Compact containment system for isolating, processing and packaging pharmaceutical products

Abstract

A compact closed system includes a mixing apparatus, a drying apparatus, and a discharge apparatus. The mixing apparatus can be used to produce a slurry or solution mixture of solvent and dry powder during pharmaceutical processing, including a dual-compartment isolator for safe removal of dry powder from a dry powder container, a mixing vessel, and a negative pressure cascade controller. The drying apparatus includes a drying unit, such as a thin film evaporator. The discharge apparatus includes a discharge spool, a vacuum supply control valve, a product inlet valve, a gas control valve, a collection control valve, and one or more collection containers. The discharge spool includes a substantially air-tight interior chamber, a housing substantially surrounding the air-tight interior chamber, a vacuum supply inlet fluidly connecting the air-tight interior chamber of the discharge spool to a vacuum source, a solids inlet fluidly connecting the interior chamber to a product reservoir of a dryer, a gas inlet fluidly connecting the air-tight interior chamber to a gas source, and a solids outlet fluidly connecting the air-tight interior chamber to a collection container. The inlets and outlets are opened and closed by operation of flow control valves connected to the inlets and outlets in order to remove or admit gas into the discharge spool, effectively depressurizing and re-pressurizing the discharge spool, while moving dried pharmaceutical product out of the dryer and through the discharge spool. A diverter assembly directs "qualified" material to a primary collection container and directs "unqualified" material to a secondary or "waste" collection container.

Description

Technical Field

[0001] The present invention relates to systems, methods and apparatus for isolating, processing and packaging pharmaceutical products in a continuous manufacturing production line, the pharmaceutical products including active pharmaceutical ingredients (“APIs”), pharmaceutical products and pharmaceutical product intermediates. Background Technology

[0002] Over the past two decades, pharmaceutical manufacturing has made considerable progress, and highly potent ingredients, products, and substances are playing an increasingly important role in combating many diseases, such as cancer. During the production and processing of these potent pharmaceutical ingredients, products, and substances, it is often necessary and / or more efficient for human operators to handle the containers using their hands (or hand-operated tools and instruments). In such cases, it is important that no potent pharmaceutical ingredients, products, or substances are contaminated by the surrounding atmosphere, released into the environment, or come into direct contact with humans.

[0003] Pharmaceutical products and ingredients are sometimes micronized. In these cases, inhalation of dust by humans is a primary concern. However, liquid pharmaceutical products and ingredients, as well as liquid drug byproducts, can also pose very serious hazards to operators and the environment. Therefore, throughout the entire manufacturing process of pharmaceutical products, from the synthesis of the active pharmaceutical ingredient to the final dispensing of the pharmaceutical product, it is essential to protect operators handling pharmaceutical products from direct contact with the products and ingredients, and to protect the products and ingredients from contamination by the surrounding environment or human contact.

[0004] Many pharmaceutical products, ingredients, and substances are manufactured and / or processed in “cleanrooms.” A cleanroom (or “clean space”) is a laboratory facility that is typically used as part of specialized industrial production or scientific research, including the production of pharmaceutical products. Cleanrooms are designed to maintain extremely low levels of particulate matter, such as dust, airborne organic matter, or evaporated particles. Cleanrooms typically have a cleanliness level quantified by the number of particles per cubic meter at a predetermined molecular weight. In a typical urban area, outdoor ambient air contains 35 million particles per cubic meter, each with a size ranging from at least 0.5 μm. This cleanliness level is equivalent to an ISO 9 cleanroom. In contrast, an ISO 1 cleanroom does not allow particles in this size range and permits only 12 particles per cubic meter, each with a size not exceeding 0.3 μm. Air entering the cleanroom from the outside is typically filtered to remove dust, and internal air is continuously recirculated through high-efficiency particulate air (HEPA) filters and / or ultra-low particulate air (ULPA) filters to remove contaminants generated inside. Staff must enter and exit through airlocks (sometimes including an air shower stage) and wear protective clothing such as hoods, face shields, gloves, boots, and work clothes. Equipment inside the cleanroom is designed to generate minimal air pollution. Only special mops and buckets are used. Cleanroom furniture is also designed to produce minimal particulate matter and must be easy to clean and decontaminate.

[0005] In certain situations, it is necessary or desirable to produce or process pharmaceuticals (pharmaceutical substances and pharmaceutical products) in a space classified as "Class C". A Class C space is one that conforms to the ISO 8 cleanroom classification when in an "operational" state (i.e., when in use) and to conform to the ISO 7 cleanroom classification when in an idle state (i.e., when not in use). Therefore, when in operation, a Class C space is one with a maximum concentration of 3,520,000 particles per cubic meter for particles ≥ 0.5 micrometers; 832,200 particles per cubic meter for particles ≥ 1 micrometer; and 29,300 particles per cubic meter for particles ≥ 5 micrometers (consistent with ISO 8). When not in use, Class C spaces have a maximum concentration of 352,000 particles per cubic meter for particles ≥ 0.5 micrometers, 83,200 particles per cubic meter for particles ≥ 1 micrometer, and 2,930 particles per cubic meter for particles ≥ 5 micrometers (consistent with ISO 7). Due to all these requirements, traditional Class C cleanrooms are extremely expensive (typically costing millions of dollars to build, maintain, and operate) and occupy a significant amount of space.

[0006] Therefore, there is a great need in the pharmaceutical industry for a closed system for processing and manufacturing drugs and for handling drug byproducts that occupies a small footprint in drug processing or manufacturing facilities and requires far less money and time in construction, maintenance and use than conventional cleanrooms. Crucially, such a closed system must allow potent drugs, drug components and drug byproducts to be handled in a manner as safe as, and preferably even safer than, conventional closed systems (such as cleanrooms) by providing triple protection: (1) protection against contamination of the drug product, (2) protection against contamination of the surrounding atmosphere, and (3) protection against direct contact between the drug product, components and byproducts and human operators during production and processing.

[0007] For industrial-scale pharmaceutical production and packaging, it may be necessary or desirable to first prepare a liquid mixture or slurry of API, pharmaceutical product (containing API plus excipients), or pharmaceutical product intermediate, and then remove all (or most) of the liquid from the liquid mixture or slurry through heating, drying, and / or evaporation steps. This process can produce API, pharmaceutical product, or pharmaceutical product intermediate in dry powder form, containing micronized or nano-sized API particles. Dry powder forms of API, pharmaceutical product, or pharmaceutical product intermediate often have increased chemical and physical stability, as well as a greater capacity for oral administration via conventional tablets and capsules. The heating, drying, and / or evaporation steps often require feeding the liquid mixture or slurry into the drying chamber of a drying apparatus, such as the evaporator of a thin-film evaporator, and raising the temperature in the drying chamber by a sufficient amount so that the more volatile liquid components in the liquid mixture and slurry are boiled, distilled, or otherwise separated from the solid particles and then removed as vapor from the drying chamber, leaving only the desired dry powder form of the API-containing pharmaceutical product in the drying chamber. However, it is not always necessary to use heat (or a heat source) to separate the liquid components from the solid particles. Depending on the vapor pressure of the solvent used, reducing the vacuum pressure in the drying chamber (without increasing the temperature) may be sufficient to separate and remove the liquid components as vapor from the drying chamber.

[0008] In most cases, the drying space of a drying apparatus is essentially enclosed and operates under vacuum conditions (i.e., at a pressure below standard atmospheric pressure) to keep the boiling point of the liquid as low as possible. Maintaining a low boiling point typically minimizes the degradation of APIs, pharmaceutical products, pharmaceutical intermediates, or pharmaceutical substances being processed. It also saves (1) a significant amount of time in the drying process, (2) the large amount of energy that would otherwise be required to heat the drying space to meet higher boiling points, and (3) a significant amount of wear and tear and cracking on heating equipment that would otherwise have to withstand extreme vacuum conditions and / or significantly higher amounts of heat.

[0009] However, on an industrial scale, there are some significant drawbacks associated with using processes involving drying liquid mixtures under vacuum pressure to produce and package pharmaceuticals. First, it is often very difficult or impossible to remove the dried pharmaceutical product from the vacuum pressure vessel of the dryer (so that the dried pharmaceutical product can be moved to the next step in the manufacturing or packaging process) without disrupting the vacuum pressure atmosphere (i.e., vacuum) that must be maintained in the dryer, to achieve optimal and efficient separation of the liquid and dried components. Therefore, whenever a sufficient amount of pharmaceutical product has been dried to form a powder and is ready to be removed from the dryer, the operation of the dryer must be temporarily stopped, and the vacuum pressure vessel in the dryer must be temporarily depressurized (i.e., brought to atmospheric pressure) so that the accumulated dried powder form of the pharmaceutical product can be safely collected from the dryer.

[0010] Typically, stopping or suspending a drying operation also requires stopping or suspending some or all upstream and downstream operations related to the drying operation, such as feeding liquid mixtures or slurries into the dryer, bagging and packaging dried powdered APIs, pharmaceutical products, or pharmaceutical intermediates after the drying step, and potentially stopping or suspending several other steps or operations on the pharmaceutical product production line. This slows down the entire production process. Worse still, repeatedly stopping and restarting pharmaceutical product production lines to accommodate the safe removal of dried pharmaceutical products from the dryer often means that pharmaceutical products can only be produced in batches, not continuously. Batch processing almost always results in pharmaceutical manufacturers losing significant opportunities, time, and money (when compared to continuous production), and frequently exposes pharmaceutical products and operators on the production line to the increased risk of contamination associated with removing pharmaceutical products from the production line in discrete batches.

[0011] Unlike batch manufacturing and packaging of pharmaceuticals, continuous pharmaceutical manufacturing and packaging allows for the production of entire batches of pharmaceutical products without interrupting or stopping the production line to remove discrete batches of finished goods. Therefore, continuous production and packaging of pharmaceutical products in dry powder form offers numerous benefits, including, for example, lower costs, more flexible control over productivity in response to market demand, shorter production times, more consistent output, and potentially improved product quality assurance through more rigorous testing and monitoring. Due to these and other advantages, continuous manufacturing and packaging of pharmaceutical products is increasingly considered an important (if not an absolute necessity) goal in the pharmaceutical manufacturing industry. Summary of the Invention

[0012] Embodiments of the present invention provide a compact, closed system for mixing dry powder with a solvent to produce a liquid mixture or slurry, drying the mixture or slurry to separate the liquid from the solid, and then collecting the dried solid from the drying apparatus without disrupting the vacuum pressure conditions present in the drying apparatus. This facilitates continuous processing and packaging of dried pharmaceutical products upstream and downstream of the drying apparatus.

[0013] Embodiments of the present invention can be advantageously used, for example, to manufacture dry, solid pharmaceutical products from raw materials such as active pharmaceutical ingredients (APIs) and pharmaceutical products, while providing triple protection against cross-contamination from human contact and / or contact with the surrounding environment. Notably, embodiments of the present invention can provide a much smaller, more portable, and cheaper Class C sorting space for the production and processing of pharmaceuticals (such as pharmaceutical substances and pharmaceutical products), thereby avoiding the time, cost, and effort required to build, maintain, and utilize conventional Class C sorting spaces.

[0014] On one hand, embodiments of the present invention provide a system and method for processing pharmaceutical products, comprising three devices: a mixing device, a drying device, and a discharging device. The mixing device enables the mixing of a solvent with a dry powder to produce a liquid mixture or slurry without exposing the dry powder, liquid mixture, or slurry to the surrounding atmosphere. The drying device, fluidly coupled to the mixing device, includes a dryer configured to separate and remove liquid components from the solid components in the liquid mixture or slurry. The dryer, operating under continuous vacuum pressure, has a product reservoir in which the solid components are deposited after the liquid components have been separated and removed from the solid components. The discharging device, fluidly coupled to the drying device, collects the solid components from the product reservoir of the dryer during dryer operation without stopping the operation of the dryer or disrupting its continuous vacuum pressure.

[0015] These three devices are arranged and configured to operate collaboratively in a continuous manufacturing line to enable the safe and efficient processing of pharmaceutical products in dry powder form, including active pharmaceutical ingredients (“APIs”), pharmaceutical products, and pharmaceutical intermediates. Typically, the compact, closed system of the present invention is configured such that the pharmaceutical product passes through sequentially, first through a mixing device, then through a drying device, and finally through a discharge device.

[0016] In another embodiment, a method for processing a pharmaceutical product is provided, comprising the steps of: (a) mixing a solvent with the pharmaceutical product to produce a liquid mixture or slurry without exposing the dry powder, liquid mixture, or slurry to the ambient atmosphere; (b) using a dryer to separate and remove the liquid components from the solid components in the liquid mixture or slurry, wherein the dryer operates under continuous vacuum pressure and has a product reservoir in which the solid components are deposited after the liquid components are separated and removed; and (c) while the dryer is operating, using a discharge device to collect the solid components from the product reservoir of the dryer without stopping the operation of the dryer or disrupting its continuous vacuum pressure.

[0017] Compact closed-loop mixing equipment

[0018] The mixing device is configured to facilitate the mixing of solvent and dry powder without exposing the dry powder to the ambient atmosphere. The dry powder is supplied to the system in a dry powder container with a sealed connection. The mixing device includes (a) a dual-compartment isolator for safely removing the dry powder from the dry powder container, and (b) a mixing vessel. The dual-compartment isolator includes a transfer compartment, a loading compartment, and a raw material inlet port connected to the transfer compartment, the raw material inlet port being configured to isolate the dry powder container from the ambient atmosphere when it is transferred to the transfer compartment. A partition separates the transfer compartment from the loading compartment. Resealable openings in the partition allow the dry powder container to be transferred out of the transfer compartment and into the loading compartment without exposing the dry powder to the ambient atmosphere.

[0019] The shut-off valve, located inside the loading compartment, has fittings suitably configured to mate with a sealing connection on the dry powder container. A negative cascade pressure controller generates negative pressure in both the transfer compartment and the loading compartment. The shut-off valve allows an operator to couple the dry powder container to a mixing vessel. The shut-off valve body may also have a shroud surrounding it to provide additional protection against any particle leakage from the shut-off valve itself, its connection to the mixing vessel, and / or the dry powder container. The shut-off valve provides an airtight conduit for transferring the dry powder from the dry powder container to the mixing vessel. The shut-off valve may include a butterfly valve or a dry-lock valve.

[0020] The mixing vessel may, but must, be made of glass, steel, polymer, or borosilicate, and for example, includes a mixing chamber and a solid charge port of a closed valve in the charge compartment of a double-compartment isolator that fluidly connects the mixing chamber to the charge compartment. The solid charge port allows dry powder to pass through the closed valve and into the mixing chamber without exposing the dry powder to the surrounding atmosphere. The mixing vessel typically includes a solvent inlet for allowing solvent to enter the mixing chamber, and in some, but not necessarily all, embodiments, the mixing vessel includes a stirrer for mixing the solvent and dry powder together in the mixing chamber. The system can be used to produce a mixture of solvent and dry powder in the mixing chamber, the mixture comprising, for example, a slurry or solution. The mixing vessel may also include an outlet valve for discharging the solvent and dry powder mixture (such as a slurry or solution) from the mixing chamber. In some embodiments of the invention, the mixing vessel is connected to a mixing vessel discharge facilitator to facilitate the discharge of the mixture from the mixing chamber of the mixing vessel via the outlet valve. The mixing vessel discharge facilitator may include, for example, a pump, a positive pressure source, or a negative pressure source, such as a vacuum.

[0021] Maintaining a negative pressure cascade within the powder and liquid sub-equipment ensures that raw materials do not escape into the surrounding environment. The negative pressure also prevents cross-contamination between the two compartments. By providing a negative pressure controller to ensure a negative pressure differential, the negative pressure controller essentially reduces or eliminates (1) the chance of airborne particles in the first compartment being transferred out of the first compartment and into the surrounding environment, and (2) the chance of airborne particles in the second compartment being transferred out of the second compartment and into the first compartment.

[0022] In an additional embodiment of the invention, the negative cascade pressure controller is configured to fill the interior of the transfer compartment and / or the interior of the loading compartment with an inert gas, such as, for example, nitrogen or argon. The negative cascade pressure controller typically provides a negative pressure differential of approximately 0.01 to approximately 0.5 inches of water column between the exterior of the dual-compartment isolator and the transfer compartment (negative pressure reference to the exterior of the dual-compartment isolator), and a second negative pressure differential of approximately 0.010 to approximately 0.500 inches of water column between the transfer compartment and the loading compartment (negative pressure reference to the interior of the transfer compartment of the dual-compartment isolator). The typical operating range of the negative pressure inside the transfer compartment (compared to the exterior of the isolator) is preferably between approximately 0.005 and 0.125 inches of water column, more preferably between approximately 0.010 and 0.100 inches of water column, and most preferably between approximately 0.015 and 0.075 inches of water column. The typical operating range of negative pressure inside the loading compartment (compared to that inside the transfer compartment) is preferably between about 0.010 and 0.125 inches of water column, more preferably between about 0.015 and 0.100 inches of water column, and most preferably between about 0.020 and 0.075 inches of water column.

[0023] Negative pressure can be generated and maintained by a ventilation system that continuously removes more gas from each chamber of the isolator than is allowed into each chamber. Both the intake and exhaust streams to the ventilator can be appropriately filtered (e.g., with HEPA filters or filter cartridges). The pressure difference (ΔP) between the external environment and the working volume inside the isolator helps prevent dry powder particles from leaking into the external environment through the physical barrier of the dual-chamber flexible isolator. In fact, dry powder particles that manage to leak through gaps will leak into the isolator, which prevents the dry powder particles from spreading. The negative pressure within the dual-chamber isolator also serves to retain the dry powder within the isolator in the event that the isolator's door or port is accidentally opened or if gloves are accidentally torn or broken. In some embodiments, the flexible isolator may include a ventilation system that can be activated to replace most or all of the oxygen (O) inside the isolator with an inert gas, such as nitrogen (N2) or argon (Ar), minimizing any degradation of the pharmaceutical substance or product and making it safer to use the isolator to handle or process potentially flammable or explosive materials.

[0024] In another embodiment of the invention, a dual-compartment isolator, a negative cascade pressure controller, and a mixing vessel are also included. The dual-compartment isolator includes a top portion and a bottom portion, which are associated together by one or more sidewalls to form an internal portion having an inner wall that divides the internal portion into a first compartment and a second compartment. One or more sleeves formed in the one or more sidewalls, terminating in a glove, extend into one or both compartments of the internal portion of the isolator. The one or more sleeves and the glove are configured to receive and protect the operator's hands, wrists, and arms when the operator handles dry powder containers inside the isolator.

[0025] A first sealable opening formed in one side wall of the first compartment allows the sealed dry powder container to be transferred from the outside of the isolator to the inside of the first compartment. Typically, the dry powder container is cleaned, disinfected, and / or sterilized within the first compartment to remove most or all of any dry powder particles or other undesirable dust particles or liquids from the outer surface of the sealed dry powder container. A second sealable opening formed in the inner wall between the first and second compartments allows the sealed dry powder container to be transferred from the first compartment to the second compartment without exposing the dry powder container to the surrounding atmosphere.

[0026] The shut-off valve located in the second compartment has an accessory suitably configured to mate with a sealing connection on the dry powder container. The negative cascade pressure controller is operable to generate sufficient negative pressure in the first and second compartments to (1) prevent airborne particles in the first compartment from being transferred out of the first compartment and into the surrounding environment through a first sealable opening in the first compartment, and (2) prevent airborne particles in the second compartment from being transferred out of the second compartment and into the first compartment through a second sealable opening formed in the inner wall between the first and second compartments.

[0027] The mixing vessel includes a mixing chamber and a solids loading port that fluidly connects the mixing chamber to a shut-off valve in the first compartment of a dual-compartment isolator. The connection between the dry powder container and the shut-off valve, and between the shut-off valve and the solids loading port on the mixing vessel, allows the dry powder to be transferred from the dry powder container through the shut-off valve into the mixing chamber without exposing the dry powder to the surrounding atmosphere. A solvent inlet on the mixing vessel allows solvent to enter the mixing chamber, where it will mix with the dry powder, preferably by activating an agitator disposed within the mixing chamber. The agitator within the mixing vessel mixes the solvent with the dry powder to produce a solvent-dry powder mixture, such as a slurry or solution. An outlet valve in the mixing vessel allows the solvent-dry powder mixture to be discharged from the mixing chamber.

[0028] In some embodiments of the invention, the dual-compartment flexible isolator includes four sidewalls arranged to define a substantially rectangular interior portion (i.e., forming an interior portion shaped like a "box" or "cube"). In other embodiments, the dual-compartment flexible isolator may include a circular or elliptical top and bottom portion and a single cylindrical sidewall hermetically connected to the circular or elliptical top and bottom portions, such that the top portion, bottom portion, and single sidewall together define an interior portion that is substantially cylindrical in shape. In other embodiments, the top portion, bottom portion, and sidewall may also be arranged and connected to define an interior portion that is substantially triangular or pyramidal in shape. Regardless of the shape of the interior portion of the dual-compartment flexible isolator, those skilled in the art will understand that the first and second compartments may be positioned adjacent to each other (i.e., horizontally or "side-by-side") or rotated such that one compartment is above or below the other (i.e., vertically configured) without departing from the scope of the invention. The sidewalls of the dual-compartment flexible isolator may be formed of any suitable flexible material, such as, for example, polyvinyl chloride, polyethylene, polypropylene (PP), or polystyrene. Some embodiments of the invention may include combinations of one or more gloves and sleeves formed in the sidewalls of two compartments of a dual-compartment flexible isolator to protect the operator's hands, wrists, and arms from direct contact with dry powders, slurries, solutions, or pharmaceutical byproducts. In some embodiments of the invention, the first sealable opening and / or the second sealable opening includes a zipper seal, or a clamp, or a coil seal, or a torsion seal; however, other types of seals may be used without departing from the scope of the claimed invention.

[0029] In some embodiments of the invention, the enclosed system further includes an additional port for connecting the flexible isolator to another system, process, or apparatus. This additional port may, for example, be selectively connected to (i) a vacuum source and (ii) an inert gas source, such that the air within the enclosure can be replaced by an inert gas.

[0030] In various embodiments of the invention, the closed system further includes a solvent tank that is fluidly connected to a mixing vessel via a solvent inlet.

[0031] In an additional embodiment of the invention, the closed system further includes a second solvent inlet on the mixing vessel, configured to allow a second solvent to enter the mixing chamber. The second solvent inlet can also be used to allow an antisolvent to enter the mixing vessel. In these embodiments of the invention, the closed system further includes an antisolvent reservoir for supplying an antisolvent to the mixture generated in the mixing chamber.

[0032] In another embodiment, the dual-compartment flexible isolator includes (i) a top portion and a bottom portion, (ii) at least one glove, (iii) a first sealable opening, (iv) a second sealable opening, (v) a shut-off valve, and (vi) a negative cascade pressure controller. The top and bottom portions are associated together by one or more sidewalls to form an internal portion including an inner wall that is sealingly connected to the one or more sidewalls and divides the internal portion into a first compartment and a second compartment. The at least one glove is formed in at least one of the sidewalls and is configured to extend into the interior of the flexible isolator. The first sealable opening is formed in one of the sidewalls and thus allows a container of dry powder material to be placed in the first compartment. The second sealable opening is formed in the inner wall and allows the dry powder container to move from the first compartment into the second compartment without exposing the dry powder to the surrounding atmosphere. The shut-off valve, located in the second compartment, has a fitting suitably configured to mate with a sealing connection on the dry powder container. The negative cascade pressure controller generates negative pressure in the first and second compartments to substantially reduce or eliminate the chance of airborne particles being transmitted out of the second compartment and into the first compartment, or out of the first compartment and into the surrounding environment.

[0033] Alternatively, or as an alternative to gloves, embodiments of the invention may be equipped with other means that allow an operator to manipulate items within the isolation space (i.e., isolation compartment). Such means include, but are not limited to, extended sleeves and robotic arms. The isolator may also have one or more inlet and outlet ports that allow access to the isolation space through side walls to facilitate the entry or removal of various products, substances, and materials, such as pressurized gas, tap water, electricity, etc.

[0034] Flexible isolators may also include one or more probes and / or sensors, with no limitations on the specific type of probe or sensor. Sensors may include, for example, temperature, pressure, p(O2) or p(N2) sensors, or alarm devices. Sensors or probes may be connected to or controlled by a computer system. Information collected by the sensors and / or probes may be transmitted to and / or stored on the computer system. Continuously monitoring the pressure inside the isolator using a pressure sensor is a method that can be used to determine whether any holes or leaks have formed in the isolator.

[0035] In yet another embodiment, the mixing apparatus includes a) a primary hermetically sealed subsystem comprising a separate butterfly valve with fittings configured to receive a sealing connection on a dry powder container and a connection to a solids loading port of a mixing vessel; and b) an auxiliary hermetically sealed subsystem comprising a mixing vessel, a dual-compartment flexible isolator, and a negative cascade pressure controller. In some embodiments, the compact hermetically sealed system of the present invention further includes a third hermetically sealed subsystem comprising a negative pressure chamber, or a downflow chamber, or a gas outlet, or a solvent outlet, or a protective floor, or a disposable protective curtain, or a combination thereof.

[0036] In some embodiments of the invention, the dual-compartment flexible isolator includes: a transfer compartment; a loading compartment; a raw material inlet port connected to the transfer compartment, the raw material inlet port being configured to isolate the dry powder container from the surrounding atmosphere when it is transferred into the transfer compartment; a partition separating the transfer compartment from the loading compartment; and a resealable opening in the partition that allows the dry powder container to be transferred out of the transfer compartment and into the loading compartment without exposing the dry powder to the surrounding atmosphere.

[0037] In another aspect, the present invention provides a method for producing a slurry or solution from a dry powder and a solvent. The method includes the following steps:

[0038] (a) Provide a dual-compartment isolator comprising a transfer compartment, a raw material inlet port connected to the transfer compartment, a loading compartment, a shut-off valve located in the loading compartment, and a partition between the transfer compartment and the loading compartment.

[0039] (b) Connect the negative cascade pressure controller to the dual-compartment isolator;

[0040] (c) A mixing vessel is provided, the mixing vessel including a solvent inlet, a mixing chamber and a solids loading port fluidly connected to the mixing chamber;

[0041] (d) Receiving a dry powder container containing dry powder, the dry powder container having a sealed connection;

[0042] (e) Activate the negative cascade pressure controller to generate negative pressure in both the transfer compartment and the loading compartment of the dual-compartment isolator;

[0043] (f) Allow dry powder containers to enter the transit compartment via the raw material inlet port;

[0044] (g) Transferring the dry powder container from the transfer compartment to the filling compartment by passing the dry powder container through a resealable opening in the partition;

[0045] (h) Close any resealable openings on the partition;

[0046] (i) Connect the sealing connection on the dry powder container to the fitting on one end of the shut-off valve in the loading compartment of the double compartment isolator;

[0047] (j) Connect the solids loading port on the mixing vessel to the opposite end of the shut-off valve;

[0048] (k) Open the sealing connection on the dry powder container, the fitting on the shut-off valve and the solids loading port on the mixer, so that the dry powder will be transferred from the dry powder container in the loading compartment of the double compartment isolator through the sealing connection, fitting and solids loading port and into the mixing chamber of the mixer.

[0049] (l) Introducing solvent into the mixing chamber of the mixing vessel via the solvent inlet; and

[0050] (m) Stir dry powder and solvent in a mixing chamber to produce a slurry or solution.

[0051] In some embodiments of the invention, the method further includes adding an antisolvent to the composition formed in the mixing chamber of a mixing vessel to form a slurry. In other embodiments of the invention, a solvent is introduced into the mixing chamber to dissolve the dry powder to produce a solution.

[0052] In an additional embodiment of the invention, the mixing vessel further includes a second solvent inlet, and the method further includes (i) introducing an antisolvent into the mixing chamber of the mixing vessel via the second solvent inlet; and (ii) stirring the dry powder and antisolvent in the mixing chamber to produce a slurry.

[0053] In other embodiments of the invention, the method further includes performing a transfer procedure while the dry powder container is inside a transfer compartment, wherein the transfer procedure includes cleaning the dry powder container. The dry powder container can be cleaned with a suitable solution such as water or alcohol. Suitable alcohols include, but are not limited to, isopropanol or methanol.

[0054] In an additional embodiment of the invention, the method further includes attaching a mixing vessel discharge device to the mixing vessel and activating the mixing vessel discharge device to facilitate the discharge of slurry or solution from the mixing vessel. The mixing vessel discharge device may include a pump, a positive pressure source, or a negative pressure source, such as a vacuum or suction device.

[0055] Compact closed-system drying equipment

[0056] Drying equipment connected to the mixing vessel of the mixing apparatus preferably includes a dryer, a vacuum pump, a wet mill, a peristaltic pump, a condenser, a thin-film evaporator, and a distillate receiver. Dryers typically include thin-film evaporators, stirred-film evaporators, scraped-film evaporators, rotary dryers, spray dryers, conical dryers, pressure filters, fluidized beds, or combinations of two or more of these.

[0057] Compact closed-loop emission equipment

[0058] A discharge device connected to the drying equipment enables the collection of pharmaceutical products from the product storage container of the pharmaceutical drying unit (i.e., the dryer) while the product storage container is maintained under continuous vacuum pressure. The discharge device includes a discharge chute, a vacuum supply control valve, a product inlet valve, a gas control valve, and a collection control valve. The discharge chute includes a substantially hermetically sealed internal chamber, a shell substantially surrounding the hermetically sealed internal chamber, a vacuum supply inlet fluidly connecting the hermetically sealed internal chamber of the discharge chute to a vacuum source, a solid inlet fluidly connecting the hermetically sealed internal chamber to the product storage container of the dryer, a gas inlet fluidly connecting the hermetically sealed internal chamber to a gas source, and a solid outlet fluidly connecting the hermetically sealed internal chamber to a collection container.

[0059] Inlets and outlets can be opened and closed by operating control valves connected to those inlets and outlets to remove gas into or allow gas to flow into an exhaust sluice, thereby effectively reducing and repressurizing the exhaust sluice while simultaneously removing dried pharmaceutical products from the dryer through the exhaust sluice. The control valves can be operated manually or, alternatively, automatically activated by a computer system programmed to generate electronic control signals and transmit them to a device that generates mechanical force in response to an electric current to actuate the valves.

[0060] The depressurization and repressurization steps of the discharge chute, as well as the drying of the pharmaceutical product, are performed in a time-coordinated manner through the movement of the discharge chute, ensuring that the vacuum pressurization conditions of the dryer are not interrupted or disrupted. In some embodiments, the discharge chute also includes a diverter assembly configured to provide the operator with the option to divert a portion of the dried powder flowing out of the discharge chute into a second (or auxiliary) collection container.

[0061] In some embodiments, the discharge device further includes a flexible isolator attached to the discharge chute, configured to surround and close the fluid connection between the product outlet and the main collection container on the discharge chute, thereby substantially isolating the fluid connection between the product outlet and the main collection container from the surrounding environment.

[0062] In another embodiment, the discharge device includes an airlock assembly for collecting solids from the product storage tank of the drying unit while the product storage tank is maintained under continuous vacuum pressure. Typically, the airlock assembly includes a discharge chute, a vacuum supply control valve, a product inlet valve, a gas control valve, and a collection control valve.

[0063] In another embodiment of the invention, the discharge device includes an automated collection system for collecting dried pharmaceutical product from the product reservoir of the dryer while the product reservoir is under continuous vacuum pressure. Typically, the automated collection system includes a computer system, at least one input / output block, a discharge chute, a main collection container, and an isolator. Typically, the discharge chute includes a plurality of sanitary short tubes connected in series to form a substantially continuous pathway extending from one end of the discharge chute to the opposite end. Preferably, at least some of the sanitary short tubes including the discharge chute have built-in instrument ports for connecting sensor instruments for performing various measurements, such as, for example, pressure sensors, temperature sensors, contact and non-contact infrared (IR) and Fourier transform infrared (FTIR) Raman spectroscopy sensors, and product height or level sensors.

[0064] In yet another embodiment, certain embodiments of the present invention provide a method for collecting pharmaceutical products from the product storage tank of a dryer using a discharge chute while the product storage tank of the dryer is under continuous vacuum pressure. The method includes the following steps:

[0065] a) Use a pressure gauge to measure the pressure level inside the discharge chute cavity;

[0066] b) Open the vacuum supply inlet valve of the discharge chute;

[0067] c) Activate the vacuum source to remove gas from the internal chamber via the vacuum supply inlet valve until the pressure gauge detects that the pressure in the internal chamber of the discharge chute is less than or equal to the continuous vacuum pressure present in the product storage tank of the dryer;

[0068] d) Open the product inlet valve on the discharge chute when the pressure level indicated by the pressure gauge in the internal chamber of the discharge chute is less than or equal to the continuous vacuum pressure present in the product reservoir of the dryer.

[0069] e) Allow at least a portion of the pharmaceutical product in the product reservoir to flow through the product inlet and into the internal chamber of the discharge chute;

[0070] f) Close the product inlet valve on the discharge chute;

[0071] g) Open the gas inlet valve of the discharge chute;

[0072] h) Activate the gas source to force gas into the internal chamber of the discharge chute through the gas inlet valve until the pressure gauge indicates that the pressure inside the internal chamber of the discharge chute has reached the ambient pressure level;

[0073] i) Open the product outlet valve when the pressure gauge indicates that the pressure inside the discharge chute is at the ambient pressure level; and

[0074] j) Allow at least some of the pharmaceutical products located in the internal chamber of the discharge chute to flow out of the internal chamber, through the product outlet valve, and into the main collection container. Attached Figure Description

[0075] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate preferred embodiments of the invention and, together with the specification, serve to explain the principles of the invention.

[0076] Figure 1 An exemplary mixing device is shown in an embodiment of a compact, hermetic system according to the present invention;

[0077] Figure 2 This is a perspective view of an exemplary mixing device in an embodiment of the compact closed system of the present invention;

[0078] Figure 3A and 3B An additional perspective view of an exemplary mixing device in an embodiment of the compact hermetic system of the present invention is shown;

[0079] Figure 4A and 4B A flowchart illustrating the operation of a mixing device configured to operate according to an embodiment of a compact hermetically sealed system according to the present invention is shown together.

[0080] Figure 5 This is a perspective view of an embodiment of the raw material inlet port of an exemplary dual-compartment flexible isolator in a mixing device according to an embodiment of a compact hermetically sealed system of the present invention;

[0081] Figure 6 This is a perspective view of the operator sleeve of an exemplary dual-compartment flexible isolator of a compact hermetically sealed system according to the present invention;

[0082] Figure 7 This is a perspective view of an embodiment of a solids loading port associated with a mixing device of a compact hermetically sealed system according to the present invention;

[0083] Figure 8 This is a perspective view of an exemplary shut-off valve used in a mixing device according to an embodiment of a closed system of the present invention;

[0084] Figure 9 An example of a dry powder container that can be used with embodiments of the present invention to supply dry powder is shown.

[0085] Figure 10 This is a perspective view of a mixing vessel attached to an exemplary dual-compartment isolator in a mixing device according to an exemplary embodiment of a compact hermetically sealed system of the present invention;

[0086] Figure 11AAn exemplary optional wet milling apparatus is shown, which can be used in conjunction with embodiments of the invention to reduce particles in mixtures, solutions, or slurries produced in a mixing apparatus to a uniform particle size, thereby resulting in faster drying times and higher quality dry powder. Figure 11B This is a perspective view of an exemplary wet mill, which can be used in certain embodiments of a closed system configured to operate according to embodiments of the present invention.

[0087] Figure 12 This is a perspective view of an antisolvent container associated with an exemplary dual-compartment isolator in an embodiment of the present invention;

[0088] Figure 13 This is a schematic perspective view illustrating an air pressure pump associated with an exemplary dual-compartment flexible isolator, according to an embodiment of a compact hermetic system based on the present invention.

[0089] Figure 14 This is a perspective view of a solvent tank used in various embodiments of a compact closed system according to the present invention;

[0090] Figure 15 This is a perspective view of exemplary solvent supply lines for various embodiments of a compact, closed system according to the present invention;

[0091] Figure 16 This is a block diagram illustrating the main components of a compact sealed system according to an embodiment of the present invention.

[0092] Figure 17 The drying equipment of the compact, closed system is shown, without mixing and emission equipment.

[0093] Figure 18 A high-level flowchart is shown, illustrating the steps and processes involved in the drying equipment of some embodiments of the compact hermetic system of the present invention.

[0094] Figure 19 and 20 Includes advanced flowcharts illustrating an exemplary startup procedure for operating a thin-film evaporator in a drying apparatus to dry a pharmaceutical product in one embodiment of the compact, closed system of the present invention, thereby separating the liquid components from the solid components of a liquid mixture or slurry previously produced by a mixing apparatus.

[0095] Figure 21 A front perspective view of an example emission device according to an embodiment of the present invention is shown.

[0096] Figure 22 It shows Figure 21 Left perspective view of the exemplary emission device shown.

[0097] Figure 23 It shows Figure 21 A more detailed perspective view of the product inlet and product inlet control valve components of the exemplary emission device shown, wherein the product inlet control valve is turned to the open position.

[0098] Figure 24 It shows Figure 21 A more detailed perspective view of the product inlet, product inlet control valve, and viewing glass assembly of the exemplary emission device shown, wherein the product inlet control valve is turned to the closed position.

[0099] Figure 25 It shows Figure 21 A more detailed perspective view of the vacuum supply inlet, vacuum supply control valve, gas inlet, and gas control valve components of the exemplary emission device shown, wherein the vacuum control valve is open and the gas control valve is closed.

[0100] Figure 26 It shows Figure 21 A more detailed perspective view of the vacuum supply inlet, vacuum supply control valve, gas inlet, and gas control valve components of the exemplary emission device shown, wherein the vacuum control valve is closed and the gas control valve is open.

[0101] Figure 27 A shunt assembly and a method for attaching a flexible isolator are shown. Figure 21 The left perspective view of an exemplary coupling system for a diverter assembly in an exemplary emission device is shown, wherein the coupling system includes a single mounting plate, a groove surrounding the periphery of the single mounting plate, and an elastic band arranged to retain a built-in O-ring of a flexible isolator within the groove.

[0102] Figure 28 It shows Figure 27 The diagram shows a perspective front view of the splitter assembly and the exemplary coupling system, as well as a close-up view of the mounting ring clamp fastened to the periphery of the mounting ring of the coupling system.

[0103] Figure 29 A left perspective view of the main outlet channel and auxiliary outlet channel of the diverter assembly, the product outlet and collection control valve, and the left side of the flexible isolator arranged according to an exemplary embodiment of the emission device according to the present invention is shown.

[0104] Figure 30 The discharge port attached to the flexible isolator is shown to facilitate the removal of the main collection container and / or auxiliary collection container filled with pharmaceutical products from inside the flexible isolator.

[0105] Figure 31 An advanced computer-aided drawing (CAD) diagram is shown, illustrating, by way of example, some of the main components of an emission device according to an embodiment of the present invention.

[0106] Figure 32 Advanced computer-aided drafting (CAD) is shown, illustrating... Figure 31 A cross-sectional view of an exemplary emission device is shown.

[0107] Figure 33A Advanced computer-aided drafting (CAD) is shown, illustrating... Figure 31 Left side view of the exemplary emission device shown.

[0108] Figure 33B Advanced computer-aided drafting (CAD) is shown, illustrating along... Figure 33A A cross-sectional view of the cut line EE of the exemplary emission device shown.

[0109] Figure 34A Advanced computer-aided drafting (CAD) is shown, illustrating... Figure 31 The right-side view of the exemplary emission device shown.

[0110] Figure 34B Advanced computer-aided drafting (CAD) is shown, illustrating along... Figure 34A A cross-sectional view of the cutting line FF of the exemplary pharmaceutical product collection device shown.

[0111] Figure 34C Advanced computer-aided drafting (CAD) is shown, illustrating along... Figure 34B A cross-sectional view of the cutting line G of the exemplary pharmaceutical product collection device shown.

[0112] Figure 35 Advanced computer-aided drafting (CAD) is shown, illustrating... Figure 31 Isometric view of the flexible isolator and built-in O-ring component of the exemplary emission device shown.

[0113] Figure 36 This illustrates advanced computer-aided drafting (CAD), which demonstrates the methods used to... Figure 35 Attached to the flexible isolator Figure 31 An isometric view of an alternative coupling system for the splitter assembly in the exemplary emission device shown, wherein the coupling system includes two separate mounting plates instead of a single mounting plate, and Figure 35 The O-ring of the flexible isolator shown is clamped between two mounting plates.

[0114] Figure 37A Advanced computer-aided drafting (CAD) is shown, illustrating... Figure 36 The left-side view of the alternative coupling system shown.

[0115] Figure 37BAdvanced computer-aided drafting (CAD) is shown, illustrating along... Figure 37A The cross-sectional view of the cutting line MM of the alternative coupling system is shown.

[0116] Figure 38 A high-level flowchart is shown, illustrating the steps that can be used to perform a method for collecting dried solids from a drying apparatus using an emission device constructed according to an embodiment of the present invention.

[0117] Figure 39 A high-level schematic diagram of an automated collection system for collecting solids from a drying apparatus according to an embodiment of the present invention is shown.

[0118] Figure 40 A high-level block diagram according to an embodiment of the present invention is shown, illustrating by way of example the architecture of a computer system configured to generate electrical signals and transmit them to an input / output board, the computer system being configured to activate a solenoid coil in a solenoid valve to open and close the solenoid valve.

[0119] Figure 41 and 42 A high-level flowchart is shown, which illustrates the steps of an algorithm by way of example. This algorithm can be executed by a computer system configured to operate according to an embodiment of an automated collection system to generate and transmit control signals to activate, open, and close solenoid valves in the solids collection system. Detailed Implementation

[0120] Examples of embodiments of the present invention will now be described in detail. It is worth noting that the exemplary embodiments described below and shown in the accompanying drawings are not intended to limit the scope of the invention or its embodiments or equivalents.

[0121] In summary, exemplary embodiments of the present invention provide a system, apparatus, and method that allows for a Good Manufacturing Practice (GMP) level of containment of raw materials (such as pharmaceutical substances or products) when raw materials are mixed with solvents to produce slurries or solutions. Advantageously, embodiments of the invention are suitable for use in small, compact spaces (relative to the space required by conventional cleanrooms used in aseptic pharmaceutical manufacturing), are flexible, easy to use, and readily dispose of after use.

[0122] Figure 1 An exemplary mixing device 100 according to an embodiment of the present invention is shown. For example... Figure 1As shown, the mixing device 100 includes a dual-compartment isolator 105 and a mixing vessel 140. The dual-compartment isolator 105, facilitating the safe removal of dry powder 124 from the dry powder container 125, has a transfer compartment 110, a loading compartment 115, and a raw material inlet port 130 connected to the transfer compartment 110. The raw material inlet port 130 is configured to isolate the dry powder container 125 from the surrounding atmosphere when it is transferred to the transfer compartment 110. A partition 120 separates the transfer compartment 110 from the loading compartment 115. The partition 120 has a resealable opening 122 that allows the dry powder container 125 to be transferred out of the transfer compartment 110 and into the loading compartment 115 without exposing the dry powder 124 to the surrounding atmosphere 190.

[0123] The mixing device 100 also includes a shut-off valve 135 located within the loading compartment 115. The shut-off valve 135 has accessories ( Figure 1 (Not shown in the image), the accessory is configured to mate with a sealing connection on the dry powder container 125. The mixing device 100 also includes a negative cascade pressure controller 185 for generating negative pressure in the transfer compartment 110 and the loading compartment 115.

[0124] The mixing apparatus 100 also includes a mixing vessel 140 for mixing dry powder with solvent 150 from a solvent vessel 155. The mixing vessel 140 includes a mixing chamber 145 and a solids loading port 160, which fluidly connects the mixing chamber 145 to a shut-off valve 135 in the loading compartment 115 of the dual-compartment isolator 105 to allow dry powder 124 to be transferred through the shut-off valve 135 from the dry powder container 125 to the mixing chamber 145 without exposing the dry powder 124 to the ambient atmosphere 190.

[0125] The mixing vessel 140 also includes a solvent inlet 165 that allows solvent 150 to enter the mixing chamber 145. Preferably, a stirrer is suspended inside the interior 170 of the mixing chamber 145. Figure 1 (Not shown) can be activated to mix solvent 150 and dry powder 124 together in mixing chamber 145, thereby producing solvent and dry powder mixture 175. Mixing vessel 140 also includes outlet port 180 for discharging solvent and dry powder mixture 175 from mixing chamber 145. Solvent and dry powder mixture may include slurry or solution.

[0126] The lid of the mixing vessel 140 preferably has the following ports: a solvent inlet 165 including a suction tube, a nitrogen supply, a sample port via the suction tube, an outlet suction tube, a butterfly valve for solid loading, and an exhaust port. Preferably, the sample port and the associated suction tube are directed to the loading compartment 115 of the dual-compartment isolator 105, facilitating closed-loop sampling in a Class C environment. The butterfly valve can be of any suitable size. However, the valve diameter is preferably from 2 to 6 inches.

[0127] Figure 2 A closed system 200 according to an embodiment of the present invention is shown, comprising a dual-compartment flexible isolator 205 having a transfer compartment 210, a loading compartment 215, a partition 217 having a resealable opening 220, and a 30-liter (30L) mixing vessel 240 having a lid 290. Figure 2 In the exemplary embodiment shown, the transfer compartment 210 and the loading compartment 215 of the dual-compartment flexible isolator 205 include four orifices 212a, 212b, 212c, and 212d, which are configured to connect four sleeve and glove assemblies ( Figure 2 (Not shown in the image), allowing the operator to insert their hands into the transfer compartment 210 and the loading compartment 215 to manipulate the dry powder container 125 as it is cleaned and transferred from one compartment to another. The 30L mixing vessel 240 may be fitted with a sheath and equipped with a pneumatic overhead agitator (an example of an agitator is shown in the image). Figure 10 (As shown in the figure, and indicated by reference numeral 1050). The solids loading port 250 on the 30L 240 vessel is connected to a shut-off valve 235 (e.g., a separate butterfly valve) located in the loading compartment 215 of the double-compartment flexible isolator 205.

[0128] Figure 3A and 3B An additional perspective view of an exemplary embodiment of a closed system configured according to the present invention is shown. Figure 3A A closed system 300 is shown, comprising a dual-compartment flexible isolator 305, which includes a transfer compartment 310 and a loading compartment 315 separated by a partition 320 having a resealable opening 322. The closed system 300 also includes a 30L mixing vessel 340 with a cover 390 and a mixing chamber 345. The mixing vessel 340 has a loading port 350 connected to a shut-off valve 335, which in turn connects to the bottom of the loading compartment 315 of the dual-compartment flexible isolator 305. Figure 3AAs shown, the transfer compartment 310 and the loading compartment 315 may further include multiple sleeve and glove assemblies 301, 302, 303, and 304. The closed system 300 may also include a solvent tank 352. Solvent stored in the solvent tank 352 may be pumped or drawn into the mixing chamber 345 of the 30L mixing vessel 340 by a suitable arrangement of the port and tubing (not shown in Figure 3 for clarity) connecting the solvent tank 352 to the cap 390 of the 30L mixing vessel 340. The outlet port 362 provides a means of extracting slurry or solution from the mixing chamber 345 of the 30L mixing vessel 340.

[0129] Figure 3B yes Figure 3A The image depicts a perspective view of the loading compartment 315 of a dual-compartment flexible isolator 305 in a closed system, including sleeve and glove assemblies 303 and 304. Figure 3B A portion of a mixing vessel 340 is also shown, including a mixing chamber 345 and a lid 390, the lid 390 including a solvent inlet port 365, an outlet port 180 and a solids loading port 360.

[0130] Figure 4A and 4B A flowchart illustrating a method for producing a slurry or solution from dry powder and solvent according to an embodiment of the present invention is shown together. As a first step 405, a dual-compartment isolator 105 is provided. The dual-compartment isolator 105 includes a transfer compartment 110, a raw material inlet port 130 connected to the transfer compartment 110, a loading compartment 115, a shut-off valve 135 located in the loading compartment 115, and a partition 120 between the transfer compartment 110 and the loading compartment 115. Step 410 provides a mixing vessel 140, which includes a solvent inlet 165, a mixing chamber 145, and a solids loading port 160 fluidly connected to the mixing chamber 145.

[0131] In step 415, a dry powder container 125 containing dry powder 124 is received. The dry powder container has a sealed connection. Then, in step 420, a negative cascade pressure controller 185 is activated to generate negative pressure in both the transfer compartment 110 and the loading compartment 115 of the dual-compartment isolator 105. In step 425, the dry powder container is permitted to enter the transfer compartment via the raw material inlet port 130. The user can pass raw materials (e.g., pharmaceutical substances or pharmaceutical products) and selected processing equipment (e.g., funnels, spoons, etc.) to the transfer compartment 110 through the raw material inlet port 130. The raw material inlet port 130 may be a polymer sleeve. The raw material inlet port 130 is then knotted to provide a seal between the compartment and the external environment.

[0132] Step 430 involves transferring the dry powder container 125 from the transfer compartment 110 to the filling compartment 115 by passing it through a resealable opening in the partition 122. Then, in step 435, the resealable opening 122 in the partition 120 is closed. In step 440, a sealing connection on the dry powder container 125 is connected to a fitting on one end of the shut-off valve 135 in the filling compartment 115 of the dual-compartment isolator 105. Then, in step 445, the solids filling port 160 on the mixing vessel 140 is connected to the opposite end of the shut-off valve 135.

[0133] Step 450 includes opening a) the sealing connection on the dry powder container 125, b) the fitting on the shut-off valve 135, and the solids loading port 160 on the mixer 140, such that the dry powder 124 will be transferred from the dry powder container 125 through the sealing connection, fitting, and solids loading port 160 from the loading compartment 115 of the dual-compartment isolator 105 and into the mixing chamber 145 of the mixer 140. The mixer 140 (e.g., a 30L mixer) may be fitted with a jacket and heated or cooled using, for example, an associated Huber unit to control the jacket temperature.

[0134] In step 455, solvent 150 is then introduced into the mixing chamber 145 of the mixing vessel 140 via solvent inlet 165. Solvent 150 is loaded into the mixing vessel 140 from a nitrogen-inert vessel or tank 155 (preferably made of stainless steel) through an inline filter, for example, a 30L vessel. Finally, in step 460, the dry powder 124 and solvent 150 are stirred in the mixing chamber 145 to produce a slurry or solution 175.

[0135] Optionally, the mixture of solvent and desired substance may be further processed by subjecting the mixture to wet milling to reduce drug particle size and improve drug solubility. Any type of grinding and milling apparatus suitable for producing nanoparticles can be used in conjunction with this invention. Exemplary types of milling operations may include, but are not limited to, wet milling, media milling, cryogenic milling, and high-pressure homogenization.

[0136] Figure 5 An exemplary raw material inlet port 530 of a dual-compartment isolator useful in the closed system of the present invention is depicted. For example... Figure 5 As shown, the raw material inlet port 530 typically comprises a flexible tubular plastic conduit, pipe, or sleeve with a diameter suitably large enough to allow the dry powder container 125 to be transferred from the external environment and into a transit compartment of a closed system. Preferably, after the dry powder container 125 is inside, the open end of the raw material inlet port 530 can be wrapped and knotted with suitable string, rope, strap, cable tie, or crimping material 532, so that little or no air or airborne particles can pass through the open end in either direction.

[0137] Figure 6 Operator sleeves 601 and 602 are shown, hermetically connected to the walls of the dual-compartment isolator of the closed system of the present invention. The operator uses the operator sleeves to manipulate materials and articles within the transfer and loading compartments of the dual-compartment flexible isolator of the present invention. Operator sleeves 601 and 602 can also be used as transfer compartments for removing waste and for introducing and removing cleaning supplies and disinfectants. Disinfectants (such as vaporized hydrogen peroxide (VHP)) can also be introduced into the dual-compartment isolator via sanitary connection ports of one or both of the dual compartments.

[0138] Figure 7 and 8 Perspective views are provided for embodiments of shut-off valves 735 and 835 associated with the closed system according to the invention. Shut-off valves 735 and 835 are separate butterfly valves connected to sealing connections 730 and 830 of dry powder containers 725 and 825, respectively. Figure 8 An embodiment of a dry powder container 825 is also shown, which has a sealing connection 830 that mates with a separate butterfly valve 835.

[0139] Figure 9 An example of a dry powder container 905 with a sealing connection 910 is shown, wherein the sealing connection 910 includes a clamp. Figure 9 As shown, the sealing connection 910 is connected to the top portion of the shut-off valve 915. In Figure 9 In the example of the dry powder container 905 shown, a flushing port 920 is provided attached to the dry powder container 905, which is configured to allow the dry powder inside the dry powder container 905 to be wetted.

[0140] Figure 10 This is a perspective view of a mixing vessel 1030, a mixing chamber 1045, and a lid 1090, which can be used in accordance with exemplary embodiments of a closed system according to the invention. The mixing vessel 1030 includes a stirrer 1050 for mixing solvents, slurries, and solutions in the mixing chamber 1045. The lid 1090 is preferably substantially flat and made of stainless steel, having multiple container ports passing through it to facilitate chemical synthesis. In alternative embodiments, the lid 1090 may be made of glass and / or may have a dome shape.

[0141] Figure 11A An exemplary wet milling apparatus 1100 is shown, which can be used in various embodiments of the invention to reduce particles in mixtures, solutions, or slurries to a smaller particle size, resulting in faster drying times and higher quality dry powder. Figure 11AAs shown, the grinding apparatus 1100 includes a wet grinding unit 1110, which can be used for the precipitation of nanocrystals, amorphous materials, or micronized crystalline materials in the range of 1-5 μm. The wet grinding unit 1110 includes a method for allowing material from a mixing vessel 140 (… Figure 1 The inlet port for the mixture, slurry, or solution to enter, and the outlet port for discharging the ground mixture, solution, or slurry into the settling vessel 1120, which may be, for example, a 100L vessel.

[0142] The settling vessel 1120 includes a first inlet valve 1130 for receiving the grinding mixture, slurry, or solution from the wet grinding apparatus 1110 and a second inlet valve 1170 for receiving the antisolvent from the antisolvent container 1160, thereby facilitating the mixing of the antisolvent and the grinding mixture, slurry, or solution. The settling vessel 1120 also includes a recirculation line valve 1140 for discharging the nanoparticle settling mixture, slurry, or solution into the wet grinding apparatus 1110 with the aid of a peristaltic pump 1150 for controlling the flow rate. The settling vessel 1120 also includes an outlet valve for discharging the nanoparticle settling mixture, slurry, or solution into another device. A second peristaltic pump 1190 is used to fill the wet grinding apparatus 1110 through the settling vessel outlet valve 1180 and maintain the flow rate. Figure 11B A more detailed illustration of an example of the grinding apparatus 1110 is shown.

[0143] Figure 12 This is a perspective view of a solvent (antisolvent) tank 1200 associated with an exemplary embodiment of the closed system of the present invention, which holds solvent or antisolvent 1205 that can be introduced into the mixing chamber 1040 of the mixing vessel 1030 via solvent inlet 1210.

[0144] Figure 13 An air pressure pump 1300 associated with an exemplary dual-compartment flexible isolator is shown as an embodiment of a closed system according to the present invention.

[0145] Figure 14 This is a perspective view of solvent tanks 1400 and 1401 used in various embodiments of the closed system according to the present invention. The solvent tanks are the solvent source provided to the mixing vessel in the closed system of the present invention.

[0146] Figure 15 This is a perspective view of an exemplary solvent supply line plate 1500 that can be used in various embodiments of the closed system according to the present invention. Figure 15 As shown, the exemplary solvent supply line plate 1500 includes two solvent inlet lines 1501 and 1502, and one solvent outlet line 1503. Connected to a valve ( Figure 15The handle (not shown) can be operated by the operator to control the amount of solvent entering the solvent supply line plate 1500 through solvent inlet lines 1501 and 1502 and leaving the solvent supply line plate 1500 through solvent outlet line 1503. Solvent inlet lines 1501 and 1502 are typically connected to solvent (or antisolvent) tanks (such as...). Figure 12 The solvent (and antisolvent) tanks shown are 1200 and Figure 14 Solvent tanks 1400 and 1401 are shown, while solvent outlet line 1503 is attached to the mixing vessel via a solvent inlet port on the mixing vessel. Figure 15 As shown, the solvent supply line plate 1500 can be suitably attached to the wall 1530 located near the connected solvent (antisolvent) tank and mixing vessel.

[0147] Figure 16 This is a block diagram illustrating the main components of a compact hermetic system 3000 configured according to an embodiment of the present invention. Figure 16 As shown, the compact closed system 3000 includes a mixing device 3010, a drying device 3020, and a discharge device 3030. The main components of the mixing device 3010 are a solvent tank 3012, a transfer disposable isolator 3014, a loading disposable isolator 3016, and a 30-liter sheathed glass mixing vessel 3018 (sometimes referred to as a "reactor") equipped with a single-threaded pneumatic overhead agitator (for simplicity...). Figure 16 (The stirrer of the sheathed glass mixing vessel 3018 is not shown). The glass mixing vessel 3018 is preferably sealed with a custom-made cap that includes the following ports: a solvent loading section via a suction tube, a nitrogen supply, a sample port via a suction tube, an outlet via a suction tube, a butterfly valve for solid loading, and an exhaust port. These and other components of the mixing apparatus 3010 have been referenced above. Figure 1-15 It was described in considerable detail.

[0148] The main components of the emission device 3030 include an emission chute 3042, a disposable isolator 3044, a qualified product collection bag 3046, and a non-qualified product collection bag 3048. See below for reference. Figure 21-42 These and other components of the emission device 3030 are described in considerable detail. References will now be made. Figure 16-20 The components and operation of the drying equipment 3020, which is physically located between the mixing equipment 3010 and the discharge equipment 3030, are described in detail.

[0149] Drying equipment

[0150] Figure 17 A drying unit 3020 of a compact, closed system is shown, without a mixing unit 3010 and an exhaust unit 3030. (As shown) Figure 17As shown, the main components of the drying apparatus 3020 include a drying unit, in this case a thin-film evaporator 3026, and a 100-liter sheathed glass container 3021 (also referred to as a reactor) with a double-threaded, pneumatic overhead stirrer (not shown). The 100-liter sheathed glass container 3021 is also sealed with a custom-made lid (not shown). Preferably, the custom-made lid includes ports for solvent loading via a suction tube, an outlet to a manifold via a suction tube, a recirculation line (which also serves as a supply from the 30-liter container), a sample port via a suction tube, an exhaust port, and a spare 3-inch butterfly valve. The drying apparatus 3020 also includes a solvent return tank 3022, a peristaltic filling pump 3023, a wet mill 3024, a peristaltic transfer pump 3025 (which is an example of an exhaust device), a vacuum pump 3027, a distillate receiver tank 3028, and a condenser 3029. The wet mill 3024 and its associated various inlet lines, outlet lines, valves, and ports are also included. Figure 11A and 11B As shown in the diagram, this has been discussed further above.

[0151] Figure 18 A high-level flow chart is shown, illustrating the steps involved in the precipitation of nanocrystalline, amorphous, or micronized crystalline materials in the 1-5 μm range, and the process flow between a 30L mixing vessel 3018, a 100L glass mixing vessel 3021, and a wet mill 3024. Figure 18As shown, the process begins at step 1805, where all raw materials and solvents are loaded into a 30L mixing vessel 3018 in a similar manner. Then, at step 1810, the active pharmaceutical ingredient and other excipients are allowed to dissolve. Next, at step 1815, the antisolvent in antisolvent tank 3022 is loaded into a 100L glass mixing vessel 3021. Then, the valves on the 100L outlet line 3034 and recirculation line 3035 are opened (step 1820). Using a peristaltic filling pump 3023, the wet mill 3024 is filled through the 100L outlet line (step 1825). Next, at step 1830, the wet mill 3024 is opened to recirculate the antisolvent in the 100L glass mixing vessel 3021. In step 1835, the valve on the 30L vessel inlet line 3032 leading to the wet mill 3024 is opened, causing the contents of the 30L mixing vessel 3018 to be pressurized and transferred into the wet mill 3024. Once the line is filled, the wet mill 3024 siphons the contents of the 30L glass mixing vessel 3018 into the 100L glass mixing vessel 3021 (step 1840). The next step, step 1845, is to recirculate the amorphous suspension in the 100L glass mixing vessel 3021 as needed. Finally, in step 1850, the contents of the 100L mixing vessel 3021 are delivered to the thin-film evaporator 3026 by controlling the flow rate from the 100L outlet 3034 to the TFE inlet 3036 using a peristaltic transfer pump 3025.

[0152] Figure 19 and 20 Includes advanced flowcharts illustrating an exemplary startup procedure for operating the thin-film evaporator 3026 of the drying apparatus 3020 to dry a pharmaceutical product in one embodiment of the compact closed system 3000 of the present invention, in order to separate the liquid components from the solid components of a liquid mixture or slurry previously produced by the mixing apparatus 3010. Figure 19 and 20 The steps shown should be performed by the operator before opening the inlet valve of the discharge chute 3042 of the discharge device 3030 to ensure that the pharmaceutical product is efficiently transferred from the collection reservoir of the thin film evaporator 3026 of the drying device 3020 to the discharge chute 3042 of the discharge device 3030.

[0153] These steps include:

[0154] (Step 1905) Open both Huber units (open the tub bath at least 1 hour before processing);

[0155] (Step 1910) Set the TFE barrel temperature;

[0156] (Step 1915) Set the condenser / distillate receiver temperature;

[0157] (Step 1920) Turn on the nitrogen flow (35 psi) to the sealed vessel;

[0158] (Step 1925) Open the ethylene glycol / water bath (10°C) in the sealed vessel and the wet grinding sealed vessel.

[0159] (Step 1930) Turn on the vacuum pump and allow it to run for up to 1 hour with the valve to the TFE closed before the processing for preheating the vacuum oil;

[0160] (Step 1935) Open the vacuum to the system and allow the pressure to equalize (approximately 10 minutes).

[0161] (Step 1940) Turn the rotor speed control in the TFE to the slowest RPM setting to allow the mechanical seal to preheat, and then slowly increase the rotor speed to the desired speed when ready for machining.

[0162] (Step 1945) Begin feeding from a 100L container; and

[0163] (Step 1950) Continue operating the evacuation equipment to isolate and remove the dried pharmaceutical product from the compact, closed system. See below for further details. Figure 38 The flowchart describes the procedures for operating the emission equipment in more detail.

[0164] emission equipment

[0165] The discharge device 3030 of the compact closed system 3000 enables the collection of pharmaceutical products from the product storage tank of a pharmaceutical drying apparatus (i.e., a dryer) while the product storage tank is maintained under continuous vacuum pressure. In one embodiment, the discharge device includes a discharge sluice, a vacuum supply control valve, a product inlet valve, a gas control valve, and a collection control valve. The discharge sluice is fluidly connected to the dryer, and more specifically, fluidly connected to the product storage tank within the dryer. The dryer may include any of a variety of different devices typically used for separating the dry components of a liquid mixture or slurry from the wet components of said liquid mixture or slurry, including but not limited to thin-film evaporators, stirred thin-film evaporators, scraped-film evaporators, rotary dryers, spray dryers, conical dryers, pressure filters, fluidized beds, or combinations of two or more of these. The discharge sluice has a shell (i.e., an outer shell or sheath formed by one or more outer walls) that defines a substantially hollow internal chamber (or void) within the discharge sluice. The housing is configured to receive and retain dried or partially dried powder discharged from the product reservoir inside the dryer after a certain amount of excess liquid and / or moisture has been evaporated or otherwise separated from the liquid mixture or slurry placed in the dryer. It is not important that all liquid or moisture in the liquid mixture or slurry placed in the dryer has been evaporated or separated from the solid particles.

[0166] In this document, the term "product reservoir" means any area, space, tank, tube, or compartment within a dryer where solids or other concentrates are collected and held for discharge after excess liquid and / or moisture has been removed from a liquid mixture or slurry by the operation of the dryer. For example, in some cases, a product reservoir may include an evaporator tank within a thin-film evaporator, a discharge nozzle connected to the evaporator tank, or both, as these are locations where powders or concentrates dried in the thin-film evaporator are collected or accumulated after the liquid mixture or slurry has been dried to remove excess liquid or moisture. Pharmaceutical products collected in the product reservoir of a dryer may include active pharmaceutical ingredients, pharmaceutical product intermediates, or pharmaceutical products. Pharmaceutical products can exist in a variety of different forms, including, but not limited to, active pharmaceutical ingredients produced by drying or partially drying liquid mixtures or slurries containing active pharmaceutical ingredients, pharmaceutical compositions containing such active pharmaceutical ingredients, dry powders, partially dried powders, solids, solid-solid mixtures, or combinations thereof. Pharmaceutical products may also exist as suspensions, viscous liquids, slurries, solid-liquid mixtures, or combinations thereof.

[0167] The discharge chute has several inlets and outlets configured to allow the dried pharmaceutical product and gases to pass into or out of the internal chamber. These inlets and outlets typically include (1) a product inlet that fluidly connects the internal chamber of the discharge chute to the product reservoir of the dryer, (2) a vacuum supply inlet that fluidly connects the internal chamber of the discharge chute to a vacuum source, (3) a gas inlet that fluidly connects the internal chamber of the discharge chute to a gas source, and (4) a product outlet that fluidly connects the internal chamber of the discharge chute to a main collection container, which is removably connected to the product outlet of the discharge chute to “capture” and / or bundle the dried pharmaceutical product solids into packaging.

[0168] Suitablely, the inlets and outlets on the discharge chute can be opened and closed by operating the aforementioned valves connected to these inlets and outlets. For example, a vacuum supply control valve is connected to the vacuum supply inlet of the discharge chute, and it can be operated (manually and / or automatically) to open the vacuum supply inlet on the discharge chute, thereby initiating the suction of gas from the internal chamber of the discharge chute through the vacuum supply inlet by operation of a vacuum source connected to a location opposite to the vacuum supply inlet fluidly connected to the internal chamber of the discharge chute. Because the internal chamber is substantially airtight when all other inlets and outlets are closed by other valves, removing gas from the internal chamber via the vacuum supply inlet through the vacuum supply source reduces the air pressure inside the internal chamber, which creates a vacuum condition (negative pressure) inside the internal chamber. Preferably, a sufficient amount of gas is removed from the internal chamber such that the pressure level inside the internal chamber decreases until it is less than or substantially equal to the pressure level of the vacuum condition present inside the product storage container of the dryer. When the desired vacuum condition is reached in the internal chamber, the vacuum supply control valve can be operated (manually or automatically) to close the vacuum supply inlet.

[0169] When the pressure level within the inner chamber of the discharge chute is less than or substantially equal to the vacuum condition present in the product reservoir of the dryer, the vacuum supply control valve closes to shut off the vacuum supply inlet, and the product inlet valve opens to open the product inlet, which fluidly connects the product reservoir of the dryer to the inner chamber of the discharge chute. Opening the product inlet allows some or all of the dried powder collected in the product reservoir during the drying process to flow out of the product reservoir (typically due to gravity) and into the inner chamber of the discharge chute through the product inlet. Advantageously, the product inlet can be opened, and pharmaceutical products can be moved from the product reservoir of the dryer to the discharge chute without disrupting the vacuum condition (negative pressure level) present inside the product reservoir. This means that the operation of the dryer does not need to be paused when the product inlet connecting the product reservoir of the dryer to the discharge chute is opened.

[0170] When sufficient, maximum, or specified quantity of pharmaceutical product has flowed out of the product reservoir and into the internal chamber of the discharge chute, the product inlet valve connected to the product inlet on the discharge chute is operated (or automatically activated) to close the product inlet of the discharge chute, thereby preventing the pharmaceutical product from flowing out of the product reservoir and into the internal chamber of the discharge chute.

[0171] Once at least some of the dried pharmaceutical product has flowed into the internal chamber of the discharge chute, the gas control valve connected to the gas inlet is operated to open the gas inlet on the discharge chute, thereby allowing gas (such as nitrogen) to flow into the internal chamber of the discharge chute, for example, through the gas source. The gas flow into the internal chamber repressurizes the internal chamber, causing the pressure level within the internal chamber to return to ambient pressure. This ambient pressure level facilitates gravity-driven flow of the pharmaceutical product within the internal chamber through the product outlet at the bottom of the internal chamber and into the main collection container connected to the bottom of the discharge chute. To allow the pharmaceutical product to begin flowing out of the internal chamber and into the main collection container under gravity, the collection control valve connected to the product outlet of the discharge chute is opened to remove any obstruction to the product outlet. The collection control valve remains open until the desired amount of pharmaceutical product within the internal chamber of the discharge chute has been delivered through the product outlet and into the main collection container.

[0172] The aforementioned control valves may include any of a variety of conventional valves, including but not limited to solenoid valves, butterfly valves, ball valves, or full-port ball valves, to name just a few.

[0173] In some embodiments, the discharge chute also includes a diverter assembly configured to give the operator the option to divert a portion of the dry powder flowing out of the discharge chute into a second (or auxiliary) collection container. In some cases, diverting some dry powder pharmaceutical products into the second collection container instead of allowing them to flow into the main collection container is to physically separate any dry powder products from the main collection container that the operator determines by observation, inspection, sensor measurements, or other means lacks necessary or desired characteristics (such as required or desired structure, dryness, particle size, etc.) and therefore should be discarded as waste. In other cases, it may be necessary or desirable to divert some dry pharmaceutical products into the second (or auxiliary) collection container when the main collection container is full and therefore needs to be removed and replaced.

[0174] Therefore, in some embodiments, the diverter assembly includes a common channel, a main outlet channel, an auxiliary outlet channel, a diverter, and a diverter controller. The main outlet channel, fluidly connected to the common channel and a main collection container, is configured such that any pharmaceutical product flowing into the main outlet channel from the common channel will flow only into the main collection container. The auxiliary outlet channel, fluidly connected to the auxiliary collection container and a common channel, is configured such that any pharmaceutical product flowing into the auxiliary outlet channel will flow only into the auxiliary collection container. The common channel, main outlet channel, and auxiliary outlet channel of the diverter assembly constitute the lower portion of the internal chamber of the discharge chute. In other words, the lower portion of the internal chamber of the discharge chute defines the common channel, which is then “split” into two channels to define the main outlet channel and the auxiliary outlet channel of the diverter assembly. The diverter located at the junction between the common channel, the main outlet channel, and the auxiliary outlet channel is configured to act as a gate, depending on the orientation of the diverter, to guide pharmaceutical product flowing out of the common channel only into the main outlet channel, or only into the auxiliary outlet channel, or into some of both the main outlet channel and the auxiliary outlet channel. The shunt may also include a solenoid valve, as will be described in more detail below.

[0175] A diverter controller, mechanically (or electromechanically) connected to the diverter at the junction between the common channel, main outlet channel, and auxiliary outlet channel, is operable to control the orientation of the diverter. It should be understood that certain embodiments of the discharge device may include a diverter assembly having three or more outlet channels configured to divert dried pharmaceutical products into three or more collection containers, without departing from the scope of the invention.

[0176] In some embodiments, the discharge device further includes a flexible isolator attached to the discharge chute, configured to surround and close the fluid connection between the product outlet and the main collection container on the discharge chute, thereby substantially isolating the fluid connection between the product outlet and the main collection container from the surrounding environment. If the device includes both a main collection container and an auxiliary collection container, the flexible isolator attached to the diverter assembly may be configured to close, surround, and protect (i) the fluid connection between the main outlet passage of the diverter assembly and the main collection container, and (ii) the fluid connection between the auxiliary outlet passage of the diverter assembly and the auxiliary collection container.

[0177] Optionally, embodiments of the emission device may further include a coupling system for attaching a flexible isolator to a splitter assembly. An exemplary coupling system may include, for example: a mounting plate on the splitter assembly; a recess around a peripheral section of the mounting plate; an opening in the wall of the flexible isolator having a size and shape substantially matching the peripheral section of the mounting plate; and an elastic band (or “O-ring”) attached to a portion of the wall of the flexible isolator adjacent to the opening. The recess around the peripheral section of the mounting plate is configured to receive both the elastic band (stretched to fit around the peripheral section of the mounting plate) and a portion of the wall of the flexible isolator adjacent to the opening to which the elastic band is attached, and to removably hold them in place. The clamp can be removably fastened to the periphery of the mounting plate such that the elastic band and a portion of the wall of the flexible isolator to which the elastic band is attached are clamped between the inner wall of the clamp and the groove surrounding the periphery of the mounting plate, ensuring that the elastic band (and the edge of the opening in the top of the flexible isolator) remain in the groove, and that no stray particles can escape from the flexible isolator by passing through the opening when the opening of the flexible isolator is fastened to the mounting plate.

[0178] The inventors anticipate that for human operators, having the option to inspect or observe the form of dried powder from the product reservoir of the drying device flowing into the discharge chute while the dried powder is still within the internal chamber of the discharge chute may be important, necessary, or desirable, enabling the operator to make informed decisions regarding whether the dried powder lacks any desired physical properties, such as flowability, particle size, or drying properties. To meet this need, embodiments of the discharge device may also include a discharge monitoring system connected to the housing of the discharge chute and configured to provide a visual indication of the quantity or physical state of the pharmaceutical product located within the internal chamber of the discharge chute. The discharge monitoring system may include, for example, sensors; observation glass; observation glass assemblies; observation glass windows; pressure-measuring elements such as scales, analytical probes, or combinations thereof.

[0179] In another embodiment of the discharge device, an airlock assembly is provided for collecting solids from a product reservoir of a drying apparatus while the product reservoir is maintained under continuous vacuum pressure. Typically, the airlock assembly includes a discharge chute, a vacuum supply control valve, a product inlet valve, a gas control valve, and a collection control valve. The discharge chute includes a substantially airtight internal chamber, a shell substantially surrounding the airtight internal chamber, a vacuum supply inlet fluidly connecting the airtight internal chamber of the discharge chute to a vacuum source, a solids inlet fluidly connecting the airtight internal chamber to a product reservoir, a gas inlet fluidly connecting the airtight internal chamber to a gas source, and a solids outlet fluidly connecting the airtight internal chamber to a collection container.

[0180] The vacuum supply control valve is connected to the vacuum supply inlet of the discharge chute and can be operated to open and close the vacuum supply inlet of the discharge chute. Opening the vacuum supply inlet by opening the vacuum supply control valve allows a vacuum source connected to the vacuum supply inlet to draw a sufficient amount of gas from the airtight internal chamber to create a negative pressure level within the airtight internal chamber that is less than or substantially equal to the vacuum pressure inside the product storage container of the drying unit.

[0181] The product inlet valve is connected to the solids inlet of the discharge chute and can be operated to open and close the solids inlet when the negative pressure level in the airtight internal chamber of the discharge chute is less than or substantially equal to the vacuum pressure in the product reservoir. When the negative pressure level in the airtight internal chamber of the discharge chute is less than or substantially equal to the vacuum pressure in the product reservoir, the solids inlet of the discharge chute is opened by opening the product inlet valve connected to the solids inlet, causing at least a portion of the solids to flow from the product reservoir through the solids inlet and into the airtight internal chamber of the discharge chute under the influence of gravity.

[0182] Because the pressure level in the internal chamber of the discharge chute is less than or substantially equal to the pressure level inside the product reservoir of the drying unit, the product inlet valve and solids inlet of the discharge chute can be safely opened without disrupting the vacuum pressurization conditions of the product reservoir. Therefore, the drying unit does not need to be shut down and can remain operational while solids flow out of the product reservoir, through the solids inlet, and into the airtight internal chamber of the discharge chute. Typically, when some (or all) of the solids collected in the product reservoir of the drying unit have flowed through the solids inlet and into the airtight internal chamber of the discharge chute, the product inlet valve is actuated again to close the solids inlet, thereby preventing solids from continuing to flow from the product reservoir into the airtight internal chamber.

[0183] A gas control valve is connected to a gas inlet on the discharge chute and can be operated to open the gas inlet, allowing a gas source connected to the opposite end of the gas inlet to force a sufficient amount of gas into the airtight internal chamber of the discharge chute to repressurize the airtight internal chamber, thereby raising the pressure level within the airtight internal chamber to ambient pressure. Because the pressure level is ambient pressure, the solids outlet in the airtight internal chamber can now be safely opened to remove (or empty) solids from the airtight internal chamber. For this purpose, a collection control valve is attached to the solids outlet and can be operated to open the solids outlet when the pressure in the airtight internal chamber is at ambient pressure. This action of opening the collection control valve to open the solids outlet in the discharge chute causes at least some of the solids in the airtight internal chamber of the discharge chute to flow out of the airtight internal chamber through the solids outlet and into the collection container under the influence of gravity. When all (or sufficient or desired) solids have flowed out of the internal chamber and into the collection container, the collection control valve can be operated to close the solids outlet of the discharge chute.

[0184] The solids outlet of the airlock assembly may include a diverter assembly to divert some solids flowing out of the airtight internal chamber of the discharge chute into a second (auxiliary or waste) collection container. The diverter assembly may include, for example, a collection branch, a waste branch, a diverter, and a diverter control switch. The collection branch is configured to allow solids to flow only into a first collection container connected to the diverter assembly. The waste branch is configured to allow solids to flow only into a waste container connected to the diverter assembly. The diverter is located at the junction between the collection branch and the waste branch and is configured to guide the solids flow into the diverter assembly such that those solids will flow only into the collection branch, only into the waste branch, or both, depending on the orientation of the diverter. The diverter control switch is mechanically coupled to the diverter and is operable to control the orientation of the diverter.

[0185] The airlock assembly implementation may also include one or more flexible isolators attached to the discharge chute, configured to close the fluid connection between the solid outlet and the collection container on the discharge chute, and thereby substantially close and isolate the fluid connection between the solid outlet and the collection container and isolate it from the surrounding atmosphere outside the discharge chute.

[0186] In another embodiment of the discharge device, an automated collection system is provided for collecting dried pharmaceutical products from the product reservoir of a dryer while the product reservoir is under continuous vacuum pressure. Typically, the automated collection system includes a computer system, at least one input / output block, a discharge spool, a main collection container, and an isolator. Typically, the discharge spool includes a plurality of sanitary spool tubes connected in series to form a substantially continuous internal chamber (or passageway) extending from one end of the discharge spool to the opposite end. Preferably, at least some of the sanitary spool tubes including the discharge spool have built-in instrument ports for connecting sensor instruments for performing various measurements, such as, for example, pressure sensors, temperature sensors, contact and non-contact infrared (IR) and Fourier transform infrared (FTIR) Raman spectroscopy sensors, and product height or level sensors.

[0187] The discharge chute of the automated collection system includes: (i) an internal chamber, (ii) a shell surrounding the internal chamber, (iii) a product inlet solenoid valve that fluidly connects the internal chamber of the discharge chute to the product storage container of the dryer, (iv) a vacuum supply inlet solenoid valve that fluidly connects the internal chamber of the discharge chute to the vacuum source, (v) a gas inlet solenoid valve that fluidly connects the internal chamber of the discharge chute to the gas source, and (vi) a product outlet solenoid valve that fluidly connects the internal chamber of the discharge chute to the main collection container.

[0188] As known in the prior art, each solenoid valve includes a solenoid coil wound around an armature, a plunger and bias spring located inside the armature, a valve body, and a cable connection electrically connected to the solenoid coil. The cable attaches the solenoid valve's cable connection to an input / output block, which in turn is electrically connected to a computer system. The solenoid coil, armature, plunger, spring, and valve body are arranged such that when a current generated by the input / output block passes through the solenoid coil via the cable connection, it generates an electromagnetic field around the coil, armature, plunger, and bias spring. This electromagnetic field pushes or pulls the plunger, thereby forcing the plunger to move within the armature to open or close a passage through the valve body. When this occurs, depending on the initial position of the plunger and bias spring, the movement of the plunger will prevent or allow the flow of fluid, gas, or large quantities of dry solids through the passage in the valve body. Therefore, the input / output blocks and solenoid valves work together to convert the control signals generated and transmitted by the computer system into mechanical forces sufficient to block and / or release obstructions for the movement of gas and dried pharmaceutical particles through the various inlets, outlets, channels, and paths of the automated collection system. Because the computer system, multiple sensors, input / output blocks, and solenoid valves cooperate to provide automatic and precise timing control of the opening and closing of the system's inlets, outlets, channels, and paths, no human operator is required to manually control the flow of fluids, gases, and dried particles by manually opening and closing valves. This automatic operation and control of the valves allows the collection system to operate faster, more reliably, and more safely compared to systems requiring manual valve operation.

[0189] The computer system includes a microprocessor, memory, and a process control application stored in the memory. This application includes programming instructions that, when executed by the microprocessor, cause the microprocessor to generate and periodically transmit control signals to an input / output block. These control signals cause the input / output block to generate and selectively transmit current to a solenoid valve. The current causes the solenoid valve to open and close at appropriate times, depending on pressure, temperature, altitude, and level measurements supplied to the input / output block and computer system, for example, by sensor instruments connected to built-in instrument ports in a sanitary sump of the discharge chute.

[0190] The automated collection system operates solenoid valves to allow gas to enter and exit the discharge chute, periodically depressurizing and repressurizing the discharge chute in a time-coordinated manner. This allows dried pharmaceutical products to flow out of the dryer's product storage container, into the discharge chute, and through the discharge chute into the main collection container without disrupting the vacuum pressure conditions within the dryer's product storage container. This avoids the need to pause dryer operation to remove the dried pharmaceutical products and enables the continuous manufacturing, processing, and packaging of dried pharmaceutical products on the production line.

[0191] In some cases, the automated collection system may further include an auxiliary collection container, a diverter assembly having a common channel, a main outlet channel, and an auxiliary outlet channel, and one or more diverter solenoid valves located at or near the connection point between the common channel, main outlet channel, and auxiliary outlet channel of the diverter assembly. The one or more solenoid valves connected to the diverter assembly may be configured to direct the flow of dried pharmaceutical product through the appropriate outlet channel and into the main collection container, the auxiliary collection container, or both, in response to current supplied to the diverter solenoid valves by an input / output block operating under the control of control signals generated by a computer system. Suitablely, the current supplied to the diverter solenoid valves to direct the flow of dried pharmaceutical product into the main outlet channel, the auxiliary outlet channel, or both outlet channels may be activated and deactivated in response to sensor readings collected by a sensor located in the discharge chute, the sensor being configured to determine whether the dried pharmaceutical product entering the discharge chute meets (or does not meet) specified requirements for the dried pharmaceutical product. For example, if a sensor detects that a dried pharmaceutical product delivered to the discharge chute is "unqualified" because it has not been dried to a specified level of dryness (i.e., it is still "too wet"), then a program running on a computer system can be configured to respond to the sensor measurement by providing or removing the current required to open or close the shunt solenoid valve, so that the "too wet" dried pharmaceutical product will flow only into the auxiliary outlet channel connected to the auxiliary collection container.

[0192] As will be described in more detail below with reference to the accompanying drawings, additional sensors and additional solenoid valves can be attached to various other components of the automated collection system to monitor conditions and control the flow of gases and solids in and through these other components of the system. For example, when the isolator is filled with nitrogen or some other gas, pressure sensors, nitrogen sources, nitrogen supply solenoid valves, and exhaust solenoid valves can be attached to the isolator and operate together under the control of control signals generated by a computer system and current delivered to the solenoid valves by an input / output block. The pressure sensors, nitrogen sources, nitrogen supply solenoid valves, and exhaust solenoid valves can be automatically operated by the computer system to maintain a constant, specified, or desired pressure level within the isolator.

[0193] In some, but not all, embodiments, the process control application may include multiple individual or integrated programming modules (subroutines and / or functions) stored in the main memory and / or auxiliary memory of a computer system. Each programming module contains program instructions executable by a microprocessor to cause the microprocessor to generate and transmit control signals to an input / output block that cause the input / output block to deliver current to a solenoid coil in a solenoid valve, thereby opening or closing the solenoid valve. The collection of programming modules may include, for example, a vacuum supply control module that, when executed by the microprocessor, causes the microprocessor to generate and send control signals to an input / output board that automatically open the vacuum supply inlet valve of the discharge chute using a vacuum supply inlet solenoid actuator. This allows a vacuum source to remove gas from the internal chamber via the vacuum supply inlet valve until a pressure gauge attached to the internal chamber of the discharge chute indicates that the measured pressure level within the internal chamber is less than or equal to the vacuum pressure present in the product reservoir of the dryer.

[0194] The collection of program modules may also include a product inlet module, which is stored in memory and communicatively coupled to the emission monitoring system and the product inlet valve. The product inlet module has program instructions that, when executed by the microprocessor, cause the microprocessor to generate and send control signals to the input / output board. These control signals cause the input / output board to transmit electrical signals to the product inlet solenoid valve to: (i) automatically open the product inlet solenoid valve on the emission chute if a pressure sensor on the emission chute indicates that the pressure level in the internal chamber of the emission chute is less than or equal to the vacuum pressure present in the product reservoir of the dryer, to allow at least a portion of the pharmaceutical product in the product reservoir to flow through the product inlet solenoid valve and into the internal chamber of the emission chute; and (ii) automatically close the product inlet solenoid valve on the emission chute if the emission monitoring system detects a specified amount of pharmaceutical product in the emission chute.

[0195] The collection of program modules may also include a gas control module, which is stored in memory and communicatively coupled to the emission monitoring system and the gas inlet solenoid valve. The product inlet module includes program instructions that, when executed by the microprocessor, cause the microprocessor to generate and send control signals to the input / output board. These control signals cause the input / output board to activate the gas inlet solenoid valve in response to the product inlet module closing the product inlet solenoid valve, thereby allowing the gas source to permit gas to enter the internal chamber of the emission chute via the gas inlet solenoid valve until a pressure sensor indicates that the pressure within the internal chamber of the emission chute has reached the ambient pressure level.

[0196] Finally, the set of program modules stored in memory may include a set of control modules communicatively coupled to the emission monitoring system and the product outlet valve. The product inlet module has program instructions that, when executed by the microprocessor, cause the microprocessor to generate and send control signals to the input / output board. These control signals cause the input / output board to activate the solenoid coil in the product outlet solenoid valve to open the product outlet solenoid valve when the emission monitoring system connected to the emission chute indicates that a specified amount of pharmaceutical product is located in the internal chamber of the emission chute and a pressure sensor indicates that the pressure level measured in the internal chamber of the emission chute is at the ambient pressure level. This allows at least some of the pharmaceutical product located in the internal chamber of the emission chute to flow out of the internal chamber, through the product outlet solenoid valve, and into the main collection container.

[0197] In the case of an automated collection system including a diverter assembly, the collection of program modules stored in the computer system's memory also includes a diverter assembly control module communicatively coupled to the emission monitoring system and the diverter solenoid valve. The diverter control module has program instructions that, when executed by a microprocessor, cause the microprocessor to generate and send control signals to the input / output board. If the emission monitoring system detects that a predetermined amount of pharmaceutical product has flowed out of the internal chamber of the emission chute through the product outlet solenoid valve and into the main collection container, the control signal causes the diverter solenoid valve to open or close.

[0198] In yet another embodiment, certain embodiments of the discharge device provide a method for collecting pharmaceutical products from the product storage tank of the dryer using a discharge chute while the product storage tank of the dryer is under continuous vacuum pressure. As in other embodiments, the discharge chute includes (i) an internal chamber, (ii) a housing surrounding the internal chamber, (iii) a product inlet valve fluidly connecting the internal chamber of the discharge chute to the product storage tank of the dryer, (iv) a vacuum supply inlet valve fluidly connecting the internal chamber of the discharge chute to a vacuum source, (v) a gas inlet valve fluidly connecting the internal chamber of the discharge chute to a gas source, and (vi) a product outlet valve fluidly connecting the internal chamber of the discharge chute to a main collection container.

[0199] The method includes the following steps:

[0200] a) Use a pressure gauge to detect the pressure level inside the discharge chute;

[0201] b) Open the vacuum supply inlet valve of the discharge chute;

[0202] c) Activate the vacuum source to remove gas from the internal chamber via the vacuum supply inlet valve until the pressure gauge detects that the pressure in the internal chamber of the discharge chute is less than or equal to the vacuum pressure present in the product storage container of the dryer;

[0203] d) When the pressure gauge indicates that the measured pressure level in the internal chamber of the discharge chute is less than or equal to the vacuum pressure present in the product reservoir of the dryer, open the product inlet valve on the discharge chute.

[0204] e) Allow at least a portion of the pharmaceutical product in the product reservoir to flow through the product inlet and into the internal chamber of the discharge chute;

[0205] f) Close the product inlet valve on the discharge chute;

[0206] g) Open the gas inlet valve of the discharge chute;

[0207] h) Activate the gas source to force gas into the internal chamber of the discharge chute through the gas inlet valve until the pressure gauge indicates that the pressure inside the internal chamber of the discharge chute has reached the ambient pressure level;

[0208] i) Open the product outlet valve when the pressure gauge indicates that the pressure inside the discharge chute is at the ambient pressure level; and

[0209] j) Allow at least some of the pharmaceutical products located in the internal chamber of the discharge chute to flow out of the internal chamber, through the product outlet valve, and into the main collection container.

[0210] In some embodiments, the method may further include the steps of connecting a discharge chute (or a product inlet on the discharge chute) to a product storage container of a dryer, and / or attaching a flexible isolator to the discharge chute to close the fluid connection between the product outlet valve on the discharge chute and the main collection container, thereby substantially isolating the fluid connection between the product outlet valve and the main collection container from the surrounding environment.

[0211] The method may further include the following steps: (a) attaching the above-described diverter assembly to the discharge chute and the main collection container, and (b) operating the diverter control to change the orientation of the diverter, thereby controlling whether the pharmaceutical product flowing out of the internal chamber of the discharge chute and into the diverter assembly will be delivered to the main outlet channel of the diverter assembly, the auxiliary outlet channel of the diverter assembly, or both.

[0212] Now let's return to the attached diagram. Figure 21 A front perspective view of an example of an emission device 10 for a continuous pharmaceutical manufacturing production line according to an embodiment of the present invention is shown; Figure 22 It shows Figure 21 A front perspective view of the exemplary emission device 10 shown. Figure 21 and 22As shown, the exemplary discharge device 10 includes a discharge chute 12, a vacuum supply control valve 14, a gas control valve 16, a product inlet valve 18, a collection control valve 20, and a flexible isolator 22. The discharge chute 10 has a product inlet 24 (in this case, the product inlet 24 is located at the top of the discharge chute 12), a vacuum supply inlet 26, a gas inlet 28, and a product outlet 30 (the product outlet 30, as shown...) at one end. Figure 29 As best shown), it is located at the bottom end of the discharge chute 12. The discharge chute also has a housing 32 (also called an outer shell or sheath) that substantially surrounds the inner chamber 34 (in Figure 32 As shown in the best embodiment, the internal chamber 34 of the discharge chute 12 is substantially airtight when all inlets and outlets are closed by the operation of all the aforementioned valves.

[0213] By attaching the product inlet 24 of the discharge chute 12 to a product reservoir (not shown) inside the drying apparatus 36, the discharge chute 12 is typically connected to a pharmaceutical product dryer 36 (e.g., a thin-film evaporator) to provide a fluid connection between the internal chamber 34 of the discharge chute 12 and the product reservoir. A vacuum supply inlet 26 fluidly connects the internal chamber 34 of the discharge chute 12 to a vacuum source 38, such as a vacuum pump, operable to expel gas from the internal chamber 34, thereby reducing the gas pressure level. A gas inlet 28 fluidly connects the internal chamber 34 of the discharge chute 12 to a gas source (not shown), such as a nitrogen tank or a tank containing some other gas. Typically, but not necessarily, the gas used will be an inert gas, depending on the material being processed. Product outlet 30 (in...) Figure 32 (As best shown) is suitable for use in the internal chamber 34 of the discharge chute 12 and the main collection container (in Figure 21 and 22 A fluid connection is provided between (not shown in the image).

[0214] In some embodiments, and such as Figure 21 As shown, the vacuum supply inlet 26 and gas inlet 28 of the discharge chute 12 may include a single inlet (or port) in the housing 32 of the discharge chute 12 to accommodate a situation where the vacuum supply inlet 26, which connects the internal chamber 34 to a vacuum source (not shown), is combined with the gas inlet 28, which connects the internal chamber 34 to a gas source, before the housing 32 reaches the housing 32. Thus, the vacuum supply and gas can travel through the extension of this section of the duct and can enter or exit the internal chamber 34 through the same opening in the housing 32. Introducing vacuum and gas into the internal chamber 34 through the same inlet in the internal chamber 34 is both convenient and efficient because it is never necessary to simultaneously pressurize the internal chamber 34 with gas and depressurize it with vacuum, as will be explained in more detail below.

[0215] Vacuum supply control valve 14 is operable to open or close the vacuum supply inlet 26 on the discharge chute 12, thereby causing or preventing gas from being drawn out of the internal chamber 34 of the discharge chute 12 through the vacuum supply inlet 26 by operation of a vacuum source (not shown). Product inlet control valve 18 is operable to open or close the product inlet 24 on the discharge chute 12, thereby causing or preventing at least a portion of the pharmaceutical product in the product reservoir of the dryer 36 from flowing into the internal chamber 34 of the discharge chute 12 through the product inlet 24. Gas control valve 16 is operable to open or close the gas inlet 28 on the discharge chute 12, which will cause or prevent the flow of gas into the internal chamber 34 of the discharge chute 12 through the gas inlet 28 by operation of a gas source (not shown). Collection control valve 20 (in Figure 29 (As shown in the best part) Operable to open or close the product outlet 30 on the internal chamber 34 of the discharge chute 12 to cause or prevent at least some of the pharmaceutical products in the internal chamber 34 of the discharge chute 12 from flowing through the product outlet 30 and into the main collection container (not shown).

[0216] In the embodiment shown in the accompanying drawings, the discharge chute 12 further includes a discharge monitoring system 43, which includes an observation glass assembly 44 containing a glass observation window 46 through which an operator can observe and monitor the pharmaceutical product (not shown) as it passes through the internal chamber 34 of the discharge chute 12.

[0217] The exemplary discharge chute 12 also has a diverter assembly 48 (in Figure 22 , 27 (As shown in 32), it is located between the observation glass assembly 44 and the product outlet 30 of the discharge chute 12. The diverter assembly 48 includes a common channel 50, a main outlet channel 52, an auxiliary outlet channel 54, and a diverter 56 (as shown in 32). Figure 32 (as shown) and a diverter controller 58. The main outlet channel 52 of the diverter assembly 48 is adapted to provide a fluid connection between the common channel 50 and the main collection container 42, and is configured such that pharmaceutical products flowing into the main outlet channel 52 from the common channel 50 will flow only into the main collection container 42 attached to the product outlet 30 of the discharge chute 12. The auxiliary outlet channel 54 of the diverter assembly 48 is adapted to provide a fluid connection between the common channel 50 and the auxiliary collection container 60 (see...). Figure 32 And it is configured such that pharmaceutical products flowing from public channel 50 into auxiliary exit channel 54 will only flow into auxiliary collection container 60.

[0218] Shunt 56 (in) Figure 32Located at the junction of the common channel 50, main outlet channel 52, and auxiliary outlet channel 54 (as best shown in the image), the diverter 56 is configured to divert pharmaceutical products passing through the common channel 50 into the main outlet channel 52, or into the auxiliary outlet channel 54, or into both, depending on the orientation of the diverter 56. A diverter controller 58 is mechanically connected to the diverter 56 and is operable to control the orientation of the diverter 56 within the diverter assembly 48.

[0219] Figure 23 It shows Figure 21 A more detailed perspective view of the product inlet 24 and product inlet control valve 18 of the exemplary discharge device 10 shown, wherein the product inlet control valve 18 is turned to the open position.

[0220] Figure 24 It shows Figure 21 A more detailed perspective view of the exemplary discharge device 10, including the product inlet 24, the product inlet control valve 18, and the viewing glass assembly 44, wherein the product inlet control valve 18 is turned to the closed position.

[0221] Figure 25 It shows Figure 21 A more detailed perspective view of the exemplary emission device 10 shown, including the vacuum supply inlet 26, vacuum supply control valve 14, gas inlet 28, and gas control valve 16, wherein the vacuum supply control valve 14 is open and the gas control valve 16 is closed.

[0222] Figure 26 It shows Figure 21 A more detailed perspective view of the exemplary emission device 10 shown, including the vacuum supply inlet 26, vacuum supply control valve 14, gas inlet 28, and gas control valve 16, wherein the vacuum supply control valve 14 is closed and the gas control valve 16 is open.

[0223] Figure 27 The shunt assembly 48 and the attachment of the flexible isolator 22 are shown. Figure 21 The left perspective view of the exemplary coupling system of the diverter assembly 48 in the exemplary drug dispensing device 10 shown, wherein the coupling system includes a single mounting plate 62, a groove 64 surrounding the periphery of the single mounting plate 62, and an elastic band 66 arranged to retain the opening of the flexible isolator 22 within the groove 64.

[0224] Figure 28 It shows Figure 27The diagram shows a perspective front view of the splitter assembly 48 and the exemplary coupling system, and a close-up view of the mounting plate clamp 68 fastened to the periphery of the mounting plate 62 of the connection system. The mounting plate clamp 68 ensures that both the elastic band 66 and the O-ring of the flexible isolator 22 remain securely fastened to the groove 64 of the mounting plate 62.

[0225] Figure 29 The diagram shows a left perspective view of the main outlet channel 52 and auxiliary outlet channel 54 of the diverter assembly 48, the product outlet 30 of the discharge chute 12 and the collection control valve 20, as well as the left side of the flexible isolator 22 arranged according to an exemplary embodiment of the discharge device 10 of the present invention.

[0226] Figure 30 An exhaust port 70 attached to a flexible isolator is shown to facilitate the removal of a main collection container 42 and / or an auxiliary collection container 60 filled with pharmaceutical products from inside the flexible isolator 22.

[0227] Figure 31 An advanced computer-aided drawing (CAD) diagram is shown, illustrating by way of example perspective views of some of the main components of an emission device 10 according to an embodiment of the present invention. Figure 32 Advanced computer-aided drafting (CAD) is shown, illustrating... Figure 31 A cross-sectional view of the exemplary emission device 10 shown.

[0228] Figure 33A Advanced computer-aided drafting (CAD) is shown, illustrating... Figure 31 Left side view of the exemplary emission device 10 shown. Figure 33B Advanced computer-aided drafting (CAD) is shown, illustrating along... Figure 33A A cross-sectional view of the cut line EE of the exemplary emission device 10 shown. Figure 34A Advanced computer-aided drafting (CAD) is shown, illustrating... Figure 31 The right-side view of the exemplary emission device 10 shown. Figure 34B Advanced computer-aided drafting (CAD) is shown, illustrating along... Figure 34A A cross-sectional view of the cut line FF of the exemplary emission device shown. Figure 34C Advanced computer-aided drafting (CAD) is shown, illustrating along... Figure 34B A cross-sectional view of the cutting line G of the exemplary emission device shown.

[0229] Figure 35 Advanced computer-aided drafting (CAD) is shown, illustrating the use of... Figure 31 An isometric view of the flexible isolator 22 of the exemplary emission device 10 shown. Figure 35As shown, the flexible isolator 22 has an opening 23 at its top, which is configured to engage with a mounting plate 62. In a preferred embodiment, the opening 23 has a built-in stretchable O-ring 21 to help ensure that the opening 23 of the flexible isolator 22 remains securely attached to the mounting plate 62 during system use. Typically, the built-in O-ring 21 is stretched and positioned into a machined groove 64 in the mounting plate 62 to help form an hermetically tight seal around the periphery of the mounting plate 62. A stainless steel clamp may be mounted on top of the built-in O-ring 21 to increase protection against leaks.

[0230] In alternative embodiments, and as Figure 36 As shown, the flexible isolator coupling system 72 may include two separate mounting plates instead of a single mounting plate with machined grooves. In this embodiment, an upper mounting plate 76a and a lower mounting plate 76b are provided, wherein the upper mounting plate 76a is located outside the flexible isolator 22 and the lower mounting plate 76b is located inside the flexible isolator 22, and the two mounting plates 76a and 76b are clamped together to securely hold the opening 23 of the flexible isolator 22. Figure 37A Advanced computer-aided drafting (CAD) is shown, illustrating... Figure 36 Left side view of the alternative coupling system 72 shown. Figure 37B Advanced computer-aided drafting (CAD) is shown, illustrating along... Figure 37A The cross-sectional view of the cutting line MM of the alternative coupling system 72 shown.

[0231] Figure 38 A high-level flowchart 1800 is shown, illustrating the process of isolating and collecting dried solids from a thin-film evaporator using an emission device constructed according to an embodiment of the invention. It should be understood that these steps may be performed manually by an operator, or alternatively, may be performed automatically under the control of a computer system, as will be referred to below. Figures 39-42 A more detailed description.

[0232] like Figure 38 As shown, the first step in this process (step 1805) is to equalize the pressure inside the discharge chute with the vacuum pressure within the product reservoir of the thin-film evaporator. This is achieved by activating a vacuum source attached to the vacuum supply inlet of the discharge chute and opening the vacuum supply inlet to allow the vacuum source to draw gas from the internal chamber of the discharge chute until the air pressure inside the internal chamber of the discharge chute drops to the same level as the pressure inside the thin-film evaporator. Next, in step 1810, the splitter controls of the splitter assembly are operated to set the orientation of the splitter inside the splitter assembly, thereby guiding the solids flowing into the splitter assembly into either the main outlet channel or the auxiliary (or waste) outlet channel, or both. Then, in step 1815, the vacuum supply inlet is closed.

[0233] With the vacuum supply inlet closed and the vacuum pressure level within the inner chamber of the discharge chute approximately equal to that within the thin-film evaporator, solids can move from the thin-film evaporator into the discharge chute. Therefore, in step 1820, the product inlet of the discharge chute is opened to allow solids to flow from the product reservoir of the thin-film evaporator into the inner chamber. These solids will pass through and fall to the bottom of the inner chamber, where they will flow into one or both of the main outlet channel and the auxiliary outlet channel of the distributor assembly. The product inlet remains open until the desired amount of solids is collected in the main outlet channel and the auxiliary outlet channel of the discharge chute's inner chamber. As pharmaceutical solids flow into the inner chamber, the operator (in the case of a manually operated collection system) or a computer system (in the case of an automated collection system) can monitor and, as needed, change the orientation of the distributor so that the solids are collected within the intended outlet channel of the distributor assembly.

[0234] Once the desired amount of solids has been transferred into the discharge chute, close the product inlet valve, activate the gas source, and open the gas inlet to allow the gas source to force gas into the internal chamber of the discharge chute until the pressure level in the internal chamber reaches substantially equal to the pressure level in the preferred collection container attached to the discharge chute (see [link to product description]). Figure 38 (Step 1825). Then, the product outlet on the discharge chute is opened to allow solids collected in the main and / or auxiliary outlet channels of the diverter assembly to flow into the preferred collection container (step 1830). At this point, as shown in step 1835, the product outlet is closed, and the operator (or computer system) determines whether the desired amount of solids has been collected in the collection container. If not, the entire process is repeated again starting from step 1805. However, if it is found in step 1835 that the desired amount of solids has been collected in the collection container, the collection container is rolled, cut, and / or heat-sealed, and then passed through the discharge port of the flexible isolator to remove the collection container from the flexible isolator (see step 1840). This completes the process.

[0235] Figure 39 A high-level schematic diagram of an automated collection system 1900 for collecting solids from a drying apparatus according to an exemplary embodiment of the present invention is shown. Figure 39As shown, the automated collection system 1900 includes a computer system 1905, two input / output blocks 1910 and 1915, a main collection container 1985, an auxiliary collection container 1990, and a flexible isolator 1965. The automated collection system 1900 also includes a discharge chute, in this case comprising a plurality of sanitary short pipes 1920, 1925, 1927, 1935, 1940, and 1945 connected in series to define a substantially continuous internal chamber and a shell surrounding the internal chamber. The internal chamber and the surrounding shell extend from the top of the discharge chute to the opposite bottom end of the discharge chute. The bottom end of the discharge chute includes a mounting plate 1950, which, as described above, is configured to receive and retain an opening at the top of the flexible isolator 1965. Appropriately, three of the multiple sanitary tubes (in this case, sanitary tubes 1927, 1940, and 1945) have built-in instrument ports for connecting sensor instruments 1928, 1941, and 1947, respectively, to perform various measurements. These measuring instruments may include, for example, one or more pressure sensors, temperature sensors, contact and non-contact infrared (IR) and Fourier transform infrared (FTIR) Raman spectroscopy sensors, or product height or level sensors, depending on the needs and preferences of the programming instructions operated on the computer system and / or by the system operator.

[0236] A sanitary short pipe 1920 of the discharge sluice fluidly connects the internal chamber of the discharge sluice to a product reservoir of an associated thin-film evaporator (or other drying device) to provide an inlet for solids in the product reservoir to flow into the discharge sluice. Therefore, a product inlet solenoid valve 1921 is connected to (or, in some embodiments, may be integrated into) the sanitary short pipe 1920 such that the fluid connection between the inlet and the product reservoir and the internal chamber of the discharge sluice can be opened or closed in response to a current flowing through (or not flowing through) the product inlet solenoid valve 1921. Therefore, the process control application executed on the computer system 1905 is configured to transmit appropriate control signals to the input / output block 1910 via the data communication link 1907, so that the input / output block 1910 provides current to the product inlet solenoid valve 1921, thereby opening the product inlet solenoid valve 1921 at the appropriate time (such as when the pressure sensor in the drying unit and the pressure sensor 1928 connected to the discharge chute indicate to the computer system 1905 that a vacuum pressure balance has been established on both sides of the product inlet solenoid valve).

[0237] Conversely, the process control application executed on computer system 1905 is also configured to transmit appropriate control signals to input / output block 1910 via data communication link 1907, so that input / output block 1910 stops current from reaching product inlet solenoid valve 1921, and thus closes product inlet solenoid valve 1921 at appropriate times (such as when other sensors in the system (such as sensors 1941 and 1947) indicate to computer system 1905 that a specified, desired, or sufficient amount of dried drug product has flowed into the internal chamber of the discharge chute).

[0238] Similarly, the fluid in the internal chamber of the discharge chute is connected to a vacuum source. Figure 39 Vacuum supply inlet solenoid valve 1926 (not shown), gas inlet solenoid valve 1931 connecting the internal chamber of the discharge chute to a gas source (also not shown), and two product outlet solenoid valves 1956 and 1961 are respectively attached to the vacuum inlet 1924, gas inlet 1930, and product outlets 1955 and 1960 of the discharge chute. All four solenoid valves 1926, 1931, 1956, and 1961 are also electrically controlled by input / output blocks 1910 and 1915, which operate under the control of a process control application running on computer system 1905.

[0239] like Figure 39 As shown, the automated collection system 1900 may include multiple additional solenoid valves 1946, 1956, 1961, 1971, and 1976, which are attached to various components of the system 1900 and controlled by a computer system 1905 to open and close various channels and passages in the system. For example, solenoid valves 1946, 1956, and 1961 may be selectively opened and closed by the computer system 1905 and input / output blocks 1910 and 1915 to control whether solids flowing through the diverter assembly flow into the main collection container 1985 via an interconnected product transfer medium 1982, or instead flow into the auxiliary collection container 1990 via another interconnected product transfer medium 1980. Furthermore, solenoid valves 1971 and 1976 can be selectively opened and closed by computer system 1905 and input / output modules 1910 and 1915 to control whether nitrogen is forced into flexible isolator 1965 through nitrogen inlet 1970 and / or allowed to leave flexible isolator 1965 through nitrogen exhaust port 1975 based on pressure measurements supplied by pressure sensor 1966 attached to flexible isolator 1965. The automated collection system 1900 may also include a nitrogen supply source (…). Figure 39(Not shown in the image), the nitrogen supply source is configured to provide the nitrogen required to clean a washable O-ring smart gasket that can be attached to the mounting plate 1950 of the shunt assembly.

[0240] Figure 40 A high-level block diagram 2000 is shown, illustrated by way of example. Figure 39 The potential architecture of the computer system 1905 is configured to generate and transmit control signals used by input / output boards 1910 and 1915, collect data provided by measuring instruments, and start and stop currents that activate and deactivate solenoid valves according to embodiments of the invention. Figure 40 As shown in the block diagram, the computer system 1905 includes a network interface 2005, a microprocessor 2010, a main memory 2040, an auxiliary memory 2060, a terminal user input device 2015, a terminal user output device 2020, a system clock 2025, and a data collector and a communication interface 2035.

[0241] The main memory 2040 stores a procedure control application program 2042, which includes multiple programming modules with program instructions that, when executed by the microprocessor 2010, cause the microprocessor 2010 to perform various functions of the system as described herein, including... Figure 38 , 41 The functions and processes are shown in flowcharts 42 and 42. These programming modules include a valve solenoid valve module 2044 for generating control signals to open and close solenoid valves, a radar level module 2046 for receiving, processing, and responding to product level measurements supplied by a radar level instrument, a spectral measurement module 2048 for receiving, processing, and responding to one or more spectral measuring instruments, an isolator valve module 2050 for opening and closing solenoid valves associated with flexible isolators 1965, and a vacuum transfer system module 2054 for receiving, processing, and responding to data associated with interconnected transfer media 1980 and 1982 for moving dried pharmaceutical products into a main collection container 1985 and an auxiliary collection container 1990. The set of programming modules also includes a pressure module 2054 and a temperature module 2056. The pressure module 2054 has program instructions for receiving, processing, and responding to pressure measurements supplied by pressure sensors in the system, and the temperature module 2056 has program instructions executable by the microprocessor 2010 for receiving, processing, and responding to temperature measurements supplied by temperature sensors in the system.

[0242] Auxiliary memory 2060 may include a collection of databases, records, fields, linked tables, arrays, registers, or other memory storage objects, configured to receive and store various operating parameters, thresholds, and settings used by the programming module of process control application 2040 to monitor conditions and control the sequence and timing of various actions, tasks, and processes performed by the system, such as generating and transmitting control signals for opening and closing solenoid valves in response to incoming instrument measurements. Figure 40 As shown in the block diagram, these data may include, but are not limited to, process operation data 2062, spectral data 2064, material capture data 2066, time data 2068, alarm data 2070, and valve position data 2072.

[0243] Computer system 1905 communicates with input / output blocks 1910 and 1915 via data collection and communication interface 2035, and can also be configured to communicate with other computers or computer networks via network interface 2005.

[0244] Figure 41 and 42 A high-level flowchart of an embodiment of an automated collection system according to the present invention is shown, which illustrates by way of example the process of... Figure 41 The block diagram illustrates the steps of the algorithm executed by the computer system 1905. (As shown...) Figure 41 As shown, the first step (step 2105) is to run startup and / or diagnostic routines, which may include, for example, performing system checks, valve status checks, instrument status checks, data communication checks, current or signal tests, alarm and fault checks. Preferably, the process control application 2042 is configured to automatically handle any fault codes or error flags that occur during these startup and diagnostic procedures.

[0245] Next, in step 2110, the process control application 2042 initializes operating parameters and startup settings, including isolator pressure, spectral measurement instrument threshold for qualified materials, and maximum level / height settings for qualified / unqualified materials. Typically, the process control application 2042 will also generate control signals to set the distributor solenoid valve to divert unqualified materials to an auxiliary outlet channel in the distributor assembly. "Qualified" material refers to material having a specified or desired structure, quality, condition, or characteristic. "Unqualified" material refers to material lacking a specified or desired structure, quality, condition, or characteristic. The process control application 2042 then closes the outlet valve and opens the vacuum supply inlet valve until the sensor indicates that the discharge chute air pressure is less than or equal to the pressure in the product reservoir of the drying unit (step 2115). When the pressure reaches equilibrium, the system then initiates a discharge cycle by generating a control signal to open the product inlet valve, allowing product to flow from the product reservoir of the drying unit into the discharge chute. See also Figure 41 Step 2120 in the process.

[0246] As product flows into the discharge chute, process control application 2042 receives and monitors instrument measurements, such as spectral data, provided to computer system 1905 via input / output panels 1910 and 1915, as shown in step 2130. In step 2135, program 2042 uses this data to determine whether the material flowing into the discharge chute is “qualified” (i.e., it has the specified and required structure, quality, and / or other characteristics). If the answer is “yes,” program 2042 activates the diverter solenoid valve to direct the product to the main outlet channel and continues filling the main outlet channel until the amount of “qualified” material collected in the main outlet channel reaches a specified, predetermined, or desired level or height. Figure 41 (Step 2145). If the amount of material in the main outlet channel reaches the specified, predetermined, or desired height or level, the process continues in step 2155, where procedure 2042 closes the product inlet solenoid valve and the vacuum supply solenoid valve.

[0247] However, if the answer to step 2135 is "no," meaning the product flowing into the discharge chute is "non-conforming," then procedure 2042 determines whether a specified or predetermined maximum level or height of "non-conforming" material has been collected in the auxiliary outlet channel (step 2140). If the answer is "no," the process returns to step 2140, where procedure 2042 receives more spectral data measurements. But if the answer to step 2140 is "yes," meaning the maximum amount of "non-conforming" material has been collected in the auxiliary outlet channel, then procedure 2042 closes the product inlet solenoid valve and the vacuum supply solenoid valve, as shown in step 2155. The process then proceeds... Figure 41 and 42 The flowchart connector FC1 continues in step 2205, where procedure 2042 opens the gas inlet solenoid valve to begin repressurizing the discharge chute. Then, as shown in step 2210, procedure 2042 opens the product inlet solenoid valve to allow qualified product accumulated in the main outlet channel to flow into the transfer medium of the main collection container, and / or to allow unqualified product accumulated in the auxiliary outlet channel to flow into the transfer medium of the auxiliary collection container.

[0248] Next, in step 2215, procedure 2042 opens the intelligent O-ring nitrogen supply solenoid valve (step 2215) and activates the push / pull powder vacuum transfer system (step 2220). After the product has flowed into the transfer medium, procedure 2042 closes the intelligent O-ring nitrogen supply solenoid valve, the product outlet solenoid valve, and the gas inlet solenoid valve in step 2225, and then deactivates the push / pull powder vacuum transfer system at step 2230 to transfer the product from the transfer medium to the collection container.

[0249] Next, in step 2235, program 2042 determines whether the maximum collection volume of the collection container has been reached. If not, the process returns to... Figure 41 In step 2115, procedure 2042 closes the outlet valve and opens the vacuum supply inlet valve until the sensor indicates that the air pressure in the discharge chute is less than or equal to the pressure in the product storage container of the drying unit. However, if the answer in step 2235 is "yes," then procedure 2042 pauses to wait for automatic or manual packaging of the collected product and replacement of the collection container, and then returns to... Figure 41 Step 2115 in the process.

[0250] Although the invention has been described in detail with reference to specific examples, it will be apparent to those skilled in the art that various modifications can be made within the scope of the invention. Therefore, the scope of the invention should not be limited by the examples described herein, but rather by the claims set forth below.

Claims

1. A system for processing pharmaceutical products in dry powder form, comprising: a) A mixing device for mixing a solvent with a dry powder to produce a liquid mixture or slurry without exposing the dry powder, liquid mixture, or slurry to the surrounding atmosphere; b) A drying apparatus fluidly coupled to the mixing device for separating and removing liquid components from solid components in the liquid mixture or slurry, the drying apparatus comprising a dryer operating under continuous vacuum pressure, the dryer having a product reservoir in which solid components are deposited after the liquid components have been separated and removed; and c) A discharge device fluidly coupled to the drying equipment for collecting solid components from the product storage tank of the dryer during operation of the dryer without stopping the operation of the dryer or disrupting its continuous vacuum pressure.

2. The system of claim 1, wherein, The mixing device includes: (a) A dual-compartment isolator for removing dry powder from a dry powder container having a sealed connection, the dual-compartment isolator comprising: transit compartment, The loading compartment A raw material inlet port, connected to a transfer compartment, is configured to isolate the dry powder container from the surrounding atmosphere when it is transferred to the transfer compartment. A partition that separates the transfer compartment from the loading compartment. The resealable opening in the partition allows the dry powder container to be transferred from the transfer compartment to the loading compartment without exposing the dry powder to the surrounding atmosphere. A shut-off valve located inside the filling compartment, the shut-off valve having fittings suitably configured to mate with a sealing connection on the dry powder container, and Negative cascade pressure controllers are used to generate negative pressure in both the transfer compartment and the loading compartment; and (b) A mixing vessel for mixing the dry powder with a solvent, the mixing vessel comprising: Mixing chamber, A solids loading port connects the mixing chamber to a sealed valve in the loading compartment of a dual-compartment isolator, allowing dry powder to pass through the sealed valve from the dry powder container and into the mixing chamber without exposing the dry powder to the surrounding atmosphere. A solvent inlet for allowing solvent to enter the mixing chamber; and A stirrer for mixing the solvent and dry powder together in the mixing chamber to produce a solvent and dry powder mixture, and An outlet valve for discharging the solvent and dry powder mixture from the mixing chamber.

3. The system of claim 2 further includes a discharge device for facilitating the discharge of the solvent and dry powder mixture from the mixing chamber via the outlet valve.

4. The system of claim 3, wherein, The emission device includes a pump, a positive pressure source, or a negative pressure source.

5. The system of claim 2, wherein, The sealing valves in the loading compartment include separate butterfly valves.

6. The system of claim 2, wherein, The mixing device also includes a solvent tank, which is fluidly connected to the mixing chamber via the solvent inlet.

7. The system of claim 2, wherein, The mixing apparatus also includes an antisolvent tank for containing the antisolvent to be introduced into the mixing chamber.

8. The system according to claim 2, wherein, The negative cascade pressure controller is configured to fill the transfer compartment with inert gas.

9. The system of claim 2, wherein, The negative cascade pressure controller is configured to fill the loading compartment with inert gas.

10. The system of claim 8 or 9, wherein, The inert gas is nitrogen or argon.

11. The system of claim 1, wherein, The dryer includes a thin-film evaporator, a stirred thin-film evaporator, a scraped film evaporator, a rotary dryer, a spray dryer, a cone dryer, a pressure filter, a fluidized bed, or a combination of two or more thereof.

12. The system of claim 1, wherein, The emission equipment includes: a) Discharge chutes, including internal chamber, The shell surrounding the internal cavity, The product inlet connects the internal chamber of the discharge chute to the product storage tank of the dryer. A vacuum supply inlet connects the internal chamber of the discharge chute to a vacuum source. The gas inlet connects the internal chamber of the discharge chute to the gas source, and Suitable for providing a fluid connection between the internal chamber of the discharge chute and the main collection container for a product outlet; b) A vacuum supply control valve operable to open or close the vacuum supply inlet on the discharge chute, thereby causing or preventing gas from being drawn out of the internal chamber of the discharge chute through the vacuum supply inlet by operation of the vacuum source; c) A product inlet valve operable to open or close the product inlet on the discharge chute, thereby inducing or preventing at least a portion of the pharmaceutical product in the product reservoir of the dryer from flowing through the product inlet and into the internal chamber of the discharge chute; d) A gas control valve operable to open or close a gas inlet on the discharge chute, thereby inducing or preventing gas flow into the internal chamber of the discharge chute through the gas inlet by operation of a gas source; and e) A collection control valve operable to open or close a product outlet on the internal chamber of the discharge chute, thereby inducing or preventing at least some of the pharmaceutical products inside the internal chamber of the discharge chute from flowing through the product outlet and into the main collection container.

13. The system of claim 12 further includes a flexible isolator attached to the discharge chute, the flexible isolator being configured to close the fluid connection between the product outlet on the discharge chute and the main collection container, thereby isolating the fluid connection between the product outlet and the main collection container from the surrounding environment.

14. The system of claim 12, wherein, The discharge chute further includes a diverter assembly, the diverter assembly comprising: a) Public passageways; b) A main outlet channel adapted to provide a fluid connection between the common channel and the main collection container, and configured such that pharmaceutical products flowing from the common channel into the main outlet channel will flow only into the main collection container; c) An auxiliary outlet channel adapted to provide a fluid connection between the common channel and the auxiliary collection container, and configured such that pharmaceutical products flowing from the common channel into the auxiliary outlet channel will flow only into the auxiliary collection container; d) A diverter located at the junction of the common channel, the main exit channel, and the auxiliary exit channel, the diverter being configured, depending on its orientation, to direct pharmaceutical products passing through the common channel to either the main exit channel, the auxiliary exit channel, or both the main exit channel and the auxiliary exit channel; and e) A splitter controller mechanically connected to the splitter, operable to control the orientation of the splitter.

15. The system of claim 14 further includes a flexible isolator attached to the splitter assembly, configured to close the fluid connection between the main outlet channel and the main collection container, thereby isolating the fluid connection between the main outlet channel and the main collection container from the surrounding environment.

16. The system of claim 15, wherein, The flexible isolator attached to the diverter assembly is also configured to close and surround the fluid connection between the auxiliary outlet channel and the auxiliary collection container, thereby isolating the following two from the surrounding environment: (i) the fluid connection between the main outlet channel of the diverter assembly and the main collection container, and (ii) the fluid connection between the auxiliary outlet channel of the diverter assembly and the auxiliary collection container.

17. The system of claim 1, wherein, The emission equipment includes: a) A discharge chute, comprising (i) an internal chamber, (ii) a housing surrounding the internal chamber, (iii) a product inlet solenoid valve fluidly connecting the internal chamber of the discharge chute to the product storage container of the dryer, (iv) a vacuum supply inlet solenoid valve fluidly connecting the internal chamber of the discharge chute to a vacuum source, (v) a gas inlet solenoid valve fluidly connecting the internal chamber of the discharge chute to a gas source, and (vi) a product outlet solenoid valve fluidly connecting the internal chamber of the discharge chute to a main collection container; b) An emission monitoring system connected to the discharge chute, the emission monitoring system being configured to detect when a specified amount of pharmaceutical product is in the internal chamber of the discharge chute; c) A pressure gauge configured to indicate when a measured pressure level in the internal chamber of the discharge chute is less than or equal to a second measured pressure level present in the product reservoir of the dryer; d) A computer system, including a microprocessor and memory for storing program instructions that can be executed by the microprocessor; e) A vacuum supply control module, stored in the memory and communicatively coupled to the pressure gauge and the vacuum supply inlet solenoid valve, the vacuum supply control module having program instructions that, when executed by a microprocessor, will cause the microprocessor to automatically open the vacuum supply inlet solenoid valve of the discharge chute to allow the vacuum source to remove gas from the internal chamber until the pressure gauge indicates that the measured pressure level in the internal chamber of the discharge chute is less than or equal to a second measured pressure level present in the product reservoir of the dryer; f) A product inlet module, stored in the memory and communicatively coupled to the emission monitoring system and the product inlet solenoid valve, the product inlet module having program instructions that, when executed by a microprocessor, cause the microprocessor to (i) automatically open the product inlet solenoid valve on the emission chute when the pressure gauge indicates that the measured pressure level in the internal chamber of the emission chute is less than or equal to a second measured pressure level present in the product reservoir of the dryer, allowing at least a portion of the pharmaceutical product in the product reservoir to flow through the product inlet solenoid valve and into the internal chamber of the emission chute, and (ii) automatically close the product inlet solenoid valve on the emission chute when the emission monitoring system detects a specified amount of pharmaceutical product in the emission chute; g) A gas control module, stored in memory and communicatively coupled to an emission monitoring system and a gas inlet solenoid valve, the gas control module having program instructions that, when executed by the microprocessor, cause the microprocessor to automatically open the gas inlet solenoid valve of the emission chute in response to the product inlet module closing the product inlet solenoid valve, thereby allowing the gas source to permit gas to enter the internal chamber of the emission chute through the gas inlet solenoid valve until the pressure gauge indicates that the pressure in the internal chamber of the emission chute has reached the ambient pressure level; and h) A collection control module, stored in memory and communicatively coupled to an emission monitoring system and a product outlet solenoid valve, has program instructions that, when executed by a microprocessor, cause the microprocessor to automatically open the product outlet solenoid valve when the emission monitoring system indicates that a specified amount of pharmaceutical product is located in the internal chamber of the emission chute and the pressure gauge indicates that the measured pressure level in the internal chamber of the emission chute is at the ambient pressure level. This allows at least some of the pharmaceutical product located in the internal chamber of the emission chute to flow out of the internal chamber through the product outlet solenoid valve and into the main collection container.

18. The system of claim 17 further includes a flexible isolator attached to the discharge chute or to a product outlet solenoid valve on the discharge chute to close the fluid connection between the product outlet solenoid valve on the discharge chute and the main collection container, thereby isolating the fluid connection between the product outlet solenoid valve and the main collection container from the surrounding environment.

19. The system of claim 17, wherein, The discharge chute also includes: a) Shunt assembly, including Public passageway A main outlet channel, which fluidly connects the common channel to a main collection container, is configured such that pharmaceutical products flowing from the common channel into the main outlet channel will flow only into the main collection container. An auxiliary outlet channel, which fluidly connects the common channel to an auxiliary collection container, is configured such that pharmaceutical products flowing from the common channel into the auxiliary outlet channel will flow only into the auxiliary collection container. A flow divider solenoid valve, located at the junction of a common channel, a main outlet channel, and an auxiliary outlet channel, is configured to, depending on the position of the plunger within the flow divider solenoid valve, guide pharmaceutical products flowing out of the common channel into only the main outlet channel, or guide pharmaceutical products flowing out of the common channel into only the auxiliary outlet channel, or guide pharmaceutical products flowing out of the common channel into both the main outlet channel and the auxiliary outlet channel; and b) A diverter control module, stored in the memory and communicatively coupled to the emission monitoring system and the diverter solenoid valve, the diverter control module having program instructions that, when executed by the microprocessor, cause the microprocessor to change the position of the plunger if the emission monitoring system detects that a predetermined amount of pharmaceutical product has flowed out of the internal chamber of the emission chute through the product outlet and into the main collection container.

20. The system of claim 19 further includes a flexible isolator attached to the splitter assembly to close the fluid connection between the main outlet channel and the main collection container of the splitter assembly, thereby isolating the fluid connection between the main outlet channel and the main collection container from the surrounding environment.

21. The system of claim 20, wherein, The flexible isolator attached to the splitter assembly is also configured to close and surround the fluid connection between the auxiliary outlet channel of the splitter assembly and the auxiliary collection container, thereby isolating the following two from the surrounding environment: (i) the fluid connection between the main outlet channel of the splitter assembly and the main collection container, and (ii) the fluid connection between the auxiliary outlet channel of the splitter assembly and the auxiliary collection container.

22. A method for processing a pharmaceutical product into a dry powder form, comprising: a) Mixing solvents with dry powder to produce liquid mixtures or slurries without exposing the dry powder, liquid mixtures, or slurries to the surrounding atmosphere; b) Using a dryer to separate and remove liquid components from solid components in a liquid mixture or slurry, wherein the dryer operates under continuous vacuum pressure and has a product reservoir in which solid components are deposited after the liquid components have been separated and removed; and c) During dryer operation, collect solid components from the product storage container of the dryer without stopping the operation of the dryer or disrupting its continuous vacuum pressure.

23. The method of claim 22, wherein, The dry powder is mixed with the solvent in the following manner: a) Provide a dual-compartment isolator, the dual-compartment isolator including a transfer compartment, a raw material inlet port connected to the transfer compartment, a loading compartment, a shut-off valve located in the loading compartment, and a partition between the transfer compartment and the loading compartment. b) Connect the negative cascade pressure controller to the dual-compartment isolator; c) Provide a mixing vessel including a solvent inlet, a mixing chamber, and a solids loading port fluidly connected to the mixing chamber; d) Receive a dry powder container containing dry powder, the dry powder container having a sealed connection; e) Activate the negative cascade pressure controller to generate negative pressure in both the transfer compartment and the loading compartment of the dual-compartment isolator; f) Permit the dry powder container to enter the transfer compartment via the raw material inlet port; g) Transferring the dry powder container from the transfer compartment to the filling compartment by passing the dry powder container through a resealable opening in the partition; h) Close the resealable opening in the partition; i) Connect the sealing connection on the dry powder container to the fitting on one end of the sealing valve in the loading compartment of the double compartment isolator; j) Connect the solids loading port on the mixing vessel to the opposite end of the shut-off valve; k) Open the sealing connection on the dry powder container and the fitting on the shut-off valve to allow the dry powder to be transferred through the sealing connection, the fitting and the solids loading port out of the dry powder container in the loading compartment of the double compartment isolator and into the mixing chamber of the mixer. l) Introducing solvent into the mixing chamber of the mixing vessel via the solvent inlet; as well as m) The dry powder and solvent are stirred in the mixing chamber to produce a slurry or solution.

24. The method according to claim 22, wherein, The pharmaceutical products include: a) Active pharmaceutical ingredients; or b) Pharmaceutical product intermediates; or c) Pharmaceutical products.

25. The method of claim 22, wherein, The pharmaceutical products include: a) Active pharmaceutical ingredients produced by drying liquid mixtures or slurries containing active pharmaceutical ingredients; b) Solid.

26. The method of claim 22, wherein, The pharmaceutical products include: a) Suspension; or b) Viscous liquids; or c) Slurry; or d) Solid-liquid mixtures; or e) A combination of two or more of them.

27. The method of claim 22, wherein, The dryer includes a thin-film evaporator, a stirred thin-film evaporator, a scraped film evaporator, a rotary dryer, a spray dryer, a cone dryer, a pressure filter, a fluidized bed, or a combination of two or more thereof.

28. The method of claim 22, wherein, The solid components are collected from the product storage container of the dryer in the following manner: a) Provide an exhaust chute comprising (i) an internal chamber, (ii) a housing surrounding the internal chamber, (iii) a product inlet valve for fluidly connecting the internal chamber of the exhaust chute to the product storage of the dryer, (iv) a vacuum supply inlet valve for fluidly connecting the internal chamber of the exhaust chute to a vacuum source, (v) a gas inlet valve for fluidly connecting the internal chamber of the exhaust chute to a gas source, and (vi) a product outlet valve for fluidly connecting the internal chamber of the exhaust chute to the main collection container; b) Use a pressure gauge to detect the pressure level inside the cavity of the discharge chute; c) Open the vacuum supply inlet valve of the discharge chute; d) Activate the vacuum source to remove gas from the internal chamber via the vacuum supply inlet valve until the pressure gauge detects that the pressure in the internal chamber of the discharge chute is less than or equal to the continuous vacuum pressure present in the product storage container of the dryer; e) When the pressure gauge indicates that the pressure level in the internal chamber of the discharge chute is less than or equal to the continuous vacuum pressure present in the product storage container of the dryer, open the product inlet valve on the discharge chute. f) Allow at least a portion of the pharmaceutical product in the product storage container to pass through the product inlet and be transferred to the internal chamber of the discharge chute; g) Close the product inlet valve on the discharge chute; h) Open the gas inlet valve of the discharge chute; i) Activate the gas source to force gas into the internal chamber of the discharge chute via the gas inlet valve until the pressure gauge indicates that the pressure in the internal chamber of the discharge chute has reached the ambient pressure level; j) When the pressure gauge indicates that the pressure inside the discharge chute is at the ambient pressure level, open the product outlet valve; and k) Allow at least some of the pharmaceutical products located in the internal chamber of the discharge chute to flow out of the internal chamber and through the product outlet valve to collect the pharmaceutical products in the main collection container.

29. The method of claim 28, further comprising attaching a flexible isolator to the discharge chute to close the fluid connection between the product outlet valve and the main collection container on the discharge chute, thereby isolating the fluid connection between the product outlet valve and the main collection container from the surrounding environment.

30. The method of claim 28, further comprising: a) Attaching the diverter assembly to the discharge chute and the main collection container, the diverter assembly including... A common channel, fluidly connected to the product outlet of the discharge chute, is configured to receive the pharmaceutical product as it flows out of the internal chamber of the discharge chute through the product outlet. A main outlet channel, which connects the common channel fluidly to the main collection container, is configured such that any pharmaceutical product flowing into the main outlet channel will flow only into the main collection container. An auxiliary outlet channel, which fluidly connects the common channel to an auxiliary collection container, is configured such that any pharmaceutical product flowing into the auxiliary outlet channel will only flow into the auxiliary collection container. A diverter, located at the junction of the common channel, the main outlet channel, and the auxiliary outlet channel, is configured to guide a pharmaceutical product through the common channel, the main outlet channel, the auxiliary outlet channel, or both, depending on the orientation of the diverter. Shunt control; and b) Operate the diverter control to change the orientation of the diverter, thereby controlling whether the pharmaceutical product flowing out of the internal chamber of the discharge chute and into the diverter assembly will be delivered to the main outlet channel of the diverter assembly, the auxiliary outlet channel of the diverter assembly, or both.

31. The method of claim 30, further comprising: a) Monitor the pharmaceutical products delivered to the internal chambers of the discharge chute to determine if the pharmaceutical products meet the specified requirements for the pharmaceutical products; and b) Operate the diverter control to change the orientation of the diverter, so that the pharmaceutical product flows out of the internal chamber of the discharge chute and into the diverter assembly, thereby being delivered only to the main outlet channel.

32. The method of claim 30, further comprising: a) Monitor the pharmaceutical products delivered to the internal chambers of the discharge chute to determine if the pharmaceutical products do not meet the specified requirements for the pharmaceutical products; and b) Operate the diverter control to change the orientation of the diverter, thereby causing the pharmaceutical product to flow out of the internal chamber of the discharge chute and into the diverter assembly, thus delivering it only to the auxiliary outlet channel.

33. The method of claim 30, further comprising attaching a flexible isolator to the splitter assembly to close the fluid connection between the main outlet channel and the main collection container of the splitter assembly, thereby isolating the fluid connection between the main outlet channel and the main collection container from the surrounding environment.

34. The method of claim 33 further comprises attaching the flexible isolator to the splitter assembly to close and enclose the fluid connection between the auxiliary outlet channel and the auxiliary collection container of the splitter assembly, thereby isolating the following from the surrounding environment: (i) the fluid connection between the main outlet channel and the main collection container of the splitter assembly and (ii) the fluid connection between the auxiliary outlet channel and the auxiliary collection container of the splitter assembly.

35. The method of claim 33, further comprising attaching the flexible isolator to the shunt assembly using a coupling system, the coupling system comprising: a) Mounting plate on the shunt assembly; b) Grooves surrounding the perimeter of the mounting plate; c) An opening in the wall of the flexible isolator, the opening having a size and shape that matches the peripheral section of the mounting plate; and d) An elastic band attached to a portion of the wall of a flexible isolator adjacent to the opening; e) wherein the groove surrounding the peripheral section of the mounting plate is configured to receive both the elastic band and a portion of the wall adjacent to the opening in the flexible isolator to which the elastic band is attached, and to removably retain both in place.

36. The method of claim 35, further comprising removably securing the clamp to a peripheral section of the mounting plate such that a portion of the wall of the elastic band and the flexible isolator to which the elastic band is attached is clamped between the inner wall of the clamp and a groove surrounding the peripheral section of the mounting plate.

37. The method of claim 22, wherein, The pharmaceutical products include: Active pharmaceutical ingredients are produced by partially drying a liquid mixture or slurry containing active pharmaceutical ingredients; or solid.

38. The method according to claim 25 or 37, wherein, The solid includes dry powder.

39. The method of claim 25 or 37, wherein, The solid includes a portion of dry powder.

40. The method of claim 25 or 37, wherein, The solid includes solid-solid mixtures.

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