as chimeric antigen receptor (CAR) technologies, tumor infiltrating lymphocytes (TILs), T cell receptor (TCR) technologies, dendritic cell-based technologies, macrophage-based technologies, and others. Though there have been tremendous development efforts and investment, fewer than a dozen commercial products in the anti-malignancy ACT area have been approved. In addition, these products usually have complicated and expensive manufacturing processes. In order to understand the potential root causes, we can trace the drug's journey from the GMP manufacturing suite back to the academic laboratory.

Approval of Kymriah's BLA in 2017, the first commercial CAR-T therapy, was followed by a burst of cell therapy development by Big Pharma and small startups. Unfortunately, the number of new approved therapies did not match the number of new products in pipelines.

To understand this phenomenon, we need to explain the gap between processes developed in academia and the realities of industry's capacity. Processes developed in the lab -often render a more efficient product compared to the scaled-up GMP-manufacturing. Technical transfer, inherently complex, is often rushed, with little time left for careful evaluation of the impact process changes have on product attributes. While companies with sufficient resources can step back and confirm the feasibility of redeveloped processes, those with limited resources either move forward to the clinical trial with unoptimized processes or do not move at all. This results in sufficient loss of effort, funds, and most important, prospective technologies never reach the patients.

The Manufacturability Discussion Should Start After A Candidate Shows Efficacy

The experimental practice within the scientific laboratory and activities in the GMP manufacturing suite differ tremendously. To be successful in the lab, the most sophisticated methodologies are often utilized. On the other hand, in the manufacturing suite, the proven and validated processes and methodologies are used, which are also potentially much less sophisticated. However, cell therapy process development starts in the lab. Researchers should begin probing manufacturability as soon as a candidate demonstrates efficacy in vitro and maybe in animal experiments.

Begin With A Closed System

Every cell therapy process developer should aim for a closed process, contained within a sterile manifold as much as possible. Media, cells, and reagents should be located in sterile bags or bioreactors connected via the sterile process of tube welding. If the academic process utilizes, for instance, petri dishes or culture plates, these are open systems — even the tissue culture flask is an open system — and most likely they will need to be replaced with a closed bioreactor or a culture bag.

Will this change the product? It could. It is better to find it out quickly before laying a path forward for the manufacturing team.

Unfortunately, research labs and drug innovators often approach the CMO with processes developed and even scaled up utilizing open systems. Sometimes, the products manufactured this way were tested and shown to be effective in Phase 1 clinical trials.

It needs to be taken into consideration that performing a Phase 1 clinical trial can be much less restrictive in terms of the allowable processes, materials, and analytics, and it can also be faster. Processes may need to be redesigned to be compliant for Phase 2, Phase 3, and commercial applications, and there will be a considerable delay if steps and equipment must be changed.

The Efficacy Milestone Should Trigger Product Characterization

It is also a good time to start thinking about the product qualities or specifications, what makes the product functional, and how specifications can be justified. This exercise includes a critical line of questions, including:

• The product might cure laboratory mice, but how many cells will be needed to cure a human being? What is the dose?
• Does the process render enough cells to meet dosage requirements? If not, is the process scalable?
• The testing might work brilliantly at benchtop scale, but will it work for the product release?
• How many analytes are measured during the test?
• Which analyte is most relevant to be used for release?
• Is the utilized method robust, and what is the coefficient of variation?
• Can the test be validated?

These questions will need answers before the analytical transfer. Additional questions include:

• Are materials and reagents used in the laboratory suitable for human use?
• What is their safety profile?
• If the process was developed using research use only (RUO) materials, are similar materials available in GMP grade?
• Will the process work the same with GMP-grade materials and will the product be as functional?

Just as researchers often use open systems for obtaining starting materials, they also often use research-only methods for purification. In general, there is a greater variety of RUO methods for cell purification than available GMP methods, and they can be more efficient in terms of target cell purification precision, but they are missing layers of material, manufacturing, and quality controls that are required for in-human use. In most cases the researchers must switch to the GMP-compliant methods.

As mentioned above, it is important to understand the product qualities and the process ranges, as well as the intermittent product characteristics. Sometimes, it might be especially difficult. For instance, when dendritic cells (DC) are used for stimulation and their preparation is a part of the process, development and definition of specific parameters for DC acceptance are needed; however, they are very often missed.

Tracking The Rise Of Off-The-Shelf Production Systems

In recent years the situation improved, at least for T cell-based therapies, as several companies developed and offered off-the-shelf GMP platforms including equipment, media, activators, and processes. These platforms are based on overall cell manufacturing experience and collaboration with multiple users. They also offer process scaling and optimization capacities together with various educational and training tools, which can lead the academic scientists to target their T cell processes for GMP compatibility.

Other self-contained platforms for, but not limited to, NK-cell based processes or gamma-delta T cell processes are also coming. However, often the off-the-shelf, ready-to-go GMP processes may not be sufficient and provide the needed results, such as cell number, cell phenotype, quality, viability, and other critical attributes. Besides, such ready-to-go processes are not available for multiple therapy types, such as, for instance, cancer vaccines or TILs. Therefore, in spite of some off-the-shelf GMP options, it is on the early development, often academic, group to design a manufacturable process.

For small molecule drugs, researchers produce a chemical formula and synthesis method. CMC teams take care of the rest. It is similar with biologics; you need the molecules and method to make them, the structure, and potential production cell lines – and then the CMC organization will take care of the rest.

It is not the same for advanced therapies. When cell therapies first became available, the manufacturers tried using the same CMC approach; in some cases, it worked, but for others, it did not.

The differences between starting materials for each manufacturing batch, problems with standardizing the processes, and issues with individual treatment’s logistics created hardships for manufacturers, impacted the margins, and resulted in several major pharmaceutical companies leaving the cell therapy field. Just recently, we've seen major departures as Takeda, Novo Nordisk, and Galapagos have announced plans to end their cell therapy research programs.

One of the approaches being actively developed in the field is moving to allogeneic cell therapies, which are non-patient-specific and produce multiple doses from each batch. Another approach is the “in vivo” cell therapy: manufacturing the substance that would trigger the response in the patient without the need for making the individual treatment. These two approaches allow companies to utilize the CMC approach with relative ease. Both methods still need to demonstrate their clinical feasibility. In the meantime, the personalized cell therapies can still find their applications; however, they cannot afford multiple process changes from academic labs to manufacturing facilities. The cell therapy processes need to be developed from the beginning with the understanding of their future manufacturability.

About The Author:

Tatiana Golovina is a seasoned expert in cell therapy, process development, and biotechnology, with over two decades of experience. She recently served as senior vice president development at BlueWhale Bio, scaling labs and driving technical innovation. At WuXi Advanced Therapies, she held leadership roles, building end-to-end cell therapy functionality and contributing to revenue growth. At Novartis AG, she optimized processes for Kymriah manufacturing and supported regulatory filings. Her career includes roles at Fraunhofer CMB, University of Pennsylvania, and Thomas Jefferson University Hospitals. Tatiana holds a Ph.D. in bioorganic chemistry and an MS in biology, with expertise spanning immunology, oncology, and gene therapy.