Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/14—Extraction; Separation; Purification
  • C07K1/34—Extraction; Separation; Purification by filtration, ultrafiltration or reverse osmosis
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F26—DRYING
  • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
  • F26B17/00—Machines or apparatus for drying materials in loose, plastic, or fluidised form, e.g. granules, staple fibres, with progressive movement
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D29/00—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D9/00—Crystallisation

Definitions

• the invention relates to a device for filtration, drying and storage of solids from a suspension (FDS unit) and carried out in this Appendix process for working up and drying of a solid suspension in particular of crystallizable therapeutic proteins or active ingredients.
• the FDS unit designed for use as a disposable system is a device with which drug crystals, with closed process control, i. can be filtered, dried, stored and reconstituted without intermediate opening or decanting, gently and safely.
• the DSP is generally based on chromatography-based separation processes.
• the requirements for the cleaning process based on several separation steps with regard to purity and freedom from contamination are constantly being increased according to the experience of recent years. This is especially true for the manufacture of pharmaceutical agents such as therapeutic peptides and proteins to eliminate unintended biological side effects from the numerous by-products produced during fermentation.
• proteins Due to the chemical and thermal instability of proteins, the processes to be used in industrial production are currently limited in downstream processing.
• pH shifts changes in ionic strength or temperature
• proteins are caused by u.a. Aggregation, hydrolysis, deamidation, isomerization, Degly k osy 1 ieru ng and oxidation or reduction can be deactivated.
• the Stabiiticiansprobieme can be minimized by protein solutions are stored at the lowest possible temperatures. This reduces the rate of possible chemical modification reactions.
• the surrounding environment of the proteins can be optimized so that the effects of denaturation are minimized.
• a stabilization of the proteins can also be done by drying, as the reactions are slowed by withdrawal of the water, so that they no longer or significantly slowed down during storage. If deamidation and hydrolysis of the proteins in solutions are the main problems, these processes play a minor role in the dried state (McNally, E.J., Pharm. Sei., 2000, 99).
• oxidation reactions decrease with decreasing residual moisture content (Franks, F., Bio / Technology, 1994, 12, 253-256, Christensen, H., Pain, RH Molten globule intermediates and protein folding, Eur. Biophys., J. 1991 , 19, 221-229).
• the main advantage of drying proteins lies in the increased thermal stability, which in turn leads to improved storage stability.
• the DSP of dried crystals causes significant risks of contamination of environment (personnel exposure) and product (cross-contamination), especially when dealing with dry powdery substances, cross-contamination between product batches and especially between different types of products
• the equipment used for the solid-liquid treatment must be subjected to an intensive cleaning procedure with subsequent cleaning validation, resulting in high expenditure of time and personnel and the open handling requires expensive rinsing environment and complex safety measures (exposure protection, protection against dust explosion etc.)
• Processing of pharmaceutically active protein crystals (or crystals of other pharmaceutically active substances) including separation, drying
• the transport, storage and reconstitution should therefore be carried out in such a way that neither employees are endangered by material leakage nor is there a danger of contamination of the product.
• the patent WO 00/44767 Al describes the use of a centrifugal dryer for the isolation (filtration), washing and drying and further processing of insulin crystals. Particular attention is paid to the introduction of a drying medium consisting of a mixture of water and a non-aqueous, water-miscible solvent having a lower vapor pressure than water. In addition, a water-moistened nitrogen stream is used for drying. The amount of water results from the optimal residual moisture for the protein (insulin and insulin derivatives).
• a disadvantage of this approach are the large apparatus complexity of the centrifugal dryer and the associated expense for the cleaning and reclamation validation.
• the object of the present invention was therefore to provide a device for filtration, washing, drying, transport, storage and optionally re-suspension / re-solubilization of crystalline active ingredient products that is simple, safe and gentle to the product , whereby a contamination risk is minimized or excluded.
• FDS unit a device which can be used as a disposable system and which is placed in a single vessel - i. without an intermediate opening - the sequential steps filtration, washing, drying, sampling, transport, storage and re-suspension / re-solubilization allows - hereinafter referred to as "FDS unit"
• FDS unit can be product gentle crystalline proteins or provide peptides without the risk of product contamination for the subsequent formulation steps, product losses or employee exposure to unintentional product release, such as hazardous dust emissions, can be minimized through closed process management.
• the first subject of the present invention is therefore a filter unit (FDS unit) for the filtration of solid particles from a suspension comprising:
• a filter housing (10) comprising a filter chamber (13), a liquid distributor (50) at the end of at least one inlet fs (15) to the filter chamber (13) and a bottom (12) and a
• Filter medium (1 1) wherein the filter chamber (13) and the bottom (12) in the region of the filter medium (11) by a compound sealingly against the environment and against the filter medium (11) are connected,
• the material of the FDS unit is selected so that the usual cleaning and sterilization processes in the pharmaceutical industry, such as autoclaving or gamma irradiation are applicable.
• filter media (1 1) usually made of fibers or sintered materials, suitable for pharmaceutical purposes filter plates or filter cloth are used, which are made of suitable materials known to the expert such as plastics, glass, metals or ceramic materials and have an optimized on the filtration process or the product quality in terms of product loss, throughput or pressure loss pore size.
• suitable materials known to the expert such as plastics, glass, metals or ceramic materials and have an optimized on the filtration process or the product quality in terms of product loss, throughput or pressure loss pore size.
• suitable materials known to the expert such as plastics, glass, metals or ceramic materials and have an optimized on the filtration process or the product quality in terms of product loss, throughput or pressure loss pore size.
• suitable materials known to the expert such as plastics, glass, metals or ceramic materials and have an optimized on the filtration process or the product quality in terms of product loss, throughput or pressure loss pore size.
• Particularly preferred for use as the FDS unit as a disposable system is the use of inexpensive materials such as sintered or sintered stainless steel mesh or
• the filter medium (11) is clamped horizontally as a filter plate (17) in the filter housing (10).
• the filter element may be designed as a continuous, preferably cylindrical tube or as a filter cartridge (18) (FIGS. 2 and 6), which may be surrounded by a concentric outer filter tube (19) (FIG. 6).
• the filtration takes place in an annular space formed by the filter tube (19) and the filter candle (18) with the gap width (58).
• the filter housing (10) is usually made of approved for drug production plastics.
• standard methods for the deformation of plastics injection molding, extrusion, etc.
• the filter housing made of thermoplastic, known in the art plastics such. Polyethylene, polypropylene, PMMA, POM, polycarbonate (especially macroion).
• the product-contacting walls of the filter chamber (13) and possibly the bottom (12) are in a preferred embodiment also made of plastic films and thus the filter housing completely or partially designed as a plastic bag.
• the upper pressure required for filtration is transferred at least within the filter chamber (13) via the bag walls to a pressure-stable holding device.
• This solution is preferably used for larger scale from about 5-50L, from which the cost of the FDS unit could otherwise complicate a single-use application.
• a closure clip eg Triclamp
• the filter housing can be screwed together (eg by means of thread or Bayonet lock).
• filter chamber chamber (13) and possibly the bottom (12) are in a preferred embodiment also made of plastic films and thus the filter housing completely or partially designed as a plastic bag.
• the upper pressure required for filtration is transferred at least within the filter chamber (13) via the bag walls to a pressure-stable holding device.
• This solution is preferably used for larger scale from about 5-50L, from which the cost of the FDS unit could otherwise complicate a single
• a re-suspension / re-solubilization of the protein crystals within the FDS unit is desirable for the closed processing of the product in closable FDS units, but for non-detachable connections between the filter chamber (13) and bottom (12) for product removal is absolutely necessary.
• the energy input required for accelerated re-suspension / re-solubilization is thereby preferably non-invasive, i. without interference with the closed system, e.g. via orbital or rotationally oscillating shaking into the FiUerhunt (13) registered.
• a suspension (30) of protein crystals is fed into the filter chamber (13).
• the filter chamber (13) is in this case vented via a closable vent pipe (22).
• the usual size of the FDS unit for the small scale is 5 mL and 500 mL, but on a large scale FDS units with a total volume of up to 50 L or larger can be produced.
• the slenderness levels (ratio of height to diameter H / D) of the filter chamber (13) depend on the type and efficiency of the liquid distribution at the head of the filter housing (10) and the optimum achievable height of the filter cake (20).
• the degree of slimming is usually selected so that a filter cake height of 1 to 20 cm, preferably between 2 to 8 cm, more preferably between 3 and 5 cm in the device can be achieved, the specific properties of the protein crystals to be filtered in particular size, stability and compressibility the crystals are taken into account.
• the suspension (30) of protic crystals is fed via the liquid component distributor (50) with at least one inlet (15) into the filter chamber (13) (FIGS. 1, 2, 4, 5, 6 and 7).
• the suspension (20) is introduced into the FDS unit so that a uniform structure of the filter cake (20) takes place.
• the uniform structure of the filter cake (20) is for the function of the FDS unit of essential importance, because this determines the duration and intensity of drying and thus the extent of unwanted, product impurities and activity losses causing side reactions.
• the suspension (30) is preferably a liquid distributor (50) consisting of a single inlet (15) with a tangential or centric axial inlet direction supplied (Fig. 1 and 2).
• a liquid distributor (50) consisting of a single inlet (15) with a tangential or centric axial inlet direction supplied (Fig. 1 and 2).
• the liquid distributor (50) are preferably equipped with a distributor plate (54)
• Distribution plates with distributor plate are often used in chromatography, but are mostly unsuitable for distribution of suspension due to the low channel height, sharp creases, dead spaces, and lack of orientation of the lines (solid settling).
• WO2010 / 138061 A I describes a tree-shaped liquid distributor with distributor plate, in which the outlet openings are arranged like a lattice.
• the complicated tree-shaped line construct is made by "free form fabrication” and is particularly easy to clean.
• the described distributor would be quite suitable for the distribution of a suspension, but is complicated to manufacture and expensive for the intended one-way application here.
• the disposable liquid distributor (50) has a pre-distributor (56) connected to a distributor plate (54) by means of hose lines (52) of the same length and diameter and thus approximately equal pressure losses (FIG. 4).
• the hose lines (52) open under spreading and possible steady gradient (avoidance of solid deposits) in vertical outlet openings (53) of a distributor plate (54).
• Useful angles of attack of the outer tube fibers are depending on the diameter of the FDS unit between 5 ° and 75 ° are particularly preferred attack angle of 20 - 60 °.
• the distribution of exit flows (53) on the distributor plate (54) is usually designed (Fig.
• the number of outlet openings per area required for a sufficient solids distribution depends on numerous factors, such as the particle density and size distribution, or the rate of descent of the particles, the Fi ltrations Aus, the height of the filter cake (20) the slenderness of the filter chamber (13) ,
• a filter chamber (13) with a diameter of 190 mm, charged via the distributor according to the invention, produced in a model experiment with 10 ⁇ g / L PANX particles an average absolute height difference of about 2% -3%, based on the cake height, about 40 mm and thus at a H / D ratio of H / D 0.5 already a sufficiently good particle distribution.
• the distributor used for this purpose has a drainage distance of approx. 63 mm at 7 outlets.
• each outlet opening is connected to a pre-distributor (56) by means of a non-branched hose line (52).
• hose line usually, silicone hoses are used as the hose line.
• the hoses are plugged into the pre-distributor, poured, welded or glued bundled
• the pre-distributor is usually supplied via an axially or tangentially arranged inlet (15) with the suspension (30).
• the filter cake For a further increase in the process scale or in the case of products which are difficult to filter, it may be advantageous to construct the filter cake non-planar, but in the annular space between a filter candle (18) and a filter tube (19) (FIG. 6). This creates the great advantage that the pressure loss is independent of the height of the filter cake is adjustable. This makes it possible to realize a slender geometry regardless of the scale, which, among other things, generates considerable advantages in terms of space requirements or the compressive strength of the apparatuses.
• the height of the Filtcrcinoplasty (18, 19) should preferably correspond as closely as possible to the height of the filter cake (20).
• the filtrate (40), which flows through the filter medium (1 1) can be discharged through the preferably central outlet (14) at the bottom (12) of the lower filter housing.
• the filter cake (20) can be washed after filtration in the FDS unit.
• the inventive FDS unit is preferably used in a plant as shown in FIG. 3 without being limited thereto.
• the remaining filtrate (40) consisting of mother liquor or washing liquid is usually displaced from the filter cake (20) by means of a gas (140), preferably sterile filtered air or nitrogen.
• the gas usually enters via the inlet (15), the gas and / or liquid outlet via the outlet (14).
• the gas (140) is raised to a defined temperature by means of a gas heater (160) and set to a minimum residual moisture content by means of a gas humidifier (165).
• the latter is intended to prevent the product from being stored at too low moisture contents, e.g. is irreversibly damaged by clumping, discoloration or caramelization. In particular, a false residual moisture can lead to denaturation or difficulties in resolubilization (loss of activity inclusive).
• the inlet and outlet of the FDS unit can be disconnected.
• hose clamps (67) with the on the inlet (15) - and drain (14) - pruned wound flexible hose lines (66), preferably from pharma-conform form silicone or C-Flex can be disconnected.
• the filtered, washed and dried protein crystals can also be left in the FDS unit during transport and subsequent storage without interim opening. In this way, a completely closed handling is possible.
• the FDS unit can be moved on a special orbital shaker (60) (Fig. 8) .
• the shaker (60) has a container (62) for receiving the FDS unit including the hoses (66) and hose clamps (Fig.
• flow-breaking elements eg polygonal cross-section or baffles
• Another object of the present invention is therefore a plant for operating the FDS unit according to the invention comprising: z a crystallization vessel (100) which via lines to one or more reservoirs for crystallization or precipitation and correction means (101) and on the other hand to one or a plurality of FDS units according to the invention in parallel, sequential or intermittent operation is connected, z a mother liquor reservoir (1 10), which is connected via to the outlet (14) of the FDS unit.
• the suspension (30) is passed preferably without particle damage while avoiding pumps, preferably by means of a slight overpressure at moderate transport speeds into the filter chamber (13) of the FDS unit.
• a gas pressure for example via a three-way stopcock (120) connected to the top of the crystallization vessel and adjusted via a pressure measurement (230).
• the filtration of the crystal suspension is usually carried out at a filtration pressure of 0.2 to 1 .5 bar, preferably at 0.5 to 1 .0 bar.
• the suspension (30) is retained by the filter medium (1 1, 17, 18 or 19 depending on the structure of the FDS unit).
• the filtrate (40) derived from the outlet (14) of the FDS unit is fed in a preferred embodiment via a further three-way valve (130) to the filtrate reservoir (110).
• the filtration is complete when the entire crystallization vessel (100) and FDS unit liquid has been squeezed out so that only the pre-dried filter cake (20) remains in the FDS unit.
• the filter cake (20) is still surrounded after filtration by the crystallization liquid.
• the crystallization liquid is now replaced by a drying gas.
• the drying gas can be passed through the filtration unit.
• compressed gas of defined residual moisture is used for drying with a pre-pressure of 1 to 3 bar, preferably at 2 to 3 bar. An apparatus conversion for drying is avoided.
• the drying unit has a drying unit comprising a separate drying gas line and three-way taps (120, 130). These are adjusted in such a way that the drying gas (with the corresponding moisture load) is bypassed by a bypass on the crystallization reactor.
• al gas heater 160 may be used e.g. a pipe with heating jacket can be used.
• the moisture content of the drying gas is set to a minimum value.
• the moisture of the drying gas is preferably adjusted prior to introduction into the drying unit and controlled by means of a moisture sensor (210). For a greater moisture requirement, the minimum moisture can be adjusted via a humidifier (165) in the gas flow.
• the drying of the filter cake is also monitored by means of a moisture sensor (220) at the output of the disposable FDS unit.
• the in the filtration in the reservoir (1 10) collected filtrate (40) is used in the drying as a washing liquid for the exhaust gas (150) to minimize potential occurring during drying dust emissions.
• the FDS unit according to the invention has a means for minimally invasive sampling of the filter cake.
• the FDS unit has a closable opening for inserting a dagger into the filter cake.
• a spade can be inserted horizontally and vertically into the filter cake.
• a further subject of the present invention is therefore a process for working up a solid suspension comprising the following steps:
• the convection drying is carried out with adjustable parameters such as temperature, volume flow or moisture content or with a combination thereof.
• the disposable FDS unit according to the invention is particularly suitable for the separation of protein crystals (pharmaceutically active peptides and proteins as well as therapeutic antibodies) without being limited thereto. It is also advantageous for the separation of other crystalline compounds, especially in cases where regulations of good manufacturing practice for pharmaceuticals must be observed.
• the FDS unit according to the invention and the installation for its application are shown schematically by way of example in FIGS. 1 to 6, without being limited to the embodiments shown.
• Fig. L FDS unit with filter plate
• Fig. 2 FDS unit with filter cartridge
• FIG. 3 Integration of the FDS unit in the system according to the invention for carrying out the filtration (filtration), drying (drying) and provision for transport and storage (storage)
• FIG. 4 fractal liquid distributor (side view: pre-distributor, distributor plate)
• FIG. 5 Fractal distributor (top view: distributor plate with example for the distribution of the outlet openings)
• FIG. 6 FDS unit with filter cartridge, filter tube and fractal distributor for the large scale formed by both Filtcrrrohren annulus Fig. 7 Top view of FDS unit for the large process scale
• Fig.8 Orbital Schüttbl Huber Drived Energy into the FDS unit for the purpose of suspension and resolubilization in closed process control.
• an FDS unit according to FIG. 1 was constructed from a filter housing (10) with a volume of the filter chamber (13) of 100 ml, a diameter of 26 mm and a slenderness ratio of 5.8 and a screw-down bottom part (12 ) made of polyoxymethylene (POM).
• the wall thicknesses of the filter housing (10) and bottom (12) were dimensioned for the selected conditions of an operating pressure up to 3 bar and a temperature of -10 ⁇ [T ° C] ⁇ 60 °.
• As a filter medium (1 1) sintered metal plates were used with a pore size of 5 ⁇ (diameter 34 mm, thickness 5 mm). Filter chamber (13), filter medium (1 1) and bottom (12) were fastened together by means of clamping connections with closing clamp (Triclamp). Crystallization
• the model protein was initially dissolved in a concentration of 10 g / L in 40 mM Na citrate (initial pH 2.7). This was followed by the addition of the precipitant (caustic soda 0.75 M, addition of 15 L in 5 minutes) to a nucleation pH of 3.2. At this pH, the solution was stirred for a further 3 hours (stirring speed 200 rpm). After the nucleation time, the precipitant was added to the solution to a final pH of 4.5. The solution was stirred at room temperature for an additional 17 hours. The determination of optimal process parameters of the subsequent filtration and drying of the protein crystals was carried out by "design-of-experiments" the optimal process parameters emerge. Filtratipn
• an optimum compressed air pres- sure of 2.5 bar ( ⁇ 0.5) was determined.
• the drying temperature (temperature of the compressed gas) depends on the temperature stability of the target protein and was set between 30 ° C to 50 ° C.
• compressed air with an optimum temperature of 45 ° C ( ⁇ 5) was used.
• the relative humidity of the compressed air of 0.5- 1.0%, could be submitted without additional humidifier. It was sufficiently sized to prevent product damage by over drying the filter cake.
• an optimal drying time of 17.5 h ( ⁇ 1) was determined.
• the gas heater (60) constructed from a pipe with a heating jacket, it was possible to heat volume flows of up to 4 m 3 / h to a temperature of 55 ° C.
• Solids / FDS unit loading capacity: 13 [g of crystalline solids / FDS unit] (Vol: 22 cm 3 ) Residual moisture content (Karl Fisher method): 4 [%] Product purity (RP-HPLC): 95 [%]

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• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Molecular Biology (AREA)
• Genetics & Genomics (AREA)
• Water Supply & Treatment (AREA)
• Analytical Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• General Health & Medical Sciences (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Medicinal Chemistry (AREA)
• Mechanical Engineering (AREA)
• General Engineering & Computer Science (AREA)
• Crystallography & Structural Chemistry (AREA)
• Peptides Or Proteins (AREA)
• Drying Of Solid Materials (AREA)
• Medicines Containing Plant Substances (AREA)
• Filtration Of Liquid (AREA)

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• 2012
  • 2012-11-14 RU RU2014124001/05A patent/RU2014124001A/ru not_active Application Discontinuation
  • 2012-11-14 BR BR112014011780A patent/BR112014011780A2/pt not_active IP Right Cessation
  • 2012-11-14 MX MX2014005591A patent/MX2014005591A/es unknown
  • 2012-11-14 KR KR1020147012758A patent/KR20150000862A/ko not_active Withdrawn
  • 2012-11-14 EP EP12787704.1A patent/EP2780355A1/de not_active Withdrawn
  • 2012-11-14 SG SG11201401646SA patent/SG11201401646SA/en unknown
  • 2012-11-14 AU AU2012338914A patent/AU2012338914A1/en not_active Abandoned
  • 2012-11-14 IN IN3291DEN2014 patent/IN2014DN03291A/en unknown
  • 2012-11-14 CA CA2855726A patent/CA2855726A1/en not_active Abandoned
  • 2012-11-14 WO PCT/EP2012/072581 patent/WO2013072348A1/de not_active Ceased
  • 2012-11-14 CN CN201280056262.9A patent/CN103930434A/zh active Pending
  • 2012-11-14 JP JP2014541635A patent/JP6192649B2/ja not_active Expired - Fee Related
  • 2012-11-14 US US14/359,065 patent/US20140317951A1/en not_active Abandoned
• 2014
  • 2014-05-07 IL IL232490A patent/IL232490A0/en unknown
  • 2014-05-14 ZA ZA2014/03471A patent/ZA201403471B/en unknown

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