FMX Applications for Antibiotics

Separation and Filtering of Culture Fluid

Background

The following is an example showing the manufacturing processes of antibiotics among various raw material medicines. The manufacturing processes of antibiotics consist of seeding, culture, fermentation, filtering & cleaning, product development, and packaging (Figure 1).

Since the raw materials treated by the main fermentation process contain various ingredients including bacteria and agar, those unnecessary ingredients are removed by the filtering process. 

Also, the liquid from the fermentation process is very difficult to treat because of its high concentration and high viscosity. The current filtering process has several problems due to the membrane fouling including low treatment flux, frequent cleaning, high costs of chemicals, and decrease of quality by non-uniformalization.

Antibiotics Filtration

The FMX was applied in the process of separating medical liquids after the fermentation process in the manufacturing processes of antibiotics. Because it was very difficult to filter the fermented liquids of more than TS 10% using the current tubular type membrane, dilution water had to be added to the liquids. The FMX is a facility appropriate for filtering high concentrated liquids. It showed an excellent performance in filtering the fermented liquid ingredients. Figure 2 shows the result (batch test data) of the fermented liquid filtered through the FMX. In section A, the filtering was performed without dilution water, and in section B, the second filtering was performed after 50% of dilution water was added.

Using the membrane of pore size of 0.05µm, the operation was stabilized with the average flux of 110 LMH ( l/ m^2*hr) at the temperature of lower than 10°C. When the operation was performed with the second dilution water added after separating medical liquid ingredients, the flux was 150 LMH which is more than the flux filtered without adding dilution water. 

When FMX was employed in the current filtering process, we were able to filter the medical liquid ingredients without dilution water and improve the filtering time by up to 50% due to its stabilized high flux. Also efficient operation was possible because the problems of filter membrane fouling and filtering delay had been resolved automatically by FMX. 

FMX Applications

2,3-Butanediol

Filtrate Product Process

Separation and Concentration Process of 2,3-Butanediol

Background

2,3-Butanediol (2,3-Butylene Glycol) is composed of three stereoisomers (Stereoisomers, 2R-3R-, 2S-3S- and 2R-3S-). Largely colorless and odorless, 2,3-Butanediol is a compound with strong hydrophilicity. 2,3-BDO is used as an intermediate in the cultivation process using biomass to produce high value chemicals such as Butadiene and MEK through the catalytic conversion process.

In addition, 2,3-BDO is an important industrial material that can be used as a food additive and a flavoring agent such as Acetoin and Diacetyl, plasticizers for thermosetting polymeric materials, and precursors of polyurethanes used in cosmetics and pharmaceutical industries. In particular, 2,3-BDO can be applied as a humectant in cosmetics and personal care materials. In the case of raw cosmetics materials or personal care products, 2,3-BDO assists in the development of natural ingredients rather than chemical synthesis. Processing techniques that maximize the efficacy of raw materials through the usage of technologies such as fermentation is actively underway.

Application

The conventional cell separation process used filter press with hollow fiber membrane, but it had low recovery rate and operating the facility proved difficult. In addition, when ED process was added after the separation process, the treatment efficiency was low due to impurities.

In order to solve this problem, FMX(MF) was applied to the culture broth and FMX (UF) was applied to protein and impurity removal. Figure 2 shows the separation purification process using FMX.

The Manufacturing Process of 2,3-BDO: Culturing Process -> MF/UF (FMX) -> ED(Electrodialysis) -> IEX (Ion Exchange) -> Distillation

MF Process: FMX-E (MF) can reduce the facility costs by simplifying the existing filter press and hollow fiber membrane process. FMX process can also increase the recovery rate to 95% from the current recovery rate of 90%, increasing our client’s total production value by 300,000 USD per year. In the production of 2,3-BDO using bio-process, raw materials such as sugar, cassava, woody raw material, sugarcane are used. 
The conventional filter presses’ recovery rate and process efficiency were affected by the type of raw material used in the process. On the other hand, FMX can achieve a recovery rate of 95% regardless of the type of material and 100% of the cells can be removed.

UF Process: FMX can be used to remove impurities such as sugar and protein, thereby reducing the load on the electrodialysis process (electrodialysis process time doubled, CIP cycle doubled). Higher recovery rates and reduced process times can increase product yield.

FMX Applications

Propanediol (PDO)

FMX Applications

Amino Acids

Application of FMX as a sidestream complement to increase L-Methionine production Utilizing a fermentation process

In the amino acid production process, achieving higher effectiveness in liquid-solid separation from fermentation effluent results in a higher purity product, simplified process train, and lower energy consumption. Conventional technology for streams with such high-solids loading include centrifugal separators and hollow fiber, filter press, and ceramic membrane filtration systems. Due to an innovative design employing rotating blades to generate vortex forces that help keep the membrane layer free of foulants, anti-fouling membrane filtration systems can facilitate higher productivity through higher concentration while lowering downtime lost to membrane fouling.

Conventional Process & Challenges

Most amino acid production processes follow a similar structure, beginning with fermentation and proceeding through cell separation from the fermented solution, ion exchange and concentration under pressure, granulation and evaporation, and ultimately refinement of the final product. Conventional production employs decant screw or centrifugal separators for the initial stage, followed by concentration of the resulting sludge using ceramic membranes. Unfortunately, neither the decant screw nor the centrifugal separator can achieve complete elimination of residual cells that lower the effectiveness of the ion exchange resin during later stages.

Used for diafiltration, ceramic membranes experience frequent fouling issues that limit concentration efficiency or product recovery from intermediate liquid streams with high viscosity and solids content. Furthermore, the residual liquid content in permeate from ceramic membranes requires high energy consumption during the drying process. As shown below, Company C’s master plan used a ceramic membrane as the main membrane filtration process with volumetric concentration factor (VCF) target 50.

After pilot tests with FMX, anti-fouling membrane filtration system, which uses rotating blades to create vortex forces that reduce membrane fouling for high solids loading, Company C set a new concentration goal using the FMX system as a side stream process preceding the membrane system. Though it is conventionally considered quite challenging to achieve even higher concentrations when treating material rejected from other membrane filtration systems, the anti-fouling membrane separation technology FMX system was able to meet the goal of VCF 100 through its full-scale diafiltration process.

FMX: DETAILED TEST RESULTS

The table below indicates the result of operation after integration of FMX into CJ's process train.

With operating pressure of 2 kgf/cm² and operating temperature of 50'C, the use of a 350 rpm to 0.1 micro MF membrane under batch-style loading produced average Flux of 70 LMH and maximum recovery rate of 99%. The following figure shows the change in flux with the use of FMX to recover Methionine broth.

The difference between the effects of the FMX and that of other membrane systems is clearly seen in the above comparison photographs. The conventional membrane could achieve concentration of only VCF 40, while a ceramic membrane managed to reach VCF 50; only with the use of FMX was it possible to reach concentration of VCF 100, appearing on the far right, maximizing the amount of permeate collected, as seen on the far left. Overall, FMX was able to increase the resulting concentration 2 times.

VERSATILE INTEGRATION INTO EXISTING PROCESS TRAIN

Also key is FMX's versatility as both a primary and secondary step at multiple points in the process train. While the FMX is capable of replacing the centrifugal separator in the initial step of the production process, Company C was able to enjoy unique benefits from integration of FMX without modifying their existing process, increasing efficiency without interrupting or affecting current production.

As seen below, the FMX can be utilized as a side stream step to process the dense permeate, deriving more value than the standard ceramic membrane by concentrating the result even further or by ensuring 100% liquid-solid separation by optimizing ion exchange and reducing the length of the drying process.

Implemented in full-scale operation successfully to the present day, integration of the FMX is expected to generate additional revenue of up to $500,000 varying per month, totaling at least $3M per year. Furthermore, the associated reduction in the process water necessary for diafiltration and energy consumption for evaporation is reflected in savings of $500,000 per year.

Ultimately, Company C hopes to take further advantage of the anti-fouling membrane system FMX's efficiency to shrink the three seven major process steps for separation from fermentation to drying into one three in essence consolidating the work of the centrifugal separator, two stage conventional ceramic membrane, vacuum evaporator, and hydro-extractor into that of a single FMX system to eliminate less efficient separation redundant dewatering separation steps.

FMX Applications

Probiotics

Industry Trends

Recent media coverage of advances in organic health supplements has highlighted the benefits of administering probiotics, non-pathogenic living microorganisms that positively affect the intestines of host humans or animals by restoring indigenous microbial balance. While applications for the relatively nascent probiotics market exist in functional foods & beverages, dietary supplements, and animal feed, significant R&D is underway to innovate new products for expanding commercial usage. With this anticipated expansion in probiotic applications alongside the ongoing surge in the functional food market, the global probiotics market is expected to witness steady growth from current day to be worth over 46 billion USD by 2020.

Conventional Process & Challenges

Probiotics Production Process

Typical probiotics production processes follow a similar structure, proceeding from raw material to cell culture in a bioreactor before entering a liquid-solid separation stage. Prior to a final drying or evaporation process, each process train may then integrate a unique set of additional stages depending on the final product goal, i.e. the introduction of a fermentation stage to achieve particular cell derivatives.

Challenges In Production

Both the cultivation broth emerging from the bioreactor and fermentation are challenging high-solids concentrate streams. When compared to current industry standards in membrane filtration, FMX is reliably capable of achieving higher recovery and higher concentration with lower run time, while offering additional economic benefits through boosting efficiency of the drying process and reducing power consumption.

FMX Applications

Animal Cell Culture Fluid