Hanno Ehring

RFID sensors as the common sensing platform for single-use biopharmaceutical manufacturing

The lack of reliable single-use sensors prevents the biopharmaceutical industry from fully embracing single-use biomanufacturing processes. Sensors based on the same detection platform for all critical parameters in single-use bioprocess components would be highly desirable to significantly simplify their installation, calibration and operation. We review here our approach for passive radio-frequency identification (RFID)-based sensing that does not rely on costly proprietary RFID memory chips with an analog input but rather implements ubiquitous passive 13.56 MHz RFID tags as inductively coupled sensors with at least 16 bit resolution provided by a sensor reader. The developed RFID sensors combine several measured parameters from the resonant sensor antenna with multivariate data analysis and deliver unique capability of multiparameter sensing and rejection of environmental interferences with a single sensor. This general sensing approach provides an elegant solution for both analytical measurement and identification and documentation of the measured location.

Passive multivariable temperature and conductivity RFID sensors for single‐use biopharmaceutical manufacturing components

Single‐use biopharmaceutical manufacturing requires monitoring of critical manufacturing parameters. We have developed an approach for passive radio‐frequency identification (RFID)‐based sensing that converts ubiquitous passive 13.56 MHz RFID tags into inductively coupled sensors. We combine several measured parameters from the resonant sensor antenna with multivariate data analysis and deliver unique capability of multiparameter sensing and rejection of environmental interferences with a single sensor. We demonstrate here the integration of these RFID sensors into single‐use biopharmaceutical manufacturing components. We have tested these sensors for over 500 h for measurements of temperature and solution conductivity with the accuracy of 0.1°C (32–48°C range) and accuracy of 0.3–2.9 mS/cm (0.5–230 mS/cm range). We further demonstrate simultaneous temperature and conductivity measurements with an individual RFID sensor with the accuracy of 0.2°C (5–60°C range) and accuracy of 0.9 mS/cm (0.5–183 mS/cm range). Developed RFID sensors provide several important features previously unavailable from other single‐use sensing technologies such as the same sensor platform for measurements of physical, chemical, and biological parameters; multi‐parameter monitoring with individual sensors; and simultaneous digital identification.

Integration of passive multivariable RFID sensors into single-use biopharmaceutical manufacturing components

Single-use biopharmaceutical manufacturing requires monitoring of critical manufacturing parameters. However, the lack of reliable single-use sensors prevents the biopharmaceutical industry from fully embracing single-use biomanufacturing processes. We report here an approach for passive radio-frequency identification (RFID)-based sensing that does not rely on costly proprietary RFID memory chips with an analog input but rather implement ubiquitous passive 13.56 MHz RFID tags as inductively coupled sensors with 16-bit resolution provided by a sensor reader. Developed RFID sensors combine several measured parameters from the resonant sensor antenna with multivariate data analysis and deliver unique capability of multiparameter sensing and rejection of environmental interferences with a single sensor. In this study we are integrating these RFID sensors into single-use biopharmaceutical manufacturing components such as buffer bags. Performance of these sensors for simultaneous solution conductivity and temperature sensing is discussed.

Passive gamma-resistant RFID tags integrated into gamma-sterilizable pharmaceutical components

The single-use bioprocessing is an attractive new approach of biopharmaceutical manufacturing. Digital identification of single-use bioprocess components is critical to facilitate their asset management, to document electronic pedigree, and to provide authentication. This identification can be achieved using radio frequency identification (RFID) tags. In this study, we critically analyze the challenges for the gamma-sterilizable RFID tag technology to retain the reliable read/write ability of the tags after their gamma irradiation. In RFID tags, the gamma radiation induced loss of device performance (i.e. the ability to reliably write and read data from an integrated circuit (IC) memory chip) originates from two independent sources such as (1) radiation effects on the non-charge-based storage memory material and (2) radiation effects on the performance of analog and digital circuit components of an IC memory chip device. Our interdisciplinary knowledge of product design, analytical instrumentation, RF engineering, and Six Sigma statistics has resulted in the design and implementation of the tag interrogation concept that insures the high reliability of tag read/write after the gamma irradiation.

Definition and dynamic control of a continuous chromatography process independent of cell culture titer and impurities

Advances in cell culture technology have enabled the production of antibody titers upwards of 30g/L. These highly productive cell culture systems can potentially lead to productivity bottlenecks in downstream purification due to lower column loadings, especially in the primary capture chromatography step. Alternative chromatography solutions to help remedy this bottleneck include the utilization of continuous processing systems such as periodic counter-current chromatography (PCC). Recent studies have provided methods to optimize and improve the design of PCC for cell culture titers up to about 3g/L. This paper defines a continuous loading strategy for PCC that is independent of cell culture background and encompasses cell culture titers up to about 31g/L. Initial experimentation showed a challenge with determining a difference in change in UV280nm signal (ie. ΔUV) between cell culture feed and monoclonal antibody (mAb) concentration. Further investigation revealed UV280nm absorbance of the cell culture feedstock without antibody was outside of the linear range of detection for a given cell pathlength. Additional experimentation showed the difference in ΔUV for various cell culture feeds can be either theoretically predicted by Beers Law given a known absorbance of the media background and impurities or experimentally determined using various UV280nm cell pathlengths. Based on these results, a 0.35mm pathlength at UV280nm was chosen for dynamic control to overcome the background signal. The pore diffusion model showed good agreement with the experimental frontal analysis data, which resulted in definition of a ΔUV setpoint range between 20 and 70% for 3C-PCC experiments. Product quality of the elution pools was acceptable between various cell culture feeds and titers up to about 41g/L. Results indicated the following ΔUV setpoints to achieve robust dynamic control and maintain 3C-PCC yield: ∼20-45% for titers greater than 10g/L depending on UV absorbance of the HCCF and ∼45-70% for titers of up to 10g/L independent of UV absorbance of the HCCF. The strategy and results presented in this paper show column loading in a continuous chromatography step can be dynamically controlled independent of the cell culture feedstock and titer, and allow for enhanced process control built into the downstream continuous operations.