Addressing Performance, Scalability, and Regulatory Challenges to Accelerate Cell Therapy Manufacturing

To date, the FDA has approved 36 cell and gene therapy products (1). In the past decade, new cell therapy modalities such as chimeric antigen receptor T-cell (CAR-T) immunotherapies have emerged as promising treatments especially for many types of cancers. There are now six FDA approved commercially available CAR-T products (2) and the development of cell therapies is continuing to gather pace with over 1600 in active clinical development (3).

Commercial and Technical Challenges

The clinical success of cell therapies is placing pressure on biopharma companies to achieve clinical milestones and regulatory approval as quickly as possible. However, the high financial burden associated with delivering a cell or gene therapy to market, which averages $1.94 billion (4), coupled with the cost per dose of CAR-T therapy ranging between $100,000 and $300,000 (5), significantly restricts patient access to treatments.

High development costs have led to a high price per dose, which must be reduced to broaden access to these life-saving therapies. One approach is to adopt automated, high-efficiency manufacturing processes to optimize the use of labor and facilities, significantly reducing cost of goods (CoGs) crucial for scaling up therapies cost-effectively.

Scalability and reproducible performance are major technical issues for cell therapies, as many are developed using very manual and highly variable, labor-intensive processes that often do not translate well to manufacturing at larger scale. If the manufacturing process is not robust and the required dose per patient is not achieved reproducibly, this may result in reimbursement being withheld.

Additionally, it can cause regulatory issues during development such as clinical holds due to adverse events. In recent years, clinical holds by the FDA with cell therapy trials have been disproportionately high when compared to other drug products (6). Most of these holds are due to chemistry, manufacturing, and controls (CMC) issues. Unfortunately, with cell therapy, there is no one-size-fits-all process for large scale manufacturing because of the diversity of cell types, media, reagents and equipment used. For example, autologous processes/transplants can take up to a couple of months to develop while allogeneic cells can be manufactured for clinical use in as little as 24 hours. Also, the source of the cells can cause manufacturing challenges due to high donor-to-donor variability. Therefore, the successful development and commercialization of cell therapies relies on establishing a scalable, reproducible manufacturing process that is compliant with regulatory guidelines as early in development as possible.

At Sartorius, we are dedicated to helping biopharma partners advance their cell therapies towards clinical development, manufacturing and regulatory approval. Through technological innovations and strategic acquisitions (Table 1), we have established a comprehensive portfolio of flexible solutions that can be seamlessly scaled from the discovery phase through to commercial manufacturing.

Table 1: Key Acquisitions for Sartorius’ Versatile End-to-End Cell Therapy Workflow

Through partnering with customers, we have gained invaluable insights into industry challenges, and more importantly have gained the know-how to solve them. Today, our products and expertise have been pivotal in helping our partners both develop and commercialize their cell therapies. In this article, we take a deep dive into approaches that could help you overcome scalability, performance and regulatory challenges with your cell therapy.

Tackling Scalability and Performance

Cell therapy developers face the challenge of scaling up their production when transitioning from development to manufacturing to meet clinical and/or commercial scale. Transferring a robust process is essential for ensuring reproducible performance and helps prevent expensive batch failures. However, cell therapies are often complex, and their production processes are highly variable compared to other biologics.

With cell therapy, variability can occur at product and process levels. For example, inherent variability in the quality and characteristics of the starting material such as cells derived from patients or donors, cell isolation and expansion, as well as harvesting and freezing strategies used can all affect overall performance of cells. Also, because the process is often complex and manual, where some therapies can be thawed and applied whilst others may require additional processing at the clinical site the experience/ability of the operator performing these tasks can be a key factor in the product’s effectiveness.

At the batch level, raw materials, media and reagents can cause variation in titer, impurity profiles, and heterogeneity of viral particles produced, where these have been used. This lack of standardization across batches can lead to unpredictable yields and out-of-specification critical quality attributes (CQAs).

Scaling a process to generate reproducible performance and quality with cells and viral vectors can be tricky, especially if the initial process has been developed in equipment where critical process parameters (CPPs) were difficult to control and there were few in-process analytics.

If the process has not been optimized and scalable technologies have not been selected early in development, then scaled-up processes may show substandard reproducibility, productivity or efficacy, resulting in process revalidation and optimization to meet CMC requirements. This can cause delays and incur significant costs if processes need to be modified, especially after regulatory approval has been granted.

In upstream processing cell behavior can also change when transitioning from small to larger-volumes or from 2D flatware to 3D bioreactors affecting for example transfection efficacy where a viral vector has been used, cell quality and therapeutic performance.

For developing a robust upstream process for cell therapy based on Quality by Design (QbD) principles, we provide high throughput automated micro and mini bioreactor systems and DoE software. The micro/mini bioreactors can be used for optimizing LV development (7), media screening, process optimization and development with suspension cells for example T-cells (8) or with microcarriers for adherent cell lines such as human mesenchymal stem cells (MSCs) (9).

For ease of scalability, we provide single-use and reusable bioreactors and a range of media, supplements and transfection reagents at both pre-clinical and cGMP grades for use with many cell types utilized as therapies. The bioreactors are scalable at the early development stage from 250 mL through to 2000 L. For example, we are collaborating with Stanford University to develop a workflow for scalable expansion of reproducible quality human induced pluripotent stem cells (iPSCs) for bioink production (10). Using the Ambr® 250 modular system to develop a process which is scalable to Univessel® Glass Bioreactors (2L) researchers at Stanford can reliably produce billions of high-quality iPSCs, which is of utmost importance for fueling their organ engineering pipeline. Using this expansion workflow, they are currently working towards a potential scale-up to 10L bioreactors and are also establishing efficient differentiation protocols to generate the billions of cardiomyocytes needed for whole heart manufacturing.

In the downstream, for high product yield and quality of LVs and cell therapies, we offer scalable Sartobind® membrane chromatography, CIMmultus® monolith chromatography, Sartoflow® single-use tangential flow filtration (TFF) and hollow fiber filtration (HFF) technologies for purification and filtration. In addition, our Sartopore® and Virosart® filtration products ensure appropriate contamination control through sterile filtration and virus filtration of buffers and media. We also provide Ambr® Crossflow for screening buffer combinations and process control conditions to optimize the downstream process. Additionally, because LVs can be difficult to filter due to their large particle size, we offer the kSep®, a scalable, single-use counterflow centrifugation system for low-shear clarification of LVs and aseptic cell processing of cell therapies.

Meeting Regulatory Compliance

The complicated and evolving regulatory environment for cell therapies can be a major barrier to successful commercialization. Adhering to the latest requirements and providing flexible production platforms are critical for maintaining regulatory compliance and ensuring rapid product approval.

To ensure reproducible quality and performance with viral vectors and cell therapies, we provide equipment for screening raw materials, as well as specialized cell analysis systems and data analytics platforms. This means we can generate full, end to end QbD and DoE data packages, which are appropriate for a CMC file.

Maintaining a robust manufacturing process requires automation utilizing cGMP closed systems and a secure global supply chain of consumables, and raw materials, supported by regulatory expertise and documentation.

Our products and services are underpinned by rigorous quality-assurance processes which include certified documentation such as drug master files, validation guides, and certificates of analysis. We supply xeno and serum-free cell culture media and reagents plus sterile, single-use systems for closed aseptic processing from a secure global supply chain.

We also provide comprehensive bioanalytical and biosafety contract testing services compliant with global pharmacopoeia standards. These are carried out in facilities accredited by regulators including the FDA and European Medicines Agency (EMA). We have in-house expert regulatory support to help meet efficacy and safety standards and our products and services have been used to support manufacturing of at least 15 commercially approved cell and gene therapies.

A Seamless Path to Commercial Manufacturing

An efficient journey to cell therapy commercialization requires trusted expertise, flexible end-to-end cGMP platforms and a secure global supply chain. These are the bedrocks for quality, performance and scalability, needed to fast track regulatory compliance. From discovery to clinical and commercial manufacturing, at Sartorius our proven solutions for cell therapy can pave the way for accelerated time to market while reducing costs, allowing broader patient access to these transformative treatments. Together, we are setting the standard in cell and gene therapy.

References

1. Food and Drug Administration.gov. Approved Cellular and Gene Therapy Products. Listing of licensed and approved products from the Office of Tissues and Advanced Therapies (OTAT). Accessed March 2024 https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
2. Y.J. Chen, B. Abila and Y. Mostafa Kamel. Cancers (Basel). 21;15 (3):663 (2023) https://doi.org/10.3390/cancers15030663
3. Clinicaltrials.gov Database Search for Clinical Trials with cell therapy. Active, not recruiting, Accessed March 2024 https://clinicaltrials.gov/search?intr=cell%20therapy&aggFilters=status:act
4. M.T. Sabatini, Chalmers, M., Pharm. Med. 37, 365–375 (2023). https://doi.org/10.1007/s40290-023-00480-0
5. G. Macdonald, “Cell & Gene Therapy Costs Drive Deals,” GEN, Oct. 4, 2023. https://www.genengnews.com/topics/bioprocessing/cell-gene-therapy-costs-drive-deals/
6. C.A. Wills, D. Drago, and R.G Pietrusko, Molecular Therapy Methods and Clinical Development, 31. (2023) https://doi.org/10.1016/j.omtm.2023.101125
7. F. Bollman, “Optimized Suspension-Based Production of Lentiviral Vectors with a DoE Approach”, GEN, Dec 3, 2020 https://www.genengnews.com/resources/optimized-suspension-based-production-of-lentiviral-vectors-with-a-doe-approach/
8. J. Hupfeld J., A. Rees-Manley, M. Albersdoerfer et al. “Optimizing T Cell Expansion in Ambr® 15 Cell Culture Using DoE and Process Transfer to Ambr® 250 Modular” online poster. https://www.sartorius.com/download/921548/ambr15-optimization-tcell-expansion-poster-en-a0-b-sartorius-1--data.pdf
9. Q.A. Rafiq, M.P. Hanga, T.R.J. Heathman et al. Biotechnol Bioeng. 114(10):2253-2266. (2017) https://doi.org/10.1002/bit.26359
10. D. L. L. Ho, S. Lee, J. Du et al. Adv. Healthcare Mater., 11, 2201138 (2022). https://doi.org/10.1002/adhm.202201138

About the authors

Paul Cashen is a process technology consultant for Separation Technologies, Susanne Deckers is a market entry strategy manager for Fluid Management & Bioreactor Technologies, and corresponding author is Rukmini Ladi, external collaborations manager in the cell therapy & gene therapy (rukmini.ladi@sartorius.com).