Patent Application
20200016552
The present invention relates to a production module for producing solid medicaments. Solid medicaments are intended to mean tablets, pills or capsules.
The processing of pharmaceutical powders to form solid medicaments has been known for some decades. The batchwise processing of pharmaceutical powders is likewise widely known. Furthermore, semi-continuous and continuous process management for the processing of pharmaceutical powders is known from EP 2 427 166 B1, CH 686343 A5, and from EP 1 157 736 A1.
These documents disclose, in particular, semi-continuously operating systems which have a premixing source, one or more wet granulators operating in parallel, and one or more fluidized-bed dryers operated in series. In the semi-continuous case, however, all these components only operate semi-automatically. The system therefore relies on a user confirming each process step manually, and in this case having to act himself A process therefore takes place as follows, for example:
Such process management, however, has some disadvantages. For instance, in the case of manual disconnection and connection of the connectors of the container and the mixing apparatus or other system components, there is always the risk of handling errors by the user. Substances that constitute a risk for humans and the environment may therefore escape. Corresponding safety measures to ensure risk-free coupling are elaborate and cost-intensive. If the granulate is furthermore stored in an intermediate container, as time goes on, it may compact under its own weight and stick together. This breaks down the granulate structure previously produced, so that an entire production batch may be lost. Because of the series connection of the fluidized-bed apparatuses, failure of the entire production occurs in the event of failure of only a single fluidized-bed apparatus.
The production module according to the invention comprising a plurality of process units for producing solid medicaments in individual lots makes it possible to process pharmaceutical powders fully automatically to form solid medicaments, in particular tablets and capsules. By the automation, automatic compliance with process limits for all important or necessary process parameters takes place in each process unit of the production module. This furthermore allows automatic detecting of technical problems that arise in each individual process unit, and reporting to a user, in particular by means of an HMI, i.e. a human-machine interface. Lastly, the automation furthermore allows automatic cleaning of the entire production module, or in particular also individual process units, after a production process. During production, delivery of defined, in particular small, product quantities, the lots, from an upstream process unit to a downstream process unit preferably takes place, without having to remove the product from the production module. The manufacturing steps within the production module may preferably be matched to such lots, mixing of the individual lots being very substantially avoided. There is furthermore a possibility of checking the product quality of each lot, preferably in each process unit. Furthermore, the recorded production data from each device and each unit are preferably linked with each respective lot and stored, so that the process path of this lot through the individual modules and units can be tracked. Furthermore, the substance name, material number, batch number, production date, mass of the respective batch and dosing factor (purity factor of the excipients and of the API) of the substances which are weighed into the powder sources (IBC) are ideally made available manually by the user or by scanning these data to the control device of the production module. Scanning is intended, in particular, to mean that said parameters are present in coded form on a storage container so that when connecting the storage container to the supply device, manual or automatic recording the coded parameters can be read out and supplied to the control device. This information is automatically linked with each of these respective batches consisting of lots. With the linking of the lots with the process, quality data and production data, as well as the material data (substance name, material number, production date, batch number, dosing factor, mass of the respective batches) of the substances weighed into the powder sources, traceability of this lot in terms of the process and real-time tracking are made possible.
The production module comprises a supply device, a mixing device, a final processing device, a cleaning device and a control device. In particular, the production module has a transport network for powder and/or for granulate produced, tablets and/or capsules, this network preferably being based on lines and nodes assigned to the individual devices. By means of this transport network, the individual devices are connected to one another. Thus, in particular, the supply device is connected to the mixing device. Furthermore, the mixing device is preferably connected to the final processing device. In this way, substances can be transported, in particular fully automatically, from the supply device to the mixing device and from the mixing device to the final processing device, without manual intervention being necessary. The mixing device, the final processing device and the supply device constitute, in particular, individual process units of the production module.
The supply unit preferably has a dosing unit for each starting substance supplied. In this way, a defined quantity of starting substances can be supplied, in particular fully automatically, to the production module, in particular the mixing device. Transport of the starting substances to the mixing device can therefore be carried out fully automatically, without the intervention of a user being necessary. In this way, in particular, the safety is increased because handling errors by the user are avoided. The supply device is used in order to supply starting substances so as thus to define each lot. The starting substances are preferably powdered pharmaceutical substances. The mixing device is used in order to mix the defined lot of the starting substances supplied. Furthermore, processing, in particular granulating and/or drying, as well as coating of the starting substances supplied, may preferably take place inside the mixing device. The final processing device is used in order to finally process the mixed and/or granulated and/or coated starting substances to form an end product. This comprises, in particular, shaping of the mixed and/or granulated and/or coated starting substances. In this way, in particular, the solid medicaments can be shaped.
Furthermore, the production module comprises a control device. The control device is configured for fully automatic driving of the supply device, mixing device and the final processing device, as well as a preferably provided cleaning device. In particular, the control device is configured to control substance transport in the form of a lot from the supply device to the mixing device and from the mixing device to the final processing device. In particular, no manual intervention is therefore necessary. An entire production cycle, starting with the supply of the starting substances required until the output of the finished solid medicaments from the final processing device, therefore preferably takes place automatically and without the intervention of a user. Furthermore, the control device makes it possible to store the production data and link these data with the individual lots. By the control device, preferably, data of all the process sensors and quality sensors of the production module which are provided can be linked with the respective lot, so that subsequent tracking of each lot, or tracking of each lot in real time, is made possible.
Delivery of each lot from the supply device to the mixing device, and from the mixing device to the final processing device, can be carried out without any back-mixing by means of collecting locks. In particular, this prevents each lot from coming into contact with other substances, which are not intended for processing of the lot. In particular, a plurality of lots can therefore be processed simultaneously in the production module, since separation of the individual lots is ensured at all times by the collecting locks.
A first collecting lock is preferably arranged between the supply device and the mixing device. The first collecting lock is used to prevent fluid communication between the supply device and the mixing device. In this way, quality assurance is made possible. Thus, the starting material can be transferred from the supply device into the first collecting lock. From the first collecting lock, the starting material can subsequently be supplied to the mixing device. Inside the first collecting lock, there is therefore always a defined quantity of starting materials, which are to be delivered to the mixing device. Furthermore, for highly accurately dosed powdered pharmaceutical substances, the first collecting lock advantageously has at least one stirring member for mixing and/or uniformizing and/or homogenizing the powdered substances, as well as ideally also at least one instrument gland for at least one quality sensor and at least one quality sensor for monitoring the purity of the dosed substances, mixing quality, particle size distribution and optionally input moisture content of the highly accurately dosed pharmaceutical powders under constant conditions. The first collecting lock preferably has at least one opening for input of the powdered substances, and an outlet.
A second collecting lock is preferably arranged between the mixing device and the final processing device. The second collecting lock is used in order to, in particular temporarily, prevent continuous fluid communication between the mixing device and the final processing device, as well as to hold material for an uninterrupted process of production in the final processing device in the event of a delay of the process in the upstream modules. In this way, again, quality assurance is made possible. From the mixing device, a product produced by mixing and/or granulating and/or coating the starting substances can therefore be transferred into the second collecting lock. From the second collecting lock, the product can be transferred into the final processing device, so that there is no direct fluid communication between the mixing device and the final processing device. This second collecting lock may ideally, like the first collecting lock, be under constant conditions equipped with at least one stirring member, at least one instrument gland for at least one quality sensor for checking the substances mixed and/or granulated and/or dried and/or coated in the mixing device in respect of purity, mixing quality, particle size distribution and optionally moisture content of the pharmaceutical substances. Furthermore, it is advantageously provided that the second collecting lock can mix the processed product from the mixing device with further substances. The further substances may, in particular, be added to the second collecting lock by means of an additional dosing unit. The further substances are, in particular, magnesium stearate or other additives referred to as an external phase.
Preferably, a bifurcation is installed between the second collecting lock and the final processing device. By means of the bifurcation, a lot can be ejected and, in particular, transferred into a refuse container. This prevents a product, which does not fulfill predefined quality criteria, from continuing to remain in the transport network of the production module. In this way, in particular, contamination of the transport network with inferior-quality products is prevented.
A third collecting lock is preferably arranged between the final processing device and a module boundary of the production module. A module boundary is in this case intended to mean a boundary of the production module, at which finished end product, i.e. solid medicaments, leaves the production module. Likewise, such a boundary at which the starting substances are introduced into the production module is preferably to be regarded as a module boundary. By the third collecting lock, fluid communication between an environment of the production module and the final processing device is thus prevented. In this way, quality assurance is again made possible. Furthermore, contamination of the production module by external influences is prevented. The third collecting lock may ideally be a dust collector or simple container. Quality sensors are preferably fitted to the third collecting lock, in order to allow quality controls under constant conditions.
Particularly advantageously, the first collecting lock and/or the second collecting lock and/or the third collecting lock and/or the fourth collecting lock allow monitoring of the product quality. Thus, in particular, at least one quality sensor is fitted inside the first collecting lock and/or the second collecting lock and/or in the third collecting lock and/or in the fourth collecting lock. With the quality sensor, a quality of the content of the respective collecting lock can be recorded. In this way, it is made possible for the control device to determine and monitor the quality of the content of the collecting locks.
By means of the supply device, at least one active pharmaceutical ingredient and at least one pharmaceutical excipient can preferably be supplied. Particularly preferably, an active pharmaceutical ingredient and a multiplicity of different pharmaceutical excipients are supplied. Both the active pharmaceutical ingredient and the pharmaceutical excipient are preferably a powder.
The final processing device preferably comprises a tablet press and/or a capsule filler. By the tablet press and/or the capsule filler, solid medicaments can be manufactured from the product produced by the mixing device by mixing the starting substances. In this way, different geometrical shapes of the solid medicaments can be produced. Depending on the application, coating of the tablets produced in an optional coating device is preferably furthermore carried out.
The supply device comprises, in particular, at least one dosing unit for highly accurate dosing of the powdered pharmaceutical constituents. Furthermore, the supply device preferably has a collection container for receiving the highly accurately dosed powdered pharmaceutical substances. Advantageously, this collection container may alternatively be equipped with at least one stirring member for mixing the powdered substances, as well as ideally also with at least one instrument gland for at least one quality sensor and at least one quality sensor for monitoring the purity of the dosed substances, mixing quality, particle size distribution and optionally input moisture content of the highly accurately dosed pharmaceutical powders. The collection container has at least one opening for introduction of the powdered substances, and an outlet.
The mixing device preferably comprises a fluidized-bed system, in which drying and/or granulation can be carried out, or a wet granulator. The wet granulator preferably comprises an extruder and/or a high-shear mixer. In particular, a mixing process in the broadest sense takes place in the mixing device. Thus, in particular, the mixing device is not intended to mean a screw doser, since only substances in ultrapure form are present in this case. The mixing process may therefore be considered to be synonymous with a drying process and/or a granulating process.
A coating device is preferably arranged downstream of the tablet press and/or the capsule filler. The coating device is used in particular for coating the tablets produced, or else the capsules produced. Preferably, provision is furthermore made for a fourth collecting lock to be arranged between the tablet press and/or capsule filler and the coating device. The fourth collecting lock again allows quality assurance to be made possible. By the fourth collecting lock, direct fluid communication between the tablet press and/or the capsule filler and the coating device is prevented. By the fourth collecting lock, fluid communication between the final processing device and the surroundings is therefore prevented. Furthermore, quality assurance is again made possible. Furthermore, contamination of the final processing device by external influences is prevented. A fourth collecting lock may, in particular, be provided even when the production module does not have a third collecting lock.
Furthermore, the production module preferably comprises a cleaning device which can be started semiautomatedly or fully automatedly by the user via a human-machine interface and can run. In this case, the supply device, the mixing device and the final processing device may ideally be cleaned together and/or separately from one another, so that partial by manual recleaning by the user (WIP—Wipe in Place), but preferably no manual recleaning (CIP—Clean in Place), is necessary.
Preferably, quality sensors are fitted to the individual process units of the mixing device, in order to enable delivery of good product, meaning that predefined quality features are fulfilled, into the transport network, or as far as possible not to let substandard product, meaning that predefined quality features are not fulfilled, enter the transport network and to eject it directly after or from the units of the mixing device manually or automatically with a suction unit into a refuse container.
In particular, the invention further relates to a method for producing solid medicaments with a production module as described above. In this case, provision is made for starting substances to be used to be dosed highly accurately into the first collecting lock by means of a dosing unit in the supply device in a fixed quantity. In this way, each lot is defined. Particularly advantageously, it is in this case provided that the same quantities are always used during production. Particularly advantageously, the same mass proportions are always dosed.
When carrying out the method described above, preferably each lot is processed separately in the supply device and subsequently separately in the mixing device and subsequently separately in the final processing device. Provision is furthermore preferably made for the respective lot to be transported after each concluded process step into a collecting lock in order to be checked there by means of quality sensors for its suitability for further processing.
Particularly advantageously, each lot is granulated and dried in the mixing device only in a process unit. As an alternative, each lot is granulated in the mixing device in an extruder or in a high-shear granulator, and subsequently dried in a process unit of the mixing device. Since the mixing device advantageously has a plurality of process units, the mixing device can simultaneously process a plurality of lots. In this case, the individual lots are preferably kept separate from one another, so that mixing of the individual lots is prevented.
Advantageously, provision is furthermore made for further substances to be supplied into the second collecting lock by at least one additional dosing unit. In this way, the further substances can be mixed with the respective lot, which is in the second collecting lock. The further substances are, in particular, magnesium stearate or other additives referred to as an external phase.
Preferably, checking of each lot by quality sensors is carried out, wherein the quality sensors are fitted in the individual process units of the mixing device. In this way, it is possible to decide whether a respective lot is released into the transport network or ejected directly after or from the process units of the mixing device manually or automatically into a refuse container. In this way, if predefined quality parameters are not achieved, each lot can be ejected through a bifurcation into a refuse container before the lot reaches the final processing device.
Exemplary embodiments of the invention will be described in detail below with reference to the appended drawing. In the drawing:
Via the supply device 2, starting substances 17, 18, 19, 20 can be supplied through a module boundary 8 to the production module 1. Furthermore, the starting substances 17, 18, 19, 20 can be transported to the mixing device 3 via the supply device 2. This is shown in
The supply device 2 comprises a first dosing unit 13, a second dosing unit 14, a third dosing unit 15 and a fourth dosing unit 16. The active pharmaceutical ingredient 17 supplied can be dosed by means of the first dosing unit 13. The first pharmaceutical excipient 18 can be dosed by means of the second dosing unit 14, the second pharmaceutical excipient 19 can be dosed by means of the third dosing unit 15, and the third pharmaceutical excipient 20 can be dosed by means of the fourth dosing unit 16. In this way, a composition of the starting substances 17, 18, 19, 20 can be adjusted precisely.
The starting substances 17, 18, 19, 20 dosed in this way are therefore present in a defined quantity. Particularly advantageously, there is a first collecting lock 6 between the supply device 2 and the mixing device 3. In this case, provision is made for the first dosing unit 13 to be connected to the first collecting lock 6 optionally by means of a first nonreturn valve 23, the second dosing unit 14 to be connected to the first collecting lock 6 optionally by means of a second nonreturn valve 24, the third dosing unit 15 to be connected to the first collecting lock 6 optionally by means of a third nonreturn valve 25, and the fourth dosing unit 16 to be connected to the first collecting lock 6 optionally by means of a fourth nonreturn valve 26. Furthermore, the collecting lock 6 has a filter 35 to allow an air flow into and out of the collecting lock 6. Preferably, the dosing units 13, 14, 15, 16 may extend into a common manifold pipe and thereby be connected to the collecting lock 6. At the same time, there is a fifth nonreturn valve 27 at an exit of the first collecting lock 6, that is to say downstream of the collecting lock 6. The fifth nonreturn valve 27 is preferably opened only when the first optional nonreturn valve 23, the second optional nonreturn valve 24, the third optional nonreturn valve 25 and the fourth optional nonreturn valve 26 are all closed. The first collecting lock 6 therefore makes it possible for direct fluid communication between the dosing units 13, 14, 15, 16 and therefore the supply device 2 and the mixing device 3 to be prevented. In this way, quality assurance can be made possible. In particular, in the first collecting lock 6, there is a quality sensor (not shown), by means of which a check of the quality of the starting substances 17, 18, 19, 20 is made possible. The quality sensor is advantageously connected to the control device 5, so that the control device 5 can carry out the quality control fully automatically. Furthermore, there is ideally at least one stirring member in the collecting lock 6 for uniformizing and homogenizing the dosed bulk material.
The at least one mixing device 3 is connected downstream of the first collecting lock 6. The mixing device 3 has a sixth nonreturn valve 28 at its entry. With the sixth nonreturn valve 28, a supply of the starting substances 17, 18, 19, 20 to the mixing device 3 can be regulated.
Mixing devices 3 are intended to mean only collections of process units in which a mixing process in the broadest sense of different materials takes place. In particular, the mixing device 3 is a fluidized-bed system, a wet granulator, preferably a high-shear mixer or extruder, or another mixing apparatus. In particular, according to the invention screw dosers are not regarded as a mixing device 3, since substances in ultrapure form are present in this case.
The mixing device 3 preferably has a multiplicity of individual process units. The process units are connected by means of a distribution system and/or a separate collection system. By means of the distribution system and/or the collection system, defined product quantities can be transported between the process units and/or the supply device and/or the final processing device, ideally gravimetrically or pneumatically.
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If a coating device 10 is present, provision is furthermore preferably made for a fourth collecting lock 12 to be present between the tablet press or the capsule filler 11 and the coating device 10. The fourth collecting lock 12 prevents fluid communication between the coating device 10 and the tablet press or the capsule filler 11. Again, the possibility of quality assurance is thus also provided.
In particular, it is provided that all the nonreturn valves 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, if present, can be driven by the control device 5. Furthermore, the supply device 2, the mixing device 3 and the final processing device 4, that is to say in particular the coating device 10 and the tablet press or the capsule filler 11, as well as the cleaning device 36, can preferably be driven by the control device 5. Fully automatic process operation inside the module boundary 8 is therefore preferably ensured. This means that no user interventions at all are necessary in order to produce the finished solid medicaments 22 starting from the starting substances 17, 18, 19, 20. In particular, it also avoids connecting processes between individual process units having to be produced manually by a user, with the result that possible leaks are avoided.
The production module 1 is, in particular, not enclosed by a housing. A housing is intended to mean a casing which would enclose all the process units, i.e. the supply device 2, the mixing device 3 and the final processing device 4, and would separate them from the immediate environment (GMP production space/clean room). Rather, provision is made for each process unit to have its own walls so as thus to shut off the process spaces from the environment (GMP room/clean room). In particular, this allows full accessibility of the individual process units in the event of maintenance or cleaning being required.
Production of solid medicaments 22 by means of the production module 1 described above preferably takes place as follows:
The, in particular powdered, starting substances 17, 18, 19, 20 are transported pneumatically, preferably gravimetrically from source containers to the supply device 2. The starting substances 17, 18, 19, 20 are introduced into the first collecting lock 6 highly accurately, automatically and in a coordinated manner by way of the dosing units 13, 14, 15, 16. Thus a lot is present inside the first collecting lock 6. Here, quality analyses can be carried out by quality sensors. In particular, quality analyses of this kind comprise recording a moisture content, a composition and a particle size distribution of the starting substances 17, 18, 19, 20, and also ideally the purity thereof. This it is made possible already at this point to perform corrections. The lot can ideally be homogenized here too. The composition can ideally be checked and ensured and corrected here by way of the dosing units 13, 14, 15, 16.
The lot from the first collecting lock 6 is delivered only when the quality is confirmed as good. During the delivery, the first nonreturn valve 23, the second nonreturn valve 24, the third nonreturn valve 25 and the fourth nonreturn valve 26, if present, are closed. Furthermore, the fifth nonreturn valve 27 is opened. This ensures that no fluid communication can take place between the supply device 2 and the mixing device 3 during the transport of the defined product quantity from the first collecting lock 6.
By means of a distribution system of the mixing device 3, the lot is delivered to preferably at least one first process unit and to preferably at least one second process unit, the process units preferably being parts of a fluidized-bed granulation system and being individual, mutually independent granulating units. A fluidized-bed granulation system therefore has a plurality of process spaces, in particular of the same type. In the process units, the supplied lot is processed, in particular mixed and/or granulated, according to a predefined method. Downstream of the mixing device 3, there is the second collecting lock 7 for collecting the products processed, in particular mixed and/or granulated and/or dried, by the mixing device 3. By quality sensors, which are optional in the individual units, in the mixing device 3, good product is delivered from the mixing device 3 via the transport network to the subsequent unit. In the case of substandard product in the individual units of the mixing device 3, a message is issued to the user on the HMI, and the user can automatically or manually remove the substandard product from the mixing device.
In the second collecting lock 7, quality control is advantageously carried out again. Defective batches can therefore already be detected early, and optionally ejected with the aid of the bifurcation 32. Furthermore, with the at least one additional dosing unit 21, it is possible to dose magnesium stearate, or other substances referred to as an external phase, highly accurately into the product being processed. By closing the optional eighth nonreturn valve 30 and opening the ninth nonreturn valve 31, the content of the second collecting lock 7 can be transported to the final processing device 4. Again, it is optionally ensured that fluid communication between the mixing device 3 and the final processing device 4 is avoided.
In particular, the content of the second collecting lock 7 is delivered to the tablet press or the capsule filler 11. Here, processing of the transferred product to form tablets or capsules is carried out. If tablets are produced, the transfer advantageously takes place into the fourth collecting lock 12. From the fourth collecting lock 12, the tablets are transferred to the coating device 10. Again, on the one hand fluid communication between the tablet press or capsule filler 11 and coating device 10 is avoided by the fourth collecting lock 12, and on the other hand the fourth collecting lock 12 makes it possible to carry out quality control.
By the coating device 10, coating of the tablets with a film is carried out. Subsequently, output of the solid medicaments 22 thereby finished takes place into a third collecting lock 9. If capsules are intended to be produced, output of the capsules, and therefore of the finished solid medicaments 22, preferably takes place from the tablet press or the capsule filler 11 into the third collecting lock 9. By the third collecting lock 9, fluid communication with the environment is again prevented, wherein a final quality test may furthermore be carried out.
The process described above can be carried out fully automatically by the control device 5. Owing to the presence of quality sensors in the collecting locks 6, 7, 9, 12 and in the supply device 2, the mixing device 3 and the final processing device 4, the first collecting lock 6, the second collecting lock 7, the third collecting lock 9, and the fourth collecting lock 12, transport and constant quality control between and in the individual units of the production module 1 is made possible. In particular no manual interventions by a user are thus necessary.
The production module 1 furthermore has the following advantages:
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2016 218 135.1 | Sep 2016 | DE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2017/068360 | 7/20/2017 | WO | 00 |
