CN106109251A - Tablet produces module and for the method producing tablet continuously - Google Patents
Tablet produces module and for the method producing tablet continuously Download PDFInfo
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- CN106109251A CN106109251A CN201610570625.0A CN201610570625A CN106109251A CN 106109251 A CN106109251 A CN 106109251A CN 201610570625 A CN201610570625 A CN 201610570625A CN 106109251 A CN106109251 A CN 106109251A
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- tablet
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J2200/00—General characteristics or adaptations
- A61J2200/20—Extrusion means, e.g. for producing pharmaceutical forms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J2200/00—General characteristics or adaptations
- A61J2200/70—Device provided with specific sensor or indicating means
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Abstract
Comprise module (1) and include the entrance for active pharmaceutical ingredient (API) and the entrance for excipient.Described entrance is in fluid communication with at least one mixed cell (41,46), and the outlet 5 of tablet press device (6) is in fluid communication with the releasable outlet for tablet.Material stream including API and excipient is mixed in mixed cell.During operation, the parameter of the inclusion of material stream is measured with one or more analyte sensors of tablet pressure setting upstream.In response to the parameter measured by tablet press device upstream, control the speed of tablet press device.Tablet has been discharged in the exit of tablet press device (6).
Description
The application be the PCT/IB2009/051885 international application in May 7 2009 applying date November 3 in 2011
Day entrance National Phase in China, national applications number are 200980159095.9, invention entitled " tablet produces module and for even
The continuous method producing tablet " divisional application.
Technical field
The present invention relates to a kind of module for producing tablet.Described module includes: for active pharmaceutical ingredient (API,
Active pharmaceutical ingredient) at least one entrance；At least one entrance for excipient；At least
One mixed cell；At least one analyte sensors；Tablet press device；And at least one outlet for tablet.Additionally,
The present invention relates to a kind of method for producing tablet continuously.
Background technology
In pharmaceuticals industry, increasingly desirable to provide high-quality product.By making it possible to before each step and
Obtain analysis result afterwards, to allow each unit operations to be controlled based on these results, including dividing parallel
The production operation of the production line of analysis or the probe of on-line analysis or sensor can provide product quality and the production efficiency of raising.
Additionally, the administrative organization giving sale authorization wishes have process reproducibility and the tightened up requirement of safety.Recently about
The idea how pharmaceutical technology should design and implement is formulated as a set of by the Food and Drug Administration (FDA) of the U.S.
Guideline.Food and Drug Administration uses term " technology analysis and calculation " (PAT), and the industry about PAT at them refers to
In south (date is in JIUYUE, 2004), it is stipulated that " for the purpose of guaranteeing end product quality, measuring (that is, in technique mistake in time
In journey) in raw material and technical process during the important quality of material and attribute of performance and each technique, seller is by PAT
As the system manufactured for design and analysis and control.Noticing that point below is important that i.e., in PAT, term ' analysis ' should
This is construed broadly to chemistry, physics, microorganism, mathematics and the risk analysis including implementing in an integrated fashion.The purpose of PAT exists
In, improve the understanding to process for making and control, this drug quality systems compliant current with us: quality can not produced
Product are tested, and ensures in the design or should be completed by design.As a result, described in this guide
Instrument and principle should be used for improving understanding to technical process, but also can be used in meeting and make manufacturing process effectively and control
The regulatory requirement of manufacturing process processed." in US2005/0137735, give the example of virtual platform being easy to automatically produce
Son, where it is proposed a kind of for providing information in technological design and processing the scheme of flow of information.
Except improving production efficiency, generally desirable to provide being safe for environment and reducing the behaviour to technical process
The technical process of the risk that author applies.In particular, various excipient and the active pharmaceutical ingredient of powder shape medicine is being manufactured
In the technical process of sheet, it may be necessary to operator's wearing protective breathing equipment or other personal protection device, such as
The working clothing that glove or clothing are connected, to prevent from being exceedingly exposed under API and excipient.At WO03/020499
(Courtoy), in, decrease the contaminated risk of surrounding and alleviate during tablet forming technique operator in pharmacy
Exposure in product, which describes a kind of rotation tablet pressure setting.
But, WO03/020499 does not accounts for technical process as more preferable in the offer described in the PAT guide of FDA
Control.
Up to the present, the typical process for making used in pharmaceutical field is (gap) in batches.In batches
Manufacturing process (that is, gap manufacturing process) has lot of advantages, and provides satisfied result in many aspects.But, due to
The application day by day extended in concrete pharmacy manufacturing process for the PAT standard being monitored and controlled, and due to by design
Requirement to quality generally increases, and is generally inadequate the monitoring and control level of quality by batch process, this is because
The fact that setting is fixing.Furthermore, it is necessary to relatively large surge volume, thus produce the undesired back-mixing of material stream with
And the tracking ability of manufactured product.As a result, the point of interest of manufacturer and consumer is transferred to continuous print technical process, wherein
Arrange can change and allow described in be arranged in design space change.In order to realize more production by batch process
Output, it would be desirable to bigger equipment, bigger surge volume and different technique are arranged, to obtain identical output.This is
Know it is scaled problem.Realize more output by continuous print technical process and have only to longer operation, and have
There is the ability keeping identical setting.Other advantages of continuous process include providing the ability of release in real time, described continuously
The inherent advantage of technical process is: inventory amount is few, quality test is few, the market-oriented time very fast, the one-tenth that used
This is less, etc..Additionally, increasingly wish that process equipment has higher robustness and hope has the more introducing of control
The ability of change, keeps the quality of tablet simultaneously.
In EP0275834A1, describe an example of continuous process for producing tablet, two of which or
The more kinds of composition of person each supply or entrance at be fed in production line, described composition be mixed, be dried and with
After compacted in conventional tablet press.Production line includes that the first mixed cell, drying unit, separation unit and the second mixing are single
Unit.
It is desirable that the total input from the output of tablet machine composition in supply or entrance is corresponding, i.e. all
Material be fed in tablet machine with continuously stream, constant speed.Due to various factors, this is infeasible in practice.
First, the output, the most several to supply material to tablet machine on schedule from mixing and drying unit is under any circumstance adjusted
It is impossible.Secondly, produce tablet continuously with desired high-quality to need to monitor carefully, control and adjusting process ginseng
Number, in order to avoid the big rejection number of tablet machine.This may cause the material on the production line waiting special process parameter to be adjusted
The accumulation of material.In turn, this inevitably needs to use intermediate buffering container, in order to the material of storage tablet press device upstream
Material.
Summary of the invention
In this context, it is an object of the invention to provide a kind of module for producing tablet and a kind of tabletting work
Skill, the most whole operating condition is enhanced.Additionally, a further object of the present invention is to reduce operator when operating described equipment to expose
Risk in the powder of API and excipient.
In the first aspect, these and other purpose, described module bag are realized by the module produced for tablet
Include: at least one entrance of active pharmaceutical ingredient (API)；At least one outlet for excipient；At least one mixing
Unit；At least one analyte sensors；Tablet press device；And at least one outlet for tablet.The spy of described module
Levy and be, described entrance and the fluid communication of at least one mixed cell described, going out of at least one mixed cell described
Mouthful with the fluid communication of described tablet press device, and the outlet of tablet press device and the outlet fluid for tablet
Connection, described module airtight (be contained), at least one analyte sensors described is positioned for analyzing tablet press
The inclusion of the upstream of device and character.
Produced the design of module by this tablet, all unit of tablet forming technique process are airtight, therefore reduce operator
Exposure and tablet press device convenient to operate because being supplied to all beam workers of the material stream of tablet press device
Make by airtight (contained), controlled in the way of be performed.Term " airtight (contained) " in present context
According to suitable measurement, limited by its leak tightness level, and be defined at least dust seal.
In another aspect, it is provided that a kind of method for producing tablet continuously, described method comprises the following steps: to carry
For comprising module, described module includes at least two entrance, at least one mixed cell, at least one analyte sensors, tablet
Pressure setting is used for the outlet of tablet with at least one；By in active pharmaceutical ingredient (API) supply to described at least two entrance
One；By the another one in excipient supply to described at least two entrance；At least one mixed cell described mixes
Condensation material stream, described material stream includes API and excipient；Described tablet press dress is measured with at least one analyte sensors described
Put the parameter of the inclusion of the material stream of upstream；Said two entrance and/or described mixed is controlled in response to measured parameter
Close unit；Material stream is continuously fed to tablet press device；In response to the parameter control measured by tablet press device upstream
The speed of pharmacy pressure setting；And tablet is discharged at least one exit described.
Contrasting with method of the prior art, the method according to the invention is totally continuous, because in production line
Each unit can run without interrupting, and need not be along production line and have big surge volume.By in tablet pressure
The upstream arrangement sensor of device processed, it is possible to achieve this totally continuous feature.This can provide and be supplied to tablet press device
The homogeneous quality of material because implementing monitoring on the unit being positioned at tablet press device upstream, controlling and adjust, be supplied to
Therefore the material of tablet press device has high, the quality of constant.Additionally, the speed controlling tablet press device makes
The condition of pressure setting upstream can be adjusted for tablet press device.Therefore, in the method according to the invention, it is intended to
The purpose improving whole operating condition is capable of, and is therefore further able in terms of speed and quality improve production efficiency, and
And the quantity being finally rejected tablet is reduced to minimum.
From claims, detailed description of preferred embodiment and for implementing the example of following method, Ke Yiqing
More details and advantage are understood in ground by Chu.
Accompanying drawing explanation
Fig. 1 illustrates the explanatory view of the embodiment comprising module of the present invention；
Fig. 2 a illustrates the explanatory view of another embodiment comprising module of the present invention, wherein for API, excipient and
The container of product is not connected with；
Fig. 2 b illustrates the explanatory view corresponding with Fig. 2 a of the embodiment comprising module of the present invention, is wherein used for
The container of API, excipient and product is connected；
Fig. 3 illustrates the explanatory view comprising module according to a further embodiment of the present invention；
Fig. 4 illustrates the schematic overview of the quantity-produced production line for performing tablet, with the reality comprising module of Fig. 3
Execute example the most corresponding；
Fig. 5 to 7 illustrates the view of other embodiments corresponding with Fig. 4；And
Fig. 8 illustrates the perspective view of the embodiment comprising module according to the present invention.
Specific embodiment
With reference now to accompanying drawing, Fig. 1 illustrates the schematic views of the module 1 according to the present invention.Module 1 is to comprise module, term
" comprise " and will be described in further detail below.In the accompanying drawings, usually, material stream (streams of raw material, granule, tablet etc.) with
And their direction arrow illustrates, and from analyte sensors flow of information broken line representation, do not flow to instruction.At Fig. 1
Embodiment in, comprise module 1 and there are two entrances, use for the releasable inlet tube 2 of active pharmaceutical ingredient and be used for
The form of the releasable inlet tube 3 of excipient.Releasable inlet tube 2,3 and the fluid communication of mixed cell 4.In the present invention
Context in, term " mixed cell " should understand according to its widest scope.Therefore, mixed cell refers to generally
Two or more component can be mixed to form the unit operations of desired form.Such as, two kinds can be done by mixed cell
Dry component, such as powder or granule, it is mixed into mixture with required uniformity, the most generally uniform.Mixed cell can also
The physical form of the dried ingredients that enough changes process in mixed cell, such as, the raw material stream of two or more powder can turn
Change the granule including powdery components into.Mixed cell can make the granulator of granule, such as drying and granulating with dried powder
Machine or roller compaction machine.Additionally, mixed cell can include such as being dried the equipment such as agitator, continuous drying agitator.Module
Moistening granulator can also be included, as mixed cell, wherein use granulation liquid that powder is made granule.Preferably, mixing
Unit is the granulator that can produce granule with powder, such as fine powder.At any of production line, it is provided that be dried
Unit, such as fluidized bed dryer.
Can analyze from mixed cell 4 with analyte sensors 51 before being directed to the entrance of tablet press device 6
Material stream.Tablet press device 6 can be to can allow for the setting to pressure setting (such as speed, fillet height, feeder
Wheel plate speed (feeder paddle speed), packed height, pre-compression force, precommpression displacement, main compression stress and/or main pressure
Condense and put) any device of suitably controlling.The setting controlling tablet press device may relate to control compression curve, i.e.
The height of the compression stress of each tablet and width and/or shape-time graph, and/or the compression energy of each tablet.
WO2007/132281 (Courtoy) discloses an example of the method controlling this tablet press device.WO03/
Disclosing the example of the tablet press device including compression unit in 020499 (Courtoy), wherein said compression unit is removable
It is arranged in unloading in the compression section of pressure setting housing.During the two document is expressly incorporated herein by reference.Leave tablet press
The tablet of device 6 can use before being transferred into outlet (in the embodiment shown, for the releasable outlet 7 of tablet)
Analyte sensors 52 is analyzed.Although as it has been described above, this rotation tablet pressure setting is best, but using other medicines
It is also possible that sheet manufactures device.Can include that briquetting is suppressed for producing this device of tablet or the similar pill shapes of formation
Device, extruder and rolling machine, extruder and microtome, etc..
The module of the present invention includes " analyte sensors ".Any analysis sensing being suitable to given tablet forming technique can be used
Device.Analyte sensors goes for the optical analysis in electromagnetic spectrum, and analyte sensors can analyze produced tablet
Parameter, such as weight, thickness and hardness and/or chemical content, fragility, decomposes, dissolves, etc..Module can also include several
Sensor, they can be same type and different types of.Sensor is intended to analyze the material stream of tablet press device upstream
Content or character, i.e. sensor should be able to analyze multiple parameters of produced powder in principle.By measured parameter
The mass flowrate of example e.g. powder stream and volume flow rate, density, particle size, humidity, API concentration, excipient concentration,
Compressibility, flow, etc..In the module of the present invention, in the technical process that will be performed, analyte sensors is positioned at any
At stage.Such as, optical analysis sensor can be analyzed and be entered excipient or the API of module by each inlet tube, mixed
Or material in pelletization, leave the material of mixed cell, enter the material of tablet press device or leave tablet press
The tablet of device.Can also be for other parameter value analyses and leave the tablet of tablet press device, such as weight, thickness and hard
Degree.Describing a kind of suitable optical analysis sensor in International Application Serial No. PCT/IB2008/051552, the content of the document is led to
Cross with reference to being incorporated herein.Sensor for optical analysis may be embodied in " probe ", and described probe also includes other skills
Art parts, such as transmit photoconduction, receive photoconduction, measurement window, deflection mirror etc., and described probe could be included for calibration
The calibrating element of analyte sensors.Calibration can be to use the form of white balance, and described white balance uses suitable white standard school
Quasi-element, or described element can be black standard school element or other kinds of calibrating element as known in the art.
Probe can also include light source and fiber optic collector.Optical analysis can be implemented with reflection, transmission or semi-transparent semi-reflecting pattern.Make
Weight and the density of the tablet produced is measured, from this sensor with electromagnetic system (microwave or other EM spectral devices)
Information, for controlling operation and the tablet press operation of supply preparation system, can include mixing, drying and granulating, fluid bed system
Grain, moistening are pelletized and/or are completed particle by spray drying and formed.Additionally, use the analysis in the downstream of tablet press device 6
The inclusion of tablet analyzed by sensor 52 or character is able to ensure that any this feature all can be used in production technology.One example
Son is to use tablet density sensor as analyte sensors to measure the density of tablet, and its result may be used for predicting continuously
The dissolution properties of the tablet produced, and by controlling the unit operations of tablet press device upstream or controlling tablet
Pressure setting, can control the dissolution properties of produced tablet.Not only tablet density sensor can be used in controlling dissolubility
Matter, any analyte sensors also is able to for controlling dissolution properties, regardless of whether where be placed on.
The module of Fig. 1 also has control unit 8, and described control unit 8 can communicate (with void with analyte sensors 51,52
Shown in line).Control unit 8 can also be with the unit operations communication of module 1, in order to send order, thus control unit is grasped
Make device (not shown order wire).Further, module can include " data processing unit ".This term represents computer or similar
Device, it can be collected from analyte sensors (one or more) signal and be converted into the understandable number of operator
According to.The data collected by analyte sensors can show operator in any suitable manner.The conversion of data can relate to
Simple statistical analysis, or " multivariate analysis " can be used to analyze described data, such as principal component analysis (PCA), master
Quantile Regression (PCR), partial-least squares (PLS) or interval PLS (iPLS) modelling；Multivariate statistical analysis is in this area
In be known, and other technologies are the most also known.Alternatively, data are supplied to
To the external unit for processing.Control unit receives from data processing unit and/or directly or indirectly from operator's
Data or input, and send commands to the different units operation device being included in described module, such as send to activating
Device, wherein said actuator controls the connection of API and excipient container and each inlet tube and API and excipient to mixing list
The flow of unit, sends to mixed cell for controlling processing speed in mixed cell, controlling to be applied to tablet press device
The flow of material and tablet compression speed (such as, rotate the swiveling head speed of tablet pressure setting), and such as send to control
The actuator of the connection between product container processed and outlet.Control unit can be for example suitable for controlling compression curve, independent of
Pressing speed.Alternatively, control unit may be adapted to control compression energy, independent of pressing speed.Control unit can also be controlled
The analyte sensors of molding block, such as, control when and where to implement the definite class of the analysis analyzed and implemented
Type.It is contemplated that data processing unit and control unit to be integrated into a unit；This integrated unit can be referred to as unchangeably
" control unit " so that indicating unless there are other, control unit belongs to the ability of above-mentioned data processing unit by also having.?
In the case of pharmacy manufacturing process, optics or electromagnetic method are suitable to analyze solid, granular materials.Based on such as powder, block material
Flash ranging, spectrophotometric or the graphical analysis of material, granule etc., these methods can be used directly on material, and suitable analysis is visited
Head can be integrated in manufacture equipment.Suitable optics or electromagnetic spectrum are analyzed the example of method and are included reflection/transmission or half
The fluorescence (LIF) that half anti-(UV, VIS, NIR, IR), fluorescence or laser cause thoroughly, biological or chemiluminescence or Raman light
Spectral method.Optical analysis is also suitably for fluent material.The speed controlling pressure setting means to change tablet press dress in principle
The rotary speed of the swiveling head put；It is also contemplated, however, that the interval being included in present disclosure in " speed controlling " concept
Operation.
In order to the difference between assessment parallel parsing and more value obtained traditionally, it is also possible to friendship is set in the module
Confirm sampler mutually.Cross-validation sampler may relate to the supplementary set of the connection similar with those described above so that sample can be by
Extract, without removing described module or even interrupting the technical process implemented in the module.The company of cross-validation sampler
Connect and will connect with material stream, thus analyzed for cross-validation；Such as, made at gravity by pipe or wiper etc.
With the help of or by pipe produce negative relative and allow material to be extracted.By providing mutual card by this way
Real sampler, can analyze the sample identical with in subsequent analysis analyzed in the module based on cross-validation sampler.
Leak tightness (containment) in tablet compression becomes the focus of attention a lot of year, is due to people
Have become increasingly aware of in the efficient material that operator is exposed to frequently involve in pharmaceutical field and can there are potential risks.Such as
Expose data and can be tested (standardization of the concentration of the airborne particles of equipment is measured) assessment by SMEPAC.SMEPAC is
It is included in ISPE guide " the granule leak tightness performance of estimation pharmaceutical equipment " (ISBN:1-931879-35-4).The present invention's
In content, term " comprise " mean in technical process use, for being formed tablet by such as API and excipient powders
Unit operations comprises in the module, is therefore isolated with surrounding.Therefore, during operation, operation need not directly
Accessing individual unit operation device, it can be accessed by each releasable inlet tube and outlet.Similarly, module is airtight
The fact mean module can be operated, without other unit operations, it can be considered as API and excipient quilt
Being carried at front end the single integrated carriage in the case of (that is, releasable inlet tube at), then it will be in rear end
(that is, releasable outlet) transmits tablet.Term " module " shall be interpreted as representing single and comprises structure or framework so that
The unit of the front baffle of rear installation can assemble and tested.So, transmit and last installation becomes more simply, more
Add cost-effective.Unit operations or parts can be installed into the frame structure of carriage shape.These unit operate
Device frame is molectron, it is possible to depends on Production Line Configured and is connected to each other.Framework can move from a processed room
To another processed room, or move to another processing workshop from a processing workshop.Comprise the flexible of module
Property so that it can be designed and configured to as portable unit, can easily with pharmaceutical factory existing production line integrated.
Required leak tightness level depends on the toxicity of API, and equipment also should be chosen therefrom.In theory, close to zero leak tightness
Level is possible, but is likely to only by whole tablet press device is put into such radical side in isolating device
Method could realize.But, processing this isolated location needs the larger numbers of time, is used for dismantling, clean and re-assemblying, this
The long downtime that cannot receive can be caused again.In reality, following such level selects required leak tightness water
Flat: to comprise or dust seal (10-100mcg/m3), de-luxe compartment contains (1-10mcg/m3) and always comprise (＜ 1mcg/m3).Further,
According to the required horizontally selected suitable equipment of leak tightness.In present context, term " comprises " to be tested according to SMEPAC
Or any corresponding suitably measure, limited by its leak tightness level, and be therefore defined as according to standard determined above
At least dust seal.
To the access comprising module during being operated by entrance and exit offer, described entrance and exit can use appoints
The form what is suitable.In illustrated above and described embodiment, releasable outlet and product (such as, tablet) can be from
Releasable outlet obtains.In this case, " releasably " means that each inlet tube and outlet are substantially closed, but can
With opening to respectively allow for applying API and excipient to module or removing tablet from module.Preferably, releasable entrance
Pipe is designed such that each releasable inlet tube includes pipe connections, it is allowed to described pipe connections is connected to complementary connection, makes
When the connector of proper inlet tube is connected with complementary connection, releasable inlet tube is by open to the outside world.Complementary connection can be arranged
At the container for API or excipient；The container being consequently for API or excipient can be by the complementation on container
Connector and the connector of each inlet tube and be connected with each inlet tube.This is by by instantly open inlet tube suitably
Allow to apply to module API or excipient.Similarly, outlet can also include that a connection piece, described connector can lead to
Cross the complementary connection on a container of the product for leaving module via outlet and be connected.The connector of inlet tube
And the complementary connection on a container can be with the connector of another inlet tube and each on another container thereof
Complementary connection is different so that the such as container for API only can be connected to the inlet tube for API, and excipient container is only
Being connected to the inlet tube for excipient, similarly, the connector of outlet and the complementary connection on product container thereof can
With different from the connector of any entry pipe or two inlet tubes.It is beneficial that, it should allow module to be opened, with bag
The mode contained is cleaned so that parts can be removed safely, to be carried out, and replaces with the parts of cleaning rapidly
Change, produce to allow unit to restart within the shortest time of putting into practice, relevant to tradition CIP with generation without postponing
Expense.
Fig. 2 a and 2b illustrates the embodiment of module, wherein the inlet tube of module 1 and outlet all include connector 21,31,
71, for the complementary connection 21 being connected to be positioned on each container 91,92 and 93 of API, excipient and tablet, 32,
72.Releasable inlet tube or outlet connector preferably employ the form of so-called seperating vale, and described seperating vale has two couplings
Valve member, the butterfly valve such as separated.Such connector allows sealed tube or mouth passage, is subsequently isolated two valve portions
Part, thus each in two matching valve components keeps its corresponding valve member to close described valve opening, and practice is not appointed
What product is leaked in environment.The suitable example of seperating vale be by GEA Pharma Systems AG (Switzerland,
Bubendorf) trade name " Buck sold" seperating vale.Often group connector and complementary connection 21&22,
The type of the butterfly valve that 31&32,71&72 preferably separate, such as Buck Valves.Fig. 2 a schematically illustrates and separates with module 1
The container 91,92,93 opened, and container 91,92,93 is shown connected to module 1 in figure 2b, thus allows API and excipient
Pass to module 1, and allow tablet to leave module 1.
Fig. 3 illustrates another embodiment of the module 1 of the present invention.In this embodiment, module 1 is designed for two kinds of differences
Excipient so that when complementary connection 32a is mated with connector 31a, first excipient can from container 92a enter module
1.When complementary connection 32b is mated with connector 31b, another kind of excipient, such as lubricant (such as, magnesium stearate) is permissible
Module 1 is entered from container 92b.Another kind of excipients is as by funnel and the material stream (example of leaving initial mixing unit 41
Granule such as, API with first excipient) together be sent to another mixed cell 42.Material stream from mixed cell 42 is entering
Analyte sensors 53 is used and analyzed before entering tablet pressure setting 6.
Module is not limited to any concrete API, and API can be dry (such as powder or granule) form, or API is permissible
It is liquid form, such as solution or the natural API for liquid.Module is not limited to single API, and module can include for difference
Several inlet tubes of API, for producing the controlled release tablet that can discharge different API simultaneously or continuously.Similarly, figuration
Agent can be powder or particle form, or solution or liquid form.The example of normally used excipient includes anti-stick
Attached dose, binding agent, coating, disintegrant, filler and diluent, spice, pigment, fluidizer, lubricant, preservative, adsorbent and
Sweetener.The object lesson of different types of excipient is well known in the art.
The module of the present invention is not limited to use in the single inlet tube of API and for the single inlet tube of excipient.Can also
Expecting, module includes the inlet tube for API and the multiple inlet tubes for different excipient, such as institute in the embodiments of figure 3
That describe and as indicated in the general survey of the production line of Fig. 4.Module could be included for several entrances of different API
Pipe.Similarly, module can include the several mixed cells being positioned in production line as needed.Such as, module can include
Inlet tube for API and the entrance for the first excipient (such as binding agent, filler, diluent, spice, pigment etc.)
Pipe, described inlet tube is such as by funnel and the fluid communication of the first mixed cell.Then, this module can include for
Another inlet tube of second excipient (such as, lubricant), the described inlet tube being used for the second excipient and the second mixed cell
Fluid communication.The outlet of the first mixed cell can also be with the fluid communication of the second mixed cell, in order to
The exit of two mixed cells obtains the material (that is, API and the first excipient) from the first mixed cell and the second excipient
The mixture of (such as, lubricant).The entrance of the second mixed cell can include leak or the like, mixes from first to receive
Close the material stream of unit and from the second excipient of its inlet tube.Then material stream from the outlet of the second mixed cell may be used
With the fluid communication with tablet press device, to be produced medicine by the mixture of API and the first excipient and the second excipient
Sheet.Tablet press device is in fluid communication with the outlet for tablet by the outlet of tablet press device.Module can include
It is positioned for analyzing the analyte sensors of the material stream in the outlet of any mixed cell and being positioned for analyzing in tablet pressure
The analyte sensors of the tablet produced in device processed.
Thus, for API and/or the inlet tube of excipient and the mixed cell relative location-dependent query in production line in
The function of given excipient.Specifically, another kind excipient introducing production line can be considered with API and first excipient at mould
The stage processed in block wishes the effect that another kind of excipient is had when comparing.Typically, entering for another kind of excipient
Mouthful pipe is introduced into the excipient in mixed cell downstream so that excipient can with in the material stream of mixed downstream unit
Mixture (such as, the homogeneous mixture) mixing of API and first excipient；Then, the heel of the introducing point of another kind of excipient
With another mixed cell, in order to the mixture of another excipient with API and first excipient is mixed.API when more than one
It is introduced into production line, such as, (such as, discharges the controlled of multiple API when hope produces the tablet including more than one API simultaneously
Release tablet, or the controlled release tablet (such as, multilamellar tablet) of the API of release difference continuously), identical consideration can be applied
Factor.
Module can be set up in the room in a building, or is designed in the container of this purpose.Module has institute
The connector (such as mains connection) of need, controlled atmosphere/ventilation, CIP (original place cleaning), possible granulation liquid, etc..Close
Cleaning in module, it is possible to clean concurrently, online or off-line, this will according to comprise module concrete application and
See which kind of mode is the most favourable.Module can airtight in a limited space, but the concept of " leak tightness " includes that design technology sets
Standby all parts makes it airtight, in general establishes " module " comprising in meaning.
Module can also according to given tablet forming technique process need include other unit operations.Such as, unit behaviour
Make device can be included to be dried the component introducing module, or include feeder, for component being operated from a unit
Device moves to the next one.Other relevant unit operations are grinder, compacting machine, etc..
Therefore, comprise module and can be considered one piece apparatus, it is allowed to the entrance of API and excipient is in an end, and
The outlet of tablet is in another end.Preferably, one piece apparatus includes that the surface physics comprising module limits or boundary.This limit
System may can be carried out with the pipeline of the specific adaptation between the unit of module for example with the form of the valve of above-mentioned design
Supplement.
With reference now to Fig. 4 to Fig. 7, description is used for performing described method and combines the module that comprises according to the present invention
It is contemplated that example.Do not point out one or more analyte sensors that the specific location in including module exists.It is only
Formed a part for production line by the unit shown in reference, for simplicity reasons, other unit are maintained at each accompanying drawing 4
In 7.
As shown in Figure 4, module 1 is designed for two kinds of different excipient so that first excipient can be together with API
Module 1 is entered in the porch passing to module, and processed in the first mixed cell 41, and the first mixed cell 41 is continuous
It is dried the form of agitator (CDB).Another excipient, such as lubricant (such as magnesium stearate), can enter module 1 and with
The material stream leaving initial mixing unit 41 is brought into another mixed cell 42 together, and another mixed cell 42 described can use
The form of continuous drying agitator.Material stream can be the most analyzed, and can enter tablet press
Device 6 is the most analyzed in any suitable position.
Replace guiding to another mixed cell 42, shown in Fig. 5 the material stream directly from initial mixing unit 41
The material stream of production line is conducted through roller compacting machine 43, and described roller compaction machine 43 enters another mixed cell 42 at material
Compacting material before.
Alternatively, mixed cell includes double spiral agitator 44 (TSB), as shown in Figure 6, enters module by entrance
The material stream of API and excipient is directed to described double spiral agitator 44.Double spiral agitator 44 followed by Double helix system
Grain machine 45 (TSG), for pressure material stream further.After this operation, material stream is directed to stage drying device 5 and enters one
Step guides to grinder 46.Another kind of excipient, such as lubricant (such as, magnesium stearate), enter at this point module and
Moved together with existing material stream, this mixture supply to before tablet press device 6 at little batch agitator
It is stirred in 47.
In further alternative embodiment, as it is shown in fig. 7, the material stream of API and excipient by together with bring initial mixing list into
In unit 41 (form of continuous drying agitator), then it is taken to Double helix granulator 45 and (therefore, does not pass through double spiral agitator
44), and further by exsiccator 5, grinder 46, little batch agitator 47, then to tablet press device 6.
In following content, the operation that comprise module 1 according to the present invention be will be further described.
" continuous print " means that technical process in the module operates in close to steady statue or is in steady statue
Under the conditions of carry out, described steady statue represents: the rate of application (expressing with mass unit) of API and excipient substantially with tablet
Throughput rate (similarly, with mass unit express) identical.But, rate of application and throughput rate are without need for given work
Skill process is identical all the time, can be adjusted as required.When for the container of API or excipient be empty time, should
Container can disconnect with its each releasable entrance, replaces with full container, without interrupting described technique.Equally
Ground, if product container is full, then can also replace with empty container, without interrupting described technique, the most releasably
Inlet tube and releasable outlet allow module to operate continuously.Another vital factor in totally continuous operation
It is the speed controlling tablet press device according to upstream units operating parts.This means to enter mould by API and excipient entrance
The raw material of block is processed with any suitable speed in the one or more mixed cell, is compacted, is dried, etc..Upper
In trip technical process, perform analysis, control and adjust, arrange in standard for any of final tablet so that powder stream is brought into.
Speed at the powder of the entrance of supply to tablet press device reduces due to the parameter adjustment of such as pressure setting upstream
In the case of, the speed of tablet press device thus reduces, and vice versa.In the porch of tablet press device, the institute of powder stream
There is parameter therefore in standard is arranged.As a result, whole module and production line can wait further processing
The amount of accumulated material be to run, i.e. in the case of surge volume is minimum in the case of minimum.With big surge volume phase
Shortcoming and the thing followed back-mixing problem of association are mitigated or even eliminate such problem.Minimize surge volume
And alleviate back-mixing problem make whole product on production line follow the tracks of ability such as can be by time stamp so that further combined with
Tablet data and for manufacture specific tablet or tablet subset powder data and by described tablet data be used for making
The data of the powder making specific tablet or tablet subset associate.Tablet data and correct tablet data associate so that
Technical process can be better understood from.
The method implemented in the module of the present invention under any circumstance can be by control unit control.Such as, list is controlled
Unit can comprise the sequence of events of pre-programmed, or control unit can pass through operator's manual operation, to control each technique
Step, or manually combine with preprogrammed operation.It is preferable, however, that control unit is programmed, process list to use from data
The data of unit control technological parameter with the operation of " feedback " type or the operation of " feedforward " type.It is therefoie, for example, can pass through
The analyte sensors analytical parameters of specific process step downstream or upstream so that data processing unit can send the signal to point
The upstream of analysis point or the unit operating parts of the step in downstream, in order to based on the data processing step from sensor.Then, to dividing
The adjustment of the processing step in analysis point upstream or downstream can cause again analysis site downstream or the adjustment of the processing step of upstream, in order to
Monolithic stability state is kept in technical process.So, the technical process of module can be controlled, produced in the module to obtain
The high-quality of tablet.As a result, control to make to use according to the module of the present invention to be obtained by mathematical model by said method
The information arrived.This includes such as predicting dissolving, the most continuously or " being similar to " provides feedback directly in technical process continuously
Step, including pelletizing, being dried and tabletting.From tablet press device information such as Weight control change, with feedback and
Adjust the character of granulating process.From the information of tablet press device, such as ejection force, may be used for controlling the interpolation of lubricant
And mixing.Be may be used for adjusting the setting of tablet press device by the information pelletized and drying steps gets, such as feeder sets
Put and compression curve.Pressure roller compensates system and may be used for so that compression curve is controlled, and unrelated with tablet press device.
Continuous process according to the present invention can run the time period of an elongated segment, such as 60 hours or more
Many.Therefore, control unit can also include timing means, and the module with analyte sensors can have properly programmed control
Unit, for performing so-called automatically analyzing according to predetermined arrangement.Then, control unit can use from analyte sensors
Data, not adjust the bar keeping desired by processing step being adjusted or is suitably kept by technological parameter
Part.Analysis of history that control unit can also record technical process and the history of any adjustment carried out in technical process.
Below with reference to Fig. 8 describe according to the embodiment comprising module of the present invention it is contemplated that of setting show
Example.In full comprising in module by 1 sign, it is shown that initial mixed cell 41, with the entrance stream for API and excipient
Body connects, and uses the form of powder funnel.Comprise module 1 and also include feedway, such as Double helix feeder.Mixed cell can
To be typical case ConsigmaTM(Collette), it is the company being designed for piston flow (that is, advanced, first go out the operation under principle)
Continuous high shear granulation and drying system, thus avoid above-mentioned undesirable back-mixing.Further, comprise module 1 and include segmental fluidized bed
Exsiccator 5.Mixed cell 41 may be mounted on column lifter (post hoist) as shown, to allow the most manually to add
Carry powder, then rise on exsiccator, be supplied in exsiccator directly vertically, under gravity.Alternatively,
ConsigmaTM(or other mixed cells) can be placed on following, supplies with bigger powder IBC and pneumatic moistening transporter
It is given in exsiccator 5.Reference 46 represents grinder, is provided with assessment unit (not shown), and is also provided with little
Batch agitator (for illustrating), to add magnesium stearate or other lubricants or other excipient.Finally, module 1 is comprised
Including tablet press device 6.The shown layout comprising module is the single building planar configuration of level, including between the various elements
Pneumatic conveyor.It is alternatively possible to use vertical configuration, replace pneumatic conveying by gravity for transport.
The present invention should not be construed as limited to the above embodiments.Several change embodiments and combination it is believed that
In scope of the following claims.
Claims (14)
1., for producing a module for tablet, described module includes:
At least one entrance for active pharmaceutical ingredient or API；
At least one entrance for excipient；
At least one mixed cell；
At least one analyte sensors；
Tablet press device；And
At least one outlet for tablet；
The fluid communication of described entrance and at least one mixed cell described, the outlet of at least one mixed cell described with
The fluid communication of described tablet press device, and the outlet of described tablet press device with for the described outlet of tablet
Fluid communication；
It is characterized in that,
Described module is airtight；
At least one analyte sensors described is positioned for analyzing inclusion or the character of the upstream of described tablet press device；
And
Described entrance includes the releasable inlet tube (2 for active pharmaceutical ingredient or API；21) releasable with for excipient
Inlet tube (3；31；31a；31b), described outlet includes the releasable outlet (7 for tablet；71) so that each inlet tube
Normally closed with outlet and can open respectively to allow API and excipient to be applied to described module or from described
Module removes tablet, described releasable inlet tube and described mixed cell (4；41；42；43；44；45；46；47) entrance fluid
Connect, and the outlet of described tablet press device (6) is in fluid communication with the described releasable outlet for tablet.
Airtight module the most according to claim 1, wherein, described module has less than 100mcg/m3Leak tightness water
Flat, preferably shorter than 10mcg/m3Leak tightness level.
3., according to airtight module in any one of the preceding claims wherein, also include control unit (8), described control unit
It is able to receive that the data from described at least one analyte sensors (51,52,53).
Airtight module the most according to claim 3, wherein, described control unit (8) is suitable to send a command to for API
And/or the entrance of excipient and/or send a command to mixed cell (4；41；42；43；44；45；46；47) and/or send order
To tablet press device (6).
Airtight module the most according to claim 4, wherein, described control unit is suitable to control described tablet press device
Speed.
6. according to airtight module in any one of the preceding claims wherein, wherein, described analyte sensors is spectrum analysis
Sensor.
7. according to airtight module in any one of the preceding claims wherein, the mixed cell that also includes adding (41,42,43,
44,45,46,47).
8., according to airtight module in any one of the preceding claims wherein, also include drying unit (5).
9. according to airtight module in any one of the preceding claims wherein, wherein, at least one analyte sensors described is fixed
Position to the described porch of described airtight module and/or be positioned at the porch of the one or more mixed cell, and/
Or be positioned at one mixed cell or the exit of the plurality of mixed cell, and/or it is positioned at described tablet press dress
The porch put.
10. according to airtight module in any one of the preceding claims wherein, wherein, described airtight module is designed to single-piece
Equipment, preferably includes physical restriction or the boundary at the interface of described airtight module.
11. 1 kinds, for the method producing tablet continuously, comprise the following steps:
Airtight module, described airtight module is provided to include at least two entrance, at least one mixed cell, at least one point
Analysis sensor, tablet press device and at least one outlet for tablet；
Active pharmaceutical ingredient or API are supplied to described at least two entrance；
By another in excipient supply to described at least two entrance；
In at least one mixed cell described, mixing includes the material stream of API and excipient；
Use and measure comprising of described material stream at least one analyte sensors described in the upstream of described tablet press device
The parameter of thing；
In response to measured state modulator said two entrance and/or described mixed cell；
Material stream is continuously fed to described tablet press device；
The speed of described tablet press device is controlled in response to the parameter measured by the upstream at described tablet press device；With
And
Tablet is discharged at least one exit described,
Wherein, described entrance includes the releasable inlet tube (2 for active pharmaceutical ingredient or API；21) with for excipient
Releasable inlet tube (3；31；31a；31b), described outlet includes the releasable outlet (7 for tablet；71) so that each
Inlet tube and outlet normally closed and can open respectively with allow to be applied to API and excipient described module or
Tablet, described releasable inlet tube and described mixed cell (4 is removed from described module；41；42；43；44；45；46；47) enter
Mouth is in fluid communication, and the outlet of described tablet press device (6) is in fluid communication with the described releasable outlet for tablet.
12. methods according to claim 11, thus perform another blend step, are wherein supplied by another kind excipient
In existing described material stream.
13. according to the method described in claim 11 or 12, thus by described material stream supply extremely described tablet press device
Perform drying steps before.
14. according to the method according to any one of claim 11 to 13, from there through the downstream of described tablet press device
At least one analyte sensors measures inclusion or the character of described tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610570625.0A CN106109251A (en) | 2009-05-07 | 2009-05-07 | Tablet produces module and for the method producing tablet continuously |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610570625.0A CN106109251A (en) | 2009-05-07 | 2009-05-07 | Tablet produces module and for the method producing tablet continuously |
| CN2009801590959A CN102438578A (en) | 2009-05-07 | 2009-05-07 | Tablet production module and method for continuous production of tablets |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801590959A Division CN102438578A (en) | 2009-05-07 | 2009-05-07 | Tablet production module and method for continuous production of tablets |
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| CN106109251A true CN106109251A (en) | 2016-11-16 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61133131A (en) * | 1984-11-29 | 1986-06-20 | Kyowa Hakko Kogyo Co Ltd | Compression molding machine provided with device for feeding fixed amount of particulate matter and mixing |
| CN1390120A (en) * | 1999-10-13 | 2003-01-08 | 协和发酵工业株式会社 | Compression molded product and production method therefor |
| WO2007107500A1 (en) * | 2006-03-20 | 2007-09-27 | Powder Systems Limited | Coupling assembly |
-
2009
- 2009-05-07 CN CN201610570625.0A patent/CN106109251A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61133131A (en) * | 1984-11-29 | 1986-06-20 | Kyowa Hakko Kogyo Co Ltd | Compression molding machine provided with device for feeding fixed amount of particulate matter and mixing |
| CN1390120A (en) * | 1999-10-13 | 2003-01-08 | 协和发酵工业株式会社 | Compression molded product and production method therefor |
| WO2007107500A1 (en) * | 2006-03-20 | 2007-09-27 | Powder Systems Limited | Coupling assembly |
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Application publication date: 20161116 |