Process analytical technology for on‐line monitoring of quality attributes during single‐use ultrafiltration/diafiltration

West, Jay M.; Feroz, Hasin; Xu, Xia; Puri, Neha; Holstein, Melissa; Ghose, Sanchayita; Ding, James; Li, Z J

doi:10.1002/bit.27741

Cited by 9 publications

(3 citation statements)

References 23 publications

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“…Furthermore, the apparent molecular weight is based on light-scattering measurements which does not allow the independent quantification of aggregates and monomeric species. West et al [ 13 ] used on-line Ultra High Performance Liquid Chromatography (UHPLC) to monitor the protein concentration, aggregate content, and the UV-active excipients. The benefit of an on-line UHPLC is the measurement accuracy, the downsides are long measurement times (5min to 15min), the preset dilution factors of the on-line samples and the limited measurability of excipients when using UV absorption for detection.…”

Section: Introductionmentioning

confidence: 99%

Monitoring of ultra- and diafiltration processes by Kalman-filtered Raman measurements

2023

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Monitoring the protein concentration and buffer composition during the Ultrafiltration/Diafiltration (UF/DF) step enables the further automation of biopharmaceutical production and supports Real-time Release Testing (RTRT). Previously, in-line Ultraviolet (UV) and Infrared (IR) measurements have been used to successfully monitor the protein concentration over a large range. The progress of the diafiltration step has been monitored with density measurements and Infrared Spectroscopy (IR). Raman spectroscopy is capable of measuring both the protein and excipient concentration while being more robust and suitable for production measurements in comparison to Infrared Spectroscopy (IR). Regardless of the spectroscopic sensor used, the low concentration of excipients poses a challenge for the sensors. By combining sensor measurements with a semi-mechanistic model through an Extended Kalman Filter (EKF), the sensitivity to determine the progress of the diafiltration can be improved. In this study, Raman measurements are combined with an EKF for three case studies. The advantages of Kalman-filtered Raman measurements for excipient monitoring are shown in comparison to density measurements. Furthermore, Raman measurements showed a higher measurement speed in comparison to Variable Pathlength (VP) UV measurement at the trade-off of a slightly worse prediction accuracy for the protein concentration. However, the Raman-based protein concentration measurements relied mostly on an increase in the background signal during the process and not on proteinaceous features, which could pose a challenge due to the potential influence of batch variability on the background signal. Overall, the combination of Raman spectroscopy and EKF is a promising tool for monitoring the UF/DF step and enables process automation by using adaptive process control.

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Section: Introductionmentioning

confidence: 99%

Monitoring of ultra- and diafiltration processes by Kalman-filtered Raman measurements

2023

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“…An advantage of monitoring the Protein A column, which is typically oversized in batch capture processes to minimize product loss, allows for the detection of product breakthroughs and permits better utilization of column capacity. At-line and on-line SEC analysis for determining mAb purity and formulation buffer excipient concentrations during a UF/DF unit operation has also been described [ 72 ], providing a further example of how PAT can be implemented into DSP operations.…”

Section: Process Analytical Technologiesmentioning

confidence: 99%

Recent Advances and Future Directions in Downstream Processing of Therapeutic Antibodies

Matte¹

2022

IJMS

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Despite the advent of many new therapies, therapeutic monoclonal antibodies remain a prominent biologics product, with a market value of billions of dollars annually. A variety of downstream processing technological advances have led to a paradigm shift in how therapeutic antibodies are developed and manufactured. A key driver of change has been the increased adoption of single-use technologies for process development and manufacturing. An early-stage developability assessment of potential lead antibodies, using both in silico and high-throughput experimental approaches, is critical to de-risk development and identify molecules amenable to manufacturing. Both statistical and mechanistic modelling approaches are being increasingly applied to downstream process development, allowing for deeper process understanding of chromatographic unit operations. Given the greater adoption of perfusion processes for antibody production, continuous and semi-continuous downstream processes are being increasingly explored as alternatives to batch processes. As part of the Quality by Design (QbD) paradigm, ever more sophisticated process analytical technologies play a key role in understanding antibody product quality in real-time. We should expect that computational prediction and modelling approaches will continue to be advanced and exploited, given the increasing sophistication and robustness of predictive methods compared to the costs, time, and resources required for experimental studies.

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“…In the development and manufacturing stage of (bio‐) pharmaceuticals, process analytical technology (PAT) is a valuable tool to obtain process knowledge or facilitate process control through monitoring to ultimately ensure a high product quality (US Department of Health and Human Services—Food and Drug Administration, 2004). Recently, PAT was implemented to monitor critical quality attributes during CFF processes of biopharmaceutical proteins (Rolinger et al, 2020; Wasalathanthri et al, 2020; West et al, 2021). In the case of VLP disassembly, PAT could reveal the effect of changing liquid phase conditions or impurity levels on diafiltration‐based disassembly and provide a solution for a data‐based endpoint detection.…”

Section: Introductionmentioning

confidence: 99%

Process monitoring framework for cross‐flow diafiltration‐based virus‐like particle disassembly: Tracing product properties and filtration performance

Hillebrandt

Vormittag

Dietrich

et al. 2022

Biotech & Bioengineering

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Virus-like particles (VLPs) are an emerging biopharmaceutical modality with great potential as a platform technology. VLPs can be applied as gene therapy vectors and prophylactic or therapeutic vaccines. For non-enveloped VLPs, recombinant production of the protein subunits leads to intracellular self-assembly. The subsequent purification process includes VLP dis-and reassembly which aim at removing encapsulated impurities and improving particle properties. Filtration-based separation and processing has proven successful for VLPs but requires large product quantities and laborious experiments in early development stages. Both challenges can be tackled by implementation of process analytical technology (PAT) to efficiently obtain extensive process information. In this study, an existing PAT setup was extended to comprehensively monitor the diafiltration-based disassembly of hepatitis B core antigen (HBcAg) VLPs. Process-related signals were monitored in-line, while product-related signals, such as ultraviolet light (UV) spectra as well as static and dynamic light scattering (SLS and DLS), were monitored on-line. The applicability of the sensors for disassembly monitoring was evaluated under varying processing conditions. HBcAg VLP subunit concentrations were accurately predicted based on UV data using ordinary and partial least squares regression models (Q 2 from 0.909 to 0.976). DLS data were used for aggregation monitoring while the SLS intensity qualitatively reflected the disassembly progress.

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Process analytical technology for on‐line monitoring of quality attributes during single‐use ultrafiltration/diafiltration

Cited by 9 publications

References 23 publications

Monitoring of ultra- and diafiltration processes by Kalman-filtered Raman measurements

Monitoring of ultra- and diafiltration processes by Kalman-filtered Raman measurements

Recent Advances and Future Directions in Downstream Processing of Therapeutic Antibodies

Process monitoring framework for cross‐flow diafiltration‐based virus‐like particle disassembly: Tracing product properties and filtration performance

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