Scale-up from laboratory microfiltration to a ceramic pilot plant: Design and performance

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Abstract

A highly instrumented pilot microfiltration (MF) plant featuring a ceramic microfiltration membrane, back-pulsing device, permeate re-circulation in co-flow to achieve uniform transmembrane pressure (UTMP) and a cooling/temperature control system was designed, built and tested successfully with transgenic whole goat milk (TGM). In a previous study, it was shown that >90% of heterologous IgG could be recovered from TGM in the permeate by adopting close process control with low UTMP and operation at the iso-electric point (pI) of the target IgG. Here, these concepts were successfully employed to recover >90% of another IgG (pI = 7.1–7.5) from TGM by MF at the pilot-scale. The pilot plant MF system gave 90% yield for the same target protein with a 50% higher permeation flux rate (47 lmh instead of 32 lmh) and increased protein transmission (70% instead of 46%) as compared with the laboratory-scale MF unit. Thus, this study demonstrated the efficacy of the pilot MF plant and reinforced the generality at larger scale of the optimization methodology reported earlier by us.

Introduction

Since the 1980s, MF has been investigated as a competing technology to centrifugation for clarification and bacteria removal of milk and whey [1], [2], [3]. However, available polymeric membranes such as polysulfone, poly(ether sulfone) and polycarbonate, were not ideal in terms of chemical stability to NaOH, Na-hypochlorite and HNO3 which form a part of the typical cleaning regimen used in the dairy industry [4]. The advent of ceramic membranes provided an excellent opportunity in terms of chemical and thermal stability as they can withstand a pH range from 0.5 to 13.5 and temperatures over 100 °C. From the standpoint of filtration, it is important to note that these membranes are quite hydrophilic, resulting in lower protein adhesion than hydrophobic membranes like polyolefins (polypropylene and polyethylene). Also, their pore size distribution is typically narrower than that of polymeric membranes. Ceramic membranes are, however, about an order of magnitude more expensive than polymeric membranes. Early processes involving MF of dairy products with ceramic membranes employed the traditional concept of conducting MF at high inlet pressures and varying transmembrane pressure (TMP) along the membrane module [5]. This resulted in high permeation flux close to the inlet leading to cake build up and operation in the pressure-independent regime. This subsequently led to a progressive decline of protein transmission and selectivity with the progress of filtration. Hence, industrial scale-up was not feasible at that time. The problems of deteriorating MF performance and fouling were largely solved by employing the concept of low uniform TMP (UTMP) pioneered and first patented by Sandblom in 1974 [6]. UTMP operation made it possible to reap the benefit of efficient particle back-transport from the membrane wall at high axial wall shear rates (at high crossflow velocities) while maintaining low TMP in the pressure-dependent regime. As elucidated by Baruah and Belfort, in this regime, the membrane deposits are sparse and solute transport through the membrane is high [7], [8]. Recent advancements have focused on alternative ways of achieving UTMP, as permeate recirculation can lead to high pumping costs and temperature rise in the system. US Filter (Warrendale, PA) has developed a module called Membralox GP, which incorporates a variation in the porosity of the membrane support matrix along the length of the module. A progressive increase in the porosity of the support along the length of the module has the effect of uniform permeation rates along the module. A similar concept has been employed by Tami (Nyons, France) for their Isoflux modules where the thickness of the membrane selective layer is decreased along the module length to give a uniform permeation rate. Holm et al. (Alfa Laval, Tumba, Sweden) have patented a process where UTMP is achieved by packing the module shell side with polymeric beads [9]. Another issue being tackled is the membrane packing density, which is low for tubular monotube configurations. Multichannel arrangements akin to hollow fiber bundles, adopted by Tami (France) and US Filter have alleviated, to some extent, the problem of membrane packing density [1]. Tami manufactures ceramic membrane modules with non-circular, square and lobe-shaped channels, whereas US Filter products like Membralox and Sterilox have circular channels.

Many of the advances in membrane technology described above have been fuelled by the demands and advances in MF technology as applied to the dairy industry. MF technology has a dual appeal for the dairy industry: removal of bacteria with minimal heat treatment and fractionation of proteins. The work conducted by Holm et al. [9] was supplemented by Piot et al. (see Saboya and Maubois [1]) and led to the development of the famous Bactocatch process patented by Tetra Pak [9]. As the name suggests, the idea here is to pass skim milk through a microfiltration membrane (1.4 μm) and trap bacteria in the retentate. The important parameters here are UTMP of 7.5 psi (0.5 bar) and a very high axial velocity of 7 m/s. The Bactocatch process has been adapted with a lower membrane pore size (0.1–0.2 μm) to filter whole or skim milk to produce bacteria free whey in the permeate [1]. Recently, Baruah and Belfort have combined the recommendations of the aggregate transport model (ATM) for the MF of complex polydisperse suspensions with charge-based principles and uniform axial transmembrane pressure in the pressure-dependent regime to predict and subsequently obtain excellent yields (>95% in 4 diavolumes) of chimeric IgG from transgenic goat milk [10].

In this body of research, a laboratory-scale microfiltration unit was scaled up to a ceramic pilot plant that incorporates the developments discussed above and the technology of back-pulsing [11], [12], [13]. Experiments conducted in this pilot plant have demonstrated 50% higher product sieving rates and permeation fluxes than experiments with a laboratory-scale polymer membrane unit without sacrificing high product yields in excess of 90%. The purpose of this paper is to provide details of the pilot plant design and its preliminary performance.

Section snippets

Pilot plant design

The design philosophy of the ceramic MF pilot plant envisaged a concept, which incorporates the benefits of UTMP operation, ceramic membrane material, turbulent regime mass transfer and back-pulsing. Sandblom [6] suggested the use of permeate recirculation in the shell side of the membrane module (Fig. 1a). Depending on the actual dimensions of the module, the permeate recirculation rate can be adjusted so that the pressure gradient on the tube side (retentate) and the shell side (permeate) can

Feed suspension

Transgenic goat milk (TGM) was supplied by GTC Biotherapeutics (Framingham, MA) from their goat farm in Charlton, MA. The human IgG concentration in the transgenic goat milk (∼8 g/l) was diluted by GTC with non-transgenic goat milk to between 0.5 and 3.25 g/l so that higher volumes of TGM were made available. The IgG existed in three iso-forms and had a pI in the range of 7–7.5 (GTC Biotherapeutics).

Ceramic pilot plant

Fig. 2, Fig. 3 show the piping and instrumentation diagram of the ceramic microfiltration pilot

Results and discussion

The pilot plant MF experiments were started after the successful optimization of (>90% yield at 5 diavolumes) the lab-scale MF plant with a heterologous IgG product B having a pI of 9.0 as reported in Baruah and Belfort [10]. For all the experiments reported here, a different IgG (pI 7–7.5) was used. To minimize the amount of milk handled, initial optimization was conducted in the laboratory-scale microfiltration plant as described in [10]. The parameters varied for optimization were pH and

Conclusions

A highly instrumented pilot plant was designed, built and tested with excellent results (90% yield of IgG at 47 lmh) with a complex polydisperse suspension like transgenic whole goat milk. This ceramic plant combines desirable features such as a hydrophilic membrane of high durability and resistance to heat and chemicals, with excellent fluid mechanics resulting from turbulent flow and uniform transmembrane pressure. Specifications and design calculations are described in detail in the Appendix

Acknowledgements

GTC Biotherapeutics (Framingham, MA) is thanked for funding the work and for supplying the transgenic goat milk. Special thanks are due to Daniel Couto, Estzer Birck-Wilson and Wesley Church for the product data, the Protein A affinity chromatography column and protocol and IgG standards. Millipore Corporation, Bedford, MA is thanked for supplying the hollow fiber modules for the laboratory-scale MF plant and Ecolab, St. Paul, MN for the detergent and surfactant. Robert van Reis (Genentech,

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Present address: Abbott Laboratories, AP-8, 100 Abbott Park Road, Abbott Park, IL 60064, USA.

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