Module design for ultrafiltration in biotechnology: Hydraulic analysis and statistical modeling

Thiess, Holger; Leuthold, Martin; Grummert, Ulrich; Strube, Jochen

doi:10.1016/j.memsci.2017.06.038

Cited by 25 publications

(27 citation statements)

References 53 publications

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“…The data presented in Figures 4 and 5 are significant in context to work published by several groups on highly concentrated protein solutions 5,6,24 where the module screen type and the buffer composition significantly affected the ability to reach high concentrations for BSA, mAbs, and Fc-Fusion proteins. The general conclusion from all these studies was that the axial pressure drop in TFF cassettes caused reverse filtration at high protein concentrations because of loss of retentate pressure at the module exit.…”

Section: Behavior Of Completely Retained Proteins (Monoclonal Antibodsupporting

confidence: 61%

Ultrafiltration behavior of partially retained proteins and completely retained proteins using equally‐staged single pass tangential flow filtration membranes

Arunkumar

Zhang

Singh

et al. 2018

Biotechnology Progress

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This work examines the ultrafiltration behavior of partially retained proteins like lysozyme and completely retained proteins like monoclonal antibodies using single pass tangential flow filtration (SPTFF) modules with different screen channels and molecular weight cut-offs. When the staging of the SPTFF used the same membrane area in each stage, there was no impact of the module screened channel or the buffer matrix on the final concentration achieved for completely retained monoclonal antibodies. A hybrid configuration containing 30 kDa membranes and 50 kDa membranes increased the maximum achievable concentration for both the monoclonal antibodies used in this work, at the same time, allowing a two-fold to four-fold increase in normalized feed flow-rate through the system compared to only the 30 kDa or only the 50 kDa membranes. The sieving coefficient of lysozyme measured and calculated using SPTFF was lower than those measured during conventional recirculation TFF indicating a more complicated concentration polarization effect than conventional recirculation TFF. Moreover, the sieving coefficients of lysozyme were the same for the 10 kDa regenerated cellulose and 50 kDa PES membranes while it was higher for the 30 kDa regenerated cellulose membrane. The difference in TFF and SPTFF behavior is important when the product of interest is desired to be permeated. This work presents the first body of data for partially and completely retained solutes together in the SPTFF mode and provides a strategy to increase protein concentration at higher feed flow rates. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018 © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1137-1148, 2018.

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Section: Behavior Of Completely Retained Proteins (Monoclonal Antibodsupporting

confidence: 61%

Ultrafiltration behavior of partially retained proteins and completely retained proteins using equally‐staged single pass tangential flow filtration membranes

Arunkumar

Zhang

Singh

et al. 2018

Biotechnology Progress

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“…Further, yield and purity must be included as a function of ionic strength, pH value, PEG content, and dissolution ratio. Thus, a development and validation concept was presented, which has already been successfully implemented for model building of valid physico-chemical models for other unit operations [49,55,56,66,72]. Due to the fact that the model is based on physical principals and laws, less experimental effort for parameter determination is necessary to transfer the model to novel material systems.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, a mechanistic model approach for the precipitation curve was presented by Großhans et al [43]. Previous work has already presented a general model development and validation concept, which can be used to construct physico-chemical models of unit operations [66][67][68][69][70][71][72]. The described process is broken down into the individual building blocks and described with physical principles and laws.…”

Section: Modeling Of Precipitationmentioning

confidence: 99%

Accelerating Biologics Manufacturing by Modeling: Process Integration of Precipitation in mAb Downstream Processing

Lohmann

Strube

2020

Processes

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The demand on biologics has been constantly rising over the past decades and has become crucial in modern medicine. Promising approaches to cope with widespread diseases like cancer and diabetes are gene therapy, plasmid DNA, virus-like particles, and exosomes. Due to progress that has been made in upstream processing (USP), difficulties arise in downstream processing and demand for innovative solutions. This work focuses on the integration of precipitation using a quality by design (QbD) approach for process development. Selective precipitation is achieved with PEG 4000 resulting in an HCP depletion of ≥80% respectively to IgG. Dissolution was executed with a sodium phosphate buffer (pH = 5/50 mM) reaching an IgG recovery of ≥95%. However, the central challenge in process development is still an optimal process design, which is transferable for a broad molecular variety of new products. This is where rigorous modeling becomes vital in order to generate digital twins to support early-stage process development and reduce the experimental overhead. Therefore, a model development and validation concept for construction of a process model for precipitation is also presented.

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“…Modeling is well established for smaller molecules in the chemical industry by chemical engineering personnel educated and trained in applying those methods. Availability of models and data, either by in-house data-bases or by experimentally standardized setups enable predictive process simulation in order to reduce experimental efforts in process design [47][48][49][50][51][52][53][54].…”

Section: Introductionmentioning

confidence: 99%

“…Statistical models: Are part of the evaluation of experimental data generated according to DoE experimental plans, which could be statistically evaluated according to accuracy and prediction by aid of statistical models [51,68].…”

mentioning

confidence: 99%

Accelerating Biologics Manufacturing by Modeling or: Is Approval under the QbD and PAT Approaches Demanded by Authorities Acceptable without a Digital-Twin?

et al. 2019

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Innovative biologics, including cell therapeutics, virus-like particles, exosomes,recombinant proteins, and peptides, seem likely to substitute monoclonal antibodies as the maintherapeutic entities in manufacturing over the next decades. This molecular variety causes agrowing need for a general change of methods as well as mindset in the process development stage,as there are no platform processes available such as those for monoclonal antibodies. Moreover,market competitiveness demands hyper-intensified processes, including accelerated decisionstoward batch or continuous operation of dedicated modular plant concepts. This indicates gaps inprocess comprehension, when operation windows need to be run at the edges of optimization. Inthis editorial, the authors review and assess potential methods and begin discussing possiblesolutions throughout the workflow, from process development through piloting to manufacturingoperation from their point of view and experience. Especially, the state-of-the-art for modeling inred biotechnology is assessed, clarifying differences and applications of statistical, rigorousphysical-chemical based models as well as cost modeling. “Digital-twins” are described and effortsvs. benefits for new applications exemplified, including the regulation-demanded QbD (quality bydesign) and PAT (process analytical technology) approaches towards digitalization or industry 4.0based on advanced process control strategies. Finally, an analysis of the obstacles and possiblesolutions for any successful and efficient industrialization of innovative methods from processdevelopment, through piloting to manufacturing, results in some recommendations. A centralquestion therefore requires attention: Considering that QbD and PAT have been required byauthorities since 2004, can any biologic manufacturing process be approved by the regulatoryagencies without being modeled by a “digital-twin” as part of the filing documentation?

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Module design for ultrafiltration in biotechnology: Hydraulic analysis and statistical modeling

Cited by 25 publications

References 53 publications

Ultrafiltration behavior of partially retained proteins and completely retained proteins using equally‐staged single pass tangential flow filtration membranes

Ultrafiltration behavior of partially retained proteins and completely retained proteins using equally‐staged single pass tangential flow filtration membranes

Accelerating Biologics Manufacturing by Modeling: Process Integration of Precipitation in mAb Downstream Processing

Accelerating Biologics Manufacturing by Modeling or: Is Approval under the QbD and PAT Approaches Demanded by Authorities Acceptable without a Digital-Twin?

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