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Jennifer Markarian is manufacturing editor of BioPharm International.
Pumps and other components meet the demands of single-use systems in biopharmaceutical downstream processing.
The growing use of single-use systems and ongoing development of continuous processing place new demands on pumps and other fluid-handling components in downstream biopharmaceutical processing. Pumps used with single-use systems include peristaltic pumps, in which the fluid flows through single-use tubing, and diaphragm pumps, which can also be single-use and move the fluid using suction created by the diaphragm. BioPharm International spoke with Andreas Frerix, product manager for diaphragm pump manufacturer Quattroflow, a product brand of PSG, a Dover Company, and Gregg Johnson, global product manager for Masterflex and Masterflex Ismatec peristaltic pumps at Cole-Parmer, about trends and best practices in fluid management.
BioPharm: What trends do you see in downstream processing and how do these relate to the requirements for the fluid pumping system?
Frerix (Quattroflow): While by far most operations in downstream processing are in batch mode, there is a trend to continuous bioprocessing because the industry is seeking ways to advance their current technologies to improve efficiency, throughput, and product consistency while reducing manufacturing costs. A typical example is chromatography. In batch mode, a column filled with resin runs through the modes of equilibration, loading, washing, elution, and regeneration, one after the other. The continuous version is called simulated moving bed chromatography. In this process, several columns operate in parallel, with each of them in one of the aforementioned modes. Complex valve configurations are used to switch the column from one mode to the other. While this setup reduces the amount of expensive resin needed, it requires several pumps to run in parallel at high consistency over a long period of time. A high degree of pump reliability and flow stability is needed because these continuous processes can run for weeks rather than for only a day when in batch mode.
Johnson (Cole-Parmer): Both single-use and continuous processing are growing trends because both offer unique advantages depending on the application need. Single-use will be prominent in personalized cell/gene therapy. Continuous processing will grow in large production volume applications, such as virus or vaccine production, as operations search for opportunities to increase output and efficiency.
Peristaltic pumps are suitable in both the single-use environment and to provide, with a simple change of material, the long running life for continuous processes. These pump systems can address both areas of single-use and continuous processing. Continuous processes would potentially be looking for longer-lived tubing.
Continuous processes and single-use processes require pumps with modularity, easy maintenance, and dosing accuracy and precision. Metering pump technology featuring single-use wetted parts connected to a driving motor, such as the tubing in peristaltic pumps and the pumphead in diaphragm pumps, satisfy the modularity and easy maintenance requirements because the parts that come into contact with the fluid are simply replaced. The accuracy and precision of these systems is determined by the sophistication of the drive, and drive features such as precision RPM [revolutions-per-minute] control, programmable interfaces, and analog signal control have become baseline.
BioPharm: What trends do you see in single-use components for fluid handling?
Johnson (Cole-Parmer): Reliability and standardization of single-use components is growing in importance to mitigate risk and ease scalability. Single-use components are used in applications such as personalized medicines and cell and gene therapy. The ability to eliminate cross-contamination and decontamination processes drives the need for single-use components.
Peristaltic technology is low-shear and mechanically simple, consisting of a single piece of material. However, some concerns with single-use tubing in peristaltic pumps, which are mentioned with some frequency by pump users, are tubing life and spallation. Both concerns can be addressed by choosing the correct tubing material for the application. For long life with minimal failure risk, thermoplastic elastomer (TPE) formulations offer the capability of running for months at a time in a ‘single-use’ capacity. When low particulates are needed, selection of a smooth tubing surface significantly reduces spallation. The primary determinant when it comes to tubing selection is chemical compatibility, then any regulatory requirements, then the life of the tubing.
Frerix (Quattroflow): There are several trends affecting single-use components. While continuous manufacturing requires lower flow rates and longer operating times, we also see a need for handling larger flow rates as the volumes of single-use bioreactors are rising, which increases the demand for single-use equipment with larger diameters. Another trend where single-use components will play an important role is personalized medicine/cell and gene therapies.
Single-use pumps are used from process development up to commercial production. The main benefits of single-use pumps are:
Looking at these benefits, single-use pumps have the most benefit when used in facilities with small to medium capacities and frequent product changes, such as clinical-trial manufacturing or contract manufacturing organizations (CMOs).
Single-use diaphragm pumps have been used for many years. For critical flow and/or pressure-controlled operations like tangential-flow filtration, chromatography, virus filtration, inline dilution, and many more, the advantages of diaphragm pumps are their low pulsation when using multiple diaphragms (such as quaternary diaphragm pumps); the capability of delivering the needed pressure, especially for chromatography or tangential-flow filtration; the proportional flow characteristics; and the shear-sensitive handling of biological products.
When it comes to processing large volumes (e.g., large-scale monoclonal antibodies [mAbs] or blood-plasma fractionation), single-use equipment has a defined limit in terms of its scalability and economics. Here, stainless-steel equipment is for some applications the preferred choice. In addition, single-use processes are widely adopted in the manufacture of mAbs from mammalian cell cultures; however, when it comes to microbial fermentation, stainless-steel equipment is mainly used.
BioPharm: How do fluid pumping requirements for the emerging areas of personalized medicine and cell and gene therapies differ from conventional biopharmaceutical processing?
Johnson (Cole-Parmer): Personalized medicine/cell and gene therapies require lower volumes of fluid, which requires the fluid handling system to have much lower flow rates, and the pump can be physically smaller. Pumps that offer independent multi-channel control and flows in the range of microliter per hour are needed to meet these new requirements.
Frerix (Quattroflow): One big difference is the batch size, especially because in autologous gene and cell therapy, the cells from individual patients have to be treated, modified within different processes, and then administered back to the patient. This technology involves one individual process per patient, along with relatively low flow rates, the need for disposable equipment, and the handling of low volumes. In these types of applications, particulate release from the pump cannot be tolerated, as these particulates can cause health risks once the modified cells are returned to the patient.
BioPharm: Is remote monitoring/predictive maintenance being used for biopharma pumps?
Frerix (Quattroflow): While diaphragm pumps are reliable when used within the specified operating conditions, it is possible to use sensors to detect leak-causing diaphragm damage and stop the process. This detection is especially helpful when multiple pumps are used in parallel in a fully automated manufacturing process.
Johnson (Cole-Parmer): We have customers asking us now if we have solutions for remote monitoring/predictive maintenance. We have a tool for remote monitoring and control in place that provides operations the ability to ‘see’ what is happening with the pump system without actually being there. Coupling this insight with existing plant line knowledge gives operations greater flexibility on how they manage the line.
We are now seeing customers asking for pumps with more connectivity and automation options such as cloud-based monitoring and control. Cloud-based record keeping is also a growing request from our downstream customers, as manufacturing floors align with market trends to move business operations to the cloud while also meeting the growing demand from regulatory bodies for more rigor and accountability in operational data.
Predictive maintenance offers improved efficiency
Preventive maintenance uses a time-based schedule to perform routine maintenance and prevent equipment breakdowns. Predictive maintenance uses sensors on equipment, such as pumps, to send data to analytics software using the Industrial Internet of Things (IIoT), to perform need-based maintenance rather than time-based. With insight into when a problem might occur, process operators and engineers can make better decisions about how to intervene with the least disruption to the process (1).
Predictive maintenance has been enabled by advances such as machine learning, which is a type of artificial intelligence. Machine-learning algorithms learn patterns of how equipment should be operating and then can identify changes (e.g., in vibration or flow) that may indicate a problem will occur. Equipment can also be compared to similar equipment in the same plant or in facilities around the world, and these large datasets improve accuracy of the predictions (1).
1. J. Markarian, Pharm. Tech. 44 (1) 36-40 (2020).
Vol. 33, No. 5
When referring to this article, please cite it as J. Markarian, "Fluid Handling Considerations," BioPharm International, 33 (5) 2020.