Modelling and prediction of non-linear scale-up from an Ultra Scale-Down membrane device to process scale tangential flow filtration

Ultra scale-down (USD) tools have demonstrated the huge potential for accelerated process development by significantly reducing the material requirements and providing better solutions, as part of the Quality by Design initiative. Key benefits of using USD techniques include the relatively small quantities of feedstock and minimal capital equipment needed to generate large volumes of statistically significant process data in a short period, leading to significant time and cost savings during process development. However, the use of small scale devices such as the stirred cell filtration units have been primarily limited to preliminary testing and initial screening due to their geometric and flow dissimilarities to tangential flow filtration at scale. As a result, process development and optimisation trials are generally carried out using the smallest c commercially available TFF cassettes, the use of which are primarily limited by time and material constraints that are invariably present at the early stages of process development. Therefore, the central focus of this work was to develop a USD methodology and model to accurately predict the performance of large scale tangential flow filtration (TFF) using a USD membrane filtration device. // The commercial package COMSOL was used to carry out computational fluid dynamics (CFD) modelling and simulation of the fluid flow dynamics in Pellicon TFF cassettes with different feed screens and a USD membrane device, in order to develop average wall shear rate correlations and channel pressure drops expressed as functions of the respective hydrodynamic conditions across scales. In addition, the impact of non-TFF related factors such as the system and cassette-specific hydraulic resistances on TFF performance was characterised using semi-empirical models. Finally, a scale-up methodology and mathematical model to predict the large scale performance using USD data was developed by combining the various resistances, channel pressure drop correlations and an empirical USD-derived model that characterises the specific feed-membrane interactions. The CFD simulations were independently verified using 2D particle imaging velocimetry to compare experimental data to the CFD simulated data. // 100-fold scale-up experiments were carried out based on equivalent averaged wall shear rates (w) as the geometry-independent parameter. Permeate flux excursions were carried out to validate the USD methodology and prediction model, by comparing USD model predictions against the large scale experimental data. Different membranes, feed screens (A, C and V) and feedstock, ranging from simple proteins like Bovine Serum Albumin (BSA) to more complex, multicomponent feed such as Escherichia coli homogenate, were used. Predicted flux and transmission results were in good agreement with the large scale experimental data, showing less than 5% difference across scales, demonstrating the robustness of the non-linear scale-up model. // Following the successful validation of the scale-up methodology and prediction model, other potential applications of the USD membrane device such as the optimisation of TFF microfiltration was demonstrated using Saccharomyces cerevisae and Chlorella sorokiniana. Fed-batch concentration experiments using Saccharomyces cerevisae were done to compare the volumetric throughput limits. The USD-predicted capacity limit of 49.2 L/m2 was very similar to the experimental large scale capacity value of 52.0 L/m2, and considered fully scalable within experimental errors. Finally, fouling studies were performed using Chlorella sorokiniana and the USD device to investigate the impact of media type and growth conditions on the filtration performance. The results indicated a strong correlation between soluble fouling species, such as exopolysaccharides and carbohydrates, rather than the algal biomass. A novel, dynamic flux control methodology was developed based on empirically determined critical fluxes expressed as a function of cell concentration. The dynamic control strategy was successfully verified by performing a 50-fold concentration experiment using a hollow fibre module and the USD device. An improvement of greater than 50% in average throughput was achieved using the 3-step flux cascade compared to the traditional flux-time/capacity optimised fluxes, with no observable increase in TMP throughout. // The work presented here demonstrates the potential of ultra scale-down tools coupled with a mathematical modelling approach to establish a predictable scale-up performance, which can be used to rapidly develop and optimise tangential flow filtration processes, regardless of differences in geometry, flow configuration and system setup

Computational fluid dynamics (CFD) approach for characterizing and improving fluid flow for membrane filtration technologies and successful scale-up

There is increasing interest in using computational fluid dynamics (CFD) techniques to obtain better understanding of fluid dynamics of various unit operations, both upstream and downstream bioprocessing, and to use simulated results for process modelling, system characterisation and design optimisation. Membrane filtration technologies and in particular, tangential flow filtration (TFF), have made use of CFD analysis to gain better insight into, for instance, velocity and concentration profiles within channels, optimising spacer geometry and configurations to maximise mass transfer for different TFF setups. The applications and benefits for TFF processes are immense since large volumes of liquid are normally required, both for cleaning and processing, and thus even small increments in efficiency can result in significant cost reductions. In this study, a novel Ultra Scale-Down (USD) membrane filtration device and spacer-filled channels in TFF cassettes were modelled using COMSOL Multiphysics. 2D-axisymmetrical and 3D models were developed, respectively, to simulate the effect of geometry, design and hydrodynamic conditions on flow, wall shear rates and pressure profiles. Laminar flow and Shear Stress Transport (SST) formulations were used and parametric sweeps employed for different geometrical and design parameters. The geometrical configuration, such as clearance of the disc, cone angle and disc diameter, and the resulting hydrodynamics within the system was seen to play a vital role in wall shear rate distributions for the USD device. The change could be attributed to the introduction of secondary recirculating flows and vortices that allow greater degree of axial and radial mixing, as seen from the CFD results. Optimal disc type, namely the axial flow impellers such as pitch-blade turbine and the hydrofoil, and positioning was also identified based on parameters such as wall shear rate distribution along the radial axis of the membrane and maximum shear stress:average wall shear stress ratio. Flow within the screened channel was observed to be very controlled and periodic, especially in regions close to and around the cylindrical fibers of the screen, and an overall accelerated flow within the channel compared to the inlet velocity was observed from the CFD simulations. The aim was to use CFD as a guiding tool to optimise the design of the USD device such that it mimics the average wall shear rate and profiles observed within the screened channels, in order to establish successful and accurate scale-up between the USD device and TFF process, at scale. Experimental validation for the CFD results are also presented, along with other potential applications of the CFD studies carried out, such as modelling flux behaviour in the channel, cake formation and pressure drops. Please click Additional Files below to see the full abstract

Directional and bidirectional causality between U.S. industry credit and stock markets and their determinants

We examine the causal links between U.S. industry-wise credits and stock markets. The full sample bootstrap Granger causality results show that all stock markets Granger cause their CDS counterparts and there is also bidirectional causality for the banking, healthcare and material industries. The short-run parametric stability tests highlight that the full sample parameters are not stable and hence less reliable. The bootstrap rolling window estimations confirm the inconsistency in the CDS-stock causality relationships where bidirectional causalities are also found between the credit and stock markets that vary over different sub-samples. Finally, we analyze the impact of different financial and macroeconomic determinants on the CDS-stock causality through a probit model. Overall, the business conditions, stock market volatility, default premiums, Treasury bond rate and the slope of the yield curve are major drivers of the CDS-stock nexus. Our findings provide possible explanation for varying and mixed previous empirical findings in the existing literature, and hence have useful investment implications

Directional and bidirectional causality between U.S. industry credit and stock markets and their determinants

We examine the causal links between U.S. industry-wise credits and stock markets. The full sample bootstrap Granger causality results show that all stock markets Granger cause their CDS counterparts and there is also bidirectional causality for the banking, healthcare and material industries. The short-run parametric stability tests highlight that the full sample parameters are not stable and hence less reliable. The bootstrap rolling window estimations confirm the inconsistency in the CDS-stock causality relationships where bidirectional causalities are also found between the credit and stock markets that vary over different sub-samples. Finally, we analyze the impact of different financial and macroeconomic determinants on the CDS-stock causality through a probit model. Overall, the business conditions, stock market volatility, default premiums, Treasury bond rate and the slope of the yield curve are major drivers of the CDS-stock nexus. Our findings provide possible explanation for varying and mixed previous empirical findings in the existing literature, and hence have useful investment implications

Catastrophic cerebral antiphospholipid syndrome presenting as cerebral infarction with haemorrhagic transformation after sudden withdrawal of warfarin in a patient with primary antiphospholipid syndrome

Catastrophic antiphospholipid syndrome (APS) is caused by thrombotic vascular occlusions that affect both small and large vessels, producing ischaemia in the affected organs. The “catastrophic” variant of the antiphospholipid syndrome (cAPS) develops over a short period of time. Although patients with cAPS represent <1% of all patients with APS, they are usually life threatening with a 50% mortality rate. A strong association with concomitant infection is thought to act as the main trigger of microthromboses in cAPS. Several theories have been proposed to explain these physiopathological features. Some of them suggest the possibility of molecular mimicry between components of infectious microorganisms and natural anticoagulants, which might be involved in the production of cross-reacting antiphospholipid antibodies. We present a case of catastrophic cerebral APS characterised by massive temporal lobe infarction and subsequent haemorrhagic transformation after sudden withdrawal of warfarin

Don’t live in a town where there are no doctors: toxic epidermal necrolysis initially misdiagnosed as oral thrush

Toxic epidermal necrolysis (TEN) is a rare but life threatening skin disease that is most commonly drug induced. The exact pathogenesis of TEN is still unknown and many drugs, including prednisolone, cyclosporin and intravenous immunoglobulin (IVIG), have been used in an attempt to halt the disease process. The use of IVIG in particular is controversial. Recently, the US Food and Drug Administration (FDA) has made a labelling change to the drug information for carbamazepine. Owing to recent data implicating the HLA allele B*1502 as a marker for carbamazepine induced Stevens–Johnson syndrome and TEN in Han Chinese, the FDA recommends genotyping all Asians for the allele. We present an interesting case of carbamazepine induced TEN which was confused with oral thrush, had no skin lesions on presentation, and had an excellent response to a 5 day course of methylprednisolone and high dose IVIG in combination

Practice of symptomatic treatment in the era of evidence-based medicine: report of 2 cases of diagnosis of Sheehan’s syndrome delayed till eighth decade

Sheehan’s syndrome, first described in 1937, is characterised by postpartum haemorrhage, pituitary necrosis, lactational failure and hypopitutarism. Presentation is variable and late presentations are not unusual due to partial ischaemic injury of the pituitary and gradual loss of endocrine function. A history of postpartum haemorrhage is usual but in some cases it is not elicited. Presentations such as malaise, fatigue, hypoglycaemia, decline in cognition, hyponatraemia, pancytopoenia, osteoporosis, secondary infertility, confusion and coma have all been reported. Two interesting cases of Sheehan’s syndrome are presented that were diagnosed in the eighth decade; one due to atypical presentation of recurrent hyponatraemia and confusion, another from hypoglycaemic coma and symptoms of malaise and lethargy