Blog | 9/12/2024

Breaking Barriers: The Evolution of Decentralized Autologous Cell Therapy Manufacturing

By Alexander George, PhD, Chris Wolfram, and Daniela Hristova-Neeley, PhD

Growth and Diversity of the Cell Therapy Pipeline

The cell therapy pipeline has seen remarkable growth and diversification over the past few years. This diversity is crucial for the exploration of various therapeutic approaches, potentially leading to more effective treatments for a wide range of diseases. Approximately half of this pipeline consists of autologous cell therapies. To make innovation in autologous cell therapy, beyond CAR-T, more accessible, it is essential to address the key manufacturing challenges.
 

Manufacturing Challenges in Autologous Cell Therapy

The current autologous cell therapy manufacturing process involves collecting cells from patients at the point of care, transporting them to a centralized manufacturing facility where multiple unit operations are performed to produce therapeutic cells, and then transporting the cells back to the patient for reinfusion, as depicted in Figure 1.

This manufacturing process is highly complex, involving multiple steps and various technologies, which present several challenges in the production of autologous cell therapies:

1. The input material, which is cells collected from individual patients, can vary significantly in quality and characteristics, especially given the typically poor health of the patients, impacting yield and efficacy of the therapy.
2. Cell engineering can be challenging and needs to be optimized to ensure efficiency and minimize off-target effects that can impact therapeutic outcomes.
3. The current manufacturing processes require significant human intervention between steps, introducing additional variability and increasing the risk of operator error and contamination.
4. Essential reagents and materials used in the manufacturing process are costly.
5. Cold chain logistics require careful coordination between multiple stakeholders and add additional complexity and costs.
6. Shipping can lead to materials being lost or damaged; in autologous cell therapies, this is especially challenging due to how little usable starting materials sick patients can give and the potential impact on their treatment schedule.

For a well-developed autologous cell therapy manufacturing process, each step must be meticulously controlled to ensure the safety and efficacy of the therapy and scalability of the manufacturing process. The use of fully closed systems and decentralized manufacturing may address some of these manufacturing challenges.
 

Bioprocessing Tools Addressing Manufacturing Challenges and Enabling Decentralization

To tackle challenges with the current centralized process, several innovative tools and technologies are being developed which hold the potential to transform the manufacturing of autologous cell therapies. Figure 2 showcases the available or emerging systems. Closed system bioprocessing solutions present particular interest.

Closed systems may improve the consistency of cell therapy quality and characteristics. Additionally, these systems minimize the need for extensive human interaction between steps, reducing variability and the potential for human error. Closed system manufacturing may also mitigate the high costs associated with essential reagents and materials by improving process efficiency. Moreover, closed system bioprocessing tools enable decentralized and potentially point-of-care manufacturing, which can streamline cold chain logistics; this would reduce the complexity and costs involved in coordinating multiple stakeholders to maintain cell viability during transportation.

These systems all rely on closed equipment and automation but take different approaches to implementation. Lonza’s Cocoon platform represents one extreme, where a single compact instrument can perform all necessary functions for cell modification and expansion. Others take a more modular approach that allows for more flexibility, such as MultiplyLabs, whose robotic modules allow for the integration of individual production instruments from different vendors into an automated closed system. This approach increases flexibility, at the expense of a larger footprint and a more involved and complex process development.

Another option is to simplify production by eliminating or reducing the specificity of many unit operations. This method has allowed Lupagen to develop a truly point-of-care platform: its Xynvivo system connects the patient directly into the closed system. It performs leukapheresis with the additional step of incubating the patient’s cells with the vector and washing out unbound vector before returning the cells to the patient. By eliminating expansion and additional purification steps, the entire process can be completed in a matter of hours, enabling any hospital with existing leukapheresis capabilities to potentially offer autologous gene-modified cell therapy without requiring facility updates.

These automated, closed production systems typically dominate discussions of distributed manufacturing for autologous cell therapies, but a promising, complementary approach is to pair distributed or point-of-care manufacturing with centralized pharmaceutical quality systems (PQS). Connecting all the local production sites and their closed production systems to a central PQS allows for real-time monitoring of conditions across sites, as well as consistent centralized management of inventory, along with qualification and release of starting materials and final products. This approach has the added benefit of keeping data organized and centralized for eventual regulatory submissions.
 

Regulatory Challenges and Precedents in Autologous Cell Therapy

Developments in cell and gene therapy technology have generally outpaced the ability of regulators to establish clear guidelines and expectations. The Food & Drug Administration (FDA) has made some progress, publishing three draft and two final guidance documents for cell and gene therapy in the past year. However, questions and uncertainties remain. Public feedback on the draft guidance for potency assurance highlights this ongoing ambiguity. In its feedback, the International Society for Cell & Gene Therapy requested strategies for managing the inherent variability of cell therapy production, including patient-to-patient differences for autologous therapies.

The regulatory landscape for distributed manufacturing of autologous therapies is particularly uncertain. While the FDA’s planned publication of a draft guidance in late 2024 will begin to clarify matters, there is still a long way to go.

There is historical precedent for point-of-care manufacturing of drugs: positron emission tomography (PET) drugs often need to be manufactured on-site and require immediate release due to their short half-lives. Regulations for the distributed production of cell therapies could draw on the established rules for PET drugs, particularly concerning release requirements, operator training, site qualification, and non-conformance investigations. However, significant differences between the two modalities make establishing clear and consistent regulations more challenging for cell therapies. Notably, there is more variation between different cell therapies in development than there is between different PET drugs. Biological production, especially when using donor material from patients, is bound to include more batch-to-batch variation than small molecule PET drugs.
 

Conclusion

Centralized manufacturing, a common practice for biopharmaceuticals, presents unique challenges for autologous cell therapies. Closed manufacturing systems, which many companies are currently developing, offer promising solutions. The FDA has also increased its focus on the manufacturing of cell therapies in recent years.

Recent advancements in technology and growing regulatory support for decentralized manufacturing are promising, yet challenges remain in standardizing processes and ensuring consistent quality. Continued investment in innovative manufacturing technologies and collaborative efforts between industry and regulators are essential for advancing decentralized autologous cell therapy manufacturing.

Looking ahead, the landscape of autologous cell therapy manufacturing will likely feature a blend of both centralized and decentralized approaches. This hybrid model can leverage the strengths of each system, ensuring more timely and accessible treatments for patients worldwide.

With these concerted efforts, the vision of decentralized, point-of-care manufacturing for autologous cell therapies could become a reality, providing consistent and high-quality treatments tailored to individual patient needs.

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Alexander George is a Consultant and subject matter expert in life science tools and bioprocessing.
Chris Wolfram is an Engagement Manager and senior team leader within the Life Sciences Tools and Services practice.
Daniela Hristova-Neeley is a Partner and a co-leader of the life science tools and services practice.