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WO2015040501A1 - Système de filtration de produits recombinants et de hdmf - Google Patents

Système de filtration de produits recombinants et de hdmf Download PDF

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Publication number
WO2015040501A1
WO2015040501A1 PCT/IB2014/058630 IB2014058630W WO2015040501A1 WO 2015040501 A1 WO2015040501 A1 WO 2015040501A1 IB 2014058630 W IB2014058630 W IB 2014058630W WO 2015040501 A1 WO2015040501 A1 WO 2015040501A1
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filter
hdmf
filtrate
biomass
broth
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Bapusaheb Malgonda PATIL
Vikrant Bapusaheb PATIL
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
    • C12M47/02—Separating microorganisms from the culture medium; Concentration of biomass

Definitions

  • the present invention addresses a High Density Microbial Fermentation (HDMF) and recombinant product filtration system. More particularly the invention relates to a HDMF and recombinant product Filtration System; useful for separation of high value liquid products in the manufacture of human biological medicinal products.
  • the invention provides enormous cost reduction due to one-step filtration; eliminates the need for centrifuging huge amount of high purity water for dilution and reduces electricity consumption. This one-step process addresses unmet industrial needs of the downstream processing stage in High Density Microbial Fermentation broth filtration and further benefits in purification thus contributes in developing entire biotechnology platform.
  • Microbial technology exploits microbial wealth for human requirement, like production of microbial metabolites and products such as enzymes, organic acids, antibiotics, drugs and pharmaceuticals, in processes like recombinant protein expressions, fermentations and downstream processing.
  • Over 151 recombinant pharmaceuticals approved for human use produced are by microbial cells either bacteria or yeast.
  • the microorganisms are important in any microbial fermentation.
  • the microorganisms in the fermentations process either produce valuable pharmaceuticals by converting the substrate to valuable fermentation products or they themselves are the products sought in the fermentation process.
  • the goal of the fermentations process is to obtain the highest number of microbes per unit volume, which may be termed as achieving high cell density fermentation.
  • enzymes are used in high volume to produce bio- products using High cell Density Microbial Fermentations(HDMF).
  • HDMF allows increased product volume for improved volumetric productivity.
  • Factors that are most critical on biopharmaceutical manufacturing costs are the fermentation titer i.e.
  • the fermentation titer depends mainly on the host cell expression system, the genetic stability of the host cell or cell line and the cell density.
  • the overall yield on the other hand is a result of the downstream processes. Purification costs are significant in biopharmaceutical production.
  • Fermentations produce wide variety of valuable recombinant proteins, Monoclonal antibodies, Vaccines, Nucleic-acid based products, Therapeutic enzymes etc. biotech-products using various microorganisms including animal cells and mammalian cells-CHO-Chinese Hamster Ovary cells for the production of complex protein such as antibodies.
  • the HDMF broth separation process requires 20 to 30 times dilution by pure water and repetitive centrifugation and filtration to produce a clear filtrate that can be used for further purification by Ion Exchange chromatography and Ultra Diafiltration for separating diluents and other constituents.
  • HDMF broth generation is around 12 KL and biomass produced is 4KL.
  • the broth is diluted 20 to 30 times by adding pure water facilitating centrifuging.
  • the water volume used as a diluent depends on the characteristic consistency of the biomass.
  • the main disadvantage associated with the Centrifuging is the compressible biomass wetcake. Due to g-force generated by 45kVh electric motor, the separated biomass forms compact wetcake along the periphery. The compacted-cake resists filtration. Hence to recover the extract i.e. the liquid from the Supernatant Biomass, the broth is diluted 20 to 30 times its volume, with pure water.
  • the decanters are expensive, consume high energy and hence they are sparingly used.
  • HDMF Broth separation typically involves serial dilution by adding high purity water, repeated use of centrifugation in 20 to 30 batches, followed by multiple microfiltration steps.
  • centrifugation and auxiliary equipments consume enormous amount of capital investment and operating costs and electricity consumptions contribute to high investment, cumbersome inappropriate centrifuging, laborious operations in sterile environment is expensive adds to the cost of end product
  • the present invention provides a highly scalable, an efficient and economical Filtration and purification system that facilitates economical quality processing of high value liquid HDMF and recombinant products in aseptic conditions.
  • the present invention devises a cost-effective method to separate high value liquid products obtained from microorganisms and recombinant products wherein repeated water dilution of the HDMF biomass for centrifugation, and repeated filtration can be avoided to ensure better and faster purification in compact unit.
  • the separation of liquid products from biomass can be carried without dilution of HDMF harvests or fermentation broths containing recombinant products.
  • the spent Biomass can be deactivated while it is still in the filtration system.
  • HDMF High Density Microbial Fermentation
  • Fig. 1 depicts a typical HDMF process with fermentation medium capacity of 15KL wherein each component with capacity is denoted as follows: Tl- Antifoam tank: 250Z; GT1 - Tank: 2 KL; GT2 - Tank: 2 KL; Fl - Seed fermenter: 2001; F2 - Production fermenter: 15 KL; T2-Trace element solution: 100Z; T3- Feed medium tank: 7 KL and T4-Batch medium tank: 7KL.
  • Fig.2 depicts a typical HDMF broth filtration system wherein each component with holding capacity is designated as follows: AA -HDMF broth feed 1 1 KL; 01- Diluent Storage Tank 15KL (450 KL); 02- Dilution Tank with Pump: 2 KL; 03-Centrifuge with motor, control. (Westphalia-HFE-45 Flow Capacity 5- 7KL/Hr with 45kW Motor); 04-Biomass Decontamination System: 7 KL; 05 - pH adjustment tank: 2 KL; 06- Heat Exchanger; 07-Storage Tank: 15 KL and 08: Filtration Unit to filter 450 KL Total Dilute Filtrate.
  • Fig 3 depicts the one step HDMF system of the instant invention wherein each component comprises
  • Fig.4 depicts the downstream processingof the present invention wherein each component of the unit and its holding capacity is designated as follows: 11- Buffer storage tank (Glycine/ CaC ) : 2 KL; 12-Buffer storage tank (NaCl):2 KL; 13A/B-Ion exchange chromatography; 14 - Storage tank: 1 KL; 15A/B-Ultra and Diafiltration Unit with Pump; 16-Feed Tank: 200Z/17- Storage tank (HCl/CaCh): 200Z; 18: CIP Tank: 200Z; 19 -Final product tank: 501;20- Heat Exchanger ; 21: Conductivity adjustment unit;
  • the present invention provides novel filtration and purification system useful for separation of high value liquid products obtained from Microbial and recombinant products from HDMF broth or otherwise.
  • the invention provides a Fermentations including HDMF Broth Filtration System, wherein the system comprises the following components: a)Rotary Leaf Filter (51), having Precoat able filter-plate stack, Geared Motor, Control Panel with Variable Frequency Drive for filter stack rotation; mounted on trolley with CIP and SIP facility; b) Control Panel for filtration system (52); c) Precoat Tank (53) to mix precoat powder with clean water by
  • Precoatfeed pump(54) to circulate precoat powder mixed in clean water by introducing air / N2- inert gas.
  • the mixture is circulated to form required fine layer on the filter plates and allow water to pass through Rotary Leaf Filter (51)through bottom nozzle back to Precoat Tank (53)till adequate layer is formed and clear filtrate/ water is obtained;
  • Guard Filter protects filtered product stored in filtrate tank (BB) in case of accidental leakage through the filter plates. It has coarse filter AISI316, to trap leaked biomass and 0.2 micron fine filter to trap fine particles if any in filtrate as a guard filter.
  • the Diaphragm pump (AA) connected to Fermenter pumps broth into the filter. The wet biomass gets deposited on filter plates and clean filtrate passes through outlet nozzle into Guard filter and then into Filtrate storage tank (BB).
  • Filtrate Product Tank equipped with centrifugal Pump feeds the particle free clear liquid product into purification system.
  • the system has interconnecting piping, valves, instruments, view glasses, control panel to monitor the entire filtration and Biomass deactivation system within main filter.
  • the system has tri- clover fittings on piping for quick assembly & dismantling,
  • Screw-press biomass in the filter after deactivation can be slurried and discharged or can be squeezed in screw-press(56), dewatered and disposed off (CC) .
  • the present invention is designed for most critical filtration of HDMF broths in a sterile environment.
  • the entire broth can be filtered with no waste in one- step without the use of centrifugation.
  • the process of the present invention can be used for the production of recombinants, enzymes, vaccines, metabolites and DNA material.
  • the real advantage of the present invention is that it is a one-step process, which does not require dilution of the HDMF or other fermentation broth containing recombinant products, centrifugation which leads to generating fine particles and series of cartridges filters and 0.22 membranes filters.
  • the instant technology of the present invention finds application in pharmaceutical and biotechnology fields to produce HDMF and recombinant products such as vaccines, enzymes, and metabolites, as well as transgenic recombinant products with great yield and high purity.
  • the process lowers the production cost by about 60% compared to commercial process currently in the marketplace.
  • This novel filtration technique eliminates dilution(20 to 30 times)hence the quantity to be filtered is less than 10KL and hence efficient than the conventional filtration- separation techniques.
  • the HDMF or otherwise broth can be fed directly into the system without dilution.
  • the filtration system performs deactivation of the biomass in the filter itself.
  • the produced filtrate is clear and suitable for chromatography that does not affect gel in column chromatography during purification.
  • the size of chromatography purification system and Diafiltration system is also reduced to process less than 10 KL liquid as against 210KL or 310KL.
  • the invention provides a cleaning in position and sterilizing in position facility wherein the filtration system can be cleaned by front and back washing and further sterilized in place. Biomass wetcake deactivation, slurring and discharging the squeezed- dewatered wetcake in solid- wetcake form is performed in the filtration system itself. This is a batch process. The undiluted filtrate having liquid product can be purified at much lower costs due to enormous reduction in filtrate volume.
  • the present invention is an enormous development in industrial biotechnology to derive high value recombinant and medicinally important biological molecules.
  • the present invention discloses novel filtration system useful for deriving HDMF and recombinant products from HDMF broth obtained from microorganisms or recombinant microorganisms
  • the present invention is designed for filtration of HDMF broths in sterile environment according to cGMP.
  • the entire HDMF broth can be filtered without 20 to 30 times dilution with high purity water and eliminating centrifugation with no waste in one- step without the use of centrifugation and serial micron filtrations.
  • the process of the present invention can be used for the production of HDMF and recombinant products-enzymes, vaccines, metabolites and DNA particulates.
  • the real advantage of the present invention is that it is a one-step process, which does not require huge quantity of high purity water for dilution affecting the downstream purification of the HDMF biomass, for centrifugation, consuming lot of electricity, intermittent storage tanks with pumps, heat exchangers, conductivity adjustments before microfiltration, Biomass deactivation system and use of series of Pre-filters and 0.22 membrane fine filters to filter enormous amount of diluted broth.
  • the invention provides HDMF filtration system as described in Fig. 3, wherein the system comprises: a) Rotary Leaf Filter (51) with filter plate stack for filtering broth after precoating; mounted on central shaft with Geared motor, Control Panel with Variable Frequency Drive to facilitate rotation, for spent wet-biomass slurry dislodging after dewatering under air pressure and deactivation; mounted on trolley with CIP and SIP facility;
  • Precoat Tank (53) with compressed air connection for proper mixing of precoat in water;
  • the centrifugal pump to circulate the chemically inert precoat slurry over the metallic proprietary Filter plates until all precoat powder is held on filter plates and clear water, free of precoat powder is seen during circulation;
  • the commercial scale HDMF filtration system is mounted on trolley with CIP and SIP facility, designed according to the invention has a capacity of 501itre.
  • the HDMF filtration unit is also be scaled to a larger capacity as per fermenter size or customer's requirement.
  • the HDMF filtration system consists of a rotary leaf filter (51) which is made up of Stainless Steel AISI 316, having a vessel diameter of 500mm with filtering area of 1M 2 and with wetcake holding capacity of about 15Z (considering maximum 350gms/litre moist wetcake).
  • a rotary leaf filter (51) which is made up of Stainless Steel AISI 316, having a vessel diameter of 500mm with filtering area of 1M 2 and with wetcake holding capacity of about 15Z (considering maximum 350gms/litre moist wetcake).
  • the rotary leaf filter (51) consists of Precoatable filter plate stack with sterile filter aid powders to aid in filtration of HDMF Broth.
  • the HDMF filtration system has wet-cake washing, dewatering, deactivation, slurring and discharging; Cleaning in Place (CIP) by Front spray washing while rotating and Back washing and Sterilizing in Place (SIP) etc. facility.
  • the Variable speed drive unit for filter stack rotation comprises of a Gear Box coupled with 1 HP (0.75 KW) Ex-proof Motor with VFD control system.
  • the Precoat Tank (53) is a Vertical Vessel with air bubbling arrangement for proper mixing of Pre-coat powder in a clean carrier water/ solvent, made up of Stainless Steel AISI316 having a vessel diameter of 450mm with water holding capacity 50 Litres.
  • the Guard Filter (55) is a Stainless Steel 316Filter vessel 035Ommwith welded dished bottom & top dish bolted with quick opening cover having a vessel diameter of with wetcake holding capacity of 30Litreshaving sintered SS316 filter plate to arrest accidental release of fine particles in filtrate storage tank (BB).
  • the Pump with motor (54)for precoating filter screen with precoat powder in water is a centrifugal type (Flow: 120 LPH) coupled with 1 HP (0.75 KW) Ex-proof Motor.
  • the centrifugal pump circulates the chemically inert precoat slurry over the metallic Filter plates until all precoat powder is held on filter plates and clear water, free of precoat powder is seen during circulation. Then the circulation is stopped and air is introduced in the filter under gentle pressure to dewater precoat layer. Then undiluted HDMF broth or feed to be filtered is introduced with pump into Filtration system.
  • the biomass gets deposited on pre-coated filter stack and sparkling clear filtrate passes into Guard Filter and then into filtrate receiver.
  • interconnecting piping, valves according to the invention are provided on the entire system with tri-clover fittings for quick assembly & dismantling.
  • the filtration system according to the invention is manufactured as per cGMP norms and Quality Control/ Quality Assurance Plan. All necessary material, inspections & tests were carried out during the course of manufacturing with full documentation.
  • the invention provides a one-step process for High Density Microbial Fermentation using the HDMF Filtration System.
  • the process comprises: a) preparing a pre-coat solution in a pre-coat tank(53) with pure water by mixing an inert pre coat powder specially selected by introducing an inert gas N2 or Compressed dry air slowly, followed by circulating pre- coat solution by pumping over filter leaves in filter vessel to achieve proper pre-coat of desired thickness;
  • the novelty and inventiveness of the instant invention lies in the use of Pre coating the Filter stack in the rotary leaf filter with suitable Sterile Filter Aid (Chemically inert pre-determined pre-coat powder based on broth characteristic)to achieve particle free clear filtrate suitable for chromatography in one-step thereby eliminating, adversely affecting high purity water for dilution for HDMF broth for centrifuging and involving series of cartridge pre-filtrations and 0.45 and 0.22 ⁇ fine filters.
  • Sterile Filter Aid Cosmetic inert pre-determined pre-coat powder based on broth characteristic
  • the pre-coat tank (53) is filled with water as required.
  • the selected particular filter aid powder is slowly added while air is introduced to make homogenous mixture.
  • Pre-coating' is a thin lto 1.5mm thick porous layer formed over metallic filter screen to filter HDMF broth to retain biomass and let out clear filtrate free of sub micronic suspended particles with least resistance.
  • Pre-coating is done by circulating mixture of pure water and inert Filter-Aid powder i.e. microcrystalline cellulose of highest purity (around 99% or better) of appropriate grade.
  • the pressure during precoating is around 2kg/cm 2 and flow velocity 1.5 times or more that of the actual slurry to be filtered.
  • Pre-coat powders as used in the invention confirm to pharmacopeia requirements or criteria from Pharm. Eur.II (inc. BP 93, BPC, DAB 10) and NF XVII. They are sterile and have different grades to suit the specific product requirements.
  • the metallic filter media supports the precoat and the micro porous powder layer provides depth filtration assuring sparkling clear liquid by retaining sub micronic suspended solids.
  • selection of pre-coat powder is important and depends on proper grade, particle shape, size distribution, surface area, surface charge, adsorption or absorption quality, process compatibility etc.
  • the above criteria need to be critically considered while selecting precoat powder to ensure sparkling particle free clear filtrate.
  • the characteristics of liquid i.e. specific gravity, surface and interfacial tensions, viscosity, nature, physical properties etc. are to be determined. Lab scale trials on actual broth are required for appropriate selection, determine quantity and precoating procedure.
  • the selection of pre-coat may also depend on the microorganism involved in production of liquid products.
  • the invention provides a one-step process for filtration having liquid product (Trypsin/Trypsinogen) that is secreted on the cells in the culture supernatant expressed by recombinant Yeast (Pichiapastories) in HDMF fed-batch fermentation. More than 18 different types of pre-coat Pharma grade Filter aid powders were tested to select most suitable pre-coat powder to filter the HDMF broth. Few such pre-coats are of Diatomite, Perlite and Cellulose origin
  • the process of Pre-coating should not take more than 15-20 minutes.
  • the resultant differential pressure for pre-coating should be within 3 psig maximum and flow velocities 1.5 times the feed flow rate.
  • Pre-coat powder required varies between 100 grams to 150 grams per square meter of filtering area. However it depends on nature of suspended solids and nature of liquid, broth etc.
  • the pre-coat layer thickness normally varies from 1mm to 1.5 mm. Further, it depends on nature of filtrate and wetcake, quantity and nature of suspended solids, size, shape etc. Pre-coating must be done using clean/ filtered fluid & on clean filter media. Under any circumstances the sticky particles in the feed should not reach filter screen/ cloth.
  • Filter stack is stationary during pre-coating, precoat dewatering, broth filtering, wetcaked watering under air pressure, vessel hold up/heel filtration and filter draining.
  • the HDMF broth is circulated until filtrate obtained is sparkling clear.
  • the feed gets filtered through the pre-coat layer and screen filtrate passes through outlet.
  • the biomass wet-cake gets deposited on the pre-coated filter screen. Circulation is continued till filtrate is clear. The clarity can be seen through the sight glass tube on the filtrate outlet line.
  • Samples are collected for lab analysis. Once the filtrate is clear, the inlet valves on the Guard Filter and Filtrate receive rare opened to allow the filtrate to pass through into Filtrate Tank.
  • the wetcake forms over filter plate stack. At the end of filtration the wetcake is dewatered for maximum product filtrate recovery.
  • the filter vessel hold-up/heel volume can be transferred back to feed tank or filtered through the Guard Filter. Slow introduction of Air/ Nitrogen at 1 to 2 kg/cm 2 displaces vessel hold-up/heel volume as much as possible. Holdup filtration and dewatering may take half an hour or more, based on the wetcake characteristic. Wetcake Washing and Dewatering:
  • wetcake washing is generally done as per process requirement by introducing water over wetcake broth under pressure. In filtering HDMF broth, cake washing is not done to avoid dilution of filtrate. However, dewatering is done by introducing clean dry compressed air/ N2 to collect entrapped liquid.
  • wetcake is washed and biomass and precoat layer de watered, it can be deactivated at 0.15 kg/cm 2 or more 121°C by steam sterilizing, as per SOP.
  • the filter is cleaned after deactivation of wetcake before and after every filtration batch as per SOP, to restore the filtration efficiency. Cleaning of filter while rotating filter stack and front-washing with jet sprays, is normal. It is possible to introduce air/ steam from filtrate side to loosen the entrapped particles if any for faster and reliable cleaning.
  • the filter stack is spun after filtration and dewatering to dislodge the wetcake. It is good practice to use spray wash to slurry the wetcake during filter stack rotation. The washed slurry can be drained and the filter screen can be cleaned by introducing compressed air from filtrate nozzle to open the blocked screen holes.
  • the present inventors have developed special spray header for effective cleaning of filter stack since HDMF broth is sticky and difficult to dislodge in position i.e. without opening the vessel.
  • the spray header is provided with unique jet sprays positioned above each filter plate. The spray header position can be adjusted for cleaning.
  • the spray forces the wash liquid to penetrate into wetcake, loosen and slurries while the filter stack rotates at slow speed. The slurry is then drained.
  • the slurry outlet valve is closed and water level is maintained above filter plates while spinning/ rotating the stack at higher speed, to loosen the fine sticky particles if clogged in filter screen.
  • filter media gets choked it is possible to backwash the filter by gently introducing clean water while introducing Air/ N2 at 0.15 kg/cm 2 pressure to assist opening of clogged filter media pores.
  • Sterilizing In Position After CIP, the complete system is Sterilized In Position (SIP) by introducing steam at 0.15 kg/cm2 at 121°C Temperature. Dry Air/ N2 is blown for final drying before next batch.
  • Pre-coat Powder IKg was mixed in 30 Litres of water with the help of blowing inert air/nitrogen for homogenizing the slurry. Pre-coating was done by circulating the premix solution at flow rate around 25 LPM (litre per minute) for about 10 minutes. The filtrate clarity was found to be excellent.
  • the technology was scaled to improve the yield of Trypsin/Trypsinogenpresent in supernatant- broth, which is produced from recombinant human Trypsin expressed on the yeast (Pichia pastories).
  • a cultural supernatant containing 300/350 grams/litre of moist biomass produced in the bioreactor containing Trypsin /Trypsin ogen was fed to the filtration system of the present invention.
  • HDM Fermentation broth about (45 Litres), from the Ferm enter, having wet cell density of approx. 350gms/litre was fed to the instant Filtration system @ lKg/cm2 @ 21°C. Filtrate was not re-circulated. Once through filtration with Guard Filter in line was done.
  • Filter stack was cleaned in position by spraying water through spray header while rotating the filter stack. Cleaning cycles took 30 minutes. After cleaning dry air was blown for 5 minutes. Finally the filtration system was sterilized in place for 30 minutes for reuse in next batch.
  • Example 5 B Comparison of the downstream processing unit employed in the instant invention with the conventional method with reference to Fig 4 is provided below:
  • Diaiiltration system with 4M 2 was not required for the instant HDMF Broth filtration purification system since the system does not require the dilution of the feed. However smaller size unit of Ultra / Diafiltration with 0.25M 2 membrane area sufficed.
  • the invention provides a filtration - purification system employing a one step process which is aseptic, easily scalable, uses lower pressure (e.g., less than 2K/cm 2 ), consumes minimal electrical power and does not require high purity water for dilutions that adversely affects downstream processing prior to centrifugation, intermittent storage tanks with pumps, heat exchangers, conductivity adjustments before microfiltration, biomass deactivation system and use of series of pre-filters and 0.22 ⁇ membrane fine filters to filter enormous amount of diluted broth.
  • lower pressure e.g., less than 2K/cm 2
  • This novel one step filtration process eliminates need of high purity water required for multiple dilutions (20 to 30 times), besides that the dilution with high purity water adversely affects the downstream purification including the gel in ion chromatography column and the product, also dilution affects pH of the broth. Moreover, in the instant invention addition of buffers or other preservatives as additives is not required.
  • the cost savings is attributed to saving of high purity water due to the elimination of multiple dilutions and not using multiple micron filters at each filtration stage i.e. 10 ⁇ /5 ⁇ ,0.45 ⁇ and 0.22 ⁇ . In prevalent commercial processes, multiple filters used after each centrifugation step, are not required by this invention.
  • the filtrate thus obtained is particle free and suitable for direct chromatography having 11.5NTU.
  • the washing and deactivation of biomass can be done in the filtration unit itself after which the spent biomass can be sold for value.
  • the biomass can be squeezed after deactivation of spent biomass and can be sold for value.
  • the one step Process for filtration of Microbial HDMF and recombinant using the Microbial HDMF and recombinant Filtration System of the instant invention is reliable, simple, user friendly and most economical for HDMF filtration.
  • the invention is highly scalable with zero discharge of effluent.
  • the present invention is an enormous development in industrial biotechnology to derive high value recombinant and medicinally important biological molecules.

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Abstract

La présente invention concerne un système de filtration caractérisé par un procédé en une étape permettant d'isoler et de purifier des produits biologiques, notamment des produits recombinants dérivés d'une fermentation microbienne à haute densité cellulaire (HDMF). Le procédé n'est pas limité aux HDMF et peut être appliqué à d'autres systèmes de fermentation à des fins de séparation de produits biologiques à haute valeur.
PCT/IB2014/058630 2013-09-23 2014-01-29 Système de filtration de produits recombinants et de hdmf Ceased WO2015040501A1 (fr)

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IN3043MU2013 2013-09-23

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JP2019505240A (ja) * 2016-02-23 2019-02-28 コーニング インコーポレイテッド 灌流バイオリアクタおよび連続細胞培養を実施するためのその使用方法
CN111205117A (zh) * 2020-02-18 2020-05-29 重庆亿创西北工业技术研究院有限公司 一种基于新能源沼气池的密封加料设备
CN112592810A (zh) * 2020-12-29 2021-04-02 大同同星抗生素有限责任公司 土霉素生产过程中的补料下料装置

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