Use of MiniColumns for linear isotherm parameter estimation and prediction of benchtop column performance

Keller, William R.; Evans, Steven T.; Ferreira, Gisela; Robbins, David J.; Cramer, Steven M.

doi:10.1016/j.chroma.2015.09.038

Cited by 41 publications

(35 citation statements)

References 31 publications

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“…For example, the used system to perform a chromatographic step is usually customized engineered for the needs of the process and differs between the processes between pumps, piping and thus dead volumes, detectors, automation platforms, and data transfer rates are used, which is less true for laboratory equipment which is usually built in a standardized way. SDD in column chromatography for resin and process window determination are commonly miniaturized robotic columns of 0.2-1 ml bed volume 1,23,7 ; in addition, these SDDs can offer a first appreciation of dynamic effects. 20,24,26 However, fluid dynamics abbreviation as well as wall and mass transfer effects are known challenges between existing SDDs and lab-scale columns.…”

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confidence: 99%

High throughput screening setup of a scale‐down device for membrane chromatography‐aggregate removal of monoclonal antibodies

Stein

Thom

Hubbuch

2020

Biotechnology Progress

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In biopharmaceutical process development, resin-based high throughput screening (HTS) is well known for overcoming experimental limitations by permitting automated parallel processing at miniaturized scale, which results in fast data generation and reduced feed consumption. For membrane adsorber (MA), HTS solutions have so far only been available to a partial extent. Three case studies were performed with the aim of aligning HTS applications for MAs with those established for column chromatography: Process parameter range determination, mechanistic modeling (MM), and scalability. In order to exploit the MA typically features, such as high mass transfer and easy scalability, for scalable high throughput process development, a scale-down device (SDD) for MA was developed. Its applicability is confirmed for a monoclonal antibody aggregate removal step. The first case study explores the experimental application of the SDD developed. It uses bind and elute mode and variations of pH and salt concentration to obtain process operation windows for ion-exchange MAs Sartobind ® S and Q. In the second case study, we successfully developed a mechanistic model based on parameters obtained from the SDD-HTS setup. The results proved to validate the use of the SDD developed for parameter estimation and thus model-based process development. The third case study shows the transferability and scalability of data from the SDD-HTS setup using both a direct scale factor and MM. Both approaches show good applicability with a deviation below 20% in the prediction of 10% dynamic breakthrough capacity and reliable scale-up from 0.42 to 800 ml. K E Y W O R D S digital twin, high throughput screening, mechanistic modeling, membrane adsorber, monoclonal antibody aggregate removal 1 | INTRODUCTION Process development for chromatographic separation in the biopharmaceutical industry is challenged by high cost, limited availability of the target entity and shortened timelines. The abundance of available chromatographic media and the broad range of possible process parameters result in high experimental effort for their determination. 1-3 These challenges can be addressed by the established process development tools of high throughput screening (HTS) robotic platforms for parallel, automated, and standardized workflows to accelerate process development efforts and to use scale-down-devices (SDD) in these workflows to reduce usage of materials and cost. 1,4-7 The fields of application for HTS are, for instance, identification of drugs, 8-10 biological libraries, 11,12 cell cultivation, 13,14 aqueous

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confidence: 99%

High throughput screening setup of a scale‐down device for membrane chromatography‐aggregate removal of monoclonal antibodies

Stein

Thom

Hubbuch

2020

Biotechnology Progress

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“…Although this approach was shown to quickly guide the selection of resins and conditions for experimental process development, we believe that this approach can be further improved to explicitly account for product yield as well as other important preparative issues such as column binding capacity and process robustness by combining state‐of‐the‐art HTS and column modelling techniques (Coffman et al, ; Keller, Evans, Ferreira, Robbins, & Cramer, ; Welsh et al, ; Welsh et al, ). Iteratively expanding the breadth and types of data underlying the algorithmic approach, as well as the classes of molecules and hosts characterized, may enable substantially reduced experimentation for designing and optimizing purification processes, and ultimately the time required to transition new products to the clinic.…”

Section: Discussionmentioning

confidence: 99%

A combined screening and in silico strategy for the rapid design of integrated downstream processes for process and product‐related impurity removal

Vecchiarello

Timmick

Goodwine

et al. 2019

Biotech & Bioengineering

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Integrated designs of chromatographic processes for purification of biopharmaceuticals provides potential gains in operational efficiency and reductions of costs and material requirements. We describe a combined method using screening and in silico algorithms for ranking chromatographic steps to rapidly design orthogonally selective integrated processes for purifying protein therapeutics from both process-and product-related impurities. IFN-α2b produced in Pichia pastoris containing a significant product variant challenge was used as a case study. The product and product-related variants were screened on a set of 14 multimodal, ion exchange, and hydrophobic charge induction chromatography resins under various pH and salt linear gradient conditions. Data generated from reversed-phase chromatography of the fractions collected were used to generate a retention database for IFN-α2b and its variants. These data, in combination with a previously constructed process-related impurity database for P. pastoris, were input into an in silico process development tool that generated and ranked all possible integrated chromatographic sequences for their ability to remove both process and product-related impurities. Top-ranking outputs guided the experimental refinement of two successful three step purification processes, one comprising all bind-elute steps and the other having two bind-elute steps and a flowthrough operation. This approach suggests a new platform-like approach for rapidly designing purification processes for a range of proteins where separations of both process-and product-related impurities are needed. K E Y W O R D Shigh throughput process development, integrated downstream processing, mixed mode chromatography, process development tool, protein chromatography, straight-through processing

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“…The product characterization experiments could be made both faster and more informative through the use of high-throughput screening to determine resin binding conditions and capacities, to evaluate product elution conditions, and to estimate model parameters for in silico process optimization (Coffman et al, 2008;Keller et al, 2015;Welsh et al, 2014;Welsh et al, 2016). Furthermore, while the method described in the current work focused on processrelated impurities, we acknowledge that product-related variants must often be mitigated and purification processes may require inclusion of specific steps to address these challenges, which is beyond the scope of this work.…”

Section: Discussionmentioning

confidence: 99%

“…Although benchtop linear gradient screens were used in the current work, it would be straightforward to use high-throughput systems to rapidly determine this bioproduct gradient elution data (Coffman, Kramarczyk, & Kelley, 2008;Keller, Evans, Ferreira, Robbins, & Cramer, 2015;Welsh et al, 2014;Welsh et al, 2016). The databases of product retention times for both biologics were then exported for use in the in silico tool.…”

Section: Chromatographic Screening Of Product Materialsmentioning

confidence: 99%

“…The databases of product retention times for both biologics were then exported for use in the in silico tool. Although benchtop linear gradient screens were used in the current work, it would be straightforward to use high-throughput systems to rapidly determine this bioproduct gradient elution data (Coffman, Kramarczyk, & Kelley, 2008;Keller, Evans, Ferreira, Robbins, & Cramer, 2015;Welsh et al, 2014;Welsh et al, 2016).…”

Section: Chromatographic Screening Of Product Materialsmentioning

confidence: 99%

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An impurity characterization based approach for the rapid development of integrated downstream purification processes

Timmick

Vecchiarello

Goodwine

et al. 2018

Biotech & Bioengineering

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In this study, we describe a new approach for the characterization of process-related impurities along with an in silico tool to generate orthogonal, integrated downstream purification processes for biological products. A one-time characterization of process-related impurities from product expression in Pichia pastoris was first carried out using linear salt and pH gradients on a library of multimodal, salt-tolerant, and hydrophobic charge induction chromatographic resins. The Reversed-phase ultra-performance liquid chromatography (UPLC) analysis of the fractions from these gradients was then used to generate large data sets of impurity profiles. A retention database of the biological product was also generated using the same linear salt and pH gradients on these resins, without fraction collection. The resulting two data sets were then analyzed using an in silico tool, which incorporated integrated manufacturing constraints to generate and rank potential three-step purification sequences based on their predicted purification performance as well as whole-process "orthogonality" for impurity removal. Highly ranked sequences were further examined to identify templates for process development. The efficacy of this approach was successfully demonstrated for the rapid development of robust integrated processes for human growth hormone and granulocyte-colony stimulating factor.

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Use of MiniColumns for linear isotherm parameter estimation and prediction of benchtop column performance

Cited by 41 publications

References 31 publications

High throughput screening setup of a scale‐down device for membrane chromatography‐aggregate removal of monoclonal antibodies

High throughput screening setup of a scale‐down device for membrane chromatography‐aggregate removal of monoclonal antibodies

A combined screening and in silico strategy for the rapid design of integrated downstream processes for process and product‐related impurity removal

An impurity characterization based approach for the rapid development of integrated downstream purification processes

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