Davies, James Lloyd; (2003) Process Synthesis for Antibiotic Recovery by Microfiltration from Saccharopolyspora erythraea Fermentations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The causes of the interactions between fermentation and microfiltration were first examined experimentally by investigating erythromycin production using two different media. Soluble complex media (SCM) broths reached maximum erythromycin concentrations more rapidly (64.2 0.3 h) than the less expensive and therefore industrially preferred oil based media (OBM) broths (176 15 h) but also attained lower titres (241 55 g.L-1 compared to 617 104 g.L-1). The OBM broths showed oxygen limitation due to the high apparent viscosity. Both broths were found to be shear thinning and exhibited different time dependant rheological profiles which could impact on the performance of the subsequent microfiltration operation. The microfiltration performance of the two broths was subsequently examined using a flat sheet membrane system (area = 60 - 120 cm2). This small-scale unit allowed the determination of flux and transmission profiles as a function of fermentation time and for membrane operation over a range of transmembrane pressures and crossflow velocities. The OBM broths were quicker to blind the membrane, achieved lower values of steady state permeate flux, which decreased over fermentation time as apparent viscosity increased. SCM broths showed no time dependant variation in steady state permeate flux. Transmission of product was higher in SCM (96.4 1.6 %) than OBM broths (89.6 1.4 %). This was attributed to the high solids content of the OBM broth in the form of the undissolved soya flour. The mass transfer of erythromycin across the membrane was similar in both cases (SCM: 1.47 0.28 x 10-6 kg.m-2.s-1, OBM: 1.38 0.20 x 10-6 kg.m-2.s-1) due to the differences between erythromycin titre and permeate flux. For the SCM broths image analysis was also used to determine if there was a relationship between bacterial morphology and microfiltration performance. No such relationship could be adequately determined. In OBM broths image analysis was used to predict the biomass concentration. Modelling of the process using on- and off-line measurements, combined with scale-down methodologies, allows unit operations to be rapidly assessed and optimised, thus reducing product lead times through the development process. The performance of the microfiltration step was successfully predicted using a simple gel polarisation model which was reliable within a fermentation 9.5 % and a model modified to take account of operation at pressure below cTMP 6.2%. This allowed prediction of steady state permeate flux at the harvest time and the critical transmembrane pressure.

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