Downstream Industrial Biotechnology: Recovery A...
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The sustainable use of resources by Nature to synthesize the required products at the right place, when they are needed, continues to be the role model for total synthesis and production in general. The combination of molecular and engineering science and technology in the biotechnological approach needs no protecting groups at all and has therefore been established for numerous large-scale routes to both natural and synthetic products in industry. The use of biobased raw materials for chemical synthesis, and the economy of molecular transformations like atom economy and step economy are of growing importance. As safety, health and environmental issues are key drivers for process improvements in the chemical industry, the development of biocatalytic reactions or pathways replacing hazardous reagents is a major focus. The integration of the biocatalytic reaction and downstream processing with product isolation has led to a variety of in situ product recovery techniques and has found numerous successful applications. With the growing collection of biocatalytic reactions, the retrosynthetic thinking can be applied to biocatalysis as well. The introduction of biocatalytic reactions is uniquely suited to cost reductions and higher quality products, as well as to more sustainable processes. The transfer of Nature's simple and robust sensing and control principles as well as its reaction and separation organization into useful technical systems can be applied to different fermentations, biotransformations and downstream processes. Biocatalyst and pathway discovery and development is the key towards new synthetic transformations in industrial biotechnology.
Itaconic acid is a promising chemical that has a wide range of applications and can be obtained in large scale using fermentation processes. One of the most important uses of this biomonomer is the environmentally sustainable production of biopolymers. Separation of itaconic acid from the fermented broth has a considerable impact in the total production cost. Therefore, optimization and high efficiency downstream processes are technological challenges to make biorefineries sustainable and economically viable. This review describes the current state of the art in recovery and purification for itaconic acid production via bioprocesses. Previous studies on the separation of itaconic acid relying on operations such as crystallization, precipitation, extraction, electrodialysis, diafiltration, pertraction, and adsorption. Although crystallization is a typical method of itaconic acid separation from fermented broth, other methods such as membrane separation and reactive extraction are promising as a recovery steps coupled to the fermentation, potentially enhancing the overall process yield. Another approach is adsorption in fixed bed columns, which efficiently separates itaconic acid. Despite recent advances in separation and recovery methods, there is still space for improvement in IA recovery and purification.
With the maturation of antibody production technologies, both economic optimization and ecological aspects have become important. Continuous downstream processing is a way to reduce the environmental footprint and improve process economics. We compared different primary recovery, capture, and fermentation methods for two output-based antibody production scales: 50 kg/year and 1000 kg/year. In addition, a fixed fermentation volume case of 1000 L was analysed in terms of total cost of goods and process mass intensity as a measure of the environmental footprint. In our scenario, a significant amount of water can be saved in downstream processing when single use equipment is utilized. The overall economic and ecological impact is governed by the product titre in our perfusion (1 g/L) and fed-batch (4 g/L). A low titre in fermentation with similar downstream purification leads to higher process mass intensity and cost of goods due to the higher media demand upstream. The economic perspective for continuous integrated biomanufacturing is very attractive, but environmental consequences should not be neglected. Here, we have shown that perfusion has a higher environmental footprint in the form of water consumption compared to fed-batch. As general guidance to improve process economics, we recommend reducing water consumption.
Downstream processing refers to the recovery and the purification of biosynthetic products, particularly pharmaceuticals, from natural sources such as animal tissue, plant tissue or fermentation broth, including the recycling of salvageable components as well as the proper treatment and disposal of waste. It is an essential step in the manufacture of pharmaceuticals such as antibiotics, hormones (e.g. insulin and human growth hormone), antibodies (e.g. infliximab and abciximab) and vaccines; antibodies and enzymes used in diagnostics; industrial enzymes; and natural fragrance and flavor compounds. Downstream processing is usually considered a specialized field in biochemical engineering, which is itself a specialization within chemical engineering. Many of the key technologies were developed by chemists and biologists for laboratory-scale separation of biological and synthetic products, whilst the role of biochemical and chemical engineers is to develop the technologies towards larger production capacities.
The Recovery Conference Series has a history spanning well over a quarter century, with the first meeting, entitled "Advances in Fermentation Recovery Process Technology", held in 1981 in Banff, Canada. Two pioneers of recovery of biologic products science and engineering, Drs. Alan Michaels (then at Stanford University) and Harvey Blanch (University of California at Berkeley), co-chaired the inaugural meeting. Their vision and ability to bring together industrial and academic leaders to define and address downstream processing challenges within the biotechnology industry, which was newly emerging at the time, remains the central mandate of the Conference Series.
Alternative downstream operations, such as precipitation using ethanol, might be used to concentrate enzymes from the clarified lysate [45]. However, additional unit operations for precipitate recovery (centrifugation or filtration) and resuspension have to be considered. Aqueous-two phase systems (ATPS) have also been effectively used for separation and purification of industrial proteins. An elegant review on this topic was published by Ansejo and Andrews [46]. The production and purification of chymosin from recombinant Aspergillus supernatant is the most successful industrial application of this technology. Silvério et al. [47] studied the separation and purification of laccase from a complex fermented medium using an ATPS system with a thermo-separating polymer. Despite the possible recovery and reutilization of the polymer, a large loss of activity was observed (88%) when compared with the classical PEG-Salt systems. In general, precipitation and ATPS are adequate if some increase in the purity level of the protein is needed [33]. Although a more comprehensive study of the possible downstream process designs would be very interesting, here we have focused on the most common downstream process configurations described in similar studies, such as those listed in the Additional file 3: Table S7 [3, 5, 48].
Biopharmaceutical downstream processing (also known as DSP) refers to the recovery and purification of a drug substance (DS) from natural sources, such as animal or bacterial cells. Biopharmaceutical downstream processing is applicable in mAb or protein processes, as well as in the manufacture of oligonucleotides, polysaccharides and various vaccines.
It is important to keep in mind that no step of a downstream process can give 100% vector recovery. Therefore, before implementing polishing, it is recommended to determine the balance between the benefit for purity and the process yield.
The details of downstream processes used to manufacture clinical grade AAV vectors are rarely communicated, especially the percentage of product recovery. This being said, every manufacturing expert will agree that a purification step can hardly give a yield higher than 90%. Considering a 5-step process (clarification, capture chromatography, polishing, TFF and sterile filtration) with 90% recovery per step, the theoretical overall yield can be no more than 60%. The value drops to 32% for a more realistic recovery per step of 80%. These yields are consistent with the ones that were obtained experimentally in our laboratory for AAV8 and AAV9 serotypes (40% and 60%, respectively) [54,55].
The recovery and purification of fermentation products is one of the most important aspects of industrial fermentation processes. The selection of suitable process of recovery and purification depends upon the nature of the end product, their concentration, the by-products present, the stability of the product and degree of purification.
PURPLEGAIN aims to create a European network to share information, facilitating technology and knowledge transfer between the academic and industrial sectors, related to PPB applications for resource recovery from organic waste sources. Resource recovery includes wastewater or organic waste, open or closed environments, in single or chain processes. The network associates fundamental-focused and applied-research groups, improving lab-scale technology optimization through mechanistic modeling. It benefits the technology transfer from applied-research groups to industry, considerably improving process design.
A major issue hindering efficient industrial ethanol fermentation from sugar-based feedstock is excessive unwanted bacterial contamination. In industrial scale fermentation, reaching complete sterility is costly, laborious, and difficult to sustain in long-term operation. A physical selective separation of a co-culture of Saccharomyces cerevisiae and an Enterobacter cl