JP5918808B2 - Tablet manufacturing module and tablet continuous manufacturing method - Google Patents

Description

  The present invention relates to a tablet manufacturing module, the module comprising at least one inlet for an active pharmaceutical ingredient (API), at least one inlet for an excipient, at least one mixing unit; At least one analytical sensor, a tablet press and at least one tablet outlet. Furthermore, this invention relates to the continuous manufacturing method of a tablet.

  Within the pharmaceutical industry, there is an increasing interest in supplying even higher quality products. By including probes and sensors that allow in-line analysis and online analysis, the process line flow provides increased product quality and process efficiency, enabling analysis results to be obtained before and after each stage. Each unit operation can be controlled based on the result. In addition, more stringent demands on process reproductivity and safety should be expected from the authorities granting marketing licenses. The recent concept of how a pharmaceutical process should be designed and implemented has been formed as a set of guidelines by the US Food and Drug Administration (FDA). The FDA uses the term “Process Analytical Technology” (PAT), and in its Guidance for Industry regarding PAT (September 2004) , The goal that PAT ensures final product quality through timely measurement of raw and raw materials and in-process raw materials and very important quality and performance attributes (ie in-process measurements) It is a system for design, analysis and production control that has a wide range of chemical analysis, physical analysis and microbiological analysis that are widely used in the PAT and are performed in an integrated manner. It is important to describe the inclusion of mathematical analysis and risk analysis, the goal of PAT is to enhance understanding and control of the manufacturing process, which is the current drug quality system Consistent with: Quality cannot be tested and put into the product; it should be incorporated, ie by design, so the tools and principles described in this guideline Should be used to obtain an understanding process and can be used to meet the need for rules to evaluate and control the manufacturing process. " An example of a de facto basis for facilitating automated manufacturing is given in US Patent Application No. 2005/0137735, where a plan for processing the information flow and applying the information to the process design was suggested. .

  In addition to improving process efficiency, there is general interest in providing a process that is more environmentally safe and imposes a low risk on the process operator. In particular, in the process of manufacturing tablets from powdered pharmaceutical ingredients (API) and various excipients, operators wear protective respirators, otherwise gloves or cover work clothes Require the wearing of special personal protective equipment to prevent excessive exposure to APIs and excipients. Similar to reducing exposure of operators to pharmaceutical products in the tableting process, reducing the risk of contamination in the surrounding environment is described in WO 03/020499 (Cotey), which describes a rotary tablet press. It has been detailed.

  However, WO 03/020499 does not take into account the provision of better process control as described in the FDA PAT guidelines.

  The typical manufacturing process employed so far in the pharmaceutical industry has the property of batch processing. The batch processing manufacturing process has numerous advantages and provides satisfactory results in many areas. However, because PAT standards are more widely used and applied for monitoring and control during specific pharmaceutical manufacturing processes, and because the demand for design quality generally increases, monitoring that can be achieved in a batch process And the level of control quality is sometimes not enough, especially due to the fact that the setting is fixed. In addition, a relatively large amount of buffer is required, causing undesirable back-mixing of the feed stream and limited traceability of the manufactured product. As a result, the focus of manufacturer and customer interest has moved to a continuous process where the settings are variable and allowed to change within the design space. In order to achieve more output in a batch process, different process settings may be used than when obtaining the same output, larger equipment and more buffering will be required. This is known as a problem of scale expansion. To obtain more output using a continuous process, it only requires longer runs using the ability to maintain the same settings. Further advantages of the continuous process include the ability to provide real-time opening and its inherent advantages, resulting in fewer products in terms of inventory, fewer quality tests, and up to market. This time is further shortened, and the included cost is further reduced. Moreover, there is an increased interest in more robust process equipment and the ability to control more changes in the future while maintaining tablet quality.

  One example of a continuous process for producing tablets is described in EP 0 275 834 A1, where two or more ingredients are fed to the process line at various feeds or entry points, the ingredients are mixed and dried conventionally. It is described that it is continuously formed by a mold tablet manufacturing machine. The process line includes a first mixing unit, a drying unit, a unit that is molded into a certain size, and a second mixing unit.

  Ideally, the output from the tablet machine corresponds to the collected input of the ingredients at the feed or entry point, i.e. all of the raw materials are fed to the tablet machine at a continuous flow and at a constant rate. Is done. This is not practically possible due to various factors. First, it is almost impossible to adjust the output from the mixing and drying unit to supply raw materials to the tablet making machine in just-in-time under any ambient environment. Secondly, the continuous production of the desired high quality tablets requires careful monitoring, control and adjustment of process parameters to avoid a large number of failures on the tablet machine. Become. This leads to the accumulation of raw materials along the process line waiting for adjustment of certain process parameters. This in turn necessitates the use of intermediate buffer vessels to store the raw material upstream of the tablet press.

US Patent Application 2005/0137735 International Publication No. WO03 / 020499 European Patent 0275834A1 International Publication No. WO2007 / 132281 International Application PCT / IB2008 / 051552

ISPE Guide “Containment Performance Evaluation of Pharmaceutical Devices” (ISBN: 1-931879-35-4)

  With this background, it is an object of the present invention to provide a tablet manufacturing module and tableting process with improved overall operating conditions. It is a further object of the present invention to reduce the risk of exposing the operator to API and excipient powders when operating the device.

  In one aspect, these challenges and further challenges are met by a tablet manufacturing module. The tablet manufacturing module includes at least one inlet for pharmaceutical ingredients (API), at least one inlet for excipients, at least one mixing unit, at least one analytical sensor, a tablet press, One tablet outlet. The module has an inlet in fluid communication with an inlet of at least one mixing unit, an outlet of at least one mixing unit is in fluid communication with an inlet of a tablet press, and an outlet of the tablet press is in fluid communication with a tablet outlet. In a state, the module is enclosed, and at least one analytical sensor is arranged upstream of the tablet press for analyzing the content and flow of properties.

  With this design of the tablet manufacturing module, all units of the tableting process are contained, so that all preparation of the raw material flow fed to the tablet press is carried out in a contained and controlled manner. The operator is less exposed and the tablet press is easier to operate. In the context of the present application, the term “containment” is defined by the level of containment according to the appropriate measurement and is defined at least as dust-proof.

  In another aspect, a method for continuously producing tablets is provided. The method provides a containment module comprising at least two inlets, at least one mixing unit, at least one analytical sensor, a tablet press, and at least one tablet outlet, and a pharmaceutical ingredient (API). Feeding one of the at least two inlets; feeding an excipient to the other of the at least two inlets; mixing a raw material stream comprising the API and the excipient in at least one mixing unit; Measuring the content parameter of the raw material stream upstream of the tablet press with at least one analytical sensor, controlling the two inlets and / or the mixing unit according to the measured parameters; The stage of continuous feed flow and the speed of the tablet press according to the parameters measured upstream of the tablet press And controlling, and a step of releasing the tablet at least one outlet.

  Contrary to prior art methods, the method according to the present invention is sufficiently continuous because each unit in the process line is operated without interruption and without requiring a large amount of buffer along the line. Is. This sufficiently continuous feature is possible by placing the sensor upstream of the tablet press. This is provided when monitoring, control and adjustment is carried out in a unit located upstream of the tablet press, so that the raw material fed to the tablet press has a high quality and substantially constant quality, Unify the quality of raw materials supplied to tablet presses. In addition, control of the speed of the tablet press allows the tablet press to be adjusted to various conditions upstream of the tablet press. In this way, the method according to the invention achieves an improvement in the targeted overall operating conditions and, as a result, improves the efficiency of the process in terms of speed and quality and eventually repels the tablets. Can be reduced to a minimum.

  Further details and advantages will become apparent from the dependent claims and from the detailed description of the preferred embodiments, from the example of carrying out the method indicated below.

Figure 2 shows a schematic view of an embodiment of a containment module of the present invention. FIG. 4 shows a schematic diagram of another embodiment of a containment module of the present invention with API and excipients, containers for disconnected products. FIG. 2b shows a schematic diagram of an embodiment of the containment module of the present invention corresponding to FIG. 2a, with API and excipients, containers for connected products. Fig. 4 shows a schematic view of a containment module according to another further embodiment of the invention. Fig. 4 shows a schematic diagram of a process line for carrying out continuous production of tablets, substantially corresponding to the containment module embodiment of Fig. 3; Corresponding to FIG. 4, an outline of a further embodiment is shown. Corresponding to FIG. 4, an outline of a further embodiment is shown. Corresponding to FIG. 4, an outline of a further embodiment is shown. FIG. 3 shows a perspective view of an embodiment of a containment module according to the present invention.

Referring now to the drawings, FIG. 1 shows a schematic diagram of a module 1 according to the present invention. Module 1 is a containment module and the term “containment” will be described in more detail below. Generally, in the drawings, the raw material flow (raw raw material, granule, tablet, etc. flow) and their directions are indicated by arrows, while the information flow from the analytical sensor is indicated by broken lines, The direction is not shown. In the embodiment of FIG. 1, the containment module 1 has two inlets in the form of a removable inlet conduit 2 for drug substance (API) and a removable inlet conduit 3 for excipients. The removable inlet conduits 2 and 3 are in fluid communication with the inlet of the mixing unit 4. In the context of the present invention, the term “mixing unit” should be understood in its broadest term. As a result, a mixing unit generally refers to a unit operation that can mix two or more components into the desired form. For example, a mixing unit could mix two dry ingredients, such as powders and granules, for example, into a mixture with a desired degree of uniformity, such as being substantially uniform. The mixing unit can also modify the physical form of the dry ingredients processed in the mixing unit, for example a feed stream of two or more powders is converted into granules with the powder ingredients Will. The mixing unit may be a granulator that produces granules from dry powder, such as a dry granulator or a roller compactor. Furthermore, the mixing unit will include equipment such as a dry blender and a continuous dry blender. The module will also have as a mixing unit a wet granulator in which the powder is granulated using a granulation liquid. The mixing unit is preferably a granulator capable of producing granules from powder such as purified powder. At one point in the process line, it will be equipped with a drying unit such as a fluid bed dryer.

The raw material stream from the mixing unit 4 will be analyzed by the analytical sensor 51 before being directed to the inlet of the tablet press 6. The tablet press 6 can be used for press machines such as speed, overfill height, feeder paddle speed, filling height, pre-compression force, pre-compression arrangement, main compression force, and / or main compression arrangement. It will optionally allow the settings to be suitably controlled. Control of tablet press settings includes control of the compression profile, i.e., the height, width and / or shape of the compression force and time curve per tablet, and / or the compression energy per tablet. Let's go. One example of a method for controlling such a tablet press is disclosed in International Publication No. WO 2007/132281 (Courtoy). An example of a tablet press includes a compression unit that is detachably disposed in a compression part of a casing of the press, and is disclosed in International Publication No. WO03 / 020499 (Cotei). Both of these documents are referenced and incorporated herein. Tablets exiting the tablet press 6 will be analyzed using an analytical sensor 52 before being directed to the outlet in an embodiment where a removable outlet port 7 for the tablet is shown. As mentioned above, such a rotary tablet press is most advantageous, but the use of other tablet manufacturing devices is conceivable as well. Such equipment for producing tablets and tablet-like shapes would include briquetting presses, extruders and spheronizers, extruders and slicers and the like.

  The module of the present invention includes an “analysis sensor”. Any analytical sensor suitable for a given tableting process will be employed. The analytical sensor is adapted for optical analysis in the electromagnetic spectrum, and the analytical sensor can be weight, thickness and stiffness, and / or chemical content, friability, disintegration, solubility ( It may be possible to analyze the parameters of manufactured tablets such as dissolution). The module also includes several sensors of the same type or different types. The sensor is intended to analyze the content and characteristics of the raw material stream upstream of the tablet press, ie the sensor can in principle analyze a number of parameters of the produced powder. It is. Examples of parameters to be measured are, for example, powder flow mass flow rate and volume flow rate, density, particle size, moisture, API concentration, excipient concentration, compression Rate, flow, etc. The analytical sensor will be placed at any stage in the process to be performed in the module of the present invention. For example, the optical analysis sensor exits the API and excipients entering the module via the respective inlet conduit, the raw material during the mixing and granulation process, the raw material exiting the mixing unit, the raw material entering the tablet press and the tablet press The tablets will be analyzed. Tablets exiting the tablet press will also be analyzed for other parameter values such as weight, thickness, firmness. A suitable optical analysis sensor is described in international application PCT / IB2008 / 051552, the contents of which are hereby incorporated by reference. The optical analysis sensor is enclosed in a “probe” and further comprises other technical parts such as a transmission light guide, a light reception guide, a measurement window, a deflection mirror. The probe also includes a calibration element for calibrating the analytical sensor. The calibration is done in the form of white balance using a suitable white standard calibration element, or the element could be a black standard calibration element or other type of calibration element known in the art. The probe will further comprise a light source and a fiber optic concentrator. Optical analysis may be performed in reflection mode, transmission mode, or semi-transmission mode. An electromagnetic system (electromagnetic wave or other EM spectrum instrument) is used to measure the weight and density of the tablets produced, and the information from this sensor is used to operate the tablet press, blending, drying granulation, fluidized bed Used for operation of the feed preparation system including granulation, wet granulation and / or particle formation by spray drying. In addition, an analytical sensor 52 downstream of the tablet press 6 for analyzing tablet content and characteristics ensures that any such features are used in the manufacturing process. One example is the measurement of tablet density with a tablet density sensor such as an analytical sensor, the result of which is by controlling the unit operation upstream of the tablet press or by controlling the tablet press. It is used to continuously predict the dissolution characteristics of manufactured tablets and to control the dissolution characteristics of manufactured tablets. Not only the tablet density sensor can be used to control the dissolution characteristics, but any analytical sensor can be used wherever it is placed.

  The module of FIG. 1 further comprises a control unit 8 (shown in broken lines) that can communicate with the analytical sensors 51, 52. The control unit 8 will also communicate with the unit operation of the module 1 to send instructions and control unit operation (not shown communication line). The module will further comprise a “data processing unit”. By using this term, it means a computer or similar device that can collect signals from analytical sensors and convert them into data understandable to the operator. Data collected by the analytical sensor will be presented to the operator in any suitable manner. The transformation of the data includes simple statistical analysis, i.e., the data is principal component analysis (PCA), principal component regression (PCR), partial least squares. (PLS), analyzed using “multivariate analysis” such as interval PLS modeling, multivariate statistical analysis is well known in the art, and other techniques are known to those skilled in the art. Would be known. Alternatively, the data is supplied to an external unit for processing. The control unit receives data and input from the data processing unit and / or directly or indirectly from the operator and sends commands to different unit controls contained in the module, eg API and excipients Raw material flow applied to the tablet press, sending the container to each inlet conduit to the API and excipient mixing unit and the actuator controlling the connection to the flow rate, controlling the processing speed in the mixing unit To the mixing unit for controlling the rate and the tablet compression speed (eg the turret speed of the rotary tablet press) and to the actuator for controlling the connection of the product container to the outlet port To do. The control unit may be adapted to control the compression profile independently of the compression speed, for example. Alternatively, the control unit would be adapted to control the compression energy independent of the press speed. The control unit will also control the analytical sensor of the module. For example, it will control when and where the analysis is performed and the exact type of analysis performed. It can be imagined that the data processing unit and the control unit are integrated into one unit, such an integrated unit is always referred to as a “control unit”, and unless otherwise indicated, the control unit is described above. Will have the ability to attribute to the data processing unit. In the case of a pharmaceutical production process, an optical method or an electromagnetic method is suitable for analyzing a solid material and a particle material. Such methods are adopted directly on raw materials, for example based on photometric analysis, spectrophotometric analysis, image analysis of powders, bulk raw materials, granules, etc., and appropriate analytical probes are integrated in the manufacturing facility Will. Examples of suitable optical and electromagnetic spectroscopic analysis methods include reflection / remission and semi-transmission (ultraviolet (UV), visible (VIS), near infrared (NIR), infrared (IR)), Fluorescence, laser induced fluorescence (LIF), biological or chemiluminescence, and Raman spectroscopy. Optical analysis is also suitable for liquid raw materials. In principle, the speed control of the press means changing the rotation speed of the turret of the tablet press, but the inclusion of the intermittent operation within the concept of “speed control” is included in the content of the present invention. I can imagine.

  In addition, a cross-validation sampling device will also be provided in the module to allow evaluation of any differences between in-line analyzes with traditionally obtained values. The cross-validation sampling device includes a complementary set of connections similar to those described above, allowing samples to be removed without disassembling the module and without even interrupting the steps performed within the module. Is possible. The connection of the cross-validation sampling device is in communication with the raw material stream that is to be analyzed for cross-validation, for example with the aid of gravity or creating a relative negative pressure in the tube, It will be in communication through tubes, slides, etc. that allow the material to be drawn. By providing a cross-validation sampling device in this manner, it is possible to analyze the same sample analyzed in the module based on the cross-validation sampling device as well as subsequent analysis.

Containment in tablet compression has been a focus of interest for many years, especially due to the increased perception of potential risks of exposing operators to highly effective substances often caused within the pharmaceutical field. It was. The exposure data will be evaluated, for example, in the SMEPAC (Standardized Measurement of Equipment Particulate Airborne Concentration) test. SMEPAC was adopted in the ISPE guide “Assessing the Particulate Containment Performance of Pharmaceutical Equipment” (ISBN: 1-931879-35-4). In the context of the present invention, the term “containment” means that the unit operation part, for example employed in the process of forming a tablet from API and excipient powder, is contained in the module, and therefore it is removed from the surrounding environment. It means being isolated. As a result, the operator need not access the individual unit controls directly during operation, but will access through the respective removable inlet conduits and outlet ports. The containment of the module likewise means that the module is operated without the need for further unit operation, and the excipient and API are mounted at the front end, ie the removable inlet conduit. Means a single integrated skid, and then means to release the tablet at the back end or removable outlet port. The term “module” means either a single enclosed structure or a framework that allows individual units of the framework to be assembled and tested prior to final installation. Should be interpreted as In this way, release and final installation are simpler and more cost effective. The unit operation unit and the component can be mounted in the state of a frame structure similar to a skid. The frames of these unit operation units can be connected to each other in a module format depending on the arrangement of process lines. The frame can be moved from one processing chamber to another or from one processing plant to another. Due to the flexibility of the containment module, it is designed and configured as a transportable unit and can be easily integrated into a process line existing in a pharmaceutical plant. The desired level of containment depends, inter alia, on the toxicity of the API and therefore the device should be selected. In theory, it can be imagined that the level of containment will approach zero, but it may only be achieved by an innovative approach in which the entire tablet press is placed in the isolator. However, handling such an isolation unit takes a great deal of time to remove, clean and reassemble, and turn around and unacceptably long interruption times. Indeed, the desired level of containment is selected from among the contained levels: dustproof (10-100 microgram / m ³ ), high containment (1-10 microgram / m ³ ), total containment (1 is selected from the level of micrograms / m less than ^3), a suitable device is selected according to the desired containment level. The term “contained” in the context of the present application is defined by the SMEPAC test, or the containment level according to any suitable measurement, so that it is defined as at least dustproof according to the standard specified above. The

Access during operation to the containment module is provided through an inlet and outlet that may take any suitable form. In the embodiment shown and described above, the removable inlet conduit and product, for example a tablet, would be obtained from a removable outlet port. In this context, the term “ detachable ” means that each inlet conduit and outlet port is generally closed, but each allows API and excipients to be applied to the module, or tablets to module. It is meant to be released for removal from. The detachable inlet conduits are preferably designed such that each comprises a conduit connection that allows the conduit connection to be connected to a complementary connection, the inlet conduit connection being a complementary connection. When connected, the removable inlet conduit is in the “open” state. A complementary connection is provided on the container for the API or excipient so that the API or excipient container can be connected to each inlet conduit via the connection and the complementary connection on the container. Connected to. This allows APIs and excipients to be applied appropriately to the module via the now open inlet conduit. Similarly, the outlet port also comprises a connection. The connection is connected via a complementary connection on the container for the product exiting the module via the outlet port. The connection between an inlet conduit on one container and a complementary connection is different from the connection between another inlet conduit on another container and its respective complementary connection, for example an API container is Only the API inlet conduit is connected, the excipient container is connected only to the excipient inlet conduit, and similarly, the connection between the outlet port on the product container and its complementary connection is the inlet conduit. One or both of them will be different. Advantageously, the module is allowed to be dismantled in a contained manner for cleaning, so that the parts can be safely removed for cleaning and quickly replaced with clean components, In the shortest practical time, without the delays and costs associated with traditional CIP, it allows the unit to resume production.

FIGS. 2a and 2b show the connection to complementary connections 22, 32 and 72 where the inlet conduit and outlet port of module 1 are located on respective containers for API 91, excipient 92 and tablet 93, respectively. 1 shows an embodiment of a module with connecting parts 21, 31, 71 for the purpose. The connection of the detachable inlet conduit or outlet port is preferably in the form of a so-called split valve, such as a split butterfly valve, having two engagement valve members. This type of connection allows the conduit or port passage to close, followed by the separation of the two valve parts, so that each of the two engaging valve members is practically manufactured. Without leaking to the surroundings, its corresponding valve part keeps the valve opening closed. A suitable example of a split valve is that marketed under the name “Back Valve®” by GEA Pharma Systems AG (Buebendorf, Switzerland). Each set 21 and 22, 31 and 32, 71 and 72 of a connection part and a complementary connection part is suitable for the type | molds of split butterfly valves, such as a back valve. FIG. 2a schematically shows containers 91, 92, 93 disconnected from module 1, while in FIG. 2b, containers 91, 92, 93 are connected to module 1, so that API and It is shown as allowing access to the module 1 of the dosage form and allowing the tablet to exit the module 1.

  FIG. 3 shows a further embodiment of the module 1 of the present invention. In this embodiment, module 1 is designed for two different excipients, and when complementary connection 32a is engaged with connection 31a, the first excipient is transferred from container 92a to module 1. enter. When the complementary connection 32b is engaged with the connection 31b, a further excipient, such as a lubricant, eg magnesium stearate, enters the module 1 from the container 92b. Further excipients, for example via hopper 20a, the raw material stream leaving the first mixing unit 41 will be directed to the further mixing unit 42 together with, for example, API and first excipient granules. The raw material stream from the mixing unit 42 will be analyzed using the analytical sensor 53 before entering the tablet press 6.

  The module is not limited to a special API, the API is in a dry form, for example in the form of a powder or granules, or the API is in the form of a fluid, for example a solution or an inherently liquid API. I will. The module is not limited to a single API, the module is several inlet conduits for different APIs with the intent to produce controlled open tablets capable of simultaneous or sequential opening of different APIs Is provided. Similarly, an excipient may be in the form of a powder or granules in a solution or liquid. Examples of commonly used excipients are anti-adherents, binders, coatings, disintegrants, fillers, diluents And different types of fragrances, flavours, colors, glidants, lubricants, preservatives, absorbents, sweeteners Special examples of excipients are well known within the art.

  The modules of the present invention are not limited to a single inlet conduit for API and a single inlet conduit for excipients. It can also be seen that the module comprises an API inlet conduit and multiple inlet conduits of different excipients as described in the embodiment of FIG. 3 and shown in the process line overview of FIG. The module also includes several inlet conduits for different APIs. Similarly, the module comprises several mixing units arranged in the process line as required. For example, the module comprises an inlet conduit for an API and an inlet conduit for a first excipient, such as a binder, filler, diluent, fragrance, pigment, etc., the inlet conduit being for example via a hopper And in fluid communication with the inlet of the first mixing unit. This module then comprises another inlet conduit for a second excipient such as a lubricant, the inlet conduit for the second excipient being in fluid communication with the inlet of the second mixing unit. Is in a state. The outlet of the first mixing unit is also the raw material from the first mixing unit, i.e. API and first excipient, and second excipient, e.g. lubricant, at the outlet of the second mixing unit. In fluid communication with the inlet of the second mixing unit. The inlet of the second mixing unit comprises a hopper or the like for receiving the raw material stream from the first mixing unit and the second excipient from its inlet conduit. The feed stream from the outlet of the second mixing unit will be in fluid communication with the inlet of the tablet press to produce tablets with the second excipient from the API and first excipient mixture. . The tablet press is in fluid communication with the outlet port for the tablet via the outlet of the tablet press. The module comprises an analytical sensor arranged for analyzing the raw material stream at the outlet of several mixing units, as well as an analytical sensor arranged in a tablet press for analyzing manufactured tablets.

  The relative position of the inlet conduit for the API and / or excipient and the mixing unit in the process line will consequently depend on the function of the given excipient. In particular, introducing additional excipients into the process line will take into account the desired effect of additional excipients compared to the API and initial excipient stages being processed in the module. Let's go. In general, the additional excipient inlet conduit directs the excipient downstream of the mixing unit, which is a mixture of the API and the first excipient in the feed stream from the downstream mixing unit, for example, In order to be mixed with the uniform mixture and to mix the additional excipient with the API and initial excipient mixture, the introduction point of the additional excipient is then followed by an additional mixing unit. The same thinking applies when two or more APIs are introduced into a process line. For example, the manufacture of a tablet containing two or more APIs, such as a controlled open tablet in which a large number of APIs are simultaneously released, or a controlled open tablet in which different APIs are successively opened, such as a multi-layer tablet, is provided. This is the case when desired.

  The module will be installed in a room or container in a building designed for the purpose. The module has the necessary connections such as, for example, powder connections, controlled atmosphere / venting, CIP (Cleaning-In-Place), possible granulating liquid. With regard to module cleaning, it is possible to clean inline, on-line or off-line as to which principle is most advantageous according to the particular field of application of the containment module. Modules are contained by being in an enclosed space, but the concept of “containment” involves designing individual parts of the process equipment for “containment” and, in the sense of containment, Including making up.

  The module also includes other unit controls necessary for a given tableting process. For example, the unit operating part may be introduced into a drying component introduced into the module, or it may be introduced into a feeder for moving the component from one unit operating part to the next. Other related unit operation units include a mill and a molding machine.

  The containment module is consequently seen as a single piece of equipment, allowing the API and excipients inlet at one end and the tablet outlet at the other end. Preferably, the single installation includes a physical confinement of the containment module interface. Such an enclosure is, for example, in the form of a valve designed as described above, and will probably be supplemented with specially applied piping between the individual units of the module.

  Referring now to FIGS. 4-7, an example of an imaginable process line for performing the method according to the present invention and incorporating a containment module will be described. Analytical sensors present at certain locations within the containment module are not shown. Only the units indicated by reference numerals form part of the process line, and the other units remain in the individual FIGS. 4 to 7 for convenience.

  In the overview diagram of FIG. 4, module 1 is designed for two different excipients, with the first excipient entering module 1 at the module entrance along with the API, in the form of a continuous dry blender (CDB). The first mixing unit 41 is processed. Additional excipients such as lubricants are taken, for example, magnesium stearate into module 1 and into the additional mixing unit 42 with the raw material flow exiting the first mixing unit 41. The additional mixing unit 42 may also be in the form of a continuous dry blender. The feed stream will be analyzed in any suitable manner and in any suitable location prior to entering the tablet press 6 as described above.

  Instead of directing the raw material stream directly from the initial mixing unit 41 to the additional mixing unit 42, before entering the additional mixing unit 42, the raw material flow in the process line overview of FIG. Oriented via machine 43.

  Alternatively, the mixing unit comprises two screw dispensers 44 (TSB), as shown in FIG. 6, through which the API and excipient feed streams entering the module through the inlet are directed. The two screw blenders 44 are followed by two screw granulators 45 (TSG) that further process the feed stream. Following this operation, the raw material stream is guided to the split dryer 5 and further to the mill 46. Additional excipients such as lubricants, such as magnesium stearate, enter the module at this point and, together with the existing raw material flow, are fed into the compact batch compounder 47 before being fed to the tablet press 6. Combined with this mixture to be formulated.

  As a further alternative embodiment, as shown in FIG. 7, the API and excipient feed streams are combined in an initial mixing unit 41 in the form of a continuous dry blender. It is then combined in two screw granulators 45 (as a result, without going through two screw compounders 44), and further through the dryer 5, mill 46, small batch compounder 47 and then tablets Take to the press 6

  In the following, the operation of the containment module 1 will be described in more detail according to the invention.

With the term “continuous”, the steps performed within the module are under the conditions being approached, or the API and excipients (as expressed in mass units) The application rate means that the tablet production rate (similarly expressed in units of mass) is approximately the same and stable. However, the application and production rate need not be the same for a given process, and may be adjusted as desired. When the API and excipient container is empty, it may be replaced with a full container without disconnecting from its respective removable inlet and interrupting the process. Similarly, if a product container is filled, it need not be interrupted and may be replaced with an empty container. The removable inlet conduit and removable outlet port thus allow the module to be operated on a continuous basis, and a further critical factor in fully continuous operation is the speed of the tablet press. It is controlled according to the upstream unit operation unit. This means that the raw material that enters the module via the API and excipients is processed, shaped, dried, etc. at any suitable rate in the mixing unit. In the upstream process, analysis, control, adjustment is performed to bring the powder flow together within any set standard for the finished tablet. If the speed of the powder supplied to the inlet of the tablet press decreases, for example due to parameter adjustment upstream of the press, the speed of the tablet press decreases accordingly and vice versa. At the entrance of the tablet press, all of the powder flow parameters are consequently in the standard set. As a result of this provision, all modules and process lines are run with the minimum amount of integrated material awaiting further processing, i.e. with a minimum amount of buffer. The disadvantages associated with large buffer volumes and the resulting return mixing are reduced and even eliminated. Minimizing the amount of buffer and return mixing allows product traceability throughout the line, for example by time stamps, and allows tablet data to be added and correlated with powder data. Powder data was once made up of special tablets or subsets of tablets. The interrelationship between tablet data and correct powder data allows for a better understanding of the process.

  The method performed in the module of the invention is controlled in any way by the control unit. For example, the control unit may include a pre-programmed event sequence, or the control unit may be manually operated by an operator to control individual process steps or to control the combination of manual and pre-programmed operations. To do. However, the control unit is programmed to adopt the data from the data processing unit and controls the processing parameters in a “feedback” type operation or a “feed forward” type operation. As a result, for example, the parameters are analyzed by an analytical sensor downstream or upstream of a processing stage, and the data processing unit is upstream or downstream of the analysis point to adjust the processing speed based on the data from the sensor. Send a signal to the unit operation unit of the stage. The adjustment of process steps upstream or downstream of the analysis then leads to the adjustment of process steps upstream or downstream of the analysis point, in order to maintain an overall robust state in the process. In this way, the processing of the module will be controlled to obtain a higher quality tablet manufactured in the module. In conclusion, control of the module according to the present invention by the disclosed method involves using information derived from the mathematical model. This includes, for example, predicting dissolution and then providing feedback for steps in the process including granulation, drying, tableting, either continuously or “semi-” continuously. Information from the tablet press is used, for example, to diversify the weight control and feed back and adjust the characteristics of the granulation process. Information from the tablet press, such as release power, is used to control the addition and formulation of lubricants. Information derived from the granulation stage and the drying stage may be used to adjust tablet press settings such as, for example, feeder settings and compression profiles. The compensation system for the compression roller is used to allow the compression profile to be controlled independently of the speed of the tablet press.

  A continuous process according to the present invention will work for an extended time, for example 60 hours or more. The control unit therefore also comprises a timekeeping part, and the module with the analysis sensor will have a control unit appropriately programmed to perform so-called automatic analysis according to a predetermined schedule. The control unit then takes the data from the analytical sensor and maintains the desired conditions by performing adjustments to the process stage or maintaining unadjusted process parameters as appropriate . The control unit will also record the process analysis history as well as the history of any adjustments made in the process.

  One example of an imaginable setting of an embodiment of a containment module according to the present invention will be described with reference to FIG. In a containment module, generally labeled 1, the first mixing unit 41 is shown and is in fluid communication with the API and the inlet for excipients, for example in the form of a powder hopper. The containment module 1 further comprises a feeder such as two screw feeders. The mixing unit is a type of Consigma ™ (Collette), which is designed for plug flow, ie a continuous high first operating on a first in first out principle. A shear granulation and drying system, so that the undesired back mixing mentioned above is avoided. Furthermore, the containment module 1 includes a split fluid bed dryer 5. The mixing unit 41, as shown, is mounted on a post hoist and takes into account the easy manual powder loading and then to the dryer by direct vertical gravity, taking into account the dryer raised above. Consider the supply of Alternatively, the Consigma ™ (or other mixing unit) can be placed downstream and is supplied with a larger powder IBC and a wet transport of air to the dryer 5. Reference numeral 46 indicates a mill, equipped with an evaluation unit (not shown), and also equipped with a small batch processing compounder (not shown) for adding magnesium stearate, other lubricants and other additional excipients. . Finally, the containment module 1 includes a tablet press 6. The arrangement shown for the containment module is a horizontal, single floor installation and includes a pneumatic carrier between the individual units. Alternatively, vertical installations can be used that involve transport by gravity rather than aerodynamic forces.

The present invention should not be considered limited to the embodiments shown and described above. Several modifications and combinations can be envisaged in the claims.
[Aspect 1]
A tablet manufacturing module,
At least one inlet for a pharmaceutical ingredient (API);
At least one entrance to the excipient;
At least one mixing unit;
At least one analytical sensor;
A tablet press,
And at least one tablet outlet,
The inlet is in fluid communication with the inlet of the at least one mixing unit;
An outlet of the at least one mixing unit is in fluid communication with an inlet of the tablet press;
The outlet of the tablet press is in fluid communication with the tablet outlet;
The module is contained,
The module, wherein the at least one analytical sensor is arranged upstream of the tablet press for analyzing content and property flow.
[Aspect 2]
In the containment module according to aspect 1,
The inlet comprises an openable inlet conduit (2; 21) for a pharmaceutical ingredient (API) and an openable inlet conduit (3; 31; 31a, 31b) for excipients;
Said outlet comprises an openable outlet port (7; 71) for tablets;
The openable inlet conduit is in fluid communication with the inlet of the mixing unit (4; 41, 42, 43, 44, 45, 46, 47);
A containment module, wherein the outlet of the tablet press (6) is in fluid communication with an openable outlet port for the tablets.
[Aspect 3]
In the containment module according to aspect 1 or 2,
The module is less than 100 micrograms / m ^3, preferably has a smaller containment levels than 10 micrograms / m ^3, the containment module.
[Aspect 4]
In the containment module according to any one of aspects 1 to 3,
A containment module further comprising a control unit (8) capable of receiving data from said at least one analytical sensor (51, 52, 53).
[Aspect 5]
The containment module according to aspect 4,
The control unit (8) may be at the inlet for API and / or excipients and / or at the mixing unit (4; 41, 42, 43, 44, 45, 46, 47) and / or Or a containment module adapted to send instructions to the tablet press (6).
[Aspect 6]
The containment module according to aspect 5,
A containment module, wherein the control unit is adapted to control the speed of the tablet press.
[Aspect 7]
The containment module according to any one of aspects 1 to 6,
The containment module, wherein the analysis sensor is a spectrophotometric analysis sensor.
[Aspect 8]
The containment module according to any one of aspects 1 to 7,
Containment module further comprising an additional mixing unit (41, 42, 43, 44, 45, 46, 47).
[Aspect 9]
The containment module according to any one of aspects 1 to 8,
A containment module further comprising a drying unit (5).
[Aspect 10]
The containment module according to any one of aspects 1 to 9,
The at least one analytical sensor may be at the inlet of the containment module and / or at the inlet of the mixing unit and / or at the outlet of the mixing unit and / or the tablet press. A containment module located at the entrance.
[Aspect 11]
The containment module according to any one of aspects 1 to 10,
The containment module is designed as a single installation, preferably a containment module designed as a single installation with a physical enclosure of the interface portion of the containment module.
[Aspect 12]
A method for continuously producing tablets,
Providing a containment module comprising at least two inlets, at least one mixing unit, at least one analytical sensor, a tablet press, and at least one outlet for tablets;
Supplying a pharmaceutical ingredient (API) to one of the at least two inlets;
Supplying an excipient to the other of the at least two inlets;
Mixing a raw material stream comprising the API and the excipient in the at least one mixing unit;
Measuring the content parameter of the raw material stream with the at least one analytical sensor upstream of the tablet press;
Controlling the two inlets and / or the mixing unit according to the measured parameters;
Continuously feeding the raw material stream to the tablet press;
Controlling the speed of the tablet press according to the parameters measured upstream of the tablet press;
Releasing the tablet at the at least one outlet;
Including a method.
[Aspect 13]
A method according to aspect 12,
A method wherein an additional mixing step is performed in which additional excipients are fed into the existing feed stream.
[Aspect 14]
In the method according to aspect 12 or 13,
A method wherein a drying step is performed before the feed stream is fed to the tablet press.
[Aspect 15]
In the method according to any one of aspects 12 to 14,
The method wherein the content or characteristics of the tablet is measured by at least one analytical sensor downstream of the tablet press.

Claims (11)

A containment module for tablet manufacture, the containment module comprising:
At least one inlet for a pharmaceutical ingredient (API);
At least one entrance for an excipient;
At least one mixing unit (4; 41, 42, 43, 44, 45, 46, 47);
A tablet press (6);
At least one tablet outlet;
Comprising at least one analytical sensor (51, 53), isolated from the surrounding environment,
The inlet for the pharmaceutical ingredient and the inlet for the excipient are both in fluid communication with the inlet of the mixing unit;
An outlet of the mixing unit is in fluid communication with an inlet of the tablet press;
The outlet of the tablet press is in fluid communication with the tablet outlet;
In the containment module, the analysis sensor is arranged upstream of the tablet press to analyze the content and characteristics,
The inlet for the pharmaceutical ingredient comprises an inlet conduit (2; 21) for the pharmaceutical ingredient that is detachably connected to the complementary connection (22) of the container (91) of the pharmaceutical ingredient,
The inlet for the excipient has an inlet conduit (3; 31; 31a, 31b) for the excipient which is detachably connected to the complementary connection (32) of the container (92) of the excipient. Prepared,
The tablet outlet comprises an outlet port (7; 71) for the tablet removably connected to the complementary connection (72) of the tablet container (93),
Each inlet conduit and outlet port is normally closed, but opened when connected to a corresponding complementary connection ,
A control unit (8) capable of receiving data from the analytical sensor;
The control unit is adapted to send instructions to the inlet for pharmaceutical ingredients and to the inlet for excipients and to the mixing unit and to the tablet press;
A containment module , wherein the control unit is adapted to control the speed of the tablet press . The containment module of claim 1,
The containment module is less than 100 micrograms / m ^3, preferably has a level of less than 10 micrograms / m ³ dustproof, containment module. The containment module according to claim 1 or 2 ,
The containment module, wherein the analysis sensor is a spectrophotometric analysis sensor. The containment module according to any one of claims 1 to 3 ,
Containment module further comprising an additional mixing unit (41, 42, 43, 44, 45, 46, 47). The containment module according to any one of claims 1 to 4 ,
A containment module further comprising a drying unit (5). The containment module according to any one of claims 1 to 5 ,
The analytical sensor may be at the inlet for the drug substance and at the inlet for the excipient and / or at the inlet of the mixing unit and / or at the outlet of the mixing unit and / or A containment module disposed at the inlet of the tablet press. The containment module according to any one of claims 1 to 6 ,
The containment module is designed as a single installation, preferably a containment module designed as a single installation with a physical enclosure of the interface portion of the containment module. A method for continuously producing tablets,
At least two inlets, at least one mixing unit (4; 41, 42, 43, 44, 45, 46, 47), at least one analytical sensor (51, 53), a tablet press (6), Providing a containment module comprising at least one tablet outlet (7; 71) and isolated from the surrounding environment;
Supplying a pharmaceutical ingredient to one of the at least two inlets;
Supplying an excipient to the other of the at least two inlets;
Mixing a raw material stream comprising the pharmaceutical raw material and the excipient in the mixing unit;
Measuring a content parameter of the raw material stream with the analytical sensor located upstream of the tablet press;
Controlling the two inlets and / or the mixing unit according to the measured parameters;
Continuously feeding the raw material stream to the tablet press;
Controlling the speed of the tablet press according to the parameters;
Releasing the tablet from the tablet outlet;
Including
The inlet is complementary to the inlet conduit (2; 21) for the drug substance and removably connected to the complementary connection (22) of the drug substance container (91) and the excipient container (92). An inlet conduit (3; 31; 31a, 31b) for said excipient that is detachably connected to a mechanical connection (32), said outlet being a complementary connection of a tablet container (93) (72) with an outlet port for the tablet removably connected, each inlet conduit and outlet port are normally closed, but allow drug ingredients and excipients to be applied to the module Or may be opened to remove the tablet from the module,
The openable inlet conduit is in fluid communication with the inlet of the mixing unit;
The method wherein the outlet of the tablet press is in fluid communication with an openable outlet port for the tablet. The method of claim 8 , wherein
A method wherein an additional mixing step is performed in which additional excipients are fed into the existing feed stream. The method according to claim 8 or 9 , wherein
A method wherein a drying step is performed before the feed stream is fed to the tablet press. A method according to any one of claims 8 to 10 ,
The method wherein the content or characteristics of the tablet is measured by the at least one analytical sensor downstream of the tablet press.