Inclined plate settlers with novel receiver section as a unit operation for complex continuous solid-liquid separation problems

Solid-liquid separation has been identified as a bottle-neck in continuous processing, especially regarding precipitate collection1. Previously, tangential flow filtration has been proposed as a means of solid-liquid separation that retains precipitate flock structure2. We have developed a novel receiver section concept for inclined plate settlers. Inclined plate settlers have been described for cell retention in perfusion processes in the 1990s3. Conventional plate settlers suffer from non-ideal flow distribution between the individual plates 4, 5,mixing effects in the receiver section and significant losses of solubilized product during withdrawal of the concentrated suspension. Consequently, conventional plate settlers are not suitable for applications outside of perfusion. We devised a novel receiver section concept employing a system of flow distributors, which overcomes the deficiencies in flow distribution and separation between inflowing suspension and sedimented solids. Furthermore, the novel concept enables wash of the collected solids and thus significantly reduces fluid carry-over into the (intermittent) discharge stream. Thereby, the application range of inclined plate settlers is expanded from cell-retention to solid-liquid separation in general. Both streams, clarified fluid as well as concentrated and washed solids, can leave the system. The separated solids can, but do not have to be returned to the process. Proof-of-concept was provided using a single plate inclined settler. Operation conditions of the inclined plate settler system were optimized for precipitated product harvest. Scale-up is demonstrated from one to multiple plates for cell removal. We demonstrated continuous operation for ~90h and once in steady-state, turbidity was reduced by 95 % at consistently high product yields. Please click Additional Files below to see the full abstract

Continuous virus inactivation using a packed-bed reactor

A critical unit operation in integrated continuous biomanufacturing is continuous virus inactivation. These reactors must provide sufficient minimum inactivation time and must have a narrow residence time. The narrow residence time is required to avoid a too short or too long incubation. Too short incubation may result in insufficient inactivation, too long may result in partial product destruction. We have developed a packed-bed continuous virus inactivation reactor (CVIR, Figure 1) with significant advantages over other continuous processing approaches, namely scalability, ease of operation and being truly continuous with undisrupted mass flow. The residence time distribution of our reactor is smaller compared to a coiled flow inverter or a jig in a box reactor. Please click Additional Files below to see the full abstract

Prognostic impact of rapid reduction of involved free light chains in multiple myeloma patients under first-line treatment with Bendamustine, Prednisone, and Bortezomib (BPV)

Introduction!#!Light chain involvement is observed in almost every patient (pt) with newly diagnosed multiple myeloma (MM). Owing to a relatively short half-life, rapid reduction in the involved free light chain (iFLC) is of potential prognostic value.!##!Methods!#!This retrospective analysis included 92 pts with newly diagnosed MM treated with bendamustine, prednisone, and bortezomib (BPV).!##!Results!#!After a median number of two (range 1-5) BPV cycles, the majority of pts (n = 86; 93%) responded with either sCR (n = 21), CR (n = 1), nCR (n = 25), VGPR (n = 20), or PR (n = 19). PFS and OS at 48 months were 39% and 67%, respectively. At baseline, 79 out of 92 pts (86%) had iFLC levels above the upper standard level and an abnormal ratio of involved to uninvolved free light chain ≥ 8. In a subgroup analysis of these pts, we evaluated the prognostic importance of an early reduction of the iFLC during the first two BPV cycles. A reduction ≥ 50% of the iFLC on day 8 of the first cycle was observed in 31 of 69 pts. These pts had a significantly better median PFS of 49 months as compared to 20 months in 38 pts with a lower iFLC reduction (p = 0.002). In contrast, OS did not differ significantly with a 48 months survival of 77% vs 69% (p > 0.05).!##!Conclusion!#!These results indicate that a rapid decrease in the iFLC on day 8 is an early prognostic marker for newly diagnosed MM pts undergoing BPV treatment