Anupam Shukla

Modeling of Filtration Processes—Microfiltration and Depth Filtration for Harvest of a Therapeutic Protein Expressed in Pichia pastoris at Constant Pressure

Filtration steps are ubiquitous in biotech processes due to the simplicity of operation, ease of scalability and the myriad of operations that they can be used for. Microfiltration, depth filtration, ultrafiltration and diafiltration are some of the most commonly used biotech unit operations. For clean feed streams, when fouling is minimal, scaling of these unit operations is performed linearly based on the filter area per unit volume of feed stream. However, for cases when considerable fouling occurs, such as the case of harvesting a therapeutic product expressed in Pichia pastoris, linear scaling may not be possible and current industrial practices involve use of 20-30% excess filter area over and above the calculated filter area to account for the uncertainty in scaling. In view of the fact that filters used for harvest are likely to have a very limited lifetime, this oversizing of the filters can add considerable cost of goods for the manufacturer. Modeling offers a way out of this conundrum. In this paper, we examine feasibility of using the various proposed models for filtration of a therapeutic product expressed in Pichia pastoris at constant pressure. It is observed that none of the individual models yield a satisfactory fit of the data, thus indicating that more than one fouling mechanism is at work. Filters with smaller pores were found to undergo fouling via complete pore blocking followed by cake filtration. On the other hand, filters with larger pores were found to undergo fouling via intermediate pore blocking followed by cake filtration. The proposed approach can be used for more accurate sizing of microfilters and depth filters.

A three plus three parameters mechanistic model for viral filtration

Viral filtration is an expensive regulatory requirement in downstream processing of monoclonal antibodies (mAbs). This process step is typically operated with an overdesigned filter in order to account for any batch to batch variability in the filter, as well as the feed characteristics. Here, we propose a simple, six‐parameter mechanistic model for viral filtration where three parameters are membrane‐specific while the other three depend on feed characteristics and membrane‐feed interactions. Viruses are considered as passive particles which are retained by the membrane on the basis of size exclusion. The model envisages that the viral filter contains two kind of pores: virus‐retentive, small‐sized pores and non‐retentive, large‐sized pores. The small‐sized pores get blocked during filtration resulting in decrease in active membrane area, while the large‐sized pores get constricted during filtration. The length of constricted part increases during filtration and contributes to increase in hydraulic resistance of the filter. Rate of these processes (blocking and constriction) are assumed to be proportional to the instantaneous rate of retention of the viral particles. The general nature of the model is validated with the experimental data on viral filtration for four different commercial membranes used in biotech industries as well as different model viruses. The proposed model has been demonstrated to describe the behavior of filters with very good accuracy. The best‐fit model parameter values indicate about the various phenomena that are responsible for differences in the behavior of the membranes as well as change in retention and flux with feed concentration. The proposed model can be used for improving design of virus filters as well as in appropriate sizing of the filters during processing.