The present invention concerns a process as well an apparatus/system for enabling the packaging of a powder, in particular an API, in a contained and GMP manner, without the requirement of a clean room around the filling area. Furthermore, the present invention concerns the use of an apparatus, and process, for pharmaceutical powders and/or for specific pharmaceutical packaging processes.

The aim of the invention is to set out a process and an apparatus, with which powder, preferably pharmaceutical powder, can be packaged in at least approximately clean room conditions, without the need to set up the proposed apparatus in a clean room.

With regard to the process this aim is achieved with the features of claim 1 and with regard to the apparatus with the features of claim 11. Advantageous further embodiments of the invention are set out in the sub-claims. The framework of the invention includes all combinations of at least two of the features disclosed in the description, the claims and/or the figures. In order to avoid repetition, features disclosed in relation to the process should also apply and be claimable in relation to the apparatus. Equally, features disclosed in relation to the apparatus should also apply and be claimable in relation to the process .

More particularly, a process is claimed according to the appended claims, which can be read in connection with the enclosed process description. While the enclosed claims claim a set of steps, this does not limit the scope of the invention, rather, protection is sought for each combination of two or more process steps that may become obvious from the enclosed process description. The full disclosure (description, claims and figures) of the European patent application with the application reference number EP 0 801 793 2.8, the priority of which is being claimed, should apply as forming part of the disclosure of the present application, in particular ^" in that at least any one feature of the present application should be combinable and claimable with any one feature of the present application and/or EP 0 801 793 2.8.

The invention is based on the concept of using a DCS (drum containment system) glove box, also claimed as an apparatus, for filling a powder with a mean particle diameter in a range between around 10 μm and around 1000 μm. This is taken to mean an apparatus which has a lower section for holding a drum comprising a first bag, and an upper section, which can be reached into manually with the aid of at least one, preferably with the aid of four, more particularly detachable sealed gloves in order, as will be explained later, to close a second bag and the first bag surrounding the second bag. Ideally the powder to be filled is exclusively in contact with the second bag and the first bag forms a second protective covering, where by the first bag and the second bag are surrounded by the apparatus, which than forms an overall protective covering and/or barrier, preferably exposed to an under pressure (negative pressure) and/or an over pressure (positive pressure) .

The process and device are particularly suitable for filling powder, more particularly API powder, with a particle size of between 1 and 1000 μm. Preferably the density of the poured powder is between 0.1 and 1 kg/dm ³ .

It is particularly preferable if a dosing device forms part of the apparatus, as described, for example in WO 2007/088022 Al by the applicant. The dosing device is preferably arranged in such a way that from it, emerging more particularly as a result of vibration, powder within the DCS glove box can flow into the second bag formed by the hose-like continuous liner. The content of the disclosure of WO 2007/088022 Al should, with regard to possible advantageous embodiments of the dosing device, apply as disclosed as part of the subject matter of the present application.

Preferably the dosing device operates on a low pressure basis in order to attract powder by way of suction. The unloading of the powder/filling of the second bag preferably takes place by way of vibration, which allows precise dosing of the powder. It is particularly preferable if a dryer is arranged upstream of the dosing device, from which the powder is transferred into a mill, more particularly an online conical mill, which is preferably arranged above the PTS feeder. From the mill the powder is then sucked in by the dosing device. The core of the process is that the powder is filled into a continuous liner, from which the second bag, surrounded by the first bag, is formed by the closing and separation of the remaining continuous liner. It is particularly preferable if the device comprises at least one inlet and/or at least one outlet volatile particle filter, more especially an HEPA particle filter, in order to avoid contamination of the surrounding area and/or the interior of the apparatus .

The process in accordance with the invention comprises the following steps:

Initially a first bag of flexible packaging material is provided, preferably within a drum, more particularly through insertion of the drum into the lower section of the DCS glove box. It is particularly expedient if doors corresponding to this are provided and the lower section of the DCS glove box is closed on all four sides after closing the doors. Alternatively the lower section is realized without doors, preferably with the front side open. Preferably, after opening the drum the first bag is attached on a lower outlet, which projects into the lower section of the DCS glove box starting from the upper section. For this the operating gloves of the upper section of the apparatus are used.

Thereafter, the continuous liner, closed at its lower end, is passed from the upper section of the DCS glove box through the lower outlet thereof into the first bag so that a second bag is provided within the first bag preferably located within the drum. The second bag is then filled with the powder, very particularly preferably via an upper outlet in the upper section of the DCS glove box. Placing the second bag into the first bag preferably takes place manually by way of the gloves, but alternatively can take place automatically through starting the filling procedure. Particularly preferably a dosing device, as described in said PCT application, is used for filling/dosing. After the filling procedure the second bag is closed and separated from the remaining continuous liner, which preferably has already been closed again at its lower end. The first bag, which fully surrounds the second bag, is then closed, and preferably closing of the optionally provided drum in the lower section of the DCS glove box takes place before the first bag and the second bag, preferably together with the drum, are removed from the lower section of the DCS glove box, preferably through a, preferably lateral, outlet door which differs from the inlet door. Preferably, for facilitated removal of the drum, a roller mechanism is provided.

The invention also relates to an apparatus, i.e. a DCS (drum containment system) glove box, for implementing the process described above. The apparatus is characterised by an upper section, comprising at least one pair of gloves, in which by way of the at least one pair of gloves, which is preferably permanently, but in a replaceably connected in a sealing manner with a housing, intervention can take place, and a lower section, in which a first bag, preferably arranged within a drum, can be accommodated. It is particularly expedient if the apparatus comprises a dosing device as described in the previously cited PCT application. It is particularly expedient if the lower connection, to which the first bag can be attached, is the only connection between the upper section and the lower section, with the continuous liner being passable from the upper section through the lower connection into the lower section. Preferably, the, more particularly, tubular lower connection is within a partition wall which isolates the upper section from the lower section.

In the event of a fault or damage to a continuous liner forming the second bag the DCS glove box prevents contamination of the product and allows the continuous liner to be replaced. The proposed apparatus, more particularly at least the upper section, preferably exclusively the upper section of the DCS glove box is, in a further development of the invention, connected to an air circulating system, which is designed so as to guarantee a high rate of air exchange. Preferably the air flows through volatile particle filters, more particularly HEPA filters, and particularly preferably at a volumetric flow of 100 NmVhour, which preferably corresponds to a gas exchange rate of 5 to 10 times per minute (depending on the volume of the upper section) . The high rate of gas exchange also prevents powder remaining in and being contaminated in the upper section and thereby guarantees additional product protection.

It is particularly expedient if, at least during the filling procedure, there is a slight over pressure within the upper section of the DCS glove box, which prevents air entering the system from outside, as a result of which the product is optimally protected. Especially in the case of filling highly toxic products, instead of bringing about a positive pressure, it can, however, be preferable to implement a negative pressure, in relation to the atmosphere, within the upper section in order to thereby rule out contamination of the surrounding area and endangering operating personnel.

It is particularly expedient if the lower section of the DCS glove box is surrounded by three side walls, more particularly arranged perpendicularly to each other, whereby in at least one side wall, preferably in the front wall, doors are provided. Alternatively the front side is open permanently. It is very particularly expedient if the rear side of a perforated plate, connected to a fan with volatile particle filters, more particularly HEPA filters, is sealed, whereby the fan is arranged and designed so that at least during removal of the drum lid and the connection of the first bag with a lower connection of the DCS glove box, an high pressure predominates. An over pressure is also preferred when dividing/separating the first bag. Particularly preferably the air flows at a maximum rate of 0.5 m/sec. Alternatively the lower section can be realized without means for providing over pressure or under pressure.

Particularly preferably the system is CIP-capable and can therefore be cleaned by means of a CIP.

Advantageous further developments of the method and apparatus are set out in the following description of preferred examples of embodiment as well as the drawings. The figures, with the accompanying descriptions, should not only form the entirety of the disclosure content, but individual figures with the accompanying description should also serve as independent disclosure sources. The figures show in

Fig. 1 to Fig. 23 Process steps of a preferred form of embodiment of a process in accordance with the concept of the invention.

Fig. 24 to

Fig. 43 A preferred method (process) for replacing and/or renewing a continuous liner

Fig. 44 A variant of embodiment of the apparatus in which both within the continuous liner as well as within the upper and lower section of the DCS glove box a high pressure is produced.

Fig. 45 An alternative embodiment variant in which there is a high pressure in the continuous liner and in the lower section of the DCS glove box, and a low pressure in the upper section outside the continuous liner

(each in relation to atmospheric pressure) .

Fig. 46 A table setting out the advantages resulting for a combination of any two barrier features for the form of embodiment in accordance with fig. 44.

Fig. 47 A table analogue to fig. 46 for the form of embodiment in accordance with fig. 45.

Fig. 48a to 48c Various views and details of a partially incompletely illustrated DCS glove box.

Fig. 49 An overall system, comprising a DCS glove box for filling powder. In the figure the same elements and elements with the same function are marked with the same reference symbol.

In fig. 2 a DCS glove box (hereinafter apparatus 1) is shown. This comprises an upper section 2 and a lower section 3 adjoining it. The lower section 3 is isolated/hermetically sealed off from the upper section 2 by means of an essentially horizontally orientated partition wall. Within the upper section 2 there is a schematically shown waste container 5. In the upper section 3, gloves 6 (operating gloves) , which are only partially shown, project into openings provided in the housing and are detachably arranged on the housing 7. In the illustrated example of embodiment on each of two sides facing away from each other there is a pair of such gloves, which are made of flexible material.

On the front of the apparatus in the plane of the drawing there are two pivoting doors for opening and closing the lower section 3 so that a drum 8 with a first bag 9 can be inserted into the lower section 3 from the front side, using a lift mechanism 10 for lifting the drum 8 with the first bag 9. Alternatively there are no doors on the front side. Preferably then the front side is permanently open.

Passing through the partition wall 4 is a lower outlet 11 (connection) to the outer circumference of which the first bag 9 can be attached. The lower outlet 11 is the only connection between the upper and the lower section 2, 3.

At a distance from the lower outlet 11 is an upper outlet 12 (connection), which projects into the upper section 2. Via the upper connection 12 the powder to be filled can be supplied, preferably by a dosing device, which is not shown, more particularly a PTS feeder. _ g -

The free end 13 of the upper outlet 12 is surrounded by a continuous liner 14 which is closed at the bottom. To close the continuous liner 14 a clip 15 or a cable binder is provided. By closing the continuous liner 14 a second bag 16 is formed from the continuous liner 14 in a lower section into which the upper outlet 12 projects.

The upper outlet 12 is surrounded by a tubular bearing structure 17 on the outer circumference of which the folded continuous liner, which preferably when unfolded is of a length of between 10 and 50 m, preferably around 30 m, is held by means of a, more particularly elastic, clamping ring.

In order to fill the first bag 9, the drum 8 is initially inserted from the front side into the lower section 3, which is delimited by three side walls, a base and the partition wall 4. A lid 18 of the initially closed drum 8 is opened within the lower section 3, as indicated in fig. 1, and parked in a corresponding holder, which is not shown.

Thereafter, as shown in fig. 3, an opening 19 of the first bag 9 is attached to the lower outlet 11, namely in an upper position 20 (cf. fig. 3) by means of an O-ring 21, with which the first bag 9 is attached to an upper circumferential groove 22. The upper position 20 is above the lower position 23 on the lower outlet 11, to which a remainder 24 of an already re-closed first bag is attached by means of an O-ring 25 in a lower circumferential groove 26. The new first bag 9 therefore also surrounds the remainder 24 of the preceding first bag.

After attaching the new first bag 9 to the outer circumference of the lower, tubular outlet 11, more specifically in an upper position 20, even more specifically in an upper circumferential groove 22 by means of the 0-ring 21, the situation as shown in fig. 4 is achieved.

In the next step of the process the drum 8 and with it the first bag 9 are moved by means of the lift mechanism 10 upwards in the plane of the drawing in the direction of the partition wall until an upper circumferential edge 27 of the drum 8 is in contact with the lower side of the partition wall 4. The previously described process is shown in both figs. 5 and 6 jointly. Preferably the, not shown, front doors are only closed now so that the lower section 3 is screened off from the outside environment. Alternatively the lower section is provided without front and/or side doors.

Joint consideration of figs. 7 and 8 shows that the remainder 24 of the preceding first bag 9 is removed with the aid of the gloves through the lower outlet 11 upwards into the upper section 2 and then transferred to the waste container 5, so that there is now a direct connection via the lower section 11 between the upper section 2 and the first bag 9.

As can be seen in fig. 9, in a lower section the continuous liner 14 is pressed from outside against the bearing structure 17 by means of an inflatable gasket 28. The upper end 29 of the folded continuous liner 14 is pressed against the bearing structure 17 by means of an 0-ring sealing. In the process step in accordance with fig. 9 and 10, gas, more particularly air, is released from the inflatable gasket 28 so that the continuous liner 14 can, by means of the gloves within the upper section 2, as shown by the arrow 31, be pulled downwards and inserted into the first bag 9 through the lower outlet 11, which is in axial alignment with the upper connection 12. A second bag 16 is therefore provided within the first bag 9, as can be seen directly in fig. 12. After the second bag 16 has been transferred into the first bag 9 the inflatable gasket is inflated again whereby the inflatable gasket 28 again presses from outside on the continuous liner 14 forcing it against the bearing structure 17, as a result of which contamination of an area above the inflatable gasket 28 can be reliably prevented.

In a next step of the process, shown in fig. 13, the first bag 9 is filled with powder 32. Below the lift mechanism 10 there are scales 33 which are connected with a control unit of the dosing device 34 in such a way that the dosing unit 34 feeds powder through the upper connection 12 until the required target weight is achieved. The dosing device 34 is connected to a low pressure line 35 for attracting powder through suction. Via a filter element 36 contamination of the low pressure line 35 is prevented. Preferably the filter element 36 can be cleaned by means of surge pressure. The dosing device 34 comprises a pump chamber 37 which emerges into an oblique pipe 28 on which a vibrator 39 is arranged in order to be able to dose the powder 32 accurately. The dosing device 34 also comprises a closing mechanism 40, preferably designed as a slide, to regulate the filling quantity and/or to stop the filling process, preferably depending on the filling weight measured by the scales.

Preferably during the filling procedure there is an over pressure in the lower section of the drum 8, related to atmospheric pressure, and within the upper section 2 outside the continuous liner 14 alternatively a low pressure or high pressure related to atmospheric pressure. Preferably, within the continuous liner 14 there is a certain high pressure, also related to atmospheric pressure, during the filling procedure.

From fig. 13 a roller mechanism 41 can be seen, which is arranged within and to the side of the lower section 3, the rollers of which may be driven by an electric motor. The roller mechanism 41 is for unloading the first bag 9/the drum 8 from the lower section 3. Fig. 13 also shows that the apparatus 1 has two operating positions 42, 43 on opposite sides. Providing two operating positions 42, 43 facilitates the renewal of the continuous liner 14, which will be explained later. Preferably there is a sliding door 44 before the roller mechanism 41.

Once the required filling weight has been reached, the continuous liner 14 is closed with a clip 15 at each of two points 45, 46 at distance from each other, as can be seen in figs. 14 and 15, and then cut through in an area between points 45, 46. This therefore results in a closed second bag 16 within the first bag 9, which in turn is arranged in the drum 8.

In a following step of the process, the result of which can be seen in fig. 17, the drum 8 is returned back down into its original position by means of the lift mechanism as shown in fig. 16. The first bag 9 it then closed at two points at a distance from each other, preferably with one clip at each point and then cut through between the two points. This results in a closed second bag 16 within the closed first bag 9.

Figs. 18 and 19 show that by cutting through the first bag 9 the remaining section 24 is moved from the upper position 20 to the lower position 23 at the lower connection 11 in order to make space for the next first bag of the next filling procedure.

In a following step which is illustrated in figs. 20 and 21 the drum 8 is closed by way of the lid 18 being put on. Thereafter, as shown in figs. 22 and 23, the drum 8 with the first and second bag 9, 16 is removed laterally via the roller mechanism 41 with the sliding door 44 open.

Below, with the aid of figs. 24 to 42, a preferred method of renewing the continuous liner 14 is described.

In order to do this a (new) continuous liner 14 within a first bag 9, in which an 0-ring seal 30 is also contained, is moved to the lower section 3 of the apparatus 1 through the front doors. As can be seen in fig. 24 the first bag 9 is closed and the contents are sterile.

As can be seen in figs. 26 and 27, the first bag 9 is fixed in the upper position 20 by means of an O-ring 21 after the remainder 24 of the preceding first bag has been moved to the lower position 23.

The remainder 24 is then taken to the waste container 5 using the gloves so that a connection is created between the upper section 2 and the first bag 9 and so that the O- ring seal 30 and the new continuous liner 13 can be removed through the lower connection 11 and/or moved into the upper section 2. From fig. 30 it can be seen that the continuous liner 14 is contained in an additional external packaging 47 within the first bag 9, whereby this external packaging is now opened. The continuous liner 14 was produced and packed under clean room conditions.

Then, as shown in both figs. 32 and 33, gas is released from the inflatable gasket 28 and a carrier structure 48 which bears the inflatable gasket 28, is removed from the tubular bearing structure 17 together with the inflatable gasket 28 (cf . fig. 32) . Prior to this the new continuous liner 14 is parked within the upper section 2 to the side of the upper connection 12. In a following step, shown in fig. 34, the upper end 29 of the new continuous liner 14 is attached to the bearing structure 17 by means of an 0-ring 30, after an upper end of a remainder 49 of the used continuous liner has been moved into a lower position. Inside, a lower end 50 of the continuous liner is passed down through the carrier structure 48 past the inflatable gasket 28. Preferably the above operating steps are carried out by two persons, located on opposite sides of the apparatus 1, each using a pair of gloves, and preferably also the following step in which the inflatable gasket with its carrier structure 48 is moved upwards and the carrier structure 48 is attached in the lower section of the tubular bearing structure 17.

In a subsequent step shown in figs. 36 and 37, the new continuous liner 14 is closed by means of a clip 15 so that consequently the remainder 49 is within the new continuous liner forming the new, second bag.

In a following step shown in figs. 38 and 39 the remainder 49 of the previous continuous liner together with its CD- ring is removed from the bearing structure 17 and transferred in full into the second bag 16 formed by the continuous liner 14, whereupon the continuous liner is, as shown in figs. 40 and 41, is closed with a clip 15 at two points at a distance from each other and the second bag 16 is separated from the continuous liner 14 in an area between the two points. The second bag 16, incorporating the remainder 49, can now fall into the first bag 9, whereupon, as shown in fig. 42, the first bag 9 is closed, whereby previously the contents of the waste container 5 , i.e. the remainders 24 of the preceding first bags are transferred from the waste container 5 into the first bag. Then only the first bag 9, filled with waste and the second bag, can be removed. The apparatus 1 is then ready for further filling procedures. Fig. 44 shows a perspective view of a device 1 with a dosing unit 34. A positive air pressure can be seen within the continuous liner 14 during the filling procedure, a positive air pressure within the upper section 2 and a positive air pressure within the lower section 3. This configuration provides optimum product protection. The table in accordance with fig. 46 summarises the result of the interaction of the various barriers.

Fig. 45 shows the identical apparatus as in fig. 44, but the air circulation in the uppers section 2 is such that within the upper section 2 outside the continuous liner 14 a low pressure predominates. In the lower section 3 as well as within the continuous liner 14 there is a slight high pressure. The effects of the interaction of two different barriers are shown in the table in accordance with fig. 47.

The views in accordance with figs. 48a to 48c show a possible embodiment variant of an apparatus 1 with a dosing unit 34. The outer walls have not been shown. Lateral openings 51 in the housing of the upper section 2 can be seen, which can be used to operate the apparatus 1 via integral system gloves, which are attached in a detachable sealed manner on the outside of the openings 51. A drum 8 can be seen, which can be moved between a lower and an upper position within the upper section 3 by means of a lift mechanism 10. The lift mechanism 10 stands on a separate weighing mechanism 52 which is connected in a signal-conducting manner to the control system of the dosing unit 34.

Fig. 48b shows a section of the dosing unit 34 with a powder supply line 53, pump chamber 37, low pressure connection 35, filter element 36, oblique pipe 38, vibrator 39 and closing mechanism 40 and/or valve. Fig 48c shows the arrangement of a preferably provided roller mechanism 41 for facilitated removal of a drum 8.

Fig. 48c shows the position of two volatile particle filters, namely an inlet air volatile particle filter 54 and an outlet air volatile particle filter 55, preferably both HEPA filters, by means of which air circulation in the upper section 2 of the apparatus 1 is brought about.

Fig. 49 shows an apparatus 1 (DCS glove box) with an upper section 2 and a lower section 3 in an overall system. It shows the dosing device 35, to which powder is supplied from a mill 56, which is turn is supplied by a dryer 57. To the side there is a sample removing device 58 from which or with which or automatically, product samples can be taken during filling.

List of reference symbols

1. Apparatus

2. Upper section 3. Lower section

4. Partition wall

5. Waste container

6. Gloves

7. Housing 8. Drum

9. First bag

10. Lift mechanism

11. Lower outlet

12. Upper outlet 13. End

14. Continuous liner

15. Clip

16. Second bag

17. Bearing structure 18. Lid

19. Opening

20. Upper position

21. 0-ring

22. Upper circumferential groove 23. Lower position

24. Remainder of the preceding first bag

25. 0-ring

26. Circumferential groove

27. Circumferential edge 28. Inflatable gasket

29. End

30. 0-ring seal

31. Arrow

32. Powder 33. Scales

34. Dosing device

35. Low pressure connection / low pressure line 36. Filter element

37. Pump chamber

38. Oblique pipe

39. Vibrator 40. Closing mechanism

41. Roller mechanism

42. Operating position

43. Operating position

44. Sliding door 45. Point

46. Point

47. External packaging

48. Carrier structure/carrying structure

49. Remainder of the preceding continuous liner 50. End

51. Housing opening

52. Weighing mechanism

53. Powder supply line

54. Inlet air volatile particle filter 55. Outlet air volatile particle filter

56. Mill

57. Dryer

58. Product removal devices / sample-taking device