Final Report Summary - IB2MARKET (Bringing innovative industrial biotechnology research to the market)
Executive Summary:
IB2Market aimed to bring industrial biotechnology from the research lab to the market and to solve the bottle-necks in industrialization. Specifically, the project targeted the development and scale-up of new industrial biotechnology processes to produce the following compounds:
1. L-fucose and fucosylated oligosaccharides, specialty carbohydrates that are very difficult to produce through extraction or chemical synthesis, targeting mainly for pharmaceutical and cosmetic applications.
2. Bola-sophorolipids, a completely new type of biosurfactants with expected a wide range of applications.
For both product lines, the fermentation process and down-stream processing are optimized at 100 l and scaled up to 15m³ scale. Sufficient amounts of product were produced for application testing and exploratory marketing, to identify the most interesting market segments.
The technical, economic and environmental sustainability of the process from feedstock to product application were assessed. A valorisation strategy and business plan were drafted for industrialization and commercialization.
To this end, there was a close collaboration within a consortium with all the required expert partners to move the process from lab scale to industrialization: an open innovation pilot plant (Bio Base Europe Pilot Plant), a biotech start-up company (Inbiose), marketing companies for surfactants (EOC-surfactants) and specialty carbohydrates (Carbosynth), the RTD organisation that developed the processes at lab-scale (Ghent University), an application developer (Innovhub) and service-providing SMEs (Nova institute and BCNP consultants).
Main results and conclusions:
- For L-Fucose, due to unanticipated patent issue, a new strategy had to be developed to guarantee freedom to operate. This caused a delay but all objectives where achieved resulting in a process, guaranteeing a sustainable supply at competitive cost with actual scale of operations as evidenced with the techno economical analysis. Actions to still improve economics are identified and feasible.
- For Fucosylated oligosaccharides iterations with the market allowed to better understand the specific requirements and expectations in terms of specifications, regulatory, legal, quality, acceptable cost of the different markets. This information was challenged with the economics and assets to draft a valorisation strategy and business plan for Inbiose. A partnership deal was concluded within the course of the project bringing the 2FL very close to market introduction, legal and regulatory work still to be done for this specific market. Other collaborations contracts are pending. This allowed Inbiose to grow as SME to above 20 employees.
- For the Bola-sophorolipids functional benefits in detergent application were identified and confirmed. Techno economic analysis and market input point out that at actual scale of operation these are not cost competitive. Pharma and agrochemical market will be prioritised. Very promising functionalities within very specific applications, which can absorb higher cost, were identified. Developing these first will allow future ramp up of scale of operations. A business plan, valorisation strategy and investment teasers were prepared to establish a start-up company to exploit the IP and foreground as developed by UGent and BBEPP.
- Collaboration between different expert partners with a specific and complementary role in the innovation process was assessed and evaluated by the partners. This open innovation approach has shown to be very valuable. This might be the most effective way for start-ups or SME’s to bring a process from lab to market. Beside an evaluation also recommendations are made for further H2020 projects.
Project Context and Objectives:
1. Context & concept
One of the main hurdles for the Key Enabling Technology industrial biotechnology, an R&D intensive technology, is bringing the developed molecules to the market. The advent of genetic engineering and synthetic biology have made it possible to create a vast variety of novel, in many cases, new to market (and sometimes new-to-nature) molecules with still untapped applications and large market potentials. This variety of new molecules originates from platform technologies, aiming at known established markets but expanding to molecule variants with unknown applications. This creates a tree-like decision model (Figure 1) to assesses market potential of each molecule by testing firstly its application potential and secondly its production process economics.
- For the new-to-market molecules, small batches of novel molecules have to be produced for market prospection and application studies by potential clients.
- For molecules with established market, the production has to be scaled up to enable a thorough economic study.
However, these processes are quite costly, and the outcome is still uncertain. As a result, only few molecules make it to the market.
Figure 1 – Decission tree for evaluating the market potential of new molecules (in uploaded annex)
In this project, two product lines will be advanced down the innovation chain, from the research lab to the market. The aforementioned bottlenecks that hinder market introduction of new production processes for established molecules (e.g. L-fucose), as well as new-to-market molecules (e.g. fucosylated oligosaccharides and bola-sophorolipids) are addressed. To this end, an interdisciplinary partnership of expert partners covering the entire innovation chain has joined its forces
1.1. Specialty Carbohydrates
InBiose (IB) is an industrial biotech spin-off company from Ghent University (Centre of expertise for Industrial Biotechnology and Biocatalysis), engaged in the development, production and commercialization of specialty carbohydrates for use as ingredients or precursors in food, feed, pharmaceutical, cosmetic or chemical sector. IB has developed and patented a unique technology platform based on the use of genetically engineered microorganisms as cell factories for high-yield production of high-quality specialty carbohydrates. In this project, some of InBiose’s lead specialty products aimed primarily at the pharmaceutical and cosmetics market are optimised, scaled-up and prepared for industrialisation and commercialisation. These lead products are L-fucose, a molecule that is already established in the market, and new-to-market fucosylated oligosaccharides.
Fucosylated oligosaccharides (fig 2) are one of the main carbohydrate fractions in mother’s milk and have many advantageous effects on the babies health. Research shows that these carbohydrates significantly affect the IQ of babies, reduce the chance on infant death syndrome, infectious illnesses, auto-immune diseases, diabetes, allergies, obesity,... For pharmaceutical research to the effects of human milk oligosaccharides, many of these carbohydrates are isolated from mother’s milk itself, as they are extremely difficult to synthesize chemically. For industrial application, extraction from mother’s milk is obviously not a scalable technology. To overcome this, Ghent University and its spin-off company InBiose have developed a generic platform technology that allows the production of specialty carbohydrates efficiently. The technology relies on fermentation with genetically engineered bacteria that efficiently produce the specialty carbohydrates from cheap substrates and that excrete the product in the medium. The process has been developed at lab scale and high product titers are routinely obtained. This new technology is both efficient and scalable, i.e. not relying on mother’s milk.
Figure 2: Structure of L-fucose (left) and 2-fucosyllactose (right) as an example of a fucosylated oligosaccharide (in uploaded annex)
L-fucose is presently produced by extraction from natural sources, It occurs in many plants, algae and the exopolysaccharide matrix of certain micro-organisms. Currently it is extracted from these organisms with very low yields, resulting in a very high price and limited availability.
Alternative L-fucose production processes are chemical synthesis or enzymatic synthesis these technologies have severe disadvantages (e.g. toxic intermediates, expensive substrates, chirality issues, low yields, hardly scalable, ... ). Due to its very high price, L-fucose currently has limited applications in pharmaceuticals and cosmetics. With the new technology developed by InBiose, L-fucose has the potential to become a significantly cheaper molecules with limitless availability, so that new applications come in sight.
1.2. Biosurfactants
Surfactants are molecules that are able to lower the surface tension between liquids, solids and gases, thereby allowing them to mix and disperse readily in water or other liquids. They are amphiphilic molecules consisting of a hydrophilic and a hydrophobic moiety that interact with the phase boundary in heterogeneous systems. The non-polar “tail” is typically a hydrocarbon or fatty acid chain whereas the polar “head” appears in many different varieties such as carbohydrates, alcohol alkoxylates, amino acids, carboxylates, sulphates, sulphonates and phosphates.
The biosurfactants subject of the IB2Market project are biologically derived surface active molecules that are fermentatively produced by microorganisms. They are promising eco-friendly substitutes for the current fossil-fuel-derived chemical surfactants. Nevertheless, penetration of these biodetergents in various applications is on the one hand hampered by the lack of diversity, distinct properties are required for a particular application. On the other hand, a lot of interesting molecules can be produced at lab scale in minor amounts and with low yields, but an economical feasible and scalable biotechnological production process is lacking. Sophorolipids are the most promising for development as one can obtain high titers from glucose and vegetable oil with the non-pathogenic yeast Starmerella bombicola. Sophorolipids are composed of the carbohydrate head sophorose, an unusual β-(1,2) disaccharide consisting of two glucose molecules linked to a long-chain hydroxylated fatty acid (Fig. 3). Recently, Ghent University has developed a metabolically engineered Starmerella bombicola yeast strain that produces bola-sophorolipids in high yield and titer, sophorolipids with an unexpected but intriguing structure: a fatty acid molecule with a carbohydrate head on both sides (fig. 4).
Figure 3: Structure of the major sophorolipid compounds as found in natural sophorolipids: Acid form (open linear) and lactonic form (closed circular) form of natural sophorolipids. (in uploaded annex)
Figure 4: Structure of the new bola-sophorolipids targeted in this project. (in uploaded annex)
These new and innovative molecules behave completely different compared to the classic sophorolipids and are expected to find many new applications in other fields due to their bolaform nature.
This project intends to industrialise and commercialise these new and innovative bola-sophorolipids. For that, the process needs to be optimised and scaled up to pilot scale at the Bio Base Europe Pilot Plant. As this new glycolipid is expected to find completely new applications, test quantities of the new molecules need to be produced and distributed to potential users for application development. For that, the partner Innovhub will explore and develop new applications for these biosurfactants. Furthermore, an exploratory marketing approach will be performed by EOC-surfactants, a leading surfactant producer and marketing company. This project is expected to lead to the industrialisation and commercialisation of the new biosurfactants, and the development of a wide range of new applications and markets.
1.3. IB2Market model of open innovation towards commercial exploitation
The project is introducing a new concept of open innovation to reach market exploitation by gathering specific players, expert partners active at each level of the innovation chain, thus creating intense collaboration between research, development, production, market-intelligence and valorisation. This type of collaboration is found inside industries (i.e. in multinationals), but has rarely been demonstrated as a collaboration model between different expert SMEs. For new products, not fitting a traditional value chain and for start-ups, this is expected to be the most efficient way to proceed from research to market.
2. Project Objectives
IB2Market aims to bring industrial biotechnology from the research lab to the market and to solve the bottle-necks in industrialization. Specifically, the project targets the development and scale-up of 2 product lines resulting from new industrial biotechnology processes. For both product lines:
1) the fermentation process and down-stream processing are optimized and scaled up to 15.000 liter scale.
2) Sufficient amounts of product are produced for application testing and exploratory marketing, in order to identify the most interesting market segments.
3) The technical, economic and environmental sustainability of the process from biomass to product application are also assessed, with particular emphasis on identifying and solving the bottlenecks in the innovation chain.
4) A valorization plan is drafted to complete the innovation chain.
The project aims for industrialization and commercialization of the developed products and processes.
The project consortium has all the required players to move a process from lab scale to industrialization: an open innovation pilot plant (Bio Base Europe Pilot Plant), a biotech start-up company (Inbiose), marketing companies for surfactants (EOC-surfactants) and specialty carbohydrates (Carbosynth), the RTD organization that developed the processes at lab-scale (Ghent University), an application developer (Innovhub) and expert service-providing SMEs (Nova institute and BCNP consultants). This open innovation approach is being evaluated, this is expected to be the most efficient way for SME’s or start-ups to proceed from research to market.
Project Results:
1. Introduction
To achieve the project objectives the following project structure was implemented:
In WP1, samples of these three new products are produced to enable exploratory marketing in WP2. Process scale-up to 100L, multiple iterations and even 4.500L fermentation scale was required to enable downstream purification process and to produce sufficient amounts of samples.
During Exploratory Marketing (WP2), the samples were made available to the wider application development community. This is achieved by distributing the products through specialised suppliers of specialty carbohydrates (partner CBS) and surfactants (partner EOC). In addition, the consortium (ISSI) is performing application studies as well on the bola-sophorolipids.
In WP3, the production processes for the three products is scaled-up to demonstration scale (up to 15.000L) and further optimised to reach techno-economic viability. In addition, data is generated for a thorough economic and environmental sustainability analysis in WP4 and WP5.
In WP4,the economic viability of the process is determined by taking technical and market data into account. In addition, the value-chain is examined and when gaps are encountered, a list of relevant candidates to fill the gaps are suggested. There is a close interaction with WP3, and alternatives in the technicalities of the process are discussed between partners active in WP3 and WP4 to find the best techno-economic solution.
WP5 is monitoring the IP situation of the three products, with specific attention for IP around the newly discovered application fields. LCA analysis of the products is also performed in WP5, and feedback is given to WP3.
In WP6, the results from all previous WPs is considered in an integrated feasibility analysis. A valorisation strategy is drafted for each product to go to the market, and to look for investors.
In WP7, the project results are communicated to the wider public. However, the emphasis is on active communication with the business community in general, and potential investors and stakeholders in the new valorisation chains that show interest in the developed processes. WP8 deals with the project management.
All WPs, and especially WP1 to WP6 are strongly interdependent, and findings in one WP is important input for another WP.
2. Main S&T results and generated foreground
2.1. WP1 Sample production of new-to-market molecules
2.1.1. Objectives
O1.1 Gram to kg scale production of fucosylated oligosaccharide for application testing
Why: To obtain enough product for application and conformity tests
How: By means of small scale bioreactor production and small scale purification systems
O1.2 Gram to kg scale production of L-fucose for application testing
Why: To obtain enough product for application and conformity tests
How: By means of small scale bioreactor production and small scale purification systems
O1.3 Kg scale production of Bola-sophorolipids for application testing
Why: To obtain enough product for application and conformity tests
How: By means of small scale bioreactor production and small scale purification systems
2.1.2. Specialty carbohydrates
For the specialty carbohydrates, first of all optimization of the established production process of 2’-fucosyllactose (Figure 1) was continued.
Figure 1: structure of 2’fucosyllactose (in uploaded annex)
As the exploratory marketing clearly learned for each application and each customer the required product specifications are different, further optimisation of the production process in both fermentation and downstream processing, was required.
Issues & challenges identified were:
- Improvement of productivity and titers required to improve techno economics: a lot of effort was put into medium optimisation & study of impact process parameters (pH, temperature, aeration, agitation, feed strategies). Design of experiment approach was used. Best combinations of parameters and medium composition were identified and scaled yielding a substantially improved titer, productivity.
- A second challenge was product purity. Depending on target market there is a different tolerance with regards to byproducts and impurities as regulatory approval is specification based. Deviations from said specifications are unacceptable. Different techniques for downstream purification were evaluated, removing impurities and byproducts but adding costs to the process. Modifications to certain process steps and parameters also substantially reduced formation of byproducts. Avoidance of byproduct formation was proven to be best strategy.
- Balance between productivity, titers and techno economics: e.g. there is a positive correlation between production environment and production efficiency, but this environment affects the other unit operations and related costs. By an integrated approach of different expertises (scientists, engineers and economic analysis) an optimal balance was identified.
For the production of 3-fucosyllactose, at BBEPP the protocol as received from Inbiose was tested at 7L scale and scaled up to 100L scale. Although production yield at 100L scale was less than at 7l scale, sufficient product was produced to evaluate downstream processing at pilot scale. It was found that the identical production and downstream processing processes for 2-fucosyllactose (2FL) can be used for the production of 3 fucosyl lactose, which is a very important advantage for scaling up the process. In addition, no by-products, were produced, so a very pure product was obtained. Still the downstream processing as established for the 2FL was challenged by exploration
Concerning the production of L-fucose (Figure 2), a potential freedom to operate issue came up. A new strategy was developed to safeguard freedom to operate which was made available for upscaling. The partners still managed to do planned work within the framework of the project and scaled up the process. Although the process is less mature and the titers and productivity are not ideal for low end markets, we managed to create a process that can guarantee a security of supply to markets such as the high end markets, for which this is of key importance.
Figure 2: structure of L-fucose (in uploaded annex)
2.1.3. Biosurfactants
For the bola sophorolipids (Figure 3), early feedback from the market, especially for detergent products, via the partner EOC showed that the price should be reduced substantially to meet the requirements of the market. So to come to an economically viable and competitive process for the detergent market it is important to maximise productivity and titers as these directly affect cost of the product.
Figure 3: Structure of bola-sophorolipids (in uploaded annex)
To increase productivity and titer the influence of a whole range of process parameters and medium components were tested by large number of experiments at shake flask level, followed by validation of the findings at 3L, 7l, 10L and 150l scale.
Impacts of initial glucose concentration, osmotic pressure, N-content and source, feed rate and feed regime, inoculum size, ... were evaluated on productivity, titers and purity of the product.
Special attention was also given to the source of the fatty acid, different sources were tested and ranked, very important differences were noticed.
Other important learning is optimisation needs to be done at reactor level, impact of a parameter at shake flask level can be dramatically different compared to reactor level. Finding the optimal parameters for a process needs to be (re)done strain by strain.
The 150 L scale fermentations were used as well to develop downstream processing procedures. Different techniques a.o. membrane filtration, chromatographic separation, ... were screened and evaluated, different separation techniques were combined as well. The techniques were evaluated in terms of recovery yield and obtained purity, but also the economics and on sustainability via the life cycle analysis. The techno economic analysis provided a list of so called “hot spots”, parameters which had the largest impact on the production cost. As productivity (g/L.h) was identified as the parameter having the largest impact on the production price, priority was given to improve this parameter. Cell recycle was explored by the end of the IB2Market project, first results confirmed feasibility and improvement of economics by reduced downtime of the process. Product yield as an associated parameter, was included in this optimisation. This was done by strain engineering at UGent on one hand and process optimization at BBEPP and UGent on the other hand.
For the strain engineering (UGhent), overexpression strains for the genes/enzymes responsible for (bola) SLs biosynthesis were generated. Interesting results were obtained, but no new strain with better inherent production capacities could be delivered to BBEPP within the IB2M project. A further expansion of the molecular toolbox is required to enable efficient and quick optimization of already existing production strains. This will be set as a goal in future research projects.
Also the production of sophorose (a specialty carbohydrate) and non-acetylated acidic SLs starting from bola SLs using alkaline hydrolysis was explored, since it is regarded as an additional volume increasing opportunity to valorize the bola sophorolipid platform under development in IB2Market. A sample of good quality were sent to CBS to evaluate the listing of the ‘new source’ of sophorose in their catalogue.
As a result of this multiple iterations several samples with different grades in purity and concentrations and consequently different cost levels were obtained for the exploratory marketing.
2.2. WP2 Exploratory marketing of new-to-market molecules
2.2.1. Objectives
O2.1 Evaluation of the fucosylated oligosaccharides in all potential applications and especially in pharma, diagnostics, and cosmetics
Why: To expand the market potential to high end markets such as cosmetics and pharma
How: Via exploratory marketing and the transfer of samples to interested companies
O2.2 Evaluation of the L-fucose in all potential applications and especially in pharma, diagnostics, and cosmetics
Why: To expand the market potential of L-fucose
How: Via exploratory marketing and the transfer of samples to interested companies
O2.3 Evaluation of the bola-sophorolipids in all potential applications to pinpoint the most promising applications
Why: To create a market for bola-sophorolipids
How: Via exploratory marketing and the transfer of samples to interested companies
2.2.2. Specialty Carbohydrates
Inbiose & BCNP identified and contacted over 48 companies, Inbiose had further discussions under NDA (non disclosure agreement) with 25 companies, ranging from cosmetics, agro, feed, pharma to medical nutrition and infant formula. In total 8 MTA’s (Material Transfer Agreements) have been negotiated for fucosylated oligosaccharides. The material is being used for application testing, formulation, and (pre-)clinical testing. Further discussions are also ongoing with academia and with ingredient manufacturers. These discussions required much more effort than expected, because it was necessary to visit some of these companies multiple times to convince them about the novel products offer by Inbiose and to negotiate NDA’s, MTA’s and potential licenses.
The second fucosylated oligosaccharide produced, 3-fucosyllactose, has been produced in large enough quantities, a specification sheet was also compiled and this product was promoted further towards the companies and academic institutions. Under the cover of MTA’s, this product was also sent out for testing. Although this product might be similar to 2’fucosyllactose, more and more data is published that show a clear differentiation in functionalities. Expectation is, that now the product is more readily available more new applications and properties will be identified for 3-fucosyllactose.
Overview of the types of companies contacted by Inbiose, 48 in total (figure in uploaded annex)
It became clear that the quality and safety management of the environment in which the products are produced, are essential for the targeted markets. Therefore a lot of effort was put into the evaluation of a quality assurance system at BBEPP and how to improve and implement such a quality assurance and control system according to the standards needed. In a first approach expertise with regards to quality management was hired externally. This did not work to satisfactory level as it requires too much iterations with expert people on the work floor. To tackle this an experienced quality manager was hired by BBEPP internally to guide the processes. The contacts with the markets showed different markets have different requirements and different expectations with regards to specifications and certificates of analysis, much more analyses than foreseen in the project applications were needed. Expertise from specialized labs with the necessary GLP certifications to analyse the samples was hired, this process was managed by the QA manager. Analysis that were done, were a.o. endotoxin, microbial contaminations and heavy metal analysis, next to carbohydrate composition, protein, DNA and water content.
In the case of L-fucose, different applications are known, security of supply is main concern. Application work is not initiated if this is not solved. The exploratory marketing actions for L-fucose were hence more to proof the possibilities of biotechnology for L-fucose synthesis. The same type of companies as for fucosylated oligosaccharides showed interest in L-fucose. Mainly companies working in the pharmaceutical field showed real interested, if the production cost is reduced further, cosmetic companies will become a future target market.
In conclusion, the availability of product enabled Inbiose to get access to a large number of companies, ranging from the infant formula and medical nutrition multi-nationals to companies in the pharmaceutical, feed, agro and cosmetic industry. By being able to talk to all these companies Inbiose gained an enormous amount of market intelligence that allowed great progress in WP 4 and 6. NDA’s limit disclosure of information that was obtained.
2.2.3. Bola sophorolipids
To support the exploratory marketing specification sheets were made for the bola-sophorolipids, these specification sheet were updated with additional information obtained during the project, but information which could still be used for IP generation was omitted. These specification sheets were made available via the website and through the partners EOC and Carbosynth (CBS).
Samples as generated within WP1 and WP2 were provide by UGhent and BBEPP to a large number of research institutions and companies. The obtained contacts were generated by a combination of active contacting and requests for samples. These requests came from people (both academia and companies) who learnt about the technology at public conferences or from the IB2Market and/or CBS website/catalogue.
The samples were used to establish general properties of the Bola Sophorolipids, as ecotoxicity, cytotoxicity, irritation, chemical stability, surface tension and CMC, supramolecular assembly, antimicrobial properties, ... .
The functionality of these samples within specific applications for specific markets was evaluated by the partners, companies and academia. Test markets were besides detergents (EOC and INNOVHUB leading the process), also specialty chemicals via CBS, agrochemicals, pharmaceuticals, advanced materials, textile and food.
Sophorose (a specialty carbohydrate) and non-acetylated acidic SLs can be perfectly derived from the Bola sophorolipids. As such they could increase the production volume, reducing the production cost. For this reason these 2 molecules were also included in the exploratory marketing. CBS is evaluating the listing of the ‘new source’ of sophorose in their catalogue.
Results obtained by EOC/Innovhub proof specific products have interesting functionalities for specific applications within the detergent market. Hand dish wash, automated dish wash, textile wash, hard surface cleaning, rinse aid, ... were evaluated, also reformulation and synergistic effects with actual ingredients were evaluated.
Exploratory work was also done by the partners on the emulsification and film forming properties, these are important properties for cosmetic products, where higher prices levels are possible, especially when added value can be proven (e.g; lower amounts of active(s) required, anti-fungal/bacterial effects,...).
Despite the interesting properties within specific detergent applications market introduction at actual scale of operation is not feasible. Price levels should be brought down by a factor 4-5 to be competitive for these applications. This will be feasible if scale of operation exceeds 1000 tpa. tons/year) and with further strain and process optimization.
From the exploratory marketing approach done within agrochemicals and pharma some interesting applications which can absorb actual cost levels at actual scale of operations were identified. These will be the primary focus for future work and were the basis or the drafted valorisation strategy and business plan.
2.3. WP3 Scale-up and demonstration of the production process
2.3.1. Objectives
O3.1 Production and downstream processing scale-up to 10.000L scale for fucosylated oligosaccharides, L-fucose and bola-sophorolipids
Why: Large scale production for market introduction
How: By means of the well-equipped Bio Base Europe pilot plant scale-up and downstream processing lines
O3.2 Demonstration of the technical feasibility of each technology at that scale
Why: As a proof of concept for the developed technologies.
How: By means of the well-equipped Bio Base Europe pilot plant scale-up and downstream processing lines
O3.3 Collection of technical data to enable economic sustainability analysis and LCA
Why: To obtain enough data to evaluate the economic feasibility of the process.
How: By means of the well-equipped Bio Base Europe pilot plant scale-up and downstream processing lines and critically assessed by skilled personnel
2.3.2. Specialty Carbohydrates
A lot of work has been put into the scale up of the 2’Fucosyllactose process. When scaling up new problems arise. Product composition stability and process reproducibility are key requirements for the targeted markets. This urged INBIOSE and BBEPP to look more closely at the medium composition and how to adapt it so it fits the larger production scale and meets expectations with regards to reproducibility and stability. To this end a large number of 5L fermentations were done by Inbiose and at BBEPP a large number of additional 7.5 10 and 150L fermentations have been done to test and validate repeatability and reproducibility. This gave the needed data to move forward to the 15m³ scale.
Additional to the production environment, the way to perform the process was altered, so process steps could be eliminated and the overall process could be simplified. This change however had to be validated on the basis of the end product composition. During the project a specification sheets were set up, which had to be matched. Hence, every process change had to verified and validated to the same required product specification.
By the end of the project a successful 15m³ fermentation was run with a yield, production rate and titer conform expectations. The higher volumes of broth also required an adapted downstream processing. At the smaller scale process flow with the unit operations were determined, but this had to be translated to the larger scale. Downstream purification process was successfully scaled up resulting in a product matching product specification set forth by the market (result of the exploratory marketing).
Another task, outside of the project is to run repetitive batches to further optimise the process parameters and proving the process stability further at scale. These runs are for regulatory instances that require repetitive batches to show process stability and to proof that the process leads to an end product that is conform a certain product specification. Regulatory application work was not included in this project.
As explained earlier in the report, Inbiose identified an obstruction in FTO on its strategy to produce L-fucose. To mitigate risk, it was decided to develop another route. This caused an important delay. It appeared a good fortune that we were able to develop a new strain quickly. Many hurdles were addressed in the scale up of 2’fucosyllactose and were not encountered anymore in the L-fucose scale up. There are however some differences between both the 2’fucosyllactose process and the L-fucose process on process performance.
The process as developed by Inbiose for the L-fucose production was validated on 7 and 10 L scale in the lab facilities of BBEPP. Subsequently, several 50 and 150 L runs were executed. Once successful at 150 L, this process was further scaled up to 15m3 scale. Due to high similarity between 2FL and L-Fucose production process and the experience established by scaling the 2FL process resulted in a swift scale-up of the L-fucose process. An analogue downstream process as used for 2FL was successfully applied. The generated broth in the scale up experiments was used to further work on improving the DSP process, new strategies for a more cost efficient unit operations were explored.
Process data generated at this scale was used to validate the assumptions used for the LCA and as input for the Techno-Economic Assessment. The actual longer fermentation time and lower end titer results in a higher cost but still competitive to known price level in the market as evidenced by the TEA. Further improvements to the overall process are feasible, which will further reduce production costs.
2.3.3. Bola-Sophorolipids
The process development and optimization of both the fermentation and downstream purification, as described above was applied at the semi-industrial 15 m³ scale to generate the first pre-industrial batches of bola sophorolipids and thereof derived acidic sophorolipids and sophorose. Due to typical scale-up problems, eg scaling factors for oxygen transfer and agitation but also very practical issues as sterilising feedstocks first 15 m³ fermentation failed. Second 15m3 fermentation and the DSP thereof was successful resulting in relatively large and pure quantities of the three targeted products.
The scale up of the processes developed during the IB2M project showed that they are both feasible and scalable. The obtained data was compared with the assumptions which were made as input for the LCA and TEA analyses to ascertain that correct conclusions were drawn from these analyses.
2.4. WP4 Market and value-chain analysis
2.4.1. Objectives
O4.1 To techno-economics for each production process
Why: To determine the costs and revenues of each target molecule and balance both
How: By means of the well equipped Bio Base Europe pilot plant scale-up and downstream processing lines
O4.3 Determining all market possibilities for the each product
Why: To determine the largest possible application range to increase the market potential of each molecule
How: Via exploratory marketing and building up a large network of potential clients
O4.4 Determining the market potential of each product on these markets
Why: To evaluate the market size of the specific target products and thus the needed production capacity
How: Via market studies of the existing markets and the markets that can be entered in the future
O4.5 Determining the gaps in the value chain for each product
Why: To ensure a smooth market introduction of the product at a competitive price
How: By understanding the value chain, from resource to product, thus analyzing each step in the whole value chain.
2.4.2. Specialty Carbohydrates
The techno-economical assessment was done for both L-fucose and fucosylated oligosaccharides based on process data and process layout resulting from WP1 and WP3. For both products, L-fucose and fucosylated oligosaccharides we were able to calculate the CAPEX need and OPEX need. For fucosylated oligosaccharides we would need to find investment for a production plant with a capacity of more than 1000 tpa, which will employ about 50 full time employees. At scale this will lead to a production cost and price of product that is well acceptable for the market. The techno-economical assessment informed also further on the hot spots of the process, where we could further optimize to drive down costs, allowing to enter even larger markets.
For L-fucose we have calculated the investment for a plant that has a capacity around 100 tpa, which will employ about 30 full time employees. The process cost and hence the price of the product is at scale also well acceptable for the market. We simulated several downstream processing operations and their related costs to guide future development work and looked where the hot spots in the process are. This knowledge will help us to further reduce costs and increase the availability of the product to more markets.
From the multiple contacts during the exploratory marketing work, a lot of (confidential) information was obtained concerning the applications of fucosylated oligosaccharides, the applications of L fucose, the current market structure of the applications of fucosylated oligosaccharides and L-fucose, the market share potential and their value chains. This information was obtained under NDA and provided Inbiose and BCNP a lot of market intelligence to pick and to prioritise future goals and to build the appropriate valorisation strategy and business plan. The main conclusion from this work is for fucosylated oligosaccharides, that the most important applications for fucosylated oligosaccharides can be found in infant and medical nutrition, an enormous market.
On the basis of this market structure market size was modelled and the market share that could be obtained was calculated.
Similarly, we identified the value chain for the cosmetic application of L-fucose. Here we understood that the market will have to be developed stepwise, first providing the necessary proof of biotechnological synthesis of L-fucose, then driving the cost down to levels that are acceptable for larger markets.
2.4.3. Bola sophorolipids
The techno-economic analysis for (bola) sophorolipids was in a first instance based on the process data and process design resulting from WP1 and WP3 and calculated for a production scale similar to the largest scale available at BBEPP, fully dedicated to bola sophorolipids production. For such scenario very reliable data was available with regard to workforce, capital expenditure for investment and operational costs. Annual production volume was calculated for this scale. The product production cost was calculated using the most efficient downstream processing option.
At this scale the majority of the costs are directly linked to the capital investment cost (45%; depreciation over 10 years) and the operating labour cost (37%). Increasing the scale of operations is obviously one method to reduce costs, however this requires sufficient demand for the product. The production cost at actual scale of operations can also be further decreased by increasing the productivity of the process as this was the biggest point for improvement highlighted by the sensitivity analysis. The most promising strategies to do this are scale up of the continuous process, of which proof of concept was delivered at the end of the IB2m project and further genetic modification of the producing micro-organism.
The most promising markets at the actual cost structure for application of (bola) SLs are the pharma and agro market. This information was used for the valorisation strategy and writing of the business plan. The cosmetic market is another possibility, which remains to be further explored and the application of the (bola) sophorolipids in (green) detergents is also still a possibility once larger scale production comes within scope. For that purpose, the price needs to be reduced a factor 4-5 which becomes possible at production volumes of over 1000 tons/year and/or by further increasing the productivity as determined in the TEA analysis. The market share assessment for the chosen applications could only be described on a qualitative base, as no numbers of the exact market structure and value was freely available.
2.5. WP5 IP and Life Cycle Analysis
2.5.1. Objectives
O5.1 Determining the IP position of fucosylated oligosaccharides, L-fucose and bola-sophorolipids in their new application fields
Why: Identifying potential IP opportunities and threats is crucial to protect the newly developed technologies and to build up a well established position in the market
How: Via IP mining and FTO analysis
O5.2 Determining LCA for fucosylated oligosaccharides, L-fucose and bola-sophorolipids
Why: Each process has a potential ecological impact and this has to be determined to ensure an environmental neutral production process.
How: Ecological sustainability of the production of these processes will be assessed based on LCA principles following ISO 14040 and ISO 14044.
2.5.2. IP analysis Specialty carbohydrates
During the project UGent and Inbiose further strengthened their patent portfolio with one filing (EP14193151.9) and UGent and/or Inbiose intend to file other patents in the near future.
Every 2 to 3 months an IP search was done to evaluate the IP position of the competition and novel applications by end users by UGent and Inbiose. Inbiose also has gone through several due diligence analysis by companies and investors. This required much more effort than expected and experts in the field of intellectual property and contract lawyer were hired to help answering questions on FTO posed by potential partners and venture capital investors.
2.5.3. IP Analysis biosurfactants
UGent performed an analysis of the IP landscape, which showed that FTO was not compromised. This was still the case at the end of the IB2M project and this information was obtained through regular checking of the IP landscape. The patent application on the bola producing strain will be further maintained by UGhent, as all claims were considered as novel, inventive and industrial applicable by an international search report.
BBEPP is considering to generate IP protection on the newly developed purification process for (bola) sophorolipids as this method could also be applied for other biosurfactants. As this purification route results in products with higher purity and a tremendous increase of the recovery during DSP, this could enhance the commercialization of other (new) biosurfactants.
Certain application work with the sophorolipids initiated, is also expected to lead to application patents. This will strengthen the position for exploitation.
2.5.4. LCA analysis specialty carbohydrates
An LCA analysis for 2-fucosyllactose was performed by Nova. The main conclusions is that a yield increase by additional recovery actions not necessarily compensate for the extra footprint, as they cause additional energy requirement, water removal was already identified as a hot spot. The hot spot analysis also indicated the substrate, sucrose, as having a major impact. This is intrinsic for the process (and actually for any biotechnological process), no alternative is available.
Furthermore the production of 2-fucosyllactose by fermentation was compared to the chemical productions process as described in patents. It showed the footprint of the fermentation process was at least an order of magnitude smaller. However, the scale of the chemical process modelled was small, which might influence the outcome.
The LCA for L-Fucose was also completed. Because of the great similarities between both processes, the conclusions are similar. Increasing the use of process water for increased product recovery does not compensate for the increased environmental impact.
Since a fermentation based production is an alternative way to produce Fucose, a comparison (benchmarking) with other production routes is meaningful, in order to derive further insights regarding its environmental favourability. Therefore a comparison between extraction-based production of L-fucose and the fermentation route developed within this project was done. This comparison clearly showed that the fermentation process is significantly more environmentally friendly.
2.5.5. LCA analysis biosurfactants
The LCA analysis for bola sophorolipids was performed by Nova. The LCA was based on data derived from the performed processes in the IB2M project in combination with assumptions for further development and scale up of the processes.
An eye opener and surprising result from this study was the learning that the use of first generation renewable resources (vegetable oil and sugar) has a tremendous effect on the environmental impact of the production of the (bola) sophorolipids. Vegetable oil was identified as one of the hot spots of the process, glucose also had a considerable impact. This impact is directly related to the agricultural processes for the production of these substrates, which is thus a step upstream of the technology investigated/described in the IB2M project.
LCA data obtained for the sophorolipids was checked towards LCA data for APG’s (alkylpolyglycosides, a chemically produced renewable biosurfactants) available to project partners, environmental impact is within the same order of magnitude.
Energy intensive processes e.g. steam generation and freeze drying (as final conditioning step for preservation) were obviously identified as additional hot spots. The latter also has a very big impact on the production price of these molecules, as was concluded from the TEA analysis and should thus be avoided. Application in markets where products are applied as liquids (e.g. the detergent market) are favourable with regards to environmental impact.
Another finding was the fact that the impact of the two compared purification routes did not significantly differ at the evaluated scale. This is important information as the combination of these two routes has a positive influence on both product purity and recovery, while the production cost/kg remains the same.
Main conclusion is the fact that maximization of the conversion yield of oil (but also sugar) to (bola) sophorolipids is key to lower the environmental impact of the production of (bola) sophorolipids. An additional option is to focus on second generation feedstocks for the production of (bola) sophorolipids if application allows this. This option will be studied in future projects.
2.6. WP6 Business plan and valorisation strategy
2.6.1. Objectives
O6.1 To develop the most suitable valorisation strategy
Why: Depending on the application and the market size a suitable business model has to be determined.
How: The techno-economical studies and the market evaluations will be used as input to determine the most optimal business model
O6.2 Connect with investors
Why: The development of platform technologies is very cost intensive and the time to market has to be bridged or the large scale market introduction has to be catalyzed by risk investors
How: The data that is generated within this project will be used to write financial and business plans to present to potential investors.
2.6.2. Specialty carbohydrates
BCNP and Inbiose started the development of business plan and valorisation strategy with a workshop about economic and technological state of the art. An existing business plan of Inbiose was analysed to identify gaps and needs for the new business plan. In the first phase of this project part BCNP and Inbiose decided to focus on 2-Fucosyllactose (2-FL) because of a shorter time-to-market than L-Fucose.
To get more information about application possibilities of 2-FL or Human Milk Oligosaccharides (HMOs). BCNP and Inbiose started to interview experts from academia and industry. This information directed the development of the valorisation strategy.
At the start several business models were developed and evaluated with respect to economic aspects. From these models BCNP and Inbiose selected two different business models to concentrate on further. To this end BCNP did research to fill in missing variables for implementation of those two business models:
• Research of Partners to complete the Value Chain.
• Research of approval requirements for different applications.
• Research of prices of comparable products.
• Analysis of Competitors
After confidential meetings with industrial partners Inbiose decided for the most promising business model as well as the most promising starting market.
As there is/was no established 2-FL market yet, only the niche application identified and still in the research and development phase, BCNP and Inbiose derived a market potential from different assumptions to the market. The estimation of the market potential was improved within the course of the project on the basis of information gathered in the market.
At the beginning, during the workshops, it was necessary to develop an attractive story line to convince potential investors as well as the different market players. This formed the basis to build the business plan and model, which consists of the business idea, business model, management team or market. There were then written down and were used as a guidance to identify potential sales and revenue. The latter is then included in the financial plan.
In the second half of the project the business plan and valorisation strategy for L-Fucose was developed. The most important part was to derive a market under the condition that Inbiose is able to produce L-Fucose to much lower prices so that a shift from niche market to mass market could be done in the future.
For such case BCNP and Inbiose derived a market potential and a sales potential for L-Fucose. This was basis for a business case developed by BCNP.
For both products, Fucosylated oligosaccharides and L-Fucose, BCNP and Inbiose created an investment teaser. Those investment teasers is being used to attracted potential investors in a first way without disclosing confidential information. If investors are interested, the business plan can be sent after signing a confidential disclosure agreement. During the project, Inbiose has also actively been discussion with multiple venture capital funds, who have been showing a lot of interest. Inbiose hopes to be able to valorise this interest with a capital increase on short notice.
2.6.3. Biosurfactants
BCNP and UGent started the development of business plan and valorisation strategy with multiple workshops to discuss technology, identified applications and projected economics. Evaluation and feedback from EOC and INNOVHUB showed the product had interesting and promising properties within detergents applications. Detergent applications were assumed most promising application prior to the start of this project. Unfortunately techno economics showed that, at the actual scale of operations, cost is too high to access this market with the Bola sophorolipids, a substantially ramp up of the scale of operation is required.
The most suitable valorisation strategy for bola sophorolipids is described in the business plan and consisted of setting up a spin off company called ‘Amphistar Solutions’, valorising the IP and foreground as generated by UGent and BBEPP. The Spin-off company would develop and market products in a first instance for the agro and pharma markets. Capital requirements to finance next phases were identified, a capital which can be acquired by bank loans and/or investors. Contact with a first possible investor were already made and investment in the company by this business angel is a possibility. Further investors will be attracted, amongst others by sending out the prepared investment teaser and further dissemination of the technology through business development and by attending public conferences.
2.7. WP7 Dissemination
2.7.1. Objectives
O7.1. The efficient dissemination of the project results
Why: Communicating results is essential for the commercialization of the newly developed production processes
How: Via websites, press releases, (scientific) articles, conferences, workshops, ... .
Dissemination actions are addressed in dedicated section.
2.8. WP8 Management
2.8.1. Objectives
O8.1. Establishment of a management scheme to ensure the fulfilment of the project objectives
Why: To ensure the successful implementation of the project and the proper valorisation of the obtained results.
How: The consortium will be managed by a supervisory board and a coordination team.
2.8.2. Organisation
The IB2Market project was managed by a supervisory board and a coordination team.
- The supervisory board consisted out of one representative of each partner and monitored the implementation of the project and did issue management, deciding on corrective actions if required.
- The Coordination team was responsible for the daily management and consisted out of the project coordinator, the operational manager, financial and administrative managers. The operational manager supervised the project at task level with the product line coordinators, to this purpose dedicated ad hoc meetings were organised with involved partners.
- The general tasks for the daily management of the IB2Market project consisted of:
o Putting together the agenda’s, sending invitations, make reservations, write minutes,.... in order to organize and report on meetings (Partners meetings, Management meetings,....)
o proofread deliverables, adjust where necessary in cooperation with the involved partners, upload the deliverables
o collecting the necessary data (from different partners) in time to complete the required EC documents for reporting
Kick-off meeting was held in Ghent 14/04/2014, 5 general project meetings within the course of the project were held 16/06/2014 in Cologne (D), 18/01/2015 Ghent (Be), 08/06/2015 Frankfurt am Main (D), 27/10/2015 in Brussels (Be) and 04/05/2016 in Desteldonk (Be). The general meetings consisted out of 2 parts:
- A plenary part (progress meeting) where all scientist, engineers, experts give an update on the work done and progress made during past period and planned work for upcoming period.
- A closed part (management meeting) where the supervisory board monitors progress, discusses issues, decides on corrective actions, typical agenda:
o Signing attendee list
o approval agenda & minutes previous meeting
o Personnel & resources
o Milestones & deliverables
o Reporting issues
o miscellaneous
Potential Impact:
1. Impact
1.1. introduction
The expected impact from the IB2market project is two-fold:
1. Real economic impact as new industrial biotechnology processes for the production of biosurfactants and specialty carbohydrates will be demonstrated and industrialised. New and innovative products will reach the market, providing economic development and employment.
2. General lessons to be learned from this project, as a case study for demonstration projects in industrial biotechnology. The collaboration between an open innovation pilot plant, industrial companies, an industrial biotechnology spin-off, application developers and the research community is quite new for a European FP7 project. This knowledge is particularly relevant for Europe as the upcoming Horizon 2020 program is expected to strongly emphasize similar demonstration projects that have a real economic impact.
1.2. Economic & societal impact
1.2.1. Biosurfactants
Market relevance:
Surfactants are used for a wide variety of applications in households, industry and agriculture. They are extensively used in cleaning applications and as a formulation aid to promote solubilisation, emulsification and dispersion of other molecules in products ranging from chemicals, cosmetics, detergents, foods, textiles, pharmaceuticals, etc. Surfactants are performance molecules that intervene in nearly every product and every aspect of human life. In terms of production numbers, surfactants are one of the most important classes of industrial chemicals with a total world production exceeding 4 million ton per year. About half of that is used in household and laundry detergents, the other half in a wide variety of industrial sectors, particularly the chemical industry, food industry, cosmetics and personal care, textile industry, health care, paper industry, agriculture, etc.
Especially for applications where their excellent biocompatibility and biodegradability is important, a large market potential for biosurfactants is available. These properties are particularly advantageous in applications that require a massive introduction and interference with the environment, for example in bioremediation, washing applications and crop protection. Bio surfactants have excellent functional properties combined with a low ecotoxicity and good biodegradability and thus offer a vastly improved environmental compatibility compared to traditional surfactants.
The main challenge their limited availability and diversity on the market, posing obvious limitations to application developers that need surfactant diversity for formulating different applications.
The targeted bola-sophorolipids provide a welcome addition for new application development, within cleaning, agrochemicals, cosmetics, pharmaceutical, thus expanding the range of biosurfactants on the market, providing more diversity and effectively turning biosurfactants into an industrial reality.
Biosurfactant market exploration:
The optimisation and upscaling of the platform technology made samples available for market exploration with known techno-economical and sustainability data. General functional properties & characteristics as ecotoxity, cytotoxicity, irritation, chemical stability, surface tension, antimicrobial properties were determined by partners or by interested prospects. The samples and data are made available to industries and academia to evaluate the performance and cost-in-use in a whole range of applications (Surfactant market by EOC and INNOVHUB), specialty chemicals market (By Carbosynth), agrochemicals (Universities and industry), Pharma market (Universities and Industries), advanced manufacturing and materials market (Universities and industries), food applications as emulsifier (industries), ...
Generated & future impact:
Feedback from the exploratory marketing challenged to actual scale of operations allowed the partners to prioritise target markets and actions. Actual scale of operations causes a high product cost. Very promising results and contacts focus actions towards pharma and agrochemical applications which can absorb actual product cost. Later on, once scale of operations will by enlarged, higher volume markets like detergent market enter into scope. To further develop the market and technology the establishment of a spin-off company is prepared with a business plan, roadmap and investment teasers. This will create new jobs and will turn bio surfactants with their renewable character and better biodegradability and biocompatibility in to industrial reality.
1.2.2. Specialty Carbohydrates
Market relevance
The current applications of L-fucose and fucosylated oligosaccharides are quite limited, due to their high price and limited availability. L-fucose is currently sold at prices between 500 – 2.500 €/kg, in quantities that are not higher than about 5000 kg per year, mainly in the pharmaceutical area.
The cosmetic field is particularly promising, as it is a large scale market and new applications in cosmetics are continuously being developed by leading cosmetic companies, e.g. company l’Oréal filed a broad patent on the application of L-fucose in skin care (WO2009034559). Despite the excellent results in the skin care application tests, the problem is the very limited availability of L-fucose, currently excluding any large scale application in cosmetics.
Furthermore, L-fucose can be an alternative for L-rhamnose in the synthesis of flavours. L-rhamnose obtained from action production methods suffers insecure and insufficient supply. If a cost reduction of L-fucose is achieved and supply is secured , it may become perfectly a large scale operation.
fucosylated oligosaccharides currently attract most attention as a Human Milk Oligosaccharide, to be used as an infant nutrition ingredient. Human milk oligosaccharides as the name does suggest are components which are found in and make human breast or mothers milk unique. Various application studies have shown excellent results for this compound, most notably for the reduction of infant intestinal infections. fucosylated oligosaccharides have been shown to bind to receptors in the intestinal tract, thus inhibiting the binding of well-known microbial pathogens such as Salmonella and pathogenic E. coli strains to the intestinal epithelium. The application of fucosylated oligosaccharides has been shown to reduce infant mortality significantly. A biotechnological platform which guarantees security of supply and at acceptable cost makes these beneficiary characteristics available to much larger market or population.
Fucosylated oligosaccharides also have application potential in pharmaceuticals, notably for the treatment of auto immune and bowel diseases. Also in the cosmetic field, fucosylated oligosaccharides are expected to have similar properties as L-fucose.
Generated & future impact
The development of the L-fucose within the IB2Market project was slowed down due to a potential FTO issue. A new strategy was developed to safeguard freedom to operate. The newly developed technology was scaled allowing validation and analysis of the techno-economics. In conclusion the actual status of the technology as developed by Ghent University and its spin-off company InBiose already offers a solution to above by providing sustainable supply at competitive cost. There is clear potential and plans for further improvement of the techno economics.
For the development of the fucosylated oligosaccharides, iterations between the market and operational level created a much better understanding with regard to the product specifications, quality expectations and requirements and their impact on operations, cost structure, legal and regulatory requirements.
These learnings challenged versus the economic aspects and assets of INBIOSE allowed to develop with BCNP the most suitable valorisation strategy and business plan.
As a result of the project INBIOSE will make 2 FL available to the market in large volumes, so everybody will have access and will benefit from the beneficiary characteristics (as described above) of 2FL. Inbiose developed a portfolio of prospects with whom negotiations are ongoing and are expected to result in new collaborations. Within the course of the project, INBIOSE grew to an SME with over 20 employees.
1.3. valorisation open innovation approach
1.3.1. Introduction
To bring new molecules to the market, an intensive collaboration between disciplines like research, development, operation, market intelligence and application/market is prerequisite. This type of collaboration is common practice internally within established (large) industries. Start-ups and SME’s in Industrial Biotech typically do not have all these capabilities and expertise in house as the technology is disruptive and value chains are new. Within the IB2Market project, an open innovation approach is pursued and collaboration is sought between different SME’s and innovation actors with the aim of bringing together the required complementary expertise within the innovation trajectory. In IB2Market, two technology providers that want to bring their new-to-market molecules to the market were assisted by (i) a pilot plant to deliver proof-of-concept and to scale the process up to industrial scale, (ii) market research specialists and (iii) business plan support services.
1.3.2. Evaluation and learnings open innovation approach
• Key success factor for the open innovation model is collaboration between partners with complementary expertise and interests to have open and swift communication, good collaboration and value sharing. Competitors and/or partners with conflicting interests within the value chain should be avoided. It’s recommendable to settle “value sharing” upfront.
• For the fucosylated oligosaccharides, infant food was identified as the most obvious and promising target market. The open innovation model and collaboration has shown to be very effective and fast to identify relevant actors and effective strategies to approach them.
• The project confirms that bringing new molecules to the market is much more than merely addressing technological issues. It is key to establish an early contact and close exchange with the market to establish and match expectations. Matching expectations and capabilities affect all disciplines within the innovation process. It is a process of iterations, back and forth, not a linear trajectory. Changing specifications of the end project can affect the production process and its economics. It might as well lead back to the primary process of strain engineering, to meet the specifications or to make the process economically viable or more sustainable.
• Quality aspects and quality management have shown to be key element, expectations differ a lot between different markets. This might lead to extra constraints, complications again affecting the techno economics and chances for market introduction.
• Life cycle analysis (LCA) and Techno-economic analysis (TEA) have shown to be a powerful instrument to identify so called “hotspots” in the process. Hotspots being the unit operations resorting the largest impact on environmental footprint or operational costs. This focusses the efforts in improving the process.
1.3.3. Conclusions & recommendations
• Access to an open demonstration infrastructure with technological expertise and flexible setup appeared essential as different target markets have different expectations in product specifications but also different expectations with regard to quality, regulatory and sustainability aspects. The impact of these expectations on the techno economics can only be assessed in an industrial relevant environment. Open access pilot & demonstration infrastructures speed up this process and reduce financial risks.
EU should study how such type of open pilot & demonstration infrastructures operating at higher TRLs can be fostered and how the use of such infrastructure in H2020 projects can be facilitated. (Within the H2020 work program on research infrastructures there are INFRADEV and INFRAIA topics typically in preparation of ESFRI projects. ESFRI projects target lower TRLs.) So EU should also consider to support infrastructure at higher TRL’s if such infrastructure are open access and crucial to bring disruptive research & innovation to market.
• The project has clearly demonstrated that entering new markets requires a multidisciplinary set of expertise, which SME’s or start-ups typically lack. Within the development of new value chains and new processes, life cycle analysis and techno economic analysis might be guiding processes. The strategy to approach the market, the position in the value chain and the value proposition might vary a lot per product-market combination. By consequence these are very dynamic processes with multiple iterations. Making such expertise available within the course of an innovation action is recommendable. Though one has to consider that the reward of the innovation lays with the technology owner not with the expert partners. Expert partners are typically for profit organisations, by consequence not 100% funded. So they have to cofinance themselves to provide services to the technology owner which benefits from the service.
• Developing a new value chain implies early exchange with application & market for new-to-market products and leads to iteration, innovation by default is not a linear trajectory. These required iterations might conflict with the rigidity of a description of work in a typical FP7/H2020 project: Extra work might be required, the scope of work might change to be able to do what is right to increase the success of the innovation, some deliverables might become obsolete. The change of scope, extra work, new partners or subcontractors might require budget changes. To overcome these hurdles, processing amendments should be a swift process, ideally with close/fast interaction with the officer.
• IB2Market is an FP7 project, where the funding rate is only 50% for demonstration and 100% for all other activities (research, management and other). Innovation (or demonstration) actually represents ‘the valley of death’: there is still a high technological risk combined with a high financial risk as piloting and demonstration is more expensive than research. We underline that the higher funding rates for innovation actions, as applied Horizon2020, are a prerequisite to promote innovation in Europe.
2. Main dissemination actions
2.1. Introducing new molecules
In support of and to enhance the introduction of new molecules to the market a dissemination and communication strategy is followed:
1) Project website was created (www.IB2market.eu) press release was made to introduce project and productlines.
2) As part of this dissemination and communication strategy presentation material for market development was created, aiming at potential business partners, investors and end-users. This presentation material consists out of
a. specification and information sheets for the different product lines were prepared, the necessary analytics were performed (in house, by partners or by expert analytical labs) to establish basic information thought relevant for the market, if new parameters identified relevant, spec sheets were adapted. General specification sheet were made available for the (bola) sophorolipids via the website & through partners Carbosynth & EOC. For the specialty carbohydrates depending on the application specification sheets differ and are part of the confidential information as exchanged with the prospect. A more general information sheet was made available through the website.
b. sample material was made available on request and under MTA via de project partners. Sample were provided under MTA to assure prospect does not take any IP position on an application based on the sample material as provided by the IB2Market partners without consent of the IP owners of the background. This to avoid unwanted limitation in fields of applications.
c. Investment teasers were prepared by the Amphistar Solution team ( UGent, BBEPP & BCNP) for the Amphistar Solutions start-up (exploiting IP on the biosurfactants). Investment teasers were prepared by Inbiose, UGent & BCNP for the technology & portfolio fucosylated oligosaccharides and for the technology and portfolio L-Fucose.
3) To engage with the industry and to communicate and demonstrate the potential for commercial application of the IB2Market product lines and its open innovation approach the partners presented posters and gave oral speeches at multiple relevant conferences, trade fairs and occasions where academia, industry and policymakers meet: a.o. EFIB 2014/2015/2016; FASEB 2015, RRB 10 & 11, FIE 2015, ... .
2.2. Valorisation open innovation approach
- A specific workshop was organised in the Showcase theatre at EFIB October 28th in Brussel were all partners promoted the project and the open innovation approach by an oral speech explaining their specific role, importance and merits in the innovation process.
- Both Inbiose and BBEPP as coordinator were present at the exhibitions in the European Parliament at the occasion of the 7th European Innovation Summit with a booth and a poster to share experiences and to promote the project. The scientific coordinator of the IB2Market project participated to panel discussion and gave on December 9th 2015 an oral presentation on “Open-access, independent pilot and demonstration infrastructures are key to bring key enabling technologies from lab to market" at this 7th European Innovation Summit.
3. Exploitation of results
3.1. Specialty carbohydrates
During the first period of the project a potential FTO-issue popped up for L-Fucose. Although this entailed a low risk, the risk was mitigate risk with a new production strategy to produce the L-Fucose, guaranteeing freedom to operate. This could not have been anticipated and caused a delay on the introduction of L-Fucose to the market. So In the first phase of this project part BCNP and Inbiose decided to focus on 2-Fucosyllactose (2-FL) because above and an expected shorter time-to-market, with a real and strong pull for nutraceutical applications.
To get more information about application possibilities, expectations and requirements of 2-FL and L-fucose, BCNP started to interview experts from academia and industry for applications identified, mainly medical nutrition, cosmetics and pharma.
Over 48 companies were contacted, over 25 NDA’s and 8 MTA’s were negotiated. This provided INBIOSE and BCNP with a lot of very valuable but confidential information. Main learnings were
- Establishing these contacts with NDA’s and MTA’s is a burdensome process for a start-up.
- Required information, specifications, quality expectations and acceptable cost level dependents very much on the targeted market as well as it might vary between players in the same market.
- Different strategies/ partnerships might be recommendable for different market.
- Required information and expectations exceed what was anticipated.
These learnings and information were challenged versus the economic aspects and assets of INBIOSE to develop with BCNP the most suitable valorisation strategy and business plan.
In conclusion 2 different business models were selected, a first business model in which INBIOSE acts as a technology provider, licensing its technological platform and a business model for specific markets in which INBIOSE is controls the manufacturing and sells the product to brand owners. To this purpose INBIOSE seeks contract manufacturers with appropriate capabilities and scale to meet specifications and volume, quality expectations of the targeted market. INBIOSE has no intention to sell consumer products.
Besides a valorisation strategy and a business plan, investment teasers were created for the technology platform on fucosylated lactose and L-Fucose.
As a results of the exploratory marketing and other work done within IB2Market
- Further negotiations are ongoing with both investors and prospects for the technology within other markets.
- Thanks to above progress INBIOSE grew to an SME with >20 employees.
For the fucosylated lactose there’s still a lot of hurdles to be taken mainly with regards to regulatory issues and toxicological studies, these processes are being or will be initiated. For L-Fucose the techno -economic feasibility was demonstrated by the end of the project, cost structure is within actual market price range. Important improvements to reduce cost are identified and feasible to ease the market introduction.
3.2. Biosurfactants
BCNP and UGent started the development of business plan and valorisation strategy with multiple workshops to discuss technology, identified applications and projected economics. Evaluation and feedback from partners EOC and INNOVHUB showed the product had interesting and promising properties within detergents applications. Detergent applications were assumed most promising application prior to the start of this project. Unfortunately techno economics showed that at the actual scale of operations cost is too high to access this market with the bola sophorolipids, a substantially ramp up of the scale of operation is required.
The most suitable valorisation strategy for bola sophorolipids is described in the business plan. Intention is to create a spin-off company called Amphistar Solutions, which will exploit IP & foreground generated by UGent and BBEPP, developing and marketing products for the agro and pharma markets.
Exploratory work done within these markets identified specific applications which do tolerate higher cost levels matching actual scale of operations. If scale of operations increases, resulting in a cost reduction, specific applications within the detergent market will enter into scope again.
An investment teaser is created to attract investors for the start-up AmphiStar to establish and to attract companies interested within the applications. Further application work is ongoing, it is anticipated that these will lead to new foreground and application patents strengthening the position of AmphiStar Solutions.
List of Websites:
http://www.ib2market.eu/en/home/
IB2Market aimed to bring industrial biotechnology from the research lab to the market and to solve the bottle-necks in industrialization. Specifically, the project targeted the development and scale-up of new industrial biotechnology processes to produce the following compounds:
1. L-fucose and fucosylated oligosaccharides, specialty carbohydrates that are very difficult to produce through extraction or chemical synthesis, targeting mainly for pharmaceutical and cosmetic applications.
2. Bola-sophorolipids, a completely new type of biosurfactants with expected a wide range of applications.
For both product lines, the fermentation process and down-stream processing are optimized at 100 l and scaled up to 15m³ scale. Sufficient amounts of product were produced for application testing and exploratory marketing, to identify the most interesting market segments.
The technical, economic and environmental sustainability of the process from feedstock to product application were assessed. A valorisation strategy and business plan were drafted for industrialization and commercialization.
To this end, there was a close collaboration within a consortium with all the required expert partners to move the process from lab scale to industrialization: an open innovation pilot plant (Bio Base Europe Pilot Plant), a biotech start-up company (Inbiose), marketing companies for surfactants (EOC-surfactants) and specialty carbohydrates (Carbosynth), the RTD organisation that developed the processes at lab-scale (Ghent University), an application developer (Innovhub) and service-providing SMEs (Nova institute and BCNP consultants).
Main results and conclusions:
- For L-Fucose, due to unanticipated patent issue, a new strategy had to be developed to guarantee freedom to operate. This caused a delay but all objectives where achieved resulting in a process, guaranteeing a sustainable supply at competitive cost with actual scale of operations as evidenced with the techno economical analysis. Actions to still improve economics are identified and feasible.
- For Fucosylated oligosaccharides iterations with the market allowed to better understand the specific requirements and expectations in terms of specifications, regulatory, legal, quality, acceptable cost of the different markets. This information was challenged with the economics and assets to draft a valorisation strategy and business plan for Inbiose. A partnership deal was concluded within the course of the project bringing the 2FL very close to market introduction, legal and regulatory work still to be done for this specific market. Other collaborations contracts are pending. This allowed Inbiose to grow as SME to above 20 employees.
- For the Bola-sophorolipids functional benefits in detergent application were identified and confirmed. Techno economic analysis and market input point out that at actual scale of operation these are not cost competitive. Pharma and agrochemical market will be prioritised. Very promising functionalities within very specific applications, which can absorb higher cost, were identified. Developing these first will allow future ramp up of scale of operations. A business plan, valorisation strategy and investment teasers were prepared to establish a start-up company to exploit the IP and foreground as developed by UGent and BBEPP.
- Collaboration between different expert partners with a specific and complementary role in the innovation process was assessed and evaluated by the partners. This open innovation approach has shown to be very valuable. This might be the most effective way for start-ups or SME’s to bring a process from lab to market. Beside an evaluation also recommendations are made for further H2020 projects.
Project Context and Objectives:
1. Context & concept
One of the main hurdles for the Key Enabling Technology industrial biotechnology, an R&D intensive technology, is bringing the developed molecules to the market. The advent of genetic engineering and synthetic biology have made it possible to create a vast variety of novel, in many cases, new to market (and sometimes new-to-nature) molecules with still untapped applications and large market potentials. This variety of new molecules originates from platform technologies, aiming at known established markets but expanding to molecule variants with unknown applications. This creates a tree-like decision model (Figure 1) to assesses market potential of each molecule by testing firstly its application potential and secondly its production process economics.
- For the new-to-market molecules, small batches of novel molecules have to be produced for market prospection and application studies by potential clients.
- For molecules with established market, the production has to be scaled up to enable a thorough economic study.
However, these processes are quite costly, and the outcome is still uncertain. As a result, only few molecules make it to the market.
Figure 1 – Decission tree for evaluating the market potential of new molecules (in uploaded annex)
In this project, two product lines will be advanced down the innovation chain, from the research lab to the market. The aforementioned bottlenecks that hinder market introduction of new production processes for established molecules (e.g. L-fucose), as well as new-to-market molecules (e.g. fucosylated oligosaccharides and bola-sophorolipids) are addressed. To this end, an interdisciplinary partnership of expert partners covering the entire innovation chain has joined its forces
1.1. Specialty Carbohydrates
InBiose (IB) is an industrial biotech spin-off company from Ghent University (Centre of expertise for Industrial Biotechnology and Biocatalysis), engaged in the development, production and commercialization of specialty carbohydrates for use as ingredients or precursors in food, feed, pharmaceutical, cosmetic or chemical sector. IB has developed and patented a unique technology platform based on the use of genetically engineered microorganisms as cell factories for high-yield production of high-quality specialty carbohydrates. In this project, some of InBiose’s lead specialty products aimed primarily at the pharmaceutical and cosmetics market are optimised, scaled-up and prepared for industrialisation and commercialisation. These lead products are L-fucose, a molecule that is already established in the market, and new-to-market fucosylated oligosaccharides.
Fucosylated oligosaccharides (fig 2) are one of the main carbohydrate fractions in mother’s milk and have many advantageous effects on the babies health. Research shows that these carbohydrates significantly affect the IQ of babies, reduce the chance on infant death syndrome, infectious illnesses, auto-immune diseases, diabetes, allergies, obesity,... For pharmaceutical research to the effects of human milk oligosaccharides, many of these carbohydrates are isolated from mother’s milk itself, as they are extremely difficult to synthesize chemically. For industrial application, extraction from mother’s milk is obviously not a scalable technology. To overcome this, Ghent University and its spin-off company InBiose have developed a generic platform technology that allows the production of specialty carbohydrates efficiently. The technology relies on fermentation with genetically engineered bacteria that efficiently produce the specialty carbohydrates from cheap substrates and that excrete the product in the medium. The process has been developed at lab scale and high product titers are routinely obtained. This new technology is both efficient and scalable, i.e. not relying on mother’s milk.
Figure 2: Structure of L-fucose (left) and 2-fucosyllactose (right) as an example of a fucosylated oligosaccharide (in uploaded annex)
L-fucose is presently produced by extraction from natural sources, It occurs in many plants, algae and the exopolysaccharide matrix of certain micro-organisms. Currently it is extracted from these organisms with very low yields, resulting in a very high price and limited availability.
Alternative L-fucose production processes are chemical synthesis or enzymatic synthesis these technologies have severe disadvantages (e.g. toxic intermediates, expensive substrates, chirality issues, low yields, hardly scalable, ... ). Due to its very high price, L-fucose currently has limited applications in pharmaceuticals and cosmetics. With the new technology developed by InBiose, L-fucose has the potential to become a significantly cheaper molecules with limitless availability, so that new applications come in sight.
1.2. Biosurfactants
Surfactants are molecules that are able to lower the surface tension between liquids, solids and gases, thereby allowing them to mix and disperse readily in water or other liquids. They are amphiphilic molecules consisting of a hydrophilic and a hydrophobic moiety that interact with the phase boundary in heterogeneous systems. The non-polar “tail” is typically a hydrocarbon or fatty acid chain whereas the polar “head” appears in many different varieties such as carbohydrates, alcohol alkoxylates, amino acids, carboxylates, sulphates, sulphonates and phosphates.
The biosurfactants subject of the IB2Market project are biologically derived surface active molecules that are fermentatively produced by microorganisms. They are promising eco-friendly substitutes for the current fossil-fuel-derived chemical surfactants. Nevertheless, penetration of these biodetergents in various applications is on the one hand hampered by the lack of diversity, distinct properties are required for a particular application. On the other hand, a lot of interesting molecules can be produced at lab scale in minor amounts and with low yields, but an economical feasible and scalable biotechnological production process is lacking. Sophorolipids are the most promising for development as one can obtain high titers from glucose and vegetable oil with the non-pathogenic yeast Starmerella bombicola. Sophorolipids are composed of the carbohydrate head sophorose, an unusual β-(1,2) disaccharide consisting of two glucose molecules linked to a long-chain hydroxylated fatty acid (Fig. 3). Recently, Ghent University has developed a metabolically engineered Starmerella bombicola yeast strain that produces bola-sophorolipids in high yield and titer, sophorolipids with an unexpected but intriguing structure: a fatty acid molecule with a carbohydrate head on both sides (fig. 4).
Figure 3: Structure of the major sophorolipid compounds as found in natural sophorolipids: Acid form (open linear) and lactonic form (closed circular) form of natural sophorolipids. (in uploaded annex)
Figure 4: Structure of the new bola-sophorolipids targeted in this project. (in uploaded annex)
These new and innovative molecules behave completely different compared to the classic sophorolipids and are expected to find many new applications in other fields due to their bolaform nature.
This project intends to industrialise and commercialise these new and innovative bola-sophorolipids. For that, the process needs to be optimised and scaled up to pilot scale at the Bio Base Europe Pilot Plant. As this new glycolipid is expected to find completely new applications, test quantities of the new molecules need to be produced and distributed to potential users for application development. For that, the partner Innovhub will explore and develop new applications for these biosurfactants. Furthermore, an exploratory marketing approach will be performed by EOC-surfactants, a leading surfactant producer and marketing company. This project is expected to lead to the industrialisation and commercialisation of the new biosurfactants, and the development of a wide range of new applications and markets.
1.3. IB2Market model of open innovation towards commercial exploitation
The project is introducing a new concept of open innovation to reach market exploitation by gathering specific players, expert partners active at each level of the innovation chain, thus creating intense collaboration between research, development, production, market-intelligence and valorisation. This type of collaboration is found inside industries (i.e. in multinationals), but has rarely been demonstrated as a collaboration model between different expert SMEs. For new products, not fitting a traditional value chain and for start-ups, this is expected to be the most efficient way to proceed from research to market.
2. Project Objectives
IB2Market aims to bring industrial biotechnology from the research lab to the market and to solve the bottle-necks in industrialization. Specifically, the project targets the development and scale-up of 2 product lines resulting from new industrial biotechnology processes. For both product lines:
1) the fermentation process and down-stream processing are optimized and scaled up to 15.000 liter scale.
2) Sufficient amounts of product are produced for application testing and exploratory marketing, in order to identify the most interesting market segments.
3) The technical, economic and environmental sustainability of the process from biomass to product application are also assessed, with particular emphasis on identifying and solving the bottlenecks in the innovation chain.
4) A valorization plan is drafted to complete the innovation chain.
The project aims for industrialization and commercialization of the developed products and processes.
The project consortium has all the required players to move a process from lab scale to industrialization: an open innovation pilot plant (Bio Base Europe Pilot Plant), a biotech start-up company (Inbiose), marketing companies for surfactants (EOC-surfactants) and specialty carbohydrates (Carbosynth), the RTD organization that developed the processes at lab-scale (Ghent University), an application developer (Innovhub) and expert service-providing SMEs (Nova institute and BCNP consultants). This open innovation approach is being evaluated, this is expected to be the most efficient way for SME’s or start-ups to proceed from research to market.
Project Results:
1. Introduction
To achieve the project objectives the following project structure was implemented:
In WP1, samples of these three new products are produced to enable exploratory marketing in WP2. Process scale-up to 100L, multiple iterations and even 4.500L fermentation scale was required to enable downstream purification process and to produce sufficient amounts of samples.
During Exploratory Marketing (WP2), the samples were made available to the wider application development community. This is achieved by distributing the products through specialised suppliers of specialty carbohydrates (partner CBS) and surfactants (partner EOC). In addition, the consortium (ISSI) is performing application studies as well on the bola-sophorolipids.
In WP3, the production processes for the three products is scaled-up to demonstration scale (up to 15.000L) and further optimised to reach techno-economic viability. In addition, data is generated for a thorough economic and environmental sustainability analysis in WP4 and WP5.
In WP4,the economic viability of the process is determined by taking technical and market data into account. In addition, the value-chain is examined and when gaps are encountered, a list of relevant candidates to fill the gaps are suggested. There is a close interaction with WP3, and alternatives in the technicalities of the process are discussed between partners active in WP3 and WP4 to find the best techno-economic solution.
WP5 is monitoring the IP situation of the three products, with specific attention for IP around the newly discovered application fields. LCA analysis of the products is also performed in WP5, and feedback is given to WP3.
In WP6, the results from all previous WPs is considered in an integrated feasibility analysis. A valorisation strategy is drafted for each product to go to the market, and to look for investors.
In WP7, the project results are communicated to the wider public. However, the emphasis is on active communication with the business community in general, and potential investors and stakeholders in the new valorisation chains that show interest in the developed processes. WP8 deals with the project management.
All WPs, and especially WP1 to WP6 are strongly interdependent, and findings in one WP is important input for another WP.
2. Main S&T results and generated foreground
2.1. WP1 Sample production of new-to-market molecules
2.1.1. Objectives
O1.1 Gram to kg scale production of fucosylated oligosaccharide for application testing
Why: To obtain enough product for application and conformity tests
How: By means of small scale bioreactor production and small scale purification systems
O1.2 Gram to kg scale production of L-fucose for application testing
Why: To obtain enough product for application and conformity tests
How: By means of small scale bioreactor production and small scale purification systems
O1.3 Kg scale production of Bola-sophorolipids for application testing
Why: To obtain enough product for application and conformity tests
How: By means of small scale bioreactor production and small scale purification systems
2.1.2. Specialty carbohydrates
For the specialty carbohydrates, first of all optimization of the established production process of 2’-fucosyllactose (Figure 1) was continued.
Figure 1: structure of 2’fucosyllactose (in uploaded annex)
As the exploratory marketing clearly learned for each application and each customer the required product specifications are different, further optimisation of the production process in both fermentation and downstream processing, was required.
Issues & challenges identified were:
- Improvement of productivity and titers required to improve techno economics: a lot of effort was put into medium optimisation & study of impact process parameters (pH, temperature, aeration, agitation, feed strategies). Design of experiment approach was used. Best combinations of parameters and medium composition were identified and scaled yielding a substantially improved titer, productivity.
- A second challenge was product purity. Depending on target market there is a different tolerance with regards to byproducts and impurities as regulatory approval is specification based. Deviations from said specifications are unacceptable. Different techniques for downstream purification were evaluated, removing impurities and byproducts but adding costs to the process. Modifications to certain process steps and parameters also substantially reduced formation of byproducts. Avoidance of byproduct formation was proven to be best strategy.
- Balance between productivity, titers and techno economics: e.g. there is a positive correlation between production environment and production efficiency, but this environment affects the other unit operations and related costs. By an integrated approach of different expertises (scientists, engineers and economic analysis) an optimal balance was identified.
For the production of 3-fucosyllactose, at BBEPP the protocol as received from Inbiose was tested at 7L scale and scaled up to 100L scale. Although production yield at 100L scale was less than at 7l scale, sufficient product was produced to evaluate downstream processing at pilot scale. It was found that the identical production and downstream processing processes for 2-fucosyllactose (2FL) can be used for the production of 3 fucosyl lactose, which is a very important advantage for scaling up the process. In addition, no by-products, were produced, so a very pure product was obtained. Still the downstream processing as established for the 2FL was challenged by exploration
Concerning the production of L-fucose (Figure 2), a potential freedom to operate issue came up. A new strategy was developed to safeguard freedom to operate which was made available for upscaling. The partners still managed to do planned work within the framework of the project and scaled up the process. Although the process is less mature and the titers and productivity are not ideal for low end markets, we managed to create a process that can guarantee a security of supply to markets such as the high end markets, for which this is of key importance.
Figure 2: structure of L-fucose (in uploaded annex)
2.1.3. Biosurfactants
For the bola sophorolipids (Figure 3), early feedback from the market, especially for detergent products, via the partner EOC showed that the price should be reduced substantially to meet the requirements of the market. So to come to an economically viable and competitive process for the detergent market it is important to maximise productivity and titers as these directly affect cost of the product.
Figure 3: Structure of bola-sophorolipids (in uploaded annex)
To increase productivity and titer the influence of a whole range of process parameters and medium components were tested by large number of experiments at shake flask level, followed by validation of the findings at 3L, 7l, 10L and 150l scale.
Impacts of initial glucose concentration, osmotic pressure, N-content and source, feed rate and feed regime, inoculum size, ... were evaluated on productivity, titers and purity of the product.
Special attention was also given to the source of the fatty acid, different sources were tested and ranked, very important differences were noticed.
Other important learning is optimisation needs to be done at reactor level, impact of a parameter at shake flask level can be dramatically different compared to reactor level. Finding the optimal parameters for a process needs to be (re)done strain by strain.
The 150 L scale fermentations were used as well to develop downstream processing procedures. Different techniques a.o. membrane filtration, chromatographic separation, ... were screened and evaluated, different separation techniques were combined as well. The techniques were evaluated in terms of recovery yield and obtained purity, but also the economics and on sustainability via the life cycle analysis. The techno economic analysis provided a list of so called “hot spots”, parameters which had the largest impact on the production cost. As productivity (g/L.h) was identified as the parameter having the largest impact on the production price, priority was given to improve this parameter. Cell recycle was explored by the end of the IB2Market project, first results confirmed feasibility and improvement of economics by reduced downtime of the process. Product yield as an associated parameter, was included in this optimisation. This was done by strain engineering at UGent on one hand and process optimization at BBEPP and UGent on the other hand.
For the strain engineering (UGhent), overexpression strains for the genes/enzymes responsible for (bola) SLs biosynthesis were generated. Interesting results were obtained, but no new strain with better inherent production capacities could be delivered to BBEPP within the IB2M project. A further expansion of the molecular toolbox is required to enable efficient and quick optimization of already existing production strains. This will be set as a goal in future research projects.
Also the production of sophorose (a specialty carbohydrate) and non-acetylated acidic SLs starting from bola SLs using alkaline hydrolysis was explored, since it is regarded as an additional volume increasing opportunity to valorize the bola sophorolipid platform under development in IB2Market. A sample of good quality were sent to CBS to evaluate the listing of the ‘new source’ of sophorose in their catalogue.
As a result of this multiple iterations several samples with different grades in purity and concentrations and consequently different cost levels were obtained for the exploratory marketing.
2.2. WP2 Exploratory marketing of new-to-market molecules
2.2.1. Objectives
O2.1 Evaluation of the fucosylated oligosaccharides in all potential applications and especially in pharma, diagnostics, and cosmetics
Why: To expand the market potential to high end markets such as cosmetics and pharma
How: Via exploratory marketing and the transfer of samples to interested companies
O2.2 Evaluation of the L-fucose in all potential applications and especially in pharma, diagnostics, and cosmetics
Why: To expand the market potential of L-fucose
How: Via exploratory marketing and the transfer of samples to interested companies
O2.3 Evaluation of the bola-sophorolipids in all potential applications to pinpoint the most promising applications
Why: To create a market for bola-sophorolipids
How: Via exploratory marketing and the transfer of samples to interested companies
2.2.2. Specialty Carbohydrates
Inbiose & BCNP identified and contacted over 48 companies, Inbiose had further discussions under NDA (non disclosure agreement) with 25 companies, ranging from cosmetics, agro, feed, pharma to medical nutrition and infant formula. In total 8 MTA’s (Material Transfer Agreements) have been negotiated for fucosylated oligosaccharides. The material is being used for application testing, formulation, and (pre-)clinical testing. Further discussions are also ongoing with academia and with ingredient manufacturers. These discussions required much more effort than expected, because it was necessary to visit some of these companies multiple times to convince them about the novel products offer by Inbiose and to negotiate NDA’s, MTA’s and potential licenses.
The second fucosylated oligosaccharide produced, 3-fucosyllactose, has been produced in large enough quantities, a specification sheet was also compiled and this product was promoted further towards the companies and academic institutions. Under the cover of MTA’s, this product was also sent out for testing. Although this product might be similar to 2’fucosyllactose, more and more data is published that show a clear differentiation in functionalities. Expectation is, that now the product is more readily available more new applications and properties will be identified for 3-fucosyllactose.
Overview of the types of companies contacted by Inbiose, 48 in total (figure in uploaded annex)
It became clear that the quality and safety management of the environment in which the products are produced, are essential for the targeted markets. Therefore a lot of effort was put into the evaluation of a quality assurance system at BBEPP and how to improve and implement such a quality assurance and control system according to the standards needed. In a first approach expertise with regards to quality management was hired externally. This did not work to satisfactory level as it requires too much iterations with expert people on the work floor. To tackle this an experienced quality manager was hired by BBEPP internally to guide the processes. The contacts with the markets showed different markets have different requirements and different expectations with regards to specifications and certificates of analysis, much more analyses than foreseen in the project applications were needed. Expertise from specialized labs with the necessary GLP certifications to analyse the samples was hired, this process was managed by the QA manager. Analysis that were done, were a.o. endotoxin, microbial contaminations and heavy metal analysis, next to carbohydrate composition, protein, DNA and water content.
In the case of L-fucose, different applications are known, security of supply is main concern. Application work is not initiated if this is not solved. The exploratory marketing actions for L-fucose were hence more to proof the possibilities of biotechnology for L-fucose synthesis. The same type of companies as for fucosylated oligosaccharides showed interest in L-fucose. Mainly companies working in the pharmaceutical field showed real interested, if the production cost is reduced further, cosmetic companies will become a future target market.
In conclusion, the availability of product enabled Inbiose to get access to a large number of companies, ranging from the infant formula and medical nutrition multi-nationals to companies in the pharmaceutical, feed, agro and cosmetic industry. By being able to talk to all these companies Inbiose gained an enormous amount of market intelligence that allowed great progress in WP 4 and 6. NDA’s limit disclosure of information that was obtained.
2.2.3. Bola sophorolipids
To support the exploratory marketing specification sheets were made for the bola-sophorolipids, these specification sheet were updated with additional information obtained during the project, but information which could still be used for IP generation was omitted. These specification sheets were made available via the website and through the partners EOC and Carbosynth (CBS).
Samples as generated within WP1 and WP2 were provide by UGhent and BBEPP to a large number of research institutions and companies. The obtained contacts were generated by a combination of active contacting and requests for samples. These requests came from people (both academia and companies) who learnt about the technology at public conferences or from the IB2Market and/or CBS website/catalogue.
The samples were used to establish general properties of the Bola Sophorolipids, as ecotoxicity, cytotoxicity, irritation, chemical stability, surface tension and CMC, supramolecular assembly, antimicrobial properties, ... .
The functionality of these samples within specific applications for specific markets was evaluated by the partners, companies and academia. Test markets were besides detergents (EOC and INNOVHUB leading the process), also specialty chemicals via CBS, agrochemicals, pharmaceuticals, advanced materials, textile and food.
Sophorose (a specialty carbohydrate) and non-acetylated acidic SLs can be perfectly derived from the Bola sophorolipids. As such they could increase the production volume, reducing the production cost. For this reason these 2 molecules were also included in the exploratory marketing. CBS is evaluating the listing of the ‘new source’ of sophorose in their catalogue.
Results obtained by EOC/Innovhub proof specific products have interesting functionalities for specific applications within the detergent market. Hand dish wash, automated dish wash, textile wash, hard surface cleaning, rinse aid, ... were evaluated, also reformulation and synergistic effects with actual ingredients were evaluated.
Exploratory work was also done by the partners on the emulsification and film forming properties, these are important properties for cosmetic products, where higher prices levels are possible, especially when added value can be proven (e.g; lower amounts of active(s) required, anti-fungal/bacterial effects,...).
Despite the interesting properties within specific detergent applications market introduction at actual scale of operation is not feasible. Price levels should be brought down by a factor 4-5 to be competitive for these applications. This will be feasible if scale of operation exceeds 1000 tpa. tons/year) and with further strain and process optimization.
From the exploratory marketing approach done within agrochemicals and pharma some interesting applications which can absorb actual cost levels at actual scale of operations were identified. These will be the primary focus for future work and were the basis or the drafted valorisation strategy and business plan.
2.3. WP3 Scale-up and demonstration of the production process
2.3.1. Objectives
O3.1 Production and downstream processing scale-up to 10.000L scale for fucosylated oligosaccharides, L-fucose and bola-sophorolipids
Why: Large scale production for market introduction
How: By means of the well-equipped Bio Base Europe pilot plant scale-up and downstream processing lines
O3.2 Demonstration of the technical feasibility of each technology at that scale
Why: As a proof of concept for the developed technologies.
How: By means of the well-equipped Bio Base Europe pilot plant scale-up and downstream processing lines
O3.3 Collection of technical data to enable economic sustainability analysis and LCA
Why: To obtain enough data to evaluate the economic feasibility of the process.
How: By means of the well-equipped Bio Base Europe pilot plant scale-up and downstream processing lines and critically assessed by skilled personnel
2.3.2. Specialty Carbohydrates
A lot of work has been put into the scale up of the 2’Fucosyllactose process. When scaling up new problems arise. Product composition stability and process reproducibility are key requirements for the targeted markets. This urged INBIOSE and BBEPP to look more closely at the medium composition and how to adapt it so it fits the larger production scale and meets expectations with regards to reproducibility and stability. To this end a large number of 5L fermentations were done by Inbiose and at BBEPP a large number of additional 7.5 10 and 150L fermentations have been done to test and validate repeatability and reproducibility. This gave the needed data to move forward to the 15m³ scale.
Additional to the production environment, the way to perform the process was altered, so process steps could be eliminated and the overall process could be simplified. This change however had to be validated on the basis of the end product composition. During the project a specification sheets were set up, which had to be matched. Hence, every process change had to verified and validated to the same required product specification.
By the end of the project a successful 15m³ fermentation was run with a yield, production rate and titer conform expectations. The higher volumes of broth also required an adapted downstream processing. At the smaller scale process flow with the unit operations were determined, but this had to be translated to the larger scale. Downstream purification process was successfully scaled up resulting in a product matching product specification set forth by the market (result of the exploratory marketing).
Another task, outside of the project is to run repetitive batches to further optimise the process parameters and proving the process stability further at scale. These runs are for regulatory instances that require repetitive batches to show process stability and to proof that the process leads to an end product that is conform a certain product specification. Regulatory application work was not included in this project.
As explained earlier in the report, Inbiose identified an obstruction in FTO on its strategy to produce L-fucose. To mitigate risk, it was decided to develop another route. This caused an important delay. It appeared a good fortune that we were able to develop a new strain quickly. Many hurdles were addressed in the scale up of 2’fucosyllactose and were not encountered anymore in the L-fucose scale up. There are however some differences between both the 2’fucosyllactose process and the L-fucose process on process performance.
The process as developed by Inbiose for the L-fucose production was validated on 7 and 10 L scale in the lab facilities of BBEPP. Subsequently, several 50 and 150 L runs were executed. Once successful at 150 L, this process was further scaled up to 15m3 scale. Due to high similarity between 2FL and L-Fucose production process and the experience established by scaling the 2FL process resulted in a swift scale-up of the L-fucose process. An analogue downstream process as used for 2FL was successfully applied. The generated broth in the scale up experiments was used to further work on improving the DSP process, new strategies for a more cost efficient unit operations were explored.
Process data generated at this scale was used to validate the assumptions used for the LCA and as input for the Techno-Economic Assessment. The actual longer fermentation time and lower end titer results in a higher cost but still competitive to known price level in the market as evidenced by the TEA. Further improvements to the overall process are feasible, which will further reduce production costs.
2.3.3. Bola-Sophorolipids
The process development and optimization of both the fermentation and downstream purification, as described above was applied at the semi-industrial 15 m³ scale to generate the first pre-industrial batches of bola sophorolipids and thereof derived acidic sophorolipids and sophorose. Due to typical scale-up problems, eg scaling factors for oxygen transfer and agitation but also very practical issues as sterilising feedstocks first 15 m³ fermentation failed. Second 15m3 fermentation and the DSP thereof was successful resulting in relatively large and pure quantities of the three targeted products.
The scale up of the processes developed during the IB2M project showed that they are both feasible and scalable. The obtained data was compared with the assumptions which were made as input for the LCA and TEA analyses to ascertain that correct conclusions were drawn from these analyses.
2.4. WP4 Market and value-chain analysis
2.4.1. Objectives
O4.1 To techno-economics for each production process
Why: To determine the costs and revenues of each target molecule and balance both
How: By means of the well equipped Bio Base Europe pilot plant scale-up and downstream processing lines
O4.3 Determining all market possibilities for the each product
Why: To determine the largest possible application range to increase the market potential of each molecule
How: Via exploratory marketing and building up a large network of potential clients
O4.4 Determining the market potential of each product on these markets
Why: To evaluate the market size of the specific target products and thus the needed production capacity
How: Via market studies of the existing markets and the markets that can be entered in the future
O4.5 Determining the gaps in the value chain for each product
Why: To ensure a smooth market introduction of the product at a competitive price
How: By understanding the value chain, from resource to product, thus analyzing each step in the whole value chain.
2.4.2. Specialty Carbohydrates
The techno-economical assessment was done for both L-fucose and fucosylated oligosaccharides based on process data and process layout resulting from WP1 and WP3. For both products, L-fucose and fucosylated oligosaccharides we were able to calculate the CAPEX need and OPEX need. For fucosylated oligosaccharides we would need to find investment for a production plant with a capacity of more than 1000 tpa, which will employ about 50 full time employees. At scale this will lead to a production cost and price of product that is well acceptable for the market. The techno-economical assessment informed also further on the hot spots of the process, where we could further optimize to drive down costs, allowing to enter even larger markets.
For L-fucose we have calculated the investment for a plant that has a capacity around 100 tpa, which will employ about 30 full time employees. The process cost and hence the price of the product is at scale also well acceptable for the market. We simulated several downstream processing operations and their related costs to guide future development work and looked where the hot spots in the process are. This knowledge will help us to further reduce costs and increase the availability of the product to more markets.
From the multiple contacts during the exploratory marketing work, a lot of (confidential) information was obtained concerning the applications of fucosylated oligosaccharides, the applications of L fucose, the current market structure of the applications of fucosylated oligosaccharides and L-fucose, the market share potential and their value chains. This information was obtained under NDA and provided Inbiose and BCNP a lot of market intelligence to pick and to prioritise future goals and to build the appropriate valorisation strategy and business plan. The main conclusion from this work is for fucosylated oligosaccharides, that the most important applications for fucosylated oligosaccharides can be found in infant and medical nutrition, an enormous market.
On the basis of this market structure market size was modelled and the market share that could be obtained was calculated.
Similarly, we identified the value chain for the cosmetic application of L-fucose. Here we understood that the market will have to be developed stepwise, first providing the necessary proof of biotechnological synthesis of L-fucose, then driving the cost down to levels that are acceptable for larger markets.
2.4.3. Bola sophorolipids
The techno-economic analysis for (bola) sophorolipids was in a first instance based on the process data and process design resulting from WP1 and WP3 and calculated for a production scale similar to the largest scale available at BBEPP, fully dedicated to bola sophorolipids production. For such scenario very reliable data was available with regard to workforce, capital expenditure for investment and operational costs. Annual production volume was calculated for this scale. The product production cost was calculated using the most efficient downstream processing option.
At this scale the majority of the costs are directly linked to the capital investment cost (45%; depreciation over 10 years) and the operating labour cost (37%). Increasing the scale of operations is obviously one method to reduce costs, however this requires sufficient demand for the product. The production cost at actual scale of operations can also be further decreased by increasing the productivity of the process as this was the biggest point for improvement highlighted by the sensitivity analysis. The most promising strategies to do this are scale up of the continuous process, of which proof of concept was delivered at the end of the IB2m project and further genetic modification of the producing micro-organism.
The most promising markets at the actual cost structure for application of (bola) SLs are the pharma and agro market. This information was used for the valorisation strategy and writing of the business plan. The cosmetic market is another possibility, which remains to be further explored and the application of the (bola) sophorolipids in (green) detergents is also still a possibility once larger scale production comes within scope. For that purpose, the price needs to be reduced a factor 4-5 which becomes possible at production volumes of over 1000 tons/year and/or by further increasing the productivity as determined in the TEA analysis. The market share assessment for the chosen applications could only be described on a qualitative base, as no numbers of the exact market structure and value was freely available.
2.5. WP5 IP and Life Cycle Analysis
2.5.1. Objectives
O5.1 Determining the IP position of fucosylated oligosaccharides, L-fucose and bola-sophorolipids in their new application fields
Why: Identifying potential IP opportunities and threats is crucial to protect the newly developed technologies and to build up a well established position in the market
How: Via IP mining and FTO analysis
O5.2 Determining LCA for fucosylated oligosaccharides, L-fucose and bola-sophorolipids
Why: Each process has a potential ecological impact and this has to be determined to ensure an environmental neutral production process.
How: Ecological sustainability of the production of these processes will be assessed based on LCA principles following ISO 14040 and ISO 14044.
2.5.2. IP analysis Specialty carbohydrates
During the project UGent and Inbiose further strengthened their patent portfolio with one filing (EP14193151.9) and UGent and/or Inbiose intend to file other patents in the near future.
Every 2 to 3 months an IP search was done to evaluate the IP position of the competition and novel applications by end users by UGent and Inbiose. Inbiose also has gone through several due diligence analysis by companies and investors. This required much more effort than expected and experts in the field of intellectual property and contract lawyer were hired to help answering questions on FTO posed by potential partners and venture capital investors.
2.5.3. IP Analysis biosurfactants
UGent performed an analysis of the IP landscape, which showed that FTO was not compromised. This was still the case at the end of the IB2M project and this information was obtained through regular checking of the IP landscape. The patent application on the bola producing strain will be further maintained by UGhent, as all claims were considered as novel, inventive and industrial applicable by an international search report.
BBEPP is considering to generate IP protection on the newly developed purification process for (bola) sophorolipids as this method could also be applied for other biosurfactants. As this purification route results in products with higher purity and a tremendous increase of the recovery during DSP, this could enhance the commercialization of other (new) biosurfactants.
Certain application work with the sophorolipids initiated, is also expected to lead to application patents. This will strengthen the position for exploitation.
2.5.4. LCA analysis specialty carbohydrates
An LCA analysis for 2-fucosyllactose was performed by Nova. The main conclusions is that a yield increase by additional recovery actions not necessarily compensate for the extra footprint, as they cause additional energy requirement, water removal was already identified as a hot spot. The hot spot analysis also indicated the substrate, sucrose, as having a major impact. This is intrinsic for the process (and actually for any biotechnological process), no alternative is available.
Furthermore the production of 2-fucosyllactose by fermentation was compared to the chemical productions process as described in patents. It showed the footprint of the fermentation process was at least an order of magnitude smaller. However, the scale of the chemical process modelled was small, which might influence the outcome.
The LCA for L-Fucose was also completed. Because of the great similarities between both processes, the conclusions are similar. Increasing the use of process water for increased product recovery does not compensate for the increased environmental impact.
Since a fermentation based production is an alternative way to produce Fucose, a comparison (benchmarking) with other production routes is meaningful, in order to derive further insights regarding its environmental favourability. Therefore a comparison between extraction-based production of L-fucose and the fermentation route developed within this project was done. This comparison clearly showed that the fermentation process is significantly more environmentally friendly.
2.5.5. LCA analysis biosurfactants
The LCA analysis for bola sophorolipids was performed by Nova. The LCA was based on data derived from the performed processes in the IB2M project in combination with assumptions for further development and scale up of the processes.
An eye opener and surprising result from this study was the learning that the use of first generation renewable resources (vegetable oil and sugar) has a tremendous effect on the environmental impact of the production of the (bola) sophorolipids. Vegetable oil was identified as one of the hot spots of the process, glucose also had a considerable impact. This impact is directly related to the agricultural processes for the production of these substrates, which is thus a step upstream of the technology investigated/described in the IB2M project.
LCA data obtained for the sophorolipids was checked towards LCA data for APG’s (alkylpolyglycosides, a chemically produced renewable biosurfactants) available to project partners, environmental impact is within the same order of magnitude.
Energy intensive processes e.g. steam generation and freeze drying (as final conditioning step for preservation) were obviously identified as additional hot spots. The latter also has a very big impact on the production price of these molecules, as was concluded from the TEA analysis and should thus be avoided. Application in markets where products are applied as liquids (e.g. the detergent market) are favourable with regards to environmental impact.
Another finding was the fact that the impact of the two compared purification routes did not significantly differ at the evaluated scale. This is important information as the combination of these two routes has a positive influence on both product purity and recovery, while the production cost/kg remains the same.
Main conclusion is the fact that maximization of the conversion yield of oil (but also sugar) to (bola) sophorolipids is key to lower the environmental impact of the production of (bola) sophorolipids. An additional option is to focus on second generation feedstocks for the production of (bola) sophorolipids if application allows this. This option will be studied in future projects.
2.6. WP6 Business plan and valorisation strategy
2.6.1. Objectives
O6.1 To develop the most suitable valorisation strategy
Why: Depending on the application and the market size a suitable business model has to be determined.
How: The techno-economical studies and the market evaluations will be used as input to determine the most optimal business model
O6.2 Connect with investors
Why: The development of platform technologies is very cost intensive and the time to market has to be bridged or the large scale market introduction has to be catalyzed by risk investors
How: The data that is generated within this project will be used to write financial and business plans to present to potential investors.
2.6.2. Specialty carbohydrates
BCNP and Inbiose started the development of business plan and valorisation strategy with a workshop about economic and technological state of the art. An existing business plan of Inbiose was analysed to identify gaps and needs for the new business plan. In the first phase of this project part BCNP and Inbiose decided to focus on 2-Fucosyllactose (2-FL) because of a shorter time-to-market than L-Fucose.
To get more information about application possibilities of 2-FL or Human Milk Oligosaccharides (HMOs). BCNP and Inbiose started to interview experts from academia and industry. This information directed the development of the valorisation strategy.
At the start several business models were developed and evaluated with respect to economic aspects. From these models BCNP and Inbiose selected two different business models to concentrate on further. To this end BCNP did research to fill in missing variables for implementation of those two business models:
• Research of Partners to complete the Value Chain.
• Research of approval requirements for different applications.
• Research of prices of comparable products.
• Analysis of Competitors
After confidential meetings with industrial partners Inbiose decided for the most promising business model as well as the most promising starting market.
As there is/was no established 2-FL market yet, only the niche application identified and still in the research and development phase, BCNP and Inbiose derived a market potential from different assumptions to the market. The estimation of the market potential was improved within the course of the project on the basis of information gathered in the market.
At the beginning, during the workshops, it was necessary to develop an attractive story line to convince potential investors as well as the different market players. This formed the basis to build the business plan and model, which consists of the business idea, business model, management team or market. There were then written down and were used as a guidance to identify potential sales and revenue. The latter is then included in the financial plan.
In the second half of the project the business plan and valorisation strategy for L-Fucose was developed. The most important part was to derive a market under the condition that Inbiose is able to produce L-Fucose to much lower prices so that a shift from niche market to mass market could be done in the future.
For such case BCNP and Inbiose derived a market potential and a sales potential for L-Fucose. This was basis for a business case developed by BCNP.
For both products, Fucosylated oligosaccharides and L-Fucose, BCNP and Inbiose created an investment teaser. Those investment teasers is being used to attracted potential investors in a first way without disclosing confidential information. If investors are interested, the business plan can be sent after signing a confidential disclosure agreement. During the project, Inbiose has also actively been discussion with multiple venture capital funds, who have been showing a lot of interest. Inbiose hopes to be able to valorise this interest with a capital increase on short notice.
2.6.3. Biosurfactants
BCNP and UGent started the development of business plan and valorisation strategy with multiple workshops to discuss technology, identified applications and projected economics. Evaluation and feedback from EOC and INNOVHUB showed the product had interesting and promising properties within detergents applications. Detergent applications were assumed most promising application prior to the start of this project. Unfortunately techno economics showed that, at the actual scale of operations, cost is too high to access this market with the Bola sophorolipids, a substantially ramp up of the scale of operation is required.
The most suitable valorisation strategy for bola sophorolipids is described in the business plan and consisted of setting up a spin off company called ‘Amphistar Solutions’, valorising the IP and foreground as generated by UGent and BBEPP. The Spin-off company would develop and market products in a first instance for the agro and pharma markets. Capital requirements to finance next phases were identified, a capital which can be acquired by bank loans and/or investors. Contact with a first possible investor were already made and investment in the company by this business angel is a possibility. Further investors will be attracted, amongst others by sending out the prepared investment teaser and further dissemination of the technology through business development and by attending public conferences.
2.7. WP7 Dissemination
2.7.1. Objectives
O7.1. The efficient dissemination of the project results
Why: Communicating results is essential for the commercialization of the newly developed production processes
How: Via websites, press releases, (scientific) articles, conferences, workshops, ... .
Dissemination actions are addressed in dedicated section.
2.8. WP8 Management
2.8.1. Objectives
O8.1. Establishment of a management scheme to ensure the fulfilment of the project objectives
Why: To ensure the successful implementation of the project and the proper valorisation of the obtained results.
How: The consortium will be managed by a supervisory board and a coordination team.
2.8.2. Organisation
The IB2Market project was managed by a supervisory board and a coordination team.
- The supervisory board consisted out of one representative of each partner and monitored the implementation of the project and did issue management, deciding on corrective actions if required.
- The Coordination team was responsible for the daily management and consisted out of the project coordinator, the operational manager, financial and administrative managers. The operational manager supervised the project at task level with the product line coordinators, to this purpose dedicated ad hoc meetings were organised with involved partners.
- The general tasks for the daily management of the IB2Market project consisted of:
o Putting together the agenda’s, sending invitations, make reservations, write minutes,.... in order to organize and report on meetings (Partners meetings, Management meetings,....)
o proofread deliverables, adjust where necessary in cooperation with the involved partners, upload the deliverables
o collecting the necessary data (from different partners) in time to complete the required EC documents for reporting
Kick-off meeting was held in Ghent 14/04/2014, 5 general project meetings within the course of the project were held 16/06/2014 in Cologne (D), 18/01/2015 Ghent (Be), 08/06/2015 Frankfurt am Main (D), 27/10/2015 in Brussels (Be) and 04/05/2016 in Desteldonk (Be). The general meetings consisted out of 2 parts:
- A plenary part (progress meeting) where all scientist, engineers, experts give an update on the work done and progress made during past period and planned work for upcoming period.
- A closed part (management meeting) where the supervisory board monitors progress, discusses issues, decides on corrective actions, typical agenda:
o Signing attendee list
o approval agenda & minutes previous meeting
o Personnel & resources
o Milestones & deliverables
o Reporting issues
o miscellaneous
Potential Impact:
1. Impact
1.1. introduction
The expected impact from the IB2market project is two-fold:
1. Real economic impact as new industrial biotechnology processes for the production of biosurfactants and specialty carbohydrates will be demonstrated and industrialised. New and innovative products will reach the market, providing economic development and employment.
2. General lessons to be learned from this project, as a case study for demonstration projects in industrial biotechnology. The collaboration between an open innovation pilot plant, industrial companies, an industrial biotechnology spin-off, application developers and the research community is quite new for a European FP7 project. This knowledge is particularly relevant for Europe as the upcoming Horizon 2020 program is expected to strongly emphasize similar demonstration projects that have a real economic impact.
1.2. Economic & societal impact
1.2.1. Biosurfactants
Market relevance:
Surfactants are used for a wide variety of applications in households, industry and agriculture. They are extensively used in cleaning applications and as a formulation aid to promote solubilisation, emulsification and dispersion of other molecules in products ranging from chemicals, cosmetics, detergents, foods, textiles, pharmaceuticals, etc. Surfactants are performance molecules that intervene in nearly every product and every aspect of human life. In terms of production numbers, surfactants are one of the most important classes of industrial chemicals with a total world production exceeding 4 million ton per year. About half of that is used in household and laundry detergents, the other half in a wide variety of industrial sectors, particularly the chemical industry, food industry, cosmetics and personal care, textile industry, health care, paper industry, agriculture, etc.
Especially for applications where their excellent biocompatibility and biodegradability is important, a large market potential for biosurfactants is available. These properties are particularly advantageous in applications that require a massive introduction and interference with the environment, for example in bioremediation, washing applications and crop protection. Bio surfactants have excellent functional properties combined with a low ecotoxicity and good biodegradability and thus offer a vastly improved environmental compatibility compared to traditional surfactants.
The main challenge their limited availability and diversity on the market, posing obvious limitations to application developers that need surfactant diversity for formulating different applications.
The targeted bola-sophorolipids provide a welcome addition for new application development, within cleaning, agrochemicals, cosmetics, pharmaceutical, thus expanding the range of biosurfactants on the market, providing more diversity and effectively turning biosurfactants into an industrial reality.
Biosurfactant market exploration:
The optimisation and upscaling of the platform technology made samples available for market exploration with known techno-economical and sustainability data. General functional properties & characteristics as ecotoxity, cytotoxicity, irritation, chemical stability, surface tension, antimicrobial properties were determined by partners or by interested prospects. The samples and data are made available to industries and academia to evaluate the performance and cost-in-use in a whole range of applications (Surfactant market by EOC and INNOVHUB), specialty chemicals market (By Carbosynth), agrochemicals (Universities and industry), Pharma market (Universities and Industries), advanced manufacturing and materials market (Universities and industries), food applications as emulsifier (industries), ...
Generated & future impact:
Feedback from the exploratory marketing challenged to actual scale of operations allowed the partners to prioritise target markets and actions. Actual scale of operations causes a high product cost. Very promising results and contacts focus actions towards pharma and agrochemical applications which can absorb actual product cost. Later on, once scale of operations will by enlarged, higher volume markets like detergent market enter into scope. To further develop the market and technology the establishment of a spin-off company is prepared with a business plan, roadmap and investment teasers. This will create new jobs and will turn bio surfactants with their renewable character and better biodegradability and biocompatibility in to industrial reality.
1.2.2. Specialty Carbohydrates
Market relevance
The current applications of L-fucose and fucosylated oligosaccharides are quite limited, due to their high price and limited availability. L-fucose is currently sold at prices between 500 – 2.500 €/kg, in quantities that are not higher than about 5000 kg per year, mainly in the pharmaceutical area.
The cosmetic field is particularly promising, as it is a large scale market and new applications in cosmetics are continuously being developed by leading cosmetic companies, e.g. company l’Oréal filed a broad patent on the application of L-fucose in skin care (WO2009034559). Despite the excellent results in the skin care application tests, the problem is the very limited availability of L-fucose, currently excluding any large scale application in cosmetics.
Furthermore, L-fucose can be an alternative for L-rhamnose in the synthesis of flavours. L-rhamnose obtained from action production methods suffers insecure and insufficient supply. If a cost reduction of L-fucose is achieved and supply is secured , it may become perfectly a large scale operation.
fucosylated oligosaccharides currently attract most attention as a Human Milk Oligosaccharide, to be used as an infant nutrition ingredient. Human milk oligosaccharides as the name does suggest are components which are found in and make human breast or mothers milk unique. Various application studies have shown excellent results for this compound, most notably for the reduction of infant intestinal infections. fucosylated oligosaccharides have been shown to bind to receptors in the intestinal tract, thus inhibiting the binding of well-known microbial pathogens such as Salmonella and pathogenic E. coli strains to the intestinal epithelium. The application of fucosylated oligosaccharides has been shown to reduce infant mortality significantly. A biotechnological platform which guarantees security of supply and at acceptable cost makes these beneficiary characteristics available to much larger market or population.
Fucosylated oligosaccharides also have application potential in pharmaceuticals, notably for the treatment of auto immune and bowel diseases. Also in the cosmetic field, fucosylated oligosaccharides are expected to have similar properties as L-fucose.
Generated & future impact
The development of the L-fucose within the IB2Market project was slowed down due to a potential FTO issue. A new strategy was developed to safeguard freedom to operate. The newly developed technology was scaled allowing validation and analysis of the techno-economics. In conclusion the actual status of the technology as developed by Ghent University and its spin-off company InBiose already offers a solution to above by providing sustainable supply at competitive cost. There is clear potential and plans for further improvement of the techno economics.
For the development of the fucosylated oligosaccharides, iterations between the market and operational level created a much better understanding with regard to the product specifications, quality expectations and requirements and their impact on operations, cost structure, legal and regulatory requirements.
These learnings challenged versus the economic aspects and assets of INBIOSE allowed to develop with BCNP the most suitable valorisation strategy and business plan.
As a result of the project INBIOSE will make 2 FL available to the market in large volumes, so everybody will have access and will benefit from the beneficiary characteristics (as described above) of 2FL. Inbiose developed a portfolio of prospects with whom negotiations are ongoing and are expected to result in new collaborations. Within the course of the project, INBIOSE grew to an SME with over 20 employees.
1.3. valorisation open innovation approach
1.3.1. Introduction
To bring new molecules to the market, an intensive collaboration between disciplines like research, development, operation, market intelligence and application/market is prerequisite. This type of collaboration is common practice internally within established (large) industries. Start-ups and SME’s in Industrial Biotech typically do not have all these capabilities and expertise in house as the technology is disruptive and value chains are new. Within the IB2Market project, an open innovation approach is pursued and collaboration is sought between different SME’s and innovation actors with the aim of bringing together the required complementary expertise within the innovation trajectory. In IB2Market, two technology providers that want to bring their new-to-market molecules to the market were assisted by (i) a pilot plant to deliver proof-of-concept and to scale the process up to industrial scale, (ii) market research specialists and (iii) business plan support services.
1.3.2. Evaluation and learnings open innovation approach
• Key success factor for the open innovation model is collaboration between partners with complementary expertise and interests to have open and swift communication, good collaboration and value sharing. Competitors and/or partners with conflicting interests within the value chain should be avoided. It’s recommendable to settle “value sharing” upfront.
• For the fucosylated oligosaccharides, infant food was identified as the most obvious and promising target market. The open innovation model and collaboration has shown to be very effective and fast to identify relevant actors and effective strategies to approach them.
• The project confirms that bringing new molecules to the market is much more than merely addressing technological issues. It is key to establish an early contact and close exchange with the market to establish and match expectations. Matching expectations and capabilities affect all disciplines within the innovation process. It is a process of iterations, back and forth, not a linear trajectory. Changing specifications of the end project can affect the production process and its economics. It might as well lead back to the primary process of strain engineering, to meet the specifications or to make the process economically viable or more sustainable.
• Quality aspects and quality management have shown to be key element, expectations differ a lot between different markets. This might lead to extra constraints, complications again affecting the techno economics and chances for market introduction.
• Life cycle analysis (LCA) and Techno-economic analysis (TEA) have shown to be a powerful instrument to identify so called “hotspots” in the process. Hotspots being the unit operations resorting the largest impact on environmental footprint or operational costs. This focusses the efforts in improving the process.
1.3.3. Conclusions & recommendations
• Access to an open demonstration infrastructure with technological expertise and flexible setup appeared essential as different target markets have different expectations in product specifications but also different expectations with regard to quality, regulatory and sustainability aspects. The impact of these expectations on the techno economics can only be assessed in an industrial relevant environment. Open access pilot & demonstration infrastructures speed up this process and reduce financial risks.
EU should study how such type of open pilot & demonstration infrastructures operating at higher TRLs can be fostered and how the use of such infrastructure in H2020 projects can be facilitated. (Within the H2020 work program on research infrastructures there are INFRADEV and INFRAIA topics typically in preparation of ESFRI projects. ESFRI projects target lower TRLs.) So EU should also consider to support infrastructure at higher TRL’s if such infrastructure are open access and crucial to bring disruptive research & innovation to market.
• The project has clearly demonstrated that entering new markets requires a multidisciplinary set of expertise, which SME’s or start-ups typically lack. Within the development of new value chains and new processes, life cycle analysis and techno economic analysis might be guiding processes. The strategy to approach the market, the position in the value chain and the value proposition might vary a lot per product-market combination. By consequence these are very dynamic processes with multiple iterations. Making such expertise available within the course of an innovation action is recommendable. Though one has to consider that the reward of the innovation lays with the technology owner not with the expert partners. Expert partners are typically for profit organisations, by consequence not 100% funded. So they have to cofinance themselves to provide services to the technology owner which benefits from the service.
• Developing a new value chain implies early exchange with application & market for new-to-market products and leads to iteration, innovation by default is not a linear trajectory. These required iterations might conflict with the rigidity of a description of work in a typical FP7/H2020 project: Extra work might be required, the scope of work might change to be able to do what is right to increase the success of the innovation, some deliverables might become obsolete. The change of scope, extra work, new partners or subcontractors might require budget changes. To overcome these hurdles, processing amendments should be a swift process, ideally with close/fast interaction with the officer.
• IB2Market is an FP7 project, where the funding rate is only 50% for demonstration and 100% for all other activities (research, management and other). Innovation (or demonstration) actually represents ‘the valley of death’: there is still a high technological risk combined with a high financial risk as piloting and demonstration is more expensive than research. We underline that the higher funding rates for innovation actions, as applied Horizon2020, are a prerequisite to promote innovation in Europe.
2. Main dissemination actions
2.1. Introducing new molecules
In support of and to enhance the introduction of new molecules to the market a dissemination and communication strategy is followed:
1) Project website was created (www.IB2market.eu) press release was made to introduce project and productlines.
2) As part of this dissemination and communication strategy presentation material for market development was created, aiming at potential business partners, investors and end-users. This presentation material consists out of
a. specification and information sheets for the different product lines were prepared, the necessary analytics were performed (in house, by partners or by expert analytical labs) to establish basic information thought relevant for the market, if new parameters identified relevant, spec sheets were adapted. General specification sheet were made available for the (bola) sophorolipids via the website & through partners Carbosynth & EOC. For the specialty carbohydrates depending on the application specification sheets differ and are part of the confidential information as exchanged with the prospect. A more general information sheet was made available through the website.
b. sample material was made available on request and under MTA via de project partners. Sample were provided under MTA to assure prospect does not take any IP position on an application based on the sample material as provided by the IB2Market partners without consent of the IP owners of the background. This to avoid unwanted limitation in fields of applications.
c. Investment teasers were prepared by the Amphistar Solution team ( UGent, BBEPP & BCNP) for the Amphistar Solutions start-up (exploiting IP on the biosurfactants). Investment teasers were prepared by Inbiose, UGent & BCNP for the technology & portfolio fucosylated oligosaccharides and for the technology and portfolio L-Fucose.
3) To engage with the industry and to communicate and demonstrate the potential for commercial application of the IB2Market product lines and its open innovation approach the partners presented posters and gave oral speeches at multiple relevant conferences, trade fairs and occasions where academia, industry and policymakers meet: a.o. EFIB 2014/2015/2016; FASEB 2015, RRB 10 & 11, FIE 2015, ... .
2.2. Valorisation open innovation approach
- A specific workshop was organised in the Showcase theatre at EFIB October 28th in Brussel were all partners promoted the project and the open innovation approach by an oral speech explaining their specific role, importance and merits in the innovation process.
- Both Inbiose and BBEPP as coordinator were present at the exhibitions in the European Parliament at the occasion of the 7th European Innovation Summit with a booth and a poster to share experiences and to promote the project. The scientific coordinator of the IB2Market project participated to panel discussion and gave on December 9th 2015 an oral presentation on “Open-access, independent pilot and demonstration infrastructures are key to bring key enabling technologies from lab to market" at this 7th European Innovation Summit.
3. Exploitation of results
3.1. Specialty carbohydrates
During the first period of the project a potential FTO-issue popped up for L-Fucose. Although this entailed a low risk, the risk was mitigate risk with a new production strategy to produce the L-Fucose, guaranteeing freedom to operate. This could not have been anticipated and caused a delay on the introduction of L-Fucose to the market. So In the first phase of this project part BCNP and Inbiose decided to focus on 2-Fucosyllactose (2-FL) because above and an expected shorter time-to-market, with a real and strong pull for nutraceutical applications.
To get more information about application possibilities, expectations and requirements of 2-FL and L-fucose, BCNP started to interview experts from academia and industry for applications identified, mainly medical nutrition, cosmetics and pharma.
Over 48 companies were contacted, over 25 NDA’s and 8 MTA’s were negotiated. This provided INBIOSE and BCNP with a lot of very valuable but confidential information. Main learnings were
- Establishing these contacts with NDA’s and MTA’s is a burdensome process for a start-up.
- Required information, specifications, quality expectations and acceptable cost level dependents very much on the targeted market as well as it might vary between players in the same market.
- Different strategies/ partnerships might be recommendable for different market.
- Required information and expectations exceed what was anticipated.
These learnings and information were challenged versus the economic aspects and assets of INBIOSE to develop with BCNP the most suitable valorisation strategy and business plan.
In conclusion 2 different business models were selected, a first business model in which INBIOSE acts as a technology provider, licensing its technological platform and a business model for specific markets in which INBIOSE is controls the manufacturing and sells the product to brand owners. To this purpose INBIOSE seeks contract manufacturers with appropriate capabilities and scale to meet specifications and volume, quality expectations of the targeted market. INBIOSE has no intention to sell consumer products.
Besides a valorisation strategy and a business plan, investment teasers were created for the technology platform on fucosylated lactose and L-Fucose.
As a results of the exploratory marketing and other work done within IB2Market
- Further negotiations are ongoing with both investors and prospects for the technology within other markets.
- Thanks to above progress INBIOSE grew to an SME with >20 employees.
For the fucosylated lactose there’s still a lot of hurdles to be taken mainly with regards to regulatory issues and toxicological studies, these processes are being or will be initiated. For L-Fucose the techno -economic feasibility was demonstrated by the end of the project, cost structure is within actual market price range. Important improvements to reduce cost are identified and feasible to ease the market introduction.
3.2. Biosurfactants
BCNP and UGent started the development of business plan and valorisation strategy with multiple workshops to discuss technology, identified applications and projected economics. Evaluation and feedback from partners EOC and INNOVHUB showed the product had interesting and promising properties within detergents applications. Detergent applications were assumed most promising application prior to the start of this project. Unfortunately techno economics showed that at the actual scale of operations cost is too high to access this market with the bola sophorolipids, a substantially ramp up of the scale of operation is required.
The most suitable valorisation strategy for bola sophorolipids is described in the business plan. Intention is to create a spin-off company called Amphistar Solutions, which will exploit IP & foreground generated by UGent and BBEPP, developing and marketing products for the agro and pharma markets.
Exploratory work done within these markets identified specific applications which do tolerate higher cost levels matching actual scale of operations. If scale of operations increases, resulting in a cost reduction, specific applications within the detergent market will enter into scope again.
An investment teaser is created to attract investors for the start-up AmphiStar to establish and to attract companies interested within the applications. Further application work is ongoing, it is anticipated that these will lead to new foreground and application patents strengthening the position of AmphiStar Solutions.
List of Websites:
http://www.ib2market.eu/en/home/
