FIELD OF THE INVENTION

The present disclosure relates to methods and devices for the continuous filtration of slurries during continuous manufacturing processes, as well semi-continuous and batch manufacturing processes.

BACKGROUND OF THE INVENTION

Integrated Continuous Manufacturing (ICM), consists of a series of unit operations that operate in flow and are integrated into a seamless end-to-end (from synthesis to final product) manufacturing process. ICM represents a shift from the batch manufacturing processes used in the pharmaceutical industry. In contrast to batch manufacturing, ICM's unit operation integration process results in significant operational advantages. ICM significantly reduces manufacturing costs (>50% reduction) and lead times (>90% reduction) has a smaller footprint (˜90% reduction) and provides higher quality drugs. These advantages were demonstrated in the first-of-its kind ICM pilot plant (capacity of 1.5 tons of Active Pharmaceutical Ingredient ((API)/year) at MIT, which was able to produce finished coated tablets from raw ingredients through a single, seamless end-to-end process. See Mascia, et al., “End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation,”Angewandte Chemie International Edition,52(47):12,359-12,363 (2013).

Current pharmaceutical manufacturing consists of unconnected individual steps in large batch units including chemical reactions, filtering, precipitating, drying, milling, and tableting. Quality is evaluated by testing at each step (e.g., quality by testing, QbT). This batch process is plagued by long lead times, geographical dispersion of unit operations, and large manufacturing footprints. It is estimated that more than $50 billion a year is wasted due to inefficient manufacturing. Meanwhile, attempts to improve quality have resulted in increasing numbers of product recalls.

In contrast to the quality by testing approach of the batch manufacturing process, for ICM processes, quality is designed into the system (Quality by Design, QbD). In QbD processes, controllers maintain quality thresholds throughout the production cycle, ensuring that the end product of the entire process meets its quality specification. To create ICM systems, devices and methods for each of the various unit operations need to be developed that can process streams of materials. Further, the unit devices require the ability to adjust to variations in the process stream and to provide feedback to the ICM process controller. The unit devices may include a variety of real-time sensors and Process Analytical Technologies (PATs) that measure different process parameters and send signals to the ICM process controller. Each sensor may operate at a different sampling frequency depending on the type of sensor and the parameter to be measured. A high sampling frequency enables rapid modification of the process in response to unwanted changes in process parameters. The ICM process controller integrates the signals across the unit operations and adjusts the parameters to limit the variation within the product stream. Current unit devices, designed to be used in batch mode are generally incompatible with ICM processes, operate at inappropriate scales, and do not provide for real time control.

There is a need for the development of unit operation processes and devices that can be incorporated into ICM methods. The present disclosure relates to and is directed to methods and devices for the filtration of slurries. The slurries may comprise a solid intermediate product or final API suspended in a liquid. In some aspects, the slurries may comprise a solid intermediate product or final API suspended in a liquid comprising one or more bi-products in solution. In other aspects, the slurries may comprise a solution of an intermediate product or final API dissolved in a liquid comprising one or more solids in suspension. Alternatively the slurries may comprise a solution of an intermediate product or final API dissolved in a liquid comprising one or more solid bi-products in suspension. The continuous filtration apparatus of the present disclosure is designed to accept a continuous stream of input slurry and output a continuous stream of an intermediate product or final API in the form of a solid filter cake or a liquid filtrate.

There exists a number of U.S. patents directed to filtration apparatus including U.S. Pat. No. 1,963,616 issued to Fischer on Jun. 19, 1934; U.S. Pat. No. 2,716,494 issued to Hursh on Aug. 30, 1955; U.S. Pat. No. 3,195,484 issued to Clancy et al. on Jul. 20, 1965; U.S. Pat. No. 3,361,262 issued to Orr et al. on Jan. 2, 1968; U.S. Pat. No. 3,478,885 issued to Jackson on Nov. 18, 1969; U.S. Pat. No. 4,230,575 issued to Lizée on Oct. 28, 1980; U.S. Pat. No. 4,539,114 issued to Mention et al. on Sep. 3, 1985; U.S. Pat. No. 6,336,561 issued to Kossik et al. on Jan. 8, 2002; United State Patent Application Number 2013/0264284, to Dixit et al., published on Oct. 10, 2013. The configurations shown in these patents typically were created to optimize high production rates, to provide long service life, and with minimal concern about product loss due to retention of the product in the filters.

During the development and manufacture of pharmaceuticals, the need to filter slurries containing an intermediate product or API, either in solution or in suspension, occurs regularly. Traditionally, solid-liquid separation for batch processing has been carried out using centrifuges, gravity filtration, vacuum filtration, and/or pressure filtration equipment. Although such equipment has been used for years, there are inherent disadvantages to its use, especially when employed in laboratory, pilot plant, or other small volume applications where time and resources are limited, and for processes in which it is critical that the materials be isolated from the outside environment.

For example, centrifuges are often relatively expensive, require significant maintenance, and are labor intensive to operate under aseptic or “clean” conditions. Other types of conventional batch type filtration equipment can also be expensive and similarly require a high degree of operator attendance. A further inherent problem with prior art batch filtration units is that the designs of small batch volume filtration units are often radically different than the designs of larger batch volume equipment, making the results of scaling up from laboratory or pilot plant volume production to industrial scale production less predictable.

An additional drawback with the use of centrifuges and other batch filtration units in the laboratory and pilot plant environments is that cleaning these units between batches requires considerable time and labor. Frequently, time and technical manpower resources in laboratory and pilot plant environments are at a premium, and such cleaning operations can become an unacceptable bottleneck. These cleaning operations also introduce an element of risk, both in terms of exposing personnel to potentially hazardous materials, and in terms of introducing contaminants into the processing equipment that may degrade the quality of, or even completely ruin, the next batch to be processed. Thus, it is desirable to provide efficient means to separate solids and liquids that is usable in continuous processing, and which does not require time consuming cleaning procedures between processing batches.

A variety of approaches have been developed for continuous solid-liquid separations, including continuous conveyor belt filters; automated, alternating agitated batch filters; continuous rotary drum filters; continuous horizontal rotary filters; and continuous horizontal rotary filter arrays, which may be used under reduced pressure, and with filter cake thickness controllers, such as blades and compartmentalized feed-distribution boxes.

A common device used for solid-liquid phase separation for continuous flow processing is the rotary filtration unit. In fact, the rotary vacuum filter is considered to be a workhorse of the chemical process industry. In this type of filter, a slurry is pumped onto a plate which rotates slowly at only a few revolutions per minute (rpm). Solids adhere to the top surface of the plate, which may be coated to aid in the collection of the solids. The slow rotational speed of the plate, as well as air flow over the portion of the plate that contains material, helps to dry the solids adhering to the plate. This solid filtrate is then removed from the rotating plate, often by a blade that scrapes the collected solids from the plate. While efficient, such units are generally quite large and expensive (larger than is necessary for the pharmaceutical industry), typically do not have washing functions (for cake and plate), and usually operate at much thicker cake heights without the same quality systems required by the pharmaceutical industry. The large footprints typical of conventional filters largely precludes their use in compact continuous production systems. Consequently, they have been used primarily in association with large-scale continuous flow processing, such as for wastewater treatment. In view of the operating efficiencies of this type of device, it would be desirable to provide a much smaller and substantially lower cost filtration unit that operates according to the principles of rotary plate filtration, but which can be used for batch or continuous processing in place of the traditional centrifuges and other batch filtering units.

Typical conventional rotary plate filters do not provide these desirable features. Prior art rotary plate filters are relatively complicated mechanical constructions and not readily adaptable to be produced with the quality required for use in pharmaceutical applications. Specifically, prior art rotary plate filters often include complicated valves to control pressure in the system to ensure the proper flow of fluid into the filter unit. Because of the relatively large size of prior art rotary drum filters, and the fact that such units are designed to have very substantial service lives, such units have often incorporated relatively expensive bearing and seal components. It would be desirable to provide a rotary plate filter that replaces these mechanically complicated pressure control schemes in the prior art with control means that are similarly effective, yet much simpler, lower cost, and more appropriate for a continuous unit. It would further be desirable to provide a rotary plate filter that does not require expensive bearing and seal components.

There are filters that are currently used in industry. For example, a Nutsche filter (e.g. MAVAZWAG®, Mavag AG, Neunkirch, Switzerland) is the industrial version of the well known laboratory scale Buchner funnel except that it is designed to operate under either on vacuum or pressure. These are large units that require personnel to remove the resultant cake creating a safety risk due to personnel exposure and also the potential for quality infractions. Further, Nutsche filters operate only in batch mode and have a minimum filter pore size of 10 microns (μm) which can result in significant product loss through the filter. Continuous filters in use in industry include the vacuum drum filter by Steadfast Equipment (U.S. Pat. No. 6,336,561). This apparatus is designed for aquatic remediation, and has been extended to other aqueous filtrations. However, it has several limitations making it unsuitable for use in most pharmaceutical applications. First it is a disposable injection-molded plastic construction, making it incompatible with organic solvents. Second, it is not cGMP-compliant. Third, the filter material (polypropylene) has a pore size of 7-30 μm, resulting in significant product loss through the filter. Finally the device does not allow for in-line filter cake or filter plate washing.

A continuous rotary filter was developed at the Novartis-MIT Center for Continuous Manufacturing. This unit operation was very effective operating at a throughput of ˜100 g/h. There were significant advantages over current filters, including a smaller footprint, continuous operations at low throughput, and a much thinner filter cake (< 1/10 that of a conventional unit) with more precisely controlled dimensions, which resulted in better purity, cleaning, washing, and filtering. The apparatus also included multiple filter cake washing points, and less solvent was required for cleaning making it more efficient. The performance of the rotary filter was satisfactory during testing, and it was easily integrated with other continuous unit operations at the Novartis-MIT Center.

However, there were areas that required improvement: (i) active control of the filter cake thickness and its distribution, (ii) homogenous distribution of the washing solvent, and (iii) overall robustness of the unit. The distributor that spreads the slurry across the filter plate was oriented perpendicularly relative to the filter plate (i.e. 90° vs. the filter plate). However, variation in the cohesive properties of the slurry often prevented an even distribution across the filter plate. Moreover, the distributor propagated the material to the rim of the continuous filter where some fell off the unit thereby reducing the yield. The filter cake wash was performed by flowing solvent through four ports on one of the arcing radii of the unit's frame. The solvent was dripped onto the filter cake, but was not sufficiently applied along the entire radius of the filter plate (i.e. it was not evenly spread over wet-cake). In addition, the filter cake was collected using an auger operating in the centrifugal direction, which resulted in significant loss of material and an even lower yield. Furthermore, the apparatus used a fixed filter plate, which was welded into the device. The filter medium itself was comprised of porous 316 stainless steel sheet, procured from the Mott Corporation (Part #1100-10-12-.047-0.5-A SHEET 316LSS). The pore size was 0.5 μM, which was determined to be the most effective size at passing unwanted contaminants and solvents through, while preventing API crystals to pass through or become lodged within the pores. As such, the filter plate could not easily be changed if a filter having different properties, (e.g., pore size, chemical compatibility, etc.) was required for a particular process.

Accordingly there exists a need to provide a continuous filtration system for incorporation into ICM processes (as well as with semi-continuous or batch manufacturing processes) that could be sufficiently robust to run continuously for at least one day, and be adjusted to accommodate changes in slurry input, changes in concentrations, and other variations inherent in a continuous process. The system further needed to be capable of performing filtrations at elevated temperatures and/or with filter aids. Furthermore, interchangeable modular filter plates would allow for different pore sizes and filter media. It was also desirable to develop a continuous filter having a small footprint so that it could be moved and adapted to different continuous production processes, or other manufacturing processes such as semi-continuous or batch, and could be isolated within an appropriate containment system, such as a fume hood. The present disclosure further provides for real-time monitoring of process parameters including the filter cake dimensions, plate rotational rate, auger speed, and impurities in the filter cake. It was further desirable to replace the often complicated, adjustable-position metallic sharp edge of prior art rotary plate filters with a simpler adjustable-position scraper to remove solids from the plate. To address the requirement for cleaning, a self-cleaning mechanism has been incorporated such that the same unit could be used for the continuous processing of material. Finally, the apparatus of the present disclosure provides for improved efficiency through better control of the wash-to-cake height ratio, more even distribution of wash solvent, and filter cake collection with minimal loss of material, thus improving yield, safety, and environmental sustainability.

SUMMARY OF THE INVENTION

The present disclosure comprises, in one form thereof, an apparatus for continuously processing a slurry comprising: a housing (1601,1602,1603,1605,1606); feed and solvent wash assembly (1300); a removable, rotatable filter plate (1101) having a porous surface for receiving the slurry from the feed and solvent wash assembly (1300); a rotatable inner plate supporting the filter plate (1101); an inner plate rotator for rotating the inner plate; a filtrate outlet (1107) in fluid communication with the filter plate (1101) adapted to convey the filtrate from the housing (1601,1602,1603,1605,1606); a scraper (1403) for removing a solid filter cake from the filter plate (1101); and a filter cake outlet (1102) adapted to convey the filter cake from the housing.

In another form, the present disclosure includes a method for continuously filtering a stream of slurry using an apparatus comprising: a housing (1601,1602,1603,1605,1606); feed and solvent wash assembly (1300); a removable, rotatable filter plate (1101) having a porous surface for receiving the slurry from the feed and solvent wash assembly (1300); a rotatable inner plate supporting the filter plate (1101); an inner plate rotator for rotating the inner plate; a filtrate outlet (1107) in fluid communication with the filter plate (1101) adapted to convey the filtrate from the housing (1601,1602,1603,1605,1606); a scraper (1403) for removing a solid filter cake from the filter plate (1101); and a filter cake outlet (1102) adapted to convey the filter cake from the housing (1601,1602,1603,1605,1606). The method comprises the steps of a) providing a slurry to the slurry feed block (1301); b) rotating the filter plate (1101); c) filtering the slurry through the filter plate (1101) to form a filtrate and a solid filter cake; d) passing the filtrate through the filtrate outlet (1107); e) removing the filter cake from the filter plate (1101); and f) passing the filter cake through the filter cake outlet (1102).

