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

Abstract

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

Streamlined process development procedure incorporating the selection of various stationary phase types established in a mAb aggregate reduction study with different mixed mode ligands

“…The used HTS SDD MA set‐up in Figure 3 was developed for process screening 57 . It comprises eight parallel MA scale down devices fixed on a holder plate.…”

“…The used HTS SDD MA set-up in Figure 3 was developed for process screening. 57 In case the targeted accuracy could not be reached, the software WinLissy ® volume correction factors of the robotic system Lissy ® 2002 GXXL/8P were adjusted.…”

“…1,[54][55][56] Addressing the above mentioned complexity, we introduced screening procedures in the past, allowing the evaluation of MA with different ligands. 57,58 Prior to this screening procedures, the large variability of potential scaffolds and backbone structures in membrane chromatography is reduced by an evaluation scheme using theoretical considerations, and an investigation into selectivity and capacity. The presented evaluation scheme includes evaluation of different scaffolds, backbones and MM ligands.…”

Ultrahigh‐speed, ultrahigh‐resolution preparative separation of protein biopharmaceuticals using membrane chromatography

“…In a membrane, the pore is analogous to the interparticle space in a resin-based column. Membrane chromatography is based on the use of membranes that have pores in the low single-digit microns, or even in the submicron range [25][26][27], which is significantly smaller than the dimension of the inter-particle space in resin-packed columns typically used for preparative protein purification (which is usually of the order of a few to tens of microns) [28]. Therefore, it could be expected that the value of A for a membrane chromatography device would be significantly smaller than that for a resin-packed preparative column.…”

Process development exploiting competitive adsorption‐based displacement effects in monoclonal antibody aggregate removal—A new high‐throughput screening procedure for membrane chromatography

“…These limitations have been addressed earlier. 10 However, optimal process development, scale up, and novel process designs depend on the limitation of the screening method used.…”