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Cited by 45Protein purification and stabilityBiosimilars and Bioanalytical MethodsSpectroscopy and Chemometric Analyses

Current PAT Landscape in the Downstream Processing of Biopharmaceuticals

Open access
Sathiyapriyan, Pavithra, Mukherjee, Shatanik, Vogel, Thomas, Essen, Lars‐Oliver, Boerema, David, Vey, Martin, Kalina, Uwe·2025·Analytical Science Advances
DOI 10.1002/ansa.70013PMC PMC12120361
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Abstract

Protein‐based therapeutics have revolutionized modern medicine, addressing complex diseases with unprecedented specificity and efficacy. The rising demand for biologics has driven the evolution of biomanufacturing practices to ensure consistent quality and operational efficiency. Traditional batch testing, with its inherent limitations, is being replaced by quality by design (QbD) frameworks and process analytical technology (PAT). PAT facilitates real‐time monitoring and control by integrating advanced analytical tools and data‐driven methodologies to optimize downstream processing (DSP). This review highlights the recent advancements in PAT tools, including spectroscopy, chromatography and biosensors. Spectroscopic techniques provide rapid, non‐invasive measurements, while biosensors offer high specificity for monitoring critical quality attributes. Additionally, the integration of chemometric modelling and digital twins enables predictive analytics and enhances process control, paving the way for real‐time release (RTR) of the product. Despite challenges in regulatory compliance and technology integration, innovations in automation and machine learning are bridging these gaps, accelerating the transition to intelligent manufacturing systems. This article provides a comprehensive evaluation of emerging analytical technologies and strategic insights into their integration, aiming to support the biopharmaceutical industry's shift towards robust, continuous and adaptive manufacturing paradigms.

AI snapshot

Written from the paper’s full text.

TL;DR

This review surveys current process analytical technology (PAT) tools for downstream processing (DSP) of biopharmaceuticals, covering spectroscopy, chromatography/hyphenated mass spectrometry, biosensors, chemometrics, and digital twins. It argues that integrated PAT plus predictive modeling can enable real-time monitoring and control and move toward real-time release, though regulatory and integration hurdles remain.

Key findings

  • DSP is cost-critical: downstream processing accounts for 80% of production expenses, largely driven by Protein A resin and virus filtration, and DSP process decisions must be made within seconds, whereas response times up to 1 h may still suffice for upstream processing.
  • Spectroscopic PAT enables rapid, non-invasive monitoring: NIR has been used on-line every 3 s for PEGylation and Protein A column breakthrough, Raman has achieved accurate quality measurements every 38 s for aggregation/fragmentation, and ATR-FTIR has monitored UFDF protein/excipient concentrations in seconds.
  • Chromatography and hyphenated MS offer high specificity but remain slower: on-line UPLC took 30 min per sample, a specialized real-time HPLC setup reduced sampling to 1.30–2.35 min, and µSMB-MS processed samples in 2–8 min, still slower than seconds-scale spectroscopy.
  • Biosensors can fill specificity/speed gaps: LSPR detected column breakthrough at product concentrations as low as 2 µg/mL and aggregates as low as 1%, while a fluorescence-based biosensor detected 5% column breakthrough; chemometric soft sensors and digital twins are presented as enablers of predictive process control and real-time release.

Methods

  • Narrative review of recent advancements in PAT for biopharmaceutical DSP; no systematic review protocol, search strategy, or primary data collection is stated.
  • Synthesizes literature and includes Table 1 summarizing recent literature from the past 5 years on analytical technologies for real-time protein DSP, listing technique, PAT mode, DSP step, CQAs monitored, and references.
  • Main analysis is qualitative synthesis of analytical techniques and data workflow, not quantitative meta-analysis.

Limitations

  • The paper states hesitancy to implement PAT at commercial scale due to perceived increased regulatory submission burden; predictive models need validation, documentation of comparability/reliability, justification of model parameters, and demonstration of comparability between routine analytical data and PAT-generated data.
  • Technique-specific limitations stated include: spectroscopy lacks high specificity and requires heavy data processing; chromatography/MS measurement times remain too long for true real-time DSP and in-line implementation is largely impractical; biosensors depend on highly specific ligands and have limited studies demonstrating real-time monitoring.
  • Evident from the text: as a narrative review, it does not systematically assess evidence quality or report inclusion/exclusion criteria, and Table 1 is limited to selected examples from the past 5 years, so coverage may not be exhaustive.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/ansa.70013

Cites

113 of 113 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

6 of 90 cited sources checked · 6 supported · 0 flagged

  • Premisecitation

    Protein aggregates have been shown to exhibit immunogenicity, leading to adverse effects.

    “The formation of aggregates during the purification process is an important attribute to monitor, as protein aggregates have shown to exhibit immunogenicity, leading to adverse effects [37].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] M. L. E. Lundahl, S. Fogli, P. E. Colavita, and E. M. Scanlan, “ Aggregation of Protein Therapeutics Enhances Their Immunogenicity: Causes and Mitigation Strategies,” RSC Chemistry Biology 2 (2021): 1004– 1020, 10.1039/d1cb00067e. PMC8341748 34458822 source
  • Premisecitation

    LSPR biosensors have been utilized for in-line monitoring of the Protein A capture step, enabling high-sensitivity detection of column breakthrough by measuring product concentrations as low as 2 μg/mL in the effluent.

    “LSPR biosensors have been utilized for in‐line monitoring of the Protein A capture step, enabling the high‐sensitivity detection of column breakthrough by measuring product concentrations as low as 2 µg/mL in the effluent, allowing for early identification of column leakage [96].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [96] T. Tran, E. Martinsson, R. Gustavsson, et al., “ Process Integrated Biosensors for Real‐Time Monitoring of Antibodies for Automated Affinity Purification,” Analytical Methods 14 (2022): 4555– 4562, 10.1039/d2ay01567f. 36314900 source
  • Premisecitation

    Helgers et al. demonstrated the integration of various spectroscopic techniques, including Raman, FTIR, fluorescence spectroscopy and UV-Vis, with a predictive modelling data workflow and DT to achieve advanced process control.

    “Helgers et al. demonstrated the integration of various spectroscopic techniques, including Raman, FTIR, fluorescence spectroscopy and UV‐Vis, with a predictive modelling data workflow and DT to achieve advanced process control (APC) [115].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [115] H. Helgers, A. Schmidt, L. J. Lohmann, et al., “ Towards Autonomous Operation by Advanced Process Control—Process Analytical Technology for Continuous Biologics Antibody Manufacturing,” Processes 9 (2021): 172, 10.3390/pr9010172. source
  • Findingnone given

    Almost all recent studies employing PAT tools for downstream process monitoring (Table 1) have extensively used chemometrics, employing one or more models to predict quality outcomes, thereby enabling real-time process control.

    “Almost all of the recent studies employing PAT tools for downstream process monitoring (Table 1) have extensively used chemometrics, employing one or more of the above‐mentioned models to predict the quality outcomes, thereby enabling real‐time process control.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Advanced Raman spectroscopic techniques depend on expensive instrumentation, often hindering their routine implementation.

    “Advanced Raman spectroscopic techniques depend on expensive instrumentation, often hindering their routine implementation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Y. K. Lin, H. Y. Leong, T. C. Ling, D.‐Q. Lin, and S.‐J. Yao, “ Raman Spectroscopy as Process Analytical Tool in Downstream Processing of Biotechnology,” Chinese Journal of Chemical Engineering 30 (2021): 204– 211, 10.1016/j.cjche.2020.12.008. source
  • May combine two claims. 52
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Premisecitation

    The IoR sensor accurately measured protein concentrations during ultrafiltration and during the capture step.

    “The sensor was able to accurately measure the protein concentrations during ultrafiltration and during the capture step [109].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [109] S. A. Harris, B. A. Patel, A. Gospodarek, et al., “ Determination of Protein Concentration in Downstream Biomanufacturing Processes by In‐Line Index of Refraction,” Biotechnology Progress 37 (2021): e3187, 10.1002/btpr.3187. 34164947 source

  • May combine two claims.

    Premisecitation

    MALS in an in-line setup during mAb purification monitored protein aggregation, leading to real-time results and immediate feedback control.

    “Its application in real‐time protein analytics was explored by using it in an in‐line setup during the mAb purification to monitor the protein aggregation, which led to real‐time results and immediate feedback control [106].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [106] B. A. Patel, A. Gospodarek, M. Larkin, et al., “ Multi‐Angle Light Scattering as a Process Analytical Technology Measuring Real‐Time Molecular Weight for Downstream Process Control,” Monoclonal Antibodies 10 (2018): 945– 950, 10.1080/19420862.2018.1505178. 30130442 PMC6204791 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    LSPR biosensing detects biomolecular interactions by monitoring shifts in the LSPR band.

    “LSPR biosensing detects biomolecular interactions by monitoring shifts in this band.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [95] H. Zhang, X. Zhou, X. Li, P. Gong, Y. Zhang, and Y. Zhao, “ Recent Advancements of LSPR Fiber‐Optic Biosensing: Combination Methods, Structure, and Prospects,” Biosensors 13 (2023): 405, 10.3390/bios13030405. 36979617 PMC10046874 source
    • cites [96] T. Tran, E. Martinsson, R. Gustavsson, et al., “ Process Integrated Biosensors for Real‐Time Monitoring of Antibodies for Automated Affinity Purification,” Analytical Methods 14 (2022): 4555– 4562, 10.1039/d2ay01567f. 36314900 source

  • May combine two claims.

    Premisecitation

    NIR spectroscopy is particularly sensitive to bonds involving hydrogen, such as C-H, N-H, and O-H bonds, making it well-suited for probing water content and organic molecules in complex matrices.

    “NIR is particularly sensitive to bonds involving hydrogen, such as C─H, N─H and O─H bonds, making it well‐suited for probing water content and organic molecules in complex matrices [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] M. B Simpson, “Near‐Infrared Spectroscopy for Process Analytical Technology: Theory Technology and Implementation,” in Process Analytical Technology (Wiley, 2010) 107– 155, 10.1002/9780470689592.ch5.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Raman spectroscopy implemented in-line measured product aggregation and fragmentation in real time, with a calibration model achieving accurate quality measurements every 38 s.

    “Wang et al. implemented Raman spectroscopy in‐line for measuring product aggregation and fragmentation in real time, developed a calibration model, achieving accurate quality measurements every 38 s.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] J. Wang, J. Chen, J. Studts, and G. Wang, “ In‐Line Product Quality Monitoring During Biopharmaceutical Manufacturing Using Computational Raman Spectroscopy,” Monoclonal Antibodies 15 (2023): 2220149, 10.1080/19420862.2023.2220149. 37288839 PMC10251777 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    PAT facilitates real-time monitoring and control by integrating advanced analytical tools and data-driven methodologies to optimize downstream processing.

    “PAT facilitates real‐time monitoring and control by integrating advanced analytical tools and data‐driven methodologies to optimize downstream processing (DSP).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Protein therapeutics have inherent advantages over small molecule drugs because they are highly specific and have complex functions in the body, causing less interference with normal biological processes and fewer adverse effects.

    “Protein therapeutics, often referred to as biopharmaceuticals or biologics, have inherent advantages over small molecule drugs as they are highly specific and have complex functions in the body. As a result, they tend to cause less interference with normal biological processes and fewer adverse effects [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] B. Leader, Q. J. Baca, and D. E. Golan, “ Protein Therapeutics: A Summary and Pharmacological Classification,” Nature Reviews Drug Discovery 7 (2008): 21– 39, 10.1038/nrd2399. 18097458 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    N-linked glycosylation is the most common post-translational modification and impacts the biological activity, pharmacokinetics, and immunogenicity of therapeutic proteins.

    “N‐linked glycosylation is the most common PTM and it impacts the biological activity, pharmacokinetics and immunogenicity of the therapeutic protein [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] A. Eon‐Duval, H. Broly, and R. Gleixner, “ Quality Attributes of Recombinant Therapeutic Proteins: An Assessment of Impact on Safety and Efficacy as Part of a Quality by Design Development Approach,” Biotechnology Progress 28 (2012): 608– 622, 10.1002/btpr.1548. 22473974 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    UV-Vis is particularly useful for analysing conjugated systems, including proteins and nucleic acids, and monitoring concentration changes in real time.

    “Since UV‐Vis primarily detects chromophores, molecular regions where electron excitation is more likely, it is particularly useful for analysing conjugated systems, including proteins and nucleic acids, and monitoring concentration changes in real time [77].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] M. S. H. Akash and K. Rehman, “ Ultraviolet‐Visible (UV‐VIS) Spectroscopy,” in Essentials of Pharmaceutical Analysis (Springer, 2019) 29– 56, 10.1007/978-981-15-1547-7_3.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Most biopharmaceuticals are produced via biosynthesis using genetically modified organisms, unlike small molecules, which are produced through chemical synthesis.

    “Unlike small molecules, which are produced through chemical synthesis, most biopharmaceuticals are produced via biosynthesis, using genetically modified organisms [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Y. B. Yu, M. B. Taraban, W. Wang, and K. T. Briggs, “ Improving Biopharmaceutical Safety Through Verification‐Based Quality Control,” Trends in Biotechnology 35 (2017): 1140– 1155, 10.1016/j.tibtech.2017.08.010. 28943031 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Raman spectroscopy is one of the most widely used techniques in PAT, and with the advent of machine learning and model development, accurate detection and predictions can be done.

    “It is one of the most widely used techniques in PAT, and with the advent of machine learning and model development, accurate detection and predictions can be done.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FT-NIR has been used for on-line monitoring of column loading in Protein A chromatography, measuring target product concentration in harvested broth and column effluent every 3 s and detecting column breakthrough with high accuracy.

    “Thakur et al. monitored the column loading using an on‐line FT‐NIR setup, where the target product concentration in both the harvested broth and column effluent from Protein A chromatography was measured in real time, for every 3 s and column breakthrough was detected successfully with high accuracy [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] G. Thakur, V. Hebbi, and A. S. Rathore, “ An NIR‐Based PAT Approach for Real‐Time Control of Loading in Protein A Chromatography in Continuous Manufacturing of Monoclonal Antibodies,” Biotechnology and Bioengineering 117 (2020): 673– 686, 10.1002/bit.27236. 31788777 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A dual wavelength LED photometric sensor configured at two wavelengths used UV absorbance to determine protein concentration during the tangential flow filtration process.

    “Another study employed a dual wavelength LED photometric sensor configured at two different wavelengths, where UV absorbance was used in determining the protein concentration during the tangential flow filtration process (TFF) [79].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] F. Westwood, M. Ponstingl, and J. E. Dickens, “ Analytical Figures of Merit of a Dual‐Wavelength Absorbance Approach for Real‐Time Broad Protein Content Monitoring for Biomanufacturing,” Journal of Pharmaceutical and Biomedical Analysis 241 (2024): 115965, 10.1016/j.jpba.2024.115965. 38237541 source

  • May combine two claims.

    Premisecitation

    In ATR-FTIR monitoring during UFDF, rapid measurements in seconds and accurate concentration predictions were achieved.

    “In both cases, rapid measurements in seconds and accurate concentration predictions were achieved.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] A. Milewska, G. Baekelandt, S. Boutaieb, V. Mozin, and A. Falconbridge, “ In‐Line Monitoring of Protein Concentration With MIR Spectroscopy During UFDF,” Engineering in Life Sciences 23 (2023): e2200050, 10.1002/elsc.202200050. 36751473 PMC9893749 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [56] D. P. Wasalathanthri, H. Feroz, N. Puri, et al., “ Real‐Time Monitoring of Quality Attributes by In‐Line Fourier Transform Infrared Spectroscopic Sensors at Ultrafiltration and Diafiltration of Bioprocess,” Biotechnology and Bioengineering 117 (2020): 3766– 3774, 10.1002/bit.27532. 32776504 source

  • May combine two claims.

    Premisecitation

    Implementing VPE systems has challenges: they are computer-controlled, can consume a significant footprint, involve various interchangeable components, and require routine cleaning and clearance verifications.

    “However, there are some challenges in implementing VPE systems as they are computer‐controlled, can consume a significant footprint, involve various interchangeable components and require routine cleaning and clearance verifications [79].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] F. Westwood, M. Ponstingl, and J. E. Dickens, “ Analytical Figures of Merit of a Dual‐Wavelength Absorbance Approach for Real‐Time Broad Protein Content Monitoring for Biomanufacturing,” Journal of Pharmaceutical and Biomedical Analysis 241 (2024): 115965, 10.1016/j.jpba.2024.115965. 38237541 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MAM is a targeted and optimized analytical solution that uses high-resolution MS data and suitable software enabling automated identification and relative quantification of important PTMs.

    “It is a targeted and optimized analytical solution that uses a combination of high‐resolution MS data and suitable software enabling automated identification and relative quantification of important PTMs [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] R. S. Rogers, N. S. Nightlinger, B. Livingston, P. Campbell, R. Bailey, and A. Balland, “ Development of a Quantitative Mass Spectrometry Multi‐Attribute Method for Characterization, Quality Control Testing and Disposition of Biologics,” Monoclonal Antibodies 7 (2015): 881– 890, 10.1080/19420862.2015.1069454. 26186204 PMC4623056 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Multiple studies have been published in recent years where Raman was employed for real-time monitoring of various downstream processing steps.

    “Multiple studies have been published in recent years where Raman was employed for real‐time monitoring of various downstream processing steps.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Spectroscopic techniques provide rapid, non-invasive measurements, while biosensors offer high specificity for monitoring critical quality attributes.

    “Spectroscopic techniques provide rapid, non‐invasive measurements, while biosensors offer high specificity for monitoring critical quality attributes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    UV-Vis absorption spectrum provides quantitative information about the concentration and chemical structure of the analyte.

    “The resulting absorbance spectrum therefore provides quantitative information about the concentration and chemical structure of the analyte [77].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] M. S. H. Akash and K. Rehman, “ Ultraviolet‐Visible (UV‐VIS) Spectroscopy,” in Essentials of Pharmaceutical Analysis (Springer, 2019) 29– 56, 10.1007/978-981-15-1547-7_3.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Spectroscopy has been the most common technique employed for real-time analysis because it is non-destructive and can be easily integrated in-line or on-line to the process stream.

    “Spectroscopy had been the most common technique employed for real‐time analysis due to its non‐destructive nature and ease of in‐line or on‐line integration to the process stream.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FT-NIR has been integrated in-line for simultaneous monitoring of protein and excipient concentrations in antibody formulations during UFDF, with quantification done in real time in a few seconds.

    “It has been integrated in‐line for the simultaneous monitoring of protein and excipient concentrations in antibody formulations during the UFDF, and the quantification was done in real time, in a few seconds [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] G. Thakur, V. Hebbi, and A. S. Rathore, “ Near Infrared Spectroscopy as a PAT Tool for Monitoring and Control of Protein and Excipient Concentration in Ultrafiltration of Highly Concentrated Antibody Formulations,” International Journal of Pharmaceutics 600 (2021): 120456, 10.1016/j.ijpharm.2021.120456. 33711473 source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Innovations in automation and machine learning are bridging gaps in regulatory compliance and technology integration, accelerating the transition to intelligent manufacturing systems.

    “Despite challenges in regulatory compliance and technology integration, innovations in automation and machine learning are bridging these gaps, accelerating the transition to intelligent manufacturing systems.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Enhanced Raman variants (resonance Raman, SERS, SERRS, TERS) provide increased Raman signal, reduced limit of detection and reduced sample volume.

    “Enhanced variants of Raman include resonance Raman, surface‐enhanced Raman (SERS), surface‐enhanced resonance Raman (SERRS) and tip‐enhanced Raman (TERS), all of which are used for their inherent advantages including increased Raman signal, reduced limit of detection and the usage of reduced sample volume [74].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] K. A. Esmonde‐White, M. Cuellar, and I. R. Lewis, “ The Role of Raman Spectroscopy in Biopharmaceuticals From Development to Manufacturing,” Analytical Bioanalytical Chemistry 414 (2022): 969– 991, 10.1007/s00216-021-03727-4. 34668998 PMC8724084 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Downstream processing accounts for 80% of production expenses, largely driven by the high cost of Protein A resin and virus filtration.

    “Purification often exceeds the cost of upstream manufacturing, with downstream processing accounting for 80% of production expenses, largely driven by the high cost of Protein A resin and virus filtration [14, 23].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] F. Demir, R. Albarri, and D. Ö. Ünal, “ An Overview of Biotechnological Drug's Various Techniques of Downstream Process, Guideline's and Different Chromatographic Analysis,” Current Pharmeutical Analysis 20 (2024), 729– 742, 10.2174/0115734129317408240903150800. source
    • cites [23] K. Pandey, M. Pandey, V. Kumar, U. Aggarwal, and B. Singhal, “ Bioprocessing 4.0 in Biomanufacturing: Paving the Way for Sustainable Bioeconomy,” System Microbiological Biomanufacturing 4 (2024): 407– 424, 10.1007/s43393-023-00206-y. source

  • May combine two claims.

    Premisecitation

    ATR-FTIR has been implemented in-line during the UFDF step to monitor protein concentration with a simple one-point calibration algorithm or both protein and various excipient concentrations with a multivariate data analysis model.

    “Recently, ATR‐FTIR has also been implemented in‐line during the UFDF step, to monitor the protein concentration with a simple one‐point calibration algorithm [55] or both protein and various excipient concentrations, with a multi‐variate data analysis (MVDA) model [56].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] A. Milewska, G. Baekelandt, S. Boutaieb, V. Mozin, and A. Falconbridge, “ In‐Line Monitoring of Protein Concentration With MIR Spectroscopy During UFDF,” Engineering in Life Sciences 23 (2023): e2200050, 10.1002/elsc.202200050. 36751473 PMC9893749 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [56] D. P. Wasalathanthri, H. Feroz, N. Puri, et al., “ Real‐Time Monitoring of Quality Attributes by In‐Line Fourier Transform Infrared Spectroscopic Sensors at Ultrafiltration and Diafiltration of Bioprocess,” Biotechnology and Bioengineering 117 (2020): 3766– 3774, 10.1002/bit.27532. 32776504 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Raman spectroscopy requires minimal sample preparation and is non-invasive and non-destructive to samples.

    “Raman requires minimal sample preparation and is non‐invasive and non‐destructive to samples.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    ATR-FTIR can monitor multiple parameters in real time and is effective when combined with algorithms for real-time prediction and control.

    “ATR‐FTIR can monitor multiple parameters in real time, and it is an effective tool when combined with algorithms to make real‐time prediction and control.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Recent advancements have addressed many Raman limitations, with multiple variants offering unique advantages over traditional methods.

    “Many of these limitations have been addressed through recent advancements, with the development of multiple variants of Raman spectroscopy techniques offering unique advantages over traditional methods.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Biopharmaceuticals are more complex than small molecule drugs, with therapeutic proteins being 50-1000 times larger.

    “The drawbacks of the quality by testing (QbT) approach are even more pronounced for biopharmaceuticals, as they are more complex and involve therapeutic proteins being 50–1000 times larger than small molecule drugs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Y. B. Yu, M. B. Taraban, W. Wang, and K. T. Briggs, “ Improving Biopharmaceutical Safety Through Verification‐Based Quality Control,” Trends in Biotechnology 35 (2017): 1140– 1155, 10.1016/j.tibtech.2017.08.010. 28943031 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The need for sample pretreatment can be a hurdle in implementing analytical techniques in an in-line or on-line fashion.

    “However, the need of sample pretreatment can be a hurdle in the implementation of analytical techniques in an in‐line or on‐line fashion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    MIR spectroscopy can provide direct information on bond-specific vibrations, making it powerful for identifying and quantifying specific molecular components and structural details in biomolecules.

    “As MIR is based on fundamental vibrations, it can provide direct information on bond‐specific vibrations, making it a powerful technique for identifying and quantifying specific molecular components and structural details in biomolecules.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] J. P Coates, Infrared Spectroscopy for Process Analytical Applications in Process Analytical Technology (Wiley, 2010): 157– 194, 10.1002/9780470689592.ch6.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    PAT is essential to implement QbD and ensure real-time release of the product.

    “This system is essential to implement QbD and ensure real‐time release (RTR) of the product [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] I. Clegg, “ Process Analytical Technology,” in Specification of Drug Substances and Products (Elsevier, 2020): 149– 173, 10.1016/b978-0-08-102824-7.00007-5.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Different structures of the same protein are often present in biopharmaceutical preparations, making them heterogeneous mixtures including post-translational modifications such as glycosylation, oxidation, deamidation, aggregates, and fragments that impact drug stability and efficacy.

    “Different structures of the same protein are often present in biopharmaceutical preparations, making them a heterogeneous mixture, including post‐translational modifications such as glycosylation, oxidation, deamidation, formation of aggregates and fragments impacting the stability and efficacy of the drug [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] M. M. Papathanasiou and C. Kontoravdi, “ Engineering Challenges in Therapeutic Protein Product and Process Design,” Current Opinion in Chemical Engineering 27 (2020): 81– 88, 10.1016/j.coche.2019.11.010. source

      Checked before — its earlier verdict is held back until a new check runs.

  • May combine two claims.

    Premisecitation

    Mass spectrometry has not been considered for PAT as it is not feasible to implement in-line or on-line due to its need for sample preparation and associated complexity.

    “However, it has not been considered for PAT as it is not feasible to implement in‐line or on‐line, due to its need for sample preparation and associated complexity [88].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] J. Diehm, L. Witting, F. Kirschhöfer, G. Brenner‐Weiß, and M. Franzreb, “ Micro Simulated Moving Bed Chromatography‐Mass Spectrometry as a Continuous On‐Line Process Analytical Tool,” Analytical Bioanalytical Chemistry 416 (2024): 373– 386, 10.1007/s00216-023-05023-9. 37946036 PMC10761468

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Common CQAs to monitor in downstream processing include process-related impurities such as host cell proteins and nucleic acids, and product-related impurities such as higher and lower molecular weight species and charge variants.

    “The common CQAs to be monitored include process‐related impurities such as host cell proteins (HCP) and nucleic acids, as well as product‐related impurities such as higher and lower molecular weight species (HMW, LMW) and charge variants [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] MJ. Traylor, P. Bernhardt, BS. Tangarone, and J. Varghese, “ Chapter 47—Analytical Methods,” Biopharmaceutical Processing (Elsevier, 2018): 1001– 1049, 10.1016/b978-0-08-100623-8.00047-5.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    On-line UPLC took 30 min of measurement time per sample, highlighting the need for speeding up separation time to use chromatography as a realistic PAT tool.

    “Though this significantly reduced the analytical turnaround time, it still took 30 min of measurement time per sample [84], highlighting the need for speeding up the separation time to be able to use chromatography as a realistic PAT tool.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] A. Godbole, L. Chen, J. Desai, et al., “ Implementation of Innovative Process Analytical Technologies to Characterize Critical Quality Attributes of Co‐Formulated Monoclonal Antibody Products,” Biotechnology and Bioengineering 122(2) (2024): 322– 332., 10.1002/bit.28881. 39511785 source

      Checked before — its earlier verdict is held back until a new check runs.

  • May combine two claims.

    Premisecitation

    μSMB processed the sample in 2-8 min, leading to continuous MS measurements of CQAs.

    “Unlike traditional chromatography methods, where there is more time needed for separation, µSMB was able to process the sample in a significantly lower amount of time (2–8 min), leading to continuous MS‐measurements of CQAs [88].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] J. Diehm, L. Witting, F. Kirschhöfer, G. Brenner‐Weiß, and M. Franzreb, “ Micro Simulated Moving Bed Chromatography‐Mass Spectrometry as a Continuous On‐Line Process Analytical Tool,” Analytical Bioanalytical Chemistry 416 (2024): 373– 386, 10.1007/s00216-023-05023-9. 37946036 PMC10761468

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FT-NIR has been utilized for monitoring continuous processing, specifically measuring concentrations in feed and retentate streams during UFDF with single-pass tangential flow filtration, with accurate concentration predictions via calibration models.

    “FT‐NIR has also been utilized for monitoring continuous processing, specifically for measuring the concentrations in feed and retentate streams during the UFDF step with single‐pass tangential flow filtration (SPTFF). By applying appropriate calibration models, accurate concentration predictions can be achieved, facilitating effective process control [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] G. Thakur, S. Thori, and A. S. Rathore, “ Implementing PAT for Single‐Pass Tangential Flow Ultrafiltration for Continuous Manufacturing of Monoclonal Antibodies,” Journal of Membrane Science 613 (2020): 118492, 10.1016/j.memsci.2020.118492.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    MIR and NIR are the two most commonly used infrared spectroscopy techniques in process analytical technology.

    “MIR and NIR are the two most commonly used Infrared spectroscopy techniques in process analytical technology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Raman signals are often weaker than those in other spectroscopic methods, leading to challenges in detecting low-concentration analytes.

    “Raman signals are often weaker than those in other spectroscopic methods, leading to challenges in detecting low‐concentration analytes [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Y. K. Lin, H. Y. Leong, T. C. Ling, D.‐Q. Lin, and S.‐J. Yao, “ Raman Spectroscopy as Process Analytical Tool in Downstream Processing of Biotechnology,” Chinese Journal of Chemical Engineering 30 (2021): 204– 211, 10.1016/j.cjche.2020.12.008. source

  • May combine two claims.

    Premisecitation

    NIR absorbance is several times lower than MIR absorbance, enabling deeper penetration and requiring minimal sample preparation.

    “The absorbance of molecules in the NIR region is several times lower than MIR, enabling deeper penetration and requiring minimal sample preparation [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] E. N. Lewis, J. W. Schoppelrei, L. Makein, L. H. Kidder, and E. Lee, “ Near‐Infrared Chemical Imaging for Product and Process Understanding,” in Process Analytical Technology (Wiley, 2010): 245– 279, 10.1002/9780470689592.ch8.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Purification of the target product in downstream processing takes only a few hours, unlike upstream processing, where several days are needed for cell culture and therapeutic protein production.

    “Unlike upstream processing, where several days are needed for cell culture and therapeutic protein production, the purification of the target product in downstream processing takes only a few hours [31].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] J. Gomis‐Fons, H. Schwarz, L. Zhang, et al., “ Model‐Based Design and Control of a Small‐Scale Integrated Continuous End‐to‐End mAb Platform,” Biotechnology Progress 36 (2020): e2995, 10.1002/btpr.2995. 32233078

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Integration of chemometric modelling and digital twins enables predictive analytics and enhances process control, paving the way for real-time release of the product.

    “Additionally, the integration of chemometric modelling and digital twins enables predictive analytics and enhances process control, paving the way for real‐time release (RTR) of the product.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Techniques such as spectroscopy, chromatography, and biosensors have emerged as promising PAT solutions.

    “Techniques such as spectroscopy, chromatography and biosensors have emerged as promising PAT solutions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Batch testing assumes that all units in a batch are uniform without variability and makes the product release decision based on analysis of one representative unit per batch, increasing the risk of poor-quality drugs.

    “(ii) this approach assumes that all the units in a batch are uniform without any variability, and the decision for product release is made based on the analysis of one representative unit for every batch [10]. This increases the risk of the distribution of poor‐quality drugs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Y. B. Yu, M. B. Taraban, W. Wang, and K. T. Briggs, “ Improving Biopharmaceutical Safety Through Verification‐Based Quality Control,” Trends in Biotechnology 35 (2017): 1140– 1155, 10.1016/j.tibtech.2017.08.010. 28943031 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An end-to-end automated online MAM system was developed for quality attributes monitoring during upstream manufacturing.

    “Its utility for real‐time analysis in a PAT setting was recently explored where an end‐to‐end automated online MAM system was developed for quality attributes monitoring during upstream manufacturing [91].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Y. Liu, C. Zhang, J. Chen, et al., “ A Fully Integrated Online Platform for Real Time Monitoring of Multiple Product Quality Attributes in Biopharmaceutical Processes for Monoclonal Antibody Therapeutics,” Journal of Pharmaceutical Sciences 111 (2022): 358– 367, 10.1016/j.xphs.2021.09.011. 34534574

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    While response times of up to 1 h are still sufficient for upstream processing, process decisions must be made within seconds for downstream processing.

    “While response times of up to 1 h are still sufficient for USP, process decisions must be made within seconds for DSP [32], demanding technologies offering faster measurements.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] A. Dürauer, A. Jungbauer, and T. Scharl, “ Sensors and Chemometrics in Downstream Processing,” Biotechnology and Bioengineering 121 (2024): 2347– 2364, 10.1002/bit.28499. 37470278

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Batch testing determines quality only after manufacture, leaving limited scope for corrective actions and potentially leading to rejected or failed batches.

    “This has two main disadvantages: (i) the quality is only known after the manufacture of the drug, leaving very limited scope for corrective actions, potentially leading to rejected or failed batches”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Y. B. Yu, M. B. Taraban, W. Wang, and K. T. Briggs, “ Improving Biopharmaceutical Safety Through Verification‐Based Quality Control,” Trends in Biotechnology 35 (2017): 1140– 1155, 10.1016/j.tibtech.2017.08.010. 28943031 source

  • May combine two claims.

    Premisecitation

    Comprehensive monitoring of all critical quality attributes cannot be achieved with a single analytical technology; an integrated approach combining multiple techniques, sensors, and control systems is essential for effective process monitoring and control.

    “The comprehensive monitoring of all critical quality attributes (CQAs) cannot be achieved with a single analytical technology; instead, an integrated approach combining multiple techniques, sensors and control systems is essential for effective process monitoring and control [20, 26].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] A. Matte, “ Recent Advances and Future Directions in Downstream Processing of Therapeutic Antibodies,” International Journal of Molecular Sciences 23 (2022): 8663, 10.3390/ijms23158663. 35955796 PMC9369434

      Not checked in the free run.

    • cites [26] A. C. Fisher, M.‐H. Kamga, C. Agarabi, K. Brorson, S. L. Lee, and S. Yoon, “ The Current Scientific and Regulatory Landscape in Advancing Integrated Continuous Biopharmaceutical Manufacturing,” Trends in Biotechnology 37 (2019): 253– 267, 10.1016/j.tibtech.2018.08.008. 30241924 source

  • May combine two claims.

    Premisecitation

    Raman spectroscopy has been employed for in-line CQA monitoring of IgG1 monoclonal antibody during Protein A chromatography, with a predictive model showing high predictive accuracy for target protein concentration and aggregates.

    “Chen et al. employed Raman spectroscopy for in‐line CQA monitoring of IgG1 monoclonal antibody (mAb) during the Protein A chromatography process, where they developed a predictive model showing high predictive accuracy for various CQAs including target protein concentration and aggregates [38].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] J. Chen, J. Wang, R. Hess, G. Wang, J. Studts, and M. Franzreb, “ Application of Raman Spectroscopy During Pharmaceutical Process Development for Determination of Critical Quality Attributes in Protein A Chromatography,” Journal of Chromatography A 1718 (2024): 464721, 10.1016/j.chroma.2024.464721. 38341902

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fully integrated continuous manufacturing provides advantages by reducing costs, improving quality, and speeding up product release.

    “A fully integrated continuous manufacturing provides advantages by reducing the costs, improving the quality while speeding up the product release [24, 26]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] K. B. Konstantinov and C. L Cooney, “ White Paper on Continuous Bioprocessing May 20–21 2014 Continuous Manufacturing Symposium,” Journal of Pharmaceutical Sciences 104 (2015): 813– 820, 10.1002/jps.24268. 28756843

      Not checked in the free run.

    • cites [26] A. C. Fisher, M.‐H. Kamga, C. Agarabi, K. Brorson, S. L. Lee, and S. Yoon, “ The Current Scientific and Regulatory Landscape in Advancing Integrated Continuous Biopharmaceutical Manufacturing,” Trends in Biotechnology 37 (2019): 253– 267, 10.1016/j.tibtech.2018.08.008. 30241924 source

  • May combine two claims.

    Premisecitation

    The UPLC effectively distinguished and identified co-formulated antibodies despite their high structural similarity, which would have been challenging with other techniques such as spectroscopy.

    “The UPLC was able to effectively distinguish and identify the co‐formulated antibodies despite their high structural similarity [84] which would have been challenging with other techniques such as spectroscopy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] A. Godbole, L. Chen, J. Desai, et al., “ Implementation of Innovative Process Analytical Technologies to Characterize Critical Quality Attributes of Co‐Formulated Monoclonal Antibody Products,” Biotechnology and Bioengineering 122(2) (2024): 322– 332., 10.1002/bit.28881. 39511785 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The FDA established the Emerging Technology Team (ETT), which collaborates with the pharmaceutical industry to provide early assessments and guidance during regulatory submissions for PAT, ensuring a smoother review process.

    “To further support this initiative, the FDA established the ‘Emerging Technology Team’ (ETT), which collaborates with the pharmaceutical industry to provide early assessments and guidance during regulatory submissions for PAT, ensuring a smoother review process [119].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] USFDA, Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization Guidance for Industry (2017), https://www.fda.gov/regulatory‐information/search‐fda‐guidance‐documents/advancement‐emerging‐technology‐applications‐pharmaceutical‐innovation‐and‐modernization‐guidance.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Digital twins have been recently constructed for IEX processes, systematically integrated with the HPLC system and a server computer; the DT predicted elution profiles, enabling automated collection control.

    “For instance, DTs have been recently constructed for ion‐exchange chromatography (IEX) processes, and are systematically integrated with the HPLC system and a server computer. The DT was able to predict the elution profiles, enabling automated collection control [114].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] C. Shi, X. Chen, X. Zhong, Y. Yang, D. Lin, and R. Chen, “ Realization of Digital Twin for Dynamic Control Toward Sample Variation of Ion Exchange Chromatography in Antibody Separation,” Biotechnology and Bioengineering 121 (2024): 1702– 1715, 10.1002/bit.28660. 38230585 source

      Checked before — its earlier verdict is held back until a new check runs.

  • May combine two claims.

    Premisecitation

    LSPR biosensors are less sensitive to changes in temperature, sample composition and vibrations, and unlike spectroscopic techniques, they do not require advanced data analysis to extract product concentrations.

    “LSPR biosensors are less sensitive to changes in temperature, sample composition and vibrations, and unlike spectroscopic techniques, they do not require advanced data analysis to extract product concentrations [96].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] T. Tran, E. Martinsson, R. Gustavsson, et al., “ Process Integrated Biosensors for Real‐Time Monitoring of Antibodies for Automated Affinity Purification,” Analytical Methods 14 (2022): 4555– 4562, 10.1039/d2ay01567f. 36314900 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Spectroscopic techniques have been widely employed in PAT due to their non-destructive nature, minimal sample preparation requirement and ease of in-line or on-line implementation.

    “Spectroscopic techniques have been widely employed in PAT, due to their non‐destructive nature, minimal sample preparation requirement and ease of in‐line or on‐line implementation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The FDA has been actively encouraging industries to adopt PAT and transition to a QbD approach.

    “Nevertheless, the FDA has been actively encouraging industries to adopt PAT and transition to a QbD approach.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    While on-line implementation of chromatography is technically feasible, in-line integration has so far been inherently impractical due to the operational nature of the technique.

    “While on‐line implementation of chromatography is technically feasible, in‐line integration has so far been inherently impractical due to the operational nature of the technique.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Spectroscopic techniques fall behind in offering high specificity, requiring heavy and advanced data processing to derive meaningful insights.

    “However, they still fall behind in terms of offering high specificity, requiring heavy and advanced data processing to derive meaningful insights.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    LSPR biosensors have a short response time (measurements in a few seconds), a large tunable dynamic range, and little need for sample pretreatment.

    “It also has a short response time where the measurements can be done in a few seconds and a large, tunable dynamic range with little need for sample pretreatment [99].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] T. Tran, O. Eskilson, F. Mayer, et al., “ Real‐Time Nanoplasmonic Sensor for IgG Monitoring in Bioproduction,” Processes 8 (2020): 1302, 10.3390/pr8101302. source

      Checked before — its earlier verdict is held back until a new check runs.

  • May combine two claims.

    Premisecitation

    Pedro et al. miniaturized a fluorescence dye-based microfluidic sensor and measured protein aggregation in under 10 min.

    “Pedro et al., explored this potential by miniaturizing a fluorescence dye–based microfluidic sensor, and the measurement of protein aggregation was performed in under 10 min.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] M. N. S. Pedro, M. Isaksson, J. Gomis‐Fons, M. H. M. Eppink, B. Nilsson, and M. Ottens, “ Real‐Time Detection of mAb Aggregates in an Integrated Downstream Process,” Biotechnology and Bioengineering 120 (2023): 2989– 3000, 10.1002/bit.28466. 37309984 source

      Checked before — its earlier verdict is held back until a new check runs.

  • May combine two claims.

    Interpretationreasoning

    On-line implementation of chromatography poses challenges, and in-line implementation currently remains largely impractical.

    “Additionally, on‐line implementation poses challenges, and in‐line implementation currently remains largely impractical.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Advances such as micro-SMB chromatography have significantly decreased sampling and measurement times, yet these remain on the order of minutes, considerably slower than the seconds-scale response achievable with spectroscopic methods.

    “Advances such as micro‐SMB chromatography have significantly decreased sampling and measurement times, yet these remain on the order of minutes, which is considerably slower than the seconds‐scale response achievable with spectroscopic methods.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Though biosensing-based techniques look promising, studies demonstrating their application in real-time monitoring are limited, indicating a clear need for further research.

    “Though biosensing‐based techniques look promising, studies demonstrating their application in real‐time monitoring are limited, indicating a clear need for further research.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Biosensors can fill the gap by offering high specificity, while being easy to implement in-line or on-line, delivering faster measurements required for real-time control.

    “Biosensors can fill in the much‐needed gap, by offering high specificity, while being easy to implement in‐line or on‐line, delivering faster measurements required for real‐time control.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MALS measures the intensity of scattered light at different scattering angles and correlates it to the molecular weight and concentrations of proteins.

    “MALS is a light scattering–based technique that measures the intensity of scattered light at different scattering angles and correlates it to the molecular weight and concentrations of proteins [104].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] E. Sahin and C. J. Roberts, “ Therapeutic Proteins, Methods and Protocols—Size‐Exclusion Chromatography With Multi‐Angle Light Scattering for Elucidating Protein Aggregation Mechanisms,” Methods in Molecular Biology 899 (2012): 403– 423, 10.1007/978-1-61779-921-1_25. 22735967

      Not checked in the free run.

66 of 66

  • The paper relies on this without support.

    Raman spectra have minimal water interference, allowing Raman spectroscopy to analyse aqueous samples or biological specimens where water is a significant component without compromising spectral clarity.

    “The advantage of Raman spectroscopy over IR spectroscopy is that Raman spectra have minimal water interference and thus can be used in analysing aqueous samples or biological specimens where water is a significant component without compromising spectral clarity.”

  • The paper relies on this without support.

    Raman spectroscopy is sensitive to sample temperature, with higher temperature causing diffuse Raman lines and requiring temperature adjustments.

    “Raman is also sensitive to the sample temperature, with higher temperature causing diffuse Raman lines, requiring temperature adjustments.”

  • The paper relies on this without support.

    In continuous manufacturing, real-time monitoring of quality attributes is essential to maintain process control and ensure product consistency.

    “In continuous manufacturing, real‐time monitoring of quality attributes is essential to maintain process control and ensure product consistency.”

  • The paper relies on this without support.

    Achieving reliable real-time analysis requires high-precision measurements and accurate interpretation of complex data.

    “Achieving reliable real‐time analysis requires not only high‐precision measurements but also accurate interpretation of complex data.”

  • The paper relies on this without support.

    For true real-time analytics in downstream processing, response time within a few seconds to minutes is essential.

    “where response time within a few seconds to minutes is essential.”

  • The paper relies on this without support.

    There is still some hesitancy to implement PAT on a commercial scale.

    “there is still some hesitancy to implement PAT on a commercial scale.”

  • The paper relies on this without support.

    The reluctancy to implement PAT on a commercial scale is largely due to the perceived increased burden of regulatory submissions.

    “This reluctancy is largely due to the perceived increased burden of regulatory submissions.”

  • The paper relies on this without support.

    The biopharmaceutical industry is experiencing a paradigm shift in manufacturing, analytics and quality control.

    “The biopharmaceutical industry is experiencing a paradigm shift in manufacturing, analytics and quality control.”

  • The paper relies on this without support.

    Significant emphasis is placed on advancing analytical instrumentation and optimizing data workflows.

    “While significant emphasis is placed on advancing analytical instrumentation and optimizing data workflows, it is equally critical to focus on implementing these advancements at a commercial scale.”
9 of 9

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Mikulic M., 2024, Global Pharmaceutical Industry—Statistics & Facts
  2. Thakur G., 2021, Near Infrared Spectroscopy as a Versatile PAT Tool for Continuous Downstream Bioprocessing, Pharmaceutical Technology, 45, 32
  3. Wasalathanthri D. P., 2020, Paving the Way for Real Time Process Monitoring in Biomanufacturing, American Pharmaceutical Review, 23, 54

Cited by

Sorted by citations

Related

Authors
Sathiyapriyan, P., Mukherjee, S., Vogel, T., Essen, L., Boerema, D., Vey, M., & Kalina, U.
Affiliations
  • Philipps University of Marburg (DE)
  • Research & Development CSL Innovation GmbH Marburg Germany
  • Research & Development CSL Behring LLC Kankakee Illinois USA
ORCID
Venue
Analytical Science Advances
Publisher
Wiley
Published
2025-05-29
Volume
6
Issue
1
Pages
e70013-e70013
ISSN
2628-5452 (ISSN-L)
DOI
10.1002/ansa.70013
PMC
PMC12120361
OpenAlex
W4410867710
Semantic Scholar
056ae7df6949ba22af4b64b19e2cee8608735e5b
Cited by
45
References
112
Citations by year
2026: 39 · 2025: 6
FWCI
3.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Analytical Science Advances (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
  • Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
  • Physical Sciences › Chemistry › Analytical Chemistry › Spectroscopy and Chemometric Analyses
Keywords
process analytical technology, downstream processing, biopharmaceuticals, therapeutic proteins, real-time monitoring, quality by design, spectroscopy, chromatography, biosensors, chemometrics, digital twin, continuous production, machine learning, bioproduction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-06.

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