Stay “Closed” or “Open” Up: Finding the right balance for cell therapy manufacturing

Cell-based therapies have emerged as a revolutionary approach in the field of regenerative medicine and as an anti-cancer therapeutic modality, offering potential treatments for a range of diseases. As the demand for cell-based therapies continues to grow, it is crucial to explore the current and future fill-finish packaging strategies to ensure the safety, efficacy, and accessibility of these therapies. Understanding the advantages and challenges associated with different modes for cell therapy packaging will allow drug manufacturers to choose a suitable system.

Chimeric Antigen Receptor (CAR) therapies are increasingly gaining momentum for treating various cancers. Currently, the approved therapies are mostly autologous in nature - cells are collected from, engineered, and then delivered to the same individual causing no immune rejection of the drug product. However, as the demand for CAR-based cell therapies increases, the current manufacturing process is becoming untenable due to high cost, time required and small production scale. These and other problems are pushing scientists to develop the next generation of cell-based therapies that will be allogeneic in nature with “off-the-shelf” options. To make cell therapies accessible, a complete overhaul of the manufacturing processes is needed, as they are not currently equipped for large batches.

Currently, the autologous CAR therapies are being produced by “closed” processing where the drug substance (cells extracted from patients) is kept isolated in a manufacturing unit which provides a controlled and sterile environment throughout its production, formulation, packaging, storage as well as transportation. This approach has several advantages which includes minimizing the risk of contamination and protecting the drug product from external pathogens during handling, storage (which can be short term for autologous and long term for allogeneic) and transit. It also shields the cells from environmental exposure, safeguarding them from temperature fluctuations and air quality issues that could compromise their sterility, viability, and potency. However, closed processing and fill-finish is also associated with many limitations. The closed system uses containment technology that requires specialized equipment and infrastructure often leading to higher capital and operational costs. As for instrumentation, two approaches are currently being followed: use of multiple modular equipment, where each piece of equipment is used for a single step (unit operation) which includes cell isolation following apheresis, genetic manipulation, expansion followed by harvest, and final drug product formulation.

The second approach includes all-in-one end-to-end equipment that encompasses the entire process and uses single-use consumables. Both approaches have their own pitfalls and advantages. Having a modular approach leads to simultaneous manufacturing of multiple drug products where each product is at a different stage of manufacturing thereby expanding the capability, whereas end-to-end instrumentation is used for manufacturing one drug product at a time. As the manufacturing needs increase, as will be in the case of allogeneics it would be imperative to optimize the use of equipment usability. Monitoring critical parameters like cell viability or cell count, may require additional sampling or sampling ports that can introduce risks of contamination and make the process essentially open. Adaptability is another issue associated with closed fill-finish as this process can encounter challenges with different manufacturing processes or product types. The current CAR cell therapy manufacturing is designed surrounding T-cells that were the first cell type to be used and remained relatively unchanged. The fixed design and infrastructure of closed fill-finish systems limits their compatibility with evolving cell therapy landscape that requires utilization of different cell types like NK cells and macrophages, among others. Modification or upgrades to the closed system may require additional validation and regulatory approval, leading to delays and increased costs. Moreover, the scalability of closed systems may be limited due to constraints in equipment size or manufacturing capacity and may require significant investments in additional closed systems or facility modifications as demand increases.

Although closed fill-finish is currently the way cell therapy industry, especially patient-specific cancer treatment, has been operating, it is vital to identify other solutions that allow scaling up the manufacturing process. Aseptic fill-finish of the cell therapy drug product that is currently being done with biologics, like mAbs, etc., can be an alternative (will hereby be referred to as “open”). The primary advantage of open fill-finish is the flexibility in terms of scalability for allogeneics as this will mostly use the current established manufacturing practices for biologics. Moreover, the ease of process optimization due to the experience gained from fill-finishing other therapeutic modalities can be advantageous for streamlining the whole process, reducing the risk of cell damage or loss. However, open fill-finish comes with its own inherent risks, like increased likelihood of contamination, requirement of strict aseptic techniques, environmental controls along with highly trained personnel to ensure proper aseptic practices to minimize contamination risk. Moreover, tweaks will be required to the current aseptic fill-finish process as cell therapy drug products unlike traditional biologics become vulnerable in relatively short time to DMSO exposure which is present in many formulations and therefore requires rapid processing.

One of the major challenges in the majority of the current closed-fill finish processes of cell therapy drug products is the final packaging container, which is usually cryo-bags. These are adopted because of their previous use as the container of choice for blood-based infusion products and their compatibility with the closed fill-finish equipment. However, various challenges have been associated with cryo-bags: bag-breakage at ultra-cold temperatures as well as the problem of dead-volume where precious samples are lost is common. Moreover, requirement of additional packaging material like over-wrap bags and aluminum cassettes, along with racking systems for storage and transportation, increases the overall price and complexity. Alternative solutions are necessary to make these therapies more affordable.

One alternative to cryo-bags is rigid vials, that offer many advantages and are well compatible with open aseptic fill-finish processes. Rigid vials provide excellent protection and stability for cell therapy products as they provide superior resistance to physical damage such as puncture or tears as compared to bags reducing the risk of contamination and sample loss. Hermetic sealing of vials provides an effective barrier against microbial contamination and maintains sterility of the product throughout its shelf life. It is always vital to visually examine the drug product before administration to patients. Availability of rigid polymer-based containers with glass-like clarity permits healthcare professionals to assess the appearance, color and particulate matter within the product allowing quick identification, ensuring high product quality. As the final drug products are cells, they are usually frozen at ultra-cold temperatures post manufacturing until administration into storage. Rigid vials are more suited for freezing as they can withstand long-term storage in ultra-low temperatures without affecting vital container closure integrity. Rigid vials also allow precise unit dosing and administration as there is no “dead-volume” problem associated with them like cryo-bags, thereby reducing the risk of dosing errors. Moreover, rigid vials have been used for a long time for other temperature sensitive therapeutics like mAbs and their use in cell therapy drug products will align with established industry practices and regulatory requirements facilitating the approval process. The compatibility, real time monitoring capabilities, sterility assurance, process development benefits and precedence of regulatory acceptance makes rigid vials well-suited for open fill-finish of cell therapy drug products which will be a requirement for allogeneic therapies due to its large manufacturing volume. It is also possible to adopt a hybrid approach where earlier steps of manufacturing are kept closed whereas the final fill-finish steps are done aseptically to get the best of both worlds.

Finally, the choice between closed and open fill-finish for cell therapy drug products involves a careful balance between safety, accessibility, efficacy and the type of cell type used. Closed manufacturing and fill-finish offers robust protection against contamination and environmental factors ensuring integrity of therapeutic cells; open aseptic fill-finish on the other hand provides greater flexibility and a way to scale up that will be a critical future requirement as more therapies gets FDA approval. Both strategies will co-exist and will need further development to ensure proper drug containment without affecting its quality. The choice for the approach will typically depend upon the application of specific therapy. By leveraging the advantages of both approaches, researchers and clinicians can optimize the safety, accessibility and efficacy of cell therapies, helping in its widespread adoption and availability resulting in improved patient outcomes.

For more information on how we can help you with your cell therapy challenges visit our Advanced Therapies page.