Trends in Process Analytical Technology: Present State in Bioprocessing

Jenzsch, Marco; Bell, Christian; Buziol, Stefan; Kepert, Felix; Hakemeyer, Christian

doi:10.1007/10_2017_18

Cited by 15 publications

(15 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[10][11][12] In the case of biopharmaceuticals, such as rAAV, attributes of the drug substance (e.g., identity) and knowledge of impurities-either product related (e.g., inactive product variants and aggregates) or process related (e.g., host cell proteins or DNA)-help identify CQAs early in development. 11,13 Although process-related attributes are not unique to rAAV manufacturing, 11,14 CQAs relating to the rAAV product or product-related impurities are just starting to be clearly identified. 15 In this review, we focus on productivity of rAAV production, the virus titer, and the fraction of capsids with a complete genome (content ratio) and the amount of aggregated capsids as potential CQAs based on their impact on product safety and efficacy.Quality attributes of rAAV are routinely analyzed using time-intensive quality control assays for batch release testing of the final product to ensure they fulfill regulatory specifications for safe use.…”

mentioning

confidence: 99%

Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies

Gimpel

Katsikis

Sha

et al. 2021

Molecular Therapy - Methods & Clinical Development

116

View full text Add to dashboard Cite

The optimization of upstream and downstream processes for production of recombinant adeno-associated virus (rAAV) with consistent quality depends on the ability to rapidly characterize critical quality attributes (CQAs). In the context of rAAV production, the virus titer, capsid content, and aggregation are identified as potential CQAs, affecting the potency, purity, and safety of rAAV-mediated gene therapy products. Analytical methods to measure these attributes commonly suffer from long turnaround times or low throughput for process development, although rapid, high-throughput methods are beginning to be developed and commercialized. These methods are not yet well established in academic or industrial practice, and supportive data are scarce. Here, we review both established and upcoming analytical methods for the quantification of rAAV quality attributes. In assessing each method, we highlight the progress toward rapid, at-line characterization of rAAV. Furthermore, we identify that a key challenge for transitioning from traditional to newer methods is the scarcity of academic and industrial experience with the latter. This literature review serves as a guide for the selection of analytical methods targeting quality attributes for rapid, high-throughput process characterization during process development of rAAV-mediated gene therapies.

show abstract

mentioning

confidence: 99%

Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies

Gimpel

Katsikis

Sha

et al. 2021

Molecular Therapy - Methods & Clinical Development

116

View full text Add to dashboard Cite

show abstract

“…In recent years, significant progress has been made in process analytical technology (PAT), which enables real‐time monitoring and control, to maintain consistent product quality (Jenzsch et al, 2018; Read, Park, et al, 2010; Read, Shah, et al, 2010). Real time bioprocess monitoring with integrated analytics at key unit operations is one of the most important necessities for realizing the real time release of biopharmaceuticals (Chemmalil et al, 2020; Wasalathanthri et al, 2020).…”

Section: Analytical Methods For Disulfide Bond Reduction Monitoring and Analysismentioning

confidence: 99%

Antibody disulfide bond reduction and recovery during biopharmaceutical process development—A review

Ren

Tan

Ehamparanathan

et al. 2021

Biotech & Bioengineering

View full text Add to dashboard Cite

Antibody disulfide bond reduction has been a challenging issue in monoclonal antibody manufacturing. It could lead to a decrease of product purity and failure to meet the targeted product profile and/or specifications. More importantly, disulfide bond reduction could also impact drug safety and efficacy. Scientists across the industry have been examining the root causes and developing mitigation strategies to address the challenge. In recent years, with the development of high titer mammalian cell culture processes to meet the rapidly growing demand for antibody biopharmaceuticals, disulfide bond reduction has been observed more frequently. Thus, it is necessary to continue evolving the disulfide reduction mitigation strategies and developing novel approaches to maintain high product quality. Additionally, in recent years as more complex molecules (such as bispecific and trispecific antibodies) emerge, the molecular heterogeneity due to incomplete formation of the interchain disulfide bonds becomes a more imperative challenging issue. Given the disulfide reduction challenges that biotech industry is facing, in this review, we provide a comprehensive scientific summary of the root cause analysis of disulfide reduction during process development of antibody therapeutics, mitigation strategies and its potential remediated recovery based on published papers. First, this paper intends to highlight different aspects of the root cause for disulfide reduction. Secondly, to provide a broader understanding of the disulfide bond reduction in downstream process, this paper discusses disulfide bond reduction impact on product stability, associated analytical methods for disulfide bond reduction detection and characterization, process control strategies as well as their manufacturing implementation. In addition, brief perspectives on the development of future mitigation strategies are also reviewed, including platform alignment, mitigation strategy application for the emerging new modalities such as bispecific and trispecific antibodies as well as using machine learning to identify molecule susceptibility of disulfide bond reduction. The data in this review are originated from the published papers.

show abstract

“…In recent years, significant progress has been made in process analytical technology (PAT), which enables realtime monitoring and control, to maintain consistent product quality through better process understanding (Jenzsch et al, 2018;. Real time monitoring of bioprocess with the integration of analytics at critical unit operations of processes is one of the paramount necessities for implementing real time release of biopharmaceuticals (Chemmalil et al, 2020;Wasalathanthri et al, 2020).…”

Section: Analytical Methods For Disulfide Bond Reduction Monitoring and Analysismentioning

confidence: 99%

Antibody Disulfide Bond Reduction and Recovery during Biopharmaceutical Process Development - A Review

Ren

Tan

Ehamparanathan

et al. 2020

Preprint

View full text Add to dashboard Cite

Disulfide bond reduction has been a challenging issue in antibody manufacturing, as it leads to reduced product purity, failed product specifications and more importantly, impacting drug safety and efficacy. Scientists across industry have been examining the root causes and developing mitigation strategies to address the challenge. In recent years, with the development of high-titer mammalian cell culture processes to meet the rapidly growing demand for antibody biopharmaceuticals, disulfide bond reduction has been observed more frequently. Thus, it is necessary to continue evolving the disulfide reduction mitigation strategy and development of novel approaches to achieve high product quality. Additionally, in recent years as more complex molecules emerge such as bispecific and trispecific antibodies, the molecular heterogeneity due to incomplete formation of the interchain disulfide bonds becomes a more imperative issue. Given the disulfide reduction challenges that our industry are facing, in this review, we provide a comprehensive contemporary scientific insight into the root cause analysis of disulfide reduction during process development of antibody therapeutics, mitigation strategies and recovery based on our expertise in commercial and clinical manufacturing of biologics. First, this paper intended to highlight different aspects of the root cause for disulfide reduction. Secondly, to provide a broader understanding of the disulfide bond reduction in downstream process, this paper discussed disulfide bond reduction impact to product stability and process performance, analytical methods for detection and characterization, process control strategies and their manufacturing implementation. In addition, brief perspectives on development of future mitigation strategies will also be reviewed, including platform alignment, mitigation strategy application for bi- and tri-specific antibodies and using machine learning to identify molecule susceptibility of disulfide bond reduction. The data in this review are originated from both the published papers and our internal development work.

show abstract

Trends in Process Analytical Technology: Present State in Bioprocessing

Cited by 15 publications

References 73 publications

Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies

Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies

Antibody disulfide bond reduction and recovery during biopharmaceutical process development—A review

Antibody Disulfide Bond Reduction and Recovery during Biopharmaceutical Process Development - A Review

Contact Info

Product

Resources

About