Enabling Fluid Transfer for Cell Therapies: An Industry Challenge

Pharmaceutical Technology, Pharmaceutical Technology-04-02-2017, Volume 41, Issue 4

The transfer of fluids is governed by different equipment requirements across the medical, biopharma, and cell therapy manufacturing industries.

The simple act of moving fluid from one location or container to another is a routine step in essentially all bioprocess manufacturing. Fluid transfer in some manner has been routinely performed for decades within the medical and biopharma industries and, more recently, as part of cell-therapy (CT) manufacturing. Interestingly, while the general purpose of fluid transfer is the same, the devices used (along with the requirements) are drastically different between the blood and biopharma industries. To complicate matters, depending on the product and process, fluid transfer within CT manufacturing can be a hybrid of three of these industries. Fluid transfer remains an essential-yet challenging-component of the CT manufacturing industry.

Historical evolution

The incorporation or use of single-use components for fluid transfer purposes, regardless of the industry, is a necessary and common practice. Single-use plastics offer numerous advantages compared with other materials, with flexibility being the main advantage (1). The medical industry has the longest history of applying single-use components for fluid transfer, with the advent of plastics and the first introduction dating back to the 1960s with polyvinyl chloride (PVC). Currently, PVC is the most widely used plastic used for medical devices, thus making it the primary choice for tubing (1). In addition to flexibility, PVC offers ease of fabrication, chemical stability, biocompatibility, and cost effectiveness. PVC is used in a wide range of applications, including blood bags, IV and fluid transfer sets, dialysis bags, and IV containers.

Within the biopharma industry, single-use solutions have been used since the 1980s, but it wasn’t until the late 1990s and early 2000s-with the introduction of large-scale tube welders and sterile connectors-that the large-scale adoption of single use occurred (2). Only recently has the cell therapy industry evolved into its current state. Process development and manufacturing practices are still evolving, combining aspects of both the medical and biopharma industries.

Fluid transfer and single-use

Given the overlap in products and process, single-use components are the predominant means for fluid transfer in both the medical and cell-therapy industries. The biopharma industry has traditionally used stainless-steel piping for fluid-transfer purposes, but hard piping transfer lines often require intensive, costly, and time-consuming cleaning and validation protocols (3). The previously described advantages and technological advances of single-use tubing and connector technology have led to its more recent adoption in manufacturing operations (2, 3).

Fluid transfer is achieved a variety of ways depending on the intended application and industry. A wide range of options are currently used today and some include spiking, luer connection, tube welding, and various aseptic connectors, which allow for sterile connection in non-sterile environments (Figure 1). Sterile tube welding (when possible) is commonly applied because it is well established and offers flexibility of enabling sterile, aseptic fluid transfer in non-sterile or uncontrolled environments (i.e., outside of a cGMP cleanroom or biosafety cabinet).

As depicted in Figure 1, the methods for connecting and transferring fluids from one container to another vary with the means of completing the transfer. The use of transfer assemblies with spikes are commonly applied in the medical industry to puncture into bags preassembled with the appropriate ports to facilitate fluid transfer. The fluid is then typically removed by gravity or by an attached syringe. Luer connections are another means of connecting syringes or fluid transfer devices to transfer or remove aliquots of fluid (i.e., blood, plasma, etc.). These two-process steps for fluid transfer are not desirable from a large-scale manufacturing standpoint, as they can expose product to the room environment.

Tube welding is preferred over open processing in each of the industries as it offers process and manufacturing flexibility. Tube welding is done routinely to sterile connect containers enabling fluid management (Figure 1). For tube welding and sealing applications, thermoplastic elastomer (TPE) tubing is required. A variety of tubing can be welded, including PVC and other proprietary formulations. Each tubing type is often designed to support unique industry needs, welds to itself (and in some cases, welds to other similar tubing), and requires specific welding devices. Fluid transfer can then be completed. Welding of PVC allows the flexibility needed for small-scale fluid transfer operations in medical applications. The other TPE tubing examples are far more common in biopharma, where large-scale fluid transfer operations are employed.

For some tubing, like silicone, which is commonly used in biopharma manufacturing as pump tubing for fluid transfer, welding is not possible and, therefore, other means of connecting are required. A number of single-use sterile connectors are available and allow two lines of tubing to be joined while maintaining a sterile fluid pathway (4). Each tubing line is pre-affixed to a connector end that has a removable membrane or valve barrier for mating to another connector end, thus providing fluid transfer flexibility where alternative connection options are not readily available (Figure 1).

 

 

Industry-specific fluid transfer requirements

Although similar in concept and intended purpose, many differences exist between the industries for fluid transfer (Table I). Fluid transfer practices within the medical industry are established with PVC as the predominant polymer used for the tubing and bag systems. For these intended uses, products including blood transfer bags and transfer sets are considered regulated medical devices. This is contrary to the biopharma industry. Furthermore, the use of luers and spikes are common in medical environments, whereas tube welding

and single-use sterile connectors predominate fluid transfer activities in biopharma.  Tubing sizes also vary within the industries, with smaller-diameter (approximately 1/8” in diameter) tubing being predominant for fluid transfer of medical products; much larger tubing (3/8” and 1/2” in diameter) is often used to accommodate fluid transfer in biopharma manufacturing activities (Table I). These differences are expected given the larger volumes of fluid commonly being transferred within biopharma (100s of L) compared with medical applications, where much smaller volumes (mL to L) are handled. For smaller volumes, syringes can be used to transfer fluids, whereas pumps and pump tubing are required to transfer the larger volumes needed for biopharma manufacturing. For the medical and biopharma industries, the requirements for incorporating and utilizing the single-use components to transfer fluids have been optimized and established to support their distinct process and product requirements.

Fluid transfer and cell therapy

Cell therapy manufacturing practices are rapidly evolving, but are far less established than other biopharma manufacturing applications. For CT and the medical industry (e.g., blood transfusion), the cells are the product, but cell therapies also have a manufacturing process that is more common in biopharma. The source materials (cells) are typically derived from a patient at a hospital or blood center, further manufactured, and then returned to the patient in what is known as autologous cell therapy. The techniques necessary for the production and transfer of products present a myriad of challenges (Table I). For the most part, cell therapy has been borrowing technologies from the medical and biopharma industries for fluid transfer practices.

As shown in Table I, cell therapy fluid transfer employs a combination of methods and requirements. With autologous therapies, where there is one product per patient, every fluid transfer step is crucial to limit cell loss and to ensure sterility, compatibility, and overall quality. A common challenge is making simple connections for fluid transfer from upstream processing steps, which often uses PVC tubing and containers, to downstream steps, where bioprocessing tubing and connectors are incorporated. Varying tubing types and sizes prevents sterile welding and requires custom products and processes. This is further complicated by the fact that the fluids (products) are patient-derived and are meant to be delivered back to the patient. Some of the components used for fluid transfer (e.g., traditional blood transfer sets and bags) are regulated as medical devices. Typically, these devices have been designed, tested, and regulated for the medical industry, but not specifically for the CT industry. Given the differences in intended use, the testing performed and configurations don’t always match the needs for CT products (e.g., cell recovery/viability, particulates, configuration, and packaging). This difference can impact the manufacturing process and final products for clinical and commercial purposes.

CT products are produced through a series of manufacturing steps. Having multiple processing steps to transfer fluids as part of the manufacturing process can generate particulates and possibly impact product quality. Particulates can be mitigated and controlled in biopharma through the inclusion of filters both upstream and downstream prior to final filling. In-line filters as part of fluid transfer and final fill for CT products, however, presents a more difficult challenge, as the final products are cell-based. Tubing and tubing sets are typically low in particulates, but handling, cutting, joining (welding), and environmental conditions used as part of the fluid transfer and manufacturing process can impact particulate load (4). It is important to monitor the process and the components used to minimize particulate load for CT products (5).

The transfer of fluids in the medical, biopharma, or CT industries is both common and necessary. Although requirements for fluid transfer exist across industries, the medical and biopharma industries have more established and controlled practices to date. Fluid transfer for cell therapies is becoming increasingly critical, and new technologies and practices will continue to be required to support the unique demands of the industry. Fluid transfer practices for CT manufacturing will have to evolve and become more standardized with time to more adequately support the process, product, and safety requirements of the industry.

References
1. T. Johnsen, “When Plastics Revolutionized Healthcare–Medical Devices in a Historical Perspective,” PVC Med Alliance, http://pvcmed.org/wp-content/uploads/2015/10/When-Plastics-Revolutionized-Healthcare-Medical-Devices-in-a-Historical-Perspective.pdf, accessed Feb. 28, 2017.
2. J. Martin, “A Brief History of Single-Use Manufacturing,” BioPharmInternational.com, Nov. 2, 2011, www.biopharminternational.com/brief-history-single-use-manufacturing, accessed Feb. 28, 2017.
3. T. Butler, “Applying Single-Use Efficiencies to Room-to-Room Fluid Transfer,” PharmaceuticalManufacturing.com, Feb. 3, 2015, www.pharmamanufacturing.com/articles/2015/applying-single-use-efficiencies-to-room-to-room-fluid-transfer/, accessed Feb. 28, 2017.
4. K. Harper and K. Strahlendorf, “A Review of Sterile Connectors,” BioPharmInternational.com (Nov. 2, 2009), www.biopharminternational.com/review-sterile-connectors, accessed Feb. 28, 2017.
5. D. Clarke et al., Cytotherapy 18 (9), 1063–1076 (September 2016).

About the Author
Dominic Clarke, PhD, is the global product manager for cell therapy and bioprocessing at Charter Medical Inc., Winston-Salem, NC 27103 (DClarke@CharterMedical.com); Dominic also serves on the process and product development committee for the International Society for Cellular Therapy (ISCT).

Article DetailsPharmaceutical Technology
Vol. 41, No. 4
Pages: 34–37
Citation: When referring to this article, please cite it as D. Clarke, "Enabling Fluid Transfer for Cell Therapies: An Industry Challenge," Pharmaceutical Technology41 (4) 2017.