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Pharmaceutical Review Pharmaceutical Review Pharm. Bioprocess. (2013) 1(5), 423–440 Emerging technologies for the integration and intensification of downstream bioprocesses Downstream processing is currently the major bottleneck for bioproduct generation. Roy N D’Souza1, In contrast to the advances in fermentation processes, the tools used for downstream Ana M Azevedo2, processes have struggled to keep pace in the last 20 years. Purification bottlenecks M Raquel Aires-Barros2, are quite serious, as these processes can account for up to 80% of the total production Nika Lendero Krajnc3, cost. Coupled with the emergence of new classes of bioproducts, for example, virus-like Petra Kramberger3, particles or plasmidic DNA, this has created a great need for superior alternatives. Maria Laura Carbajal4, In this review, improved downstream technologies, including aqueous two-phase Mariano Grasselli4, systems, expanded bed adsorption chromatography, convective flow systems, and Roland Meyer5 & Marcelo fibre-based adsorbent systems, have been discussed. These adaptive methods are Fernández-Lahore*1 more suited to the burgeoning downstream processing needs of the future, enabling 1School of Engineering & Science, the cost-efficient production of new classes biomaterials with a high degree of purity, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany and thereby hold the promise to become indispensable tools in the pharmaceutical 2Institute for Biotechnology & and food industries. Bioengineering, Centre for Biological & Chemical Engineering, Department of Bioengineering, Instituto Superior Técnico, Technical University of Lisbon, Av. Rovisco Pais, 1049–001 Lisbon, The downstream processing (DSP) of limits and are unable to meet current prod- Portugal biopharmaceuticals is generally more cost- uct demand, not only in terms of space 3BIA Separations d.o.o., Mirce 21, 5270 intensive than corresponding upstream (fer- requirements, but also in terms of cost, Ajdovščina, Slovenia mentation) processes in the biotech industry resource consumption and process time. 4Laboratorio de Materiales and can account for up to 80% of production Consequently, technologies that offer pro- Biotecnológicos, Universidad Nacional de Quilmes – IMBICE (CONICET), costs. Moreover, with significant advances cess integration, that is, a reduction in the Roque Saenz Peña 352, (B1876BXD) in fermentation technologies, which have number of unit operations in the initial iso- Bernal, Argentina resulted in titers of over 20 g/l [1], related lation and purification steps while maintain- 5InfoConsult Gesellschaft für developments in downstream bioprocessing ing high product recovery and purity, would Informationstechnik mbH, Stolzenauer have failed to keep up in terms of scale and not only increase process economy but also Street 3, 28207 Bremen, Germany *Author for correspondence: product recovery. An additional challenge reduce process time. However, chromato- E-mail: m.fernandez-lahore@ that modern downstream practices need graphic separations, which require extensive jacobs-university.de to address is the targeting of new classes of feedstock pre-treatment, have been among bioparticles, such as monoclonal antibodies the most essential operations in the down- (mAbs), pDNA, virus-like particles (VLPs) stream processing of biopharmaceutical or nanoplexes, as well as whole cells products. Additionally, several chromato- (e.g., stem cells). These different bioproducts graphic steps are needed to fulfil the high and expression systems require a toolbox demands regarding product purity, consis- of robust and scalable techniques to satisfy tency, and safety [2,3]. Chromatography is a desired purity and yield in a sustainable and relatively slow process and requires expen- cost-effective manner. sive separation media and large volumes of Linear scale-up of traditional DSP meth- aqueous mobile phases. Therefore, faster ods of harvest clarification, concentration, production cycles, reduced consumable and primary recovery have reached their needs, and/or a reduction of chromato- future science group 10.4155/PBP.13.55 © 2013 Marcelo Fernández-Lahore ISSN 2048-9145 423 Review D’Souza, Azevedo, Aires-Barros et al. Key Terms graphic steps within established The successful scale-up of convective flow systems, Monoclonal antibodies: Class of downstream processes would result an example of which are the so-called monoliths [8], biological therapeutics based in a significant decrease of overall have also allowed unprecedented reductions in pro- on antibodies of the exact same production cost [4,5]. The concept of cess times as well as increased recovery rates for the structure and properties that have process intensification refers to any purification of extremely large biomolecules, such risen to prominence in the last decade for targeted treatment of process adaptation or optimization as pDNA and VLPs [9–11] . These unique chromato- various diseases. that results in a less resource-inten- graphic media have overcome the limitations of con- pDNA: Circular DNA used for sive biomanufacturing scheme, ventional porous bead adsorbents, which were initially gene therapy and vaccine including, but not limited to, lower designed for much smaller molecules. Convective formulations; A novel class water consumption, energy demand forces, such as flow rate, the ability to control mass of emerging therapeutic bioproducts. and environmental burden. transport in these systems, and larger external pore This review will primarily focus sizes can consequently accommodate increasingly Virus-like particle: Novel class of very large molecule used for on multifaceted approaches address- larger biomolecules [12] . vaccination purposes, bearing ing process integration and intensi- Finally, innovative fibrous adsorbent media that structural similarity to actual fication based on the utilization of offer faster process times and are easily integrated viruses, without the infectious non-traditional chromatographic or within current infrastructures can also lead to high- payload, which are difficult to process due to their large size. extractive methods, which include performance disposable systems that meet strict Aqueous two-phase separation: advances in bioprocess material health, safety, and quality requirements. For example, Process of selective product development, hardware design and cellulose and other natural polymers have been tra- isolation from complex mixtures advantageous modes of operation. ditionally used in the recovery and purification of by employing two immiscible While adsorptive methods, such proteins; they have been industrially processed into aqueous phases. as chromatography, are widely used specific shapes, such as spherical adsorptive micro- Expanded bed adsorption in industry as a key purification particles [13] and thin ultra/microfiltration membranes, chromatography: Chromatographic method technology, liquid–liquid extraction among others [14] . A novel composite fibre technology employing a fluidized bed technologies, such as aqueous two- known as gPore has been introduced, and offers new for product capture and phase separation (ATPS) systems, are kinds of adsorptive supports based on natural fibrous concentration from complex elegant emerging examples of pro- materials, which are packed in various open-structure feedstock in a single step. cess integration. In this technique, arrangements. More recently, they have been delivered Monolith: Macroporous single- block chromatographic material direct extraction of bioproducts as non-woven structures as well, which have exhibited enabling mass transfer solely from crude feedstocks can be accom- reproducible packing properties as well as compatibility by convection, which facilitate plished by the use of two incompat- with non-clarified feedstock. high flow rates leading to faster ible polymers or of a polymer and a Another important trend that has generated an process times. salt in an aqueous environment. It is increasing amount of interest lately is the transition a powerful technique that combines from traditional batch-based downstream process- moderate to high selectivity, high recovery and high ing regimens to continuous processes [15,16] . In this biocompatibility. respect, methods to transform the technologies dis- A complementary solid–liquid extraction technique, cussed in this review into continuous processes exist which also allows for the direct sequestration of a tar- in the form of simulated moving bed-type systems geted bioproduct directly from a crude feed, thereby and their variants [17–20] . Alternatively, promising integrating conventional clarification, concentration, methods, such as continuous countercurrent tan- and initial purification into a single unit operation, gential chromatography have shown exceptional is expanded bed adsorption (EBA) chromatography results [21,22]. Despite the considerable inertia of the (Figure 1) [6,7]. Converse to traditional packed-bed biopharmaceutical industry to move away from their chromatography, EBA employs a fluidized adsorbent established methods, the move towards continuous bed, where fluidization is driven by the flow rate of the processing could potentially revolutionize the way mobile phase, which is entering the system from the bioproducts, especially pharmaceuticals, are pro- bottom of the column. Larger biological particles, such duced, in a way similar to how continuous operation as whole cells or cell debris, are allowed to flow unhin- modes have done in case of other industries,
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