An ampoule carrier used in manufacture of pre-filled ampoules and method for manufacture of pre-filled ampoules using an ampoule carrier

The present invention relates to an ampoule carrier kit for use in the production of pre-filled ampoules and a method for making pre-filled ampoules using an ampoule carrier kit.

Ampoules pre-filled with various ingredients and made for various purposes are known in the art. A representative example are pre-filled ampoules for medicines or medical products that are subject to severe requirements in terms of integrity, sealing, sterility, cleanliness, quantities, stiffness etc. The ampoules can be ordinary break-through ampoules, sealed vials etc. More refined ampoule types have additional requirements, e.g., syringe-type ampoules have additional requirements for friction, piston seal and front end seals, while two- or multi-chamber ampoules additionally require the use of openable seals between chambers and mixing or sequential feeding systems. The quality and tolerance requirements of each product translate into the corresponding problems associated with the occurrence of many components and stages of production with indirect control. The components of the ampoules can be a source of impurities, for example when glass, rubber or aluminum particles are released from the ampoules, seals or stoppers. Most production steps need to be carried out in a clean or even sterile zone except for some initial and final stages. The use of operators in sterile environments is difficult, and fully mechanized production becomes complicated when there are a large number of stages and components. Mass machining of components is simple, but usually involves damage or destruction of components, while single machining complicates tooling and reduces throughput. The use of cassettes or carriers for numerous components is an example of choice between extreme alternatives. When the ampoules are to contain the lyophilized ingredient, then further requirements are imposed on them, because the equipment used in stages such as closing the ampoules must be introduced into the freezing and drying chamber and should ensure e.g. steam transfer and uniform heat exchange and should be adapted to changes in temperature and pressure. Syringe type ampoules generally give limited access to the interior as they have holes adapted to attach the pistons and the needle and changes in temperature and pressure can move the inserted pistons. Multi-chamber ampoules may require rotation and bi-directional access, and additional design features such as bypasses complicate the handling of such ampoules. A typical two-chamber syringe-type ampoule and a method for automatically producing such pre-filled ampoules is described in Neue Verpackung, No. 3, 1988, pp. 50-52; Second Made in Germany, Vol. 30, pp. 136-140 (1987); Pharm, Ind. 46, No. 10, 1984, pp. 1045-1048 and Pharm. Ind., No. 3 (1984) pp. 317-318. The syringe-type ampoule is a two-chamber device with a bottle-type front opening for attaching the needle, two pistons and an external-type bypass to mix the freeze-dried powder in the anterior chamber with the reconstituting fluid in the posterior chamber. The described method of making such ampoules includes the main stages of washing and siliconizing the syringe barrels, inserting a plurality of barrels into the conveyor trays, sterilizing, introducing the middle piston through the rear end of the barrel, turning the trays upside down, introducing the powder solution through the front opening, freeze drying to dry powder, closing the front hole during freeze drying of the chamber, turning the trays, introducing the reproduction fluid through the rear end of the sleeve, inserting the rear piston, removal of products from trays and final inspection and packaging. This known method has most of the general disadvantages outlined above, and is limited to the specific ampoule-type product being processed, e.g., by requiring a special closure system and by seating the sleeve outside the ampoule bypass.

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U.S. Patent No. 5,435,076 describes a twin-chamber syringe-type ampoule with reduced requirements for attaching and maintaining structures on the ampoule. In the exemplary embodiments shown, the central sleeve is surrounded by a sleeve extending from the front opening to the rear end of the sleeve, thereby making unnecessary fastening structures on the sleeve itself. The use of a sleeve makes it possible to fix the sealant in the sealing position and eliminate the need for separate plugging. At the rear end, a handle, piston or delivery mechanism can be attached to the sleeve portion. Despite the simplicity of the sleeve design, the sealant and sleeve can, if desired, be combined into one closure component, allowing sealing by a simple axial movement, also in the lyophilization chamber. The sleeve also protects the middle sleeve and e.g. the housing against damage, and also protects the sleeve remnants from spreading to other products or to the installation itself.

The object of the invention is to develop a simplified construction of a carrier kit with pre-filled ampoules, preferably two or multi-chamber, especially a syringe type, better adapted to the requirements and avoiding the above described problems, easily adaptable to product varieties, suitable for highly automated production and for use with lyophilization steps. The next goal is to develop a method for producing ampoules using such a carrier, characterized by greater reliability and more reproducible results.

Ampoule carrier kit, used in the manufacture of pre-filled ampoules, the body of the carrier having at least one ampoule seat defining a channel for axial insertion and radial holding of the ampoule, and the ampoule placed in the socket contains a container whose upper end and bottom end define between them the axis of the ampoule, wherein at least at the front end of the container there is an opening, according to the invention it is characterized by that each carrier body channel has the form of a cavity, the walls along the axis of the ampoule having a height at least the same as the height of the ampoule, the walls of this cavity being substantially continuous around the axis and along the height of the ampoule container.

The ampoule container is preferably selected from the group consisting of a tube, a vessel, a bag, a vial, a capsule, a rod, a syringe barrel and combinations thereof.

The container is preferably at least partially symmetrical and has a constant cross section around the symmetry axis.

The container preferably has the shape of a tube.

The ampoule preferably includes a syringe barrel having a front opening and a rear opening.

The ampoule is preferably substantially cylindrical.

The sleeve is preferably of the double or multi-chamber type, and has at least one valve or bypass system.

The cavity is preferably formed as a bore in a portion of the preferably monolithic carrier body.

The width of the carrier body channel is preferably approximately the same as the largest width of the ampoule.

The cross-sectional profile of the carrier body channel is preferably similar to the cross-sectional profile of the ampoule.

The carrier body channel preferably has a length at least corresponding to the length of the ampoule.

The channel is preferably longer than the length of the ampoule.

The carrier body preferably includes stops located in the channels at the front end of the ampoules.

The stops are placed thorns in the channels.

The carrier koipus nest preferably includes at least one lock, attached to the carrier body and restricting the axial movement of the ampoule.

The lock has a locking surface that enters the carrier body socket channel at the front and / or rear end of the ampoule.

The locking surface of the lock only partially covers the cross-section of the channel.

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The locking surface of the lock only partially covers the end surface of the ampoule.

A single lock has locking surfaces for more than one slot.

The locking surfaces are on at least one bar or zipper strip extending over more than one channel of the carrier body.

The zipper is removable to the carrier body.

The carrier's koipus socket contains two locks with a spacer with a height at least equal to the height of the ampoule.

The height of the spacer is greater than the height of the ampoule.

Between the locks there is an ampoule and a stop.

The carrier body includes locks arranged movably axially with respect to at least one channel and having a part extending into the channel.

The lock is located at least at the upper end of the carrier body.

The lock has the form of a carrier body lock.

The lock has parts that, with axial moss, simultaneously enter several channels of the carrier body.

The carrier body has guide elements for the axial movement of the lock.

Each channel of the carrier copy is equipped with individual guidance elements.

The guide elements have the form of cut-outs and contain a stopping surface for axial movement disappears towards the channel.

The alignment elements include cutouts in the carrier body.

The cutouts reach only part of the depth of the channel.

The carrier includes vent lines at least between the front end of the ampoule and the outside of the carrier.

The venting hoses are formed as recesses in the carrier body.

Ampoule carrier kit used in the production of pre-filled ampoules, the body of the carrier having at least one ampoule seat defining a channel for axial insertion and radial holding of the ampoule, and the ampoule placed in the socket contains a container whose upper end and bottom end define between them the axis of the ampoule, wherein at least at the front end of the container there is an opening, according to the invention it is characterized by that the length of each carrier koipus channel is greater than the height of the ampoule, and that the portion of the channel outside the ampoule comprises an inner surface located around the periphery of the carrier koipus channel.

The inner surface around the perimeter of the channel is generally tubular at least above the axial portion of the channel.

The inner surface around the perimeter of the channel has substantially the same cross-sectional profile as the portion of the channel occupied by the ampoule.

A stop is located at the inner surface around the perimeter of the channel.

The stop is placed with thorns relative to the inner surface around the perimeter of the channel.

The stopper is located above the front opening of the ampoule.

The carrier's koipus has several channels, each with an internal surface.

A method for producing pre-filled ampoules using an ampoule carrier kit, the carrier body in the kit comprising at least one cavity defining a channel, holding the ampoule radially, consisting of axially inserting at least one ampoule into the channel in the socket, according to the invention characterized in that inserting the ampoules into the channels of the carrier body, the ampoules are filled with medical material, then the ampoule holes are sealed with stoppers and the ampoules are removed from the channels.

The ampoules are inserted through the first end of the carrier body channel and through the same end of the channel an additional operation is selected, selected from the group consisting of inserting the plunger into the ampoule container, filling the ampoule container with the desired substance, evaporating the component from the container, inserting the stopper into the carrier body channel, removing ampoules from the canal and a combination of these operations.

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Prior to the stages of insertion and filling of the ampoule, the first end of the carrier body channel is kept upright.

The upper end of the carrier koipus is used as the first end of the channel.

A freeze-drying step is carried out in the evaporation step.

An additional step selected from said group of operations is performed from the other end of the channel.

Before carrying out this additional step selected from said group of operations, the carrier body rotates upside down.

An exchange stage selected from the group consisting of gas exchange, heat exchange and exchange of pressure is carried out between the inside of the ampoule and the outside of the carrier coopus.

The exchange step includes a sterilization and / or lyophilization step.

After inserting the ampoules into the channels, gas is passed through the ampoules.

The sterilization stage uses hot sterilization gas.

The stops are inserted into the channels of the carrier body to a rest position in a non-sealing relationship with respect to the ampoule openings.

After inserting the limiters, the step of performing freeze-drying is used.

The stops are moved in the carrier body channels from the rest position to sealing contact with the ampoule holes.

The stops are held in a rest position by friction between the stops and the inner walls of the carrier body channels.

The stops are secured with a cap.

Before the securing step, a step of removing the ampoules from the channels of the carrier body is used.

The ampoule carrier according to the invention has significant advantages in the production of pre-filled ampoules. The carrier can be used at most production stages, reducing mass processing and the corresponding risk of damaging the ampoules. The carrier contains one or more channels for individual ampoules. The channels are formed as cavities in the carrier body and essentially surround the ampoule, giving it protection and closure of impurities similar to the known sleeve. As it turned out, the cavity facilitates uniform heat transfer and radiation shielding, which is of particular importance in freeze-drying processes. If desired, the cavity can be made to support the ampoule radially over a considerable length and the carrier structure can be made, e.g., by separators, to match ampoules of different lengths and widths, thereby providing valuable diversity. The carrier preferably cooperates with ampoules of the general cylindrical shape described. A channel longer than the ampoule can be used to maintain the sealant in a drifting, but protected, position above, but concentrically with the ampoule opening for subsequent individual centered and guided axial movement to the closed position, which is an option of particular value in the freeze-drying step, to allow first steam passes out of the sealant and then closes the powder chamber in situ. When using a carrier with ampoules with a cylindrical sleeve type and slightly behind the large sealant, it is advantageous to insert the ampoule into the channel from the seat side of the carrier sealant, without the need for additional guidance structures. Upper and lower locking surfaces protruding into the channel can be used to limit the axial movement of the ampoule. Separating the surface of at least the height of the ampoule allows the ampoule to be embedded between the surfaces. Thus, the ends of the ampoule are used for axial fastening, making unnecessary any intermediate structures such as flanges, recesses, bottle holes, bypasses, etc., making the carrier compatible with most of the described smooth ampoule designs. A further advantage is that all forces applied to the ampoule during production, such as insertion, filling, plunger insertion, sealing and removal, are in a favorable axial direction, which significantly reduces the risk of ampoule damage and plant contamination. However, the releasable locks used can make both sides of the channel accessible both for direct production stages and for intermediate stages, such as probing and weighing the ampoule, providing considerable flexibility in use, especially in connection with rotary carrier systems.

190 718 useful in installations for many types of ampoules or multi-chamber ampoules. The movable locking surfaces can be supplemented with stopping surfaces fixed to each channel to further reduce the risk of adverse compression and excessive forces, which is important in cases where exact size and support tolerances cannot be guaranteed.

The ampoule carrier of the invention can be used for a wide range of ampoule devices or systems. It is possible to use a carrier for the production of ampoules as such, i.e. empty ampoules, e.g. for later filling or for use as mixing or preparation chambers, but it is recommended to use the invention in combination with pre-filled ampoules and their methods of preparation, i.e. containing filling steps . The nature of the pre-fill material or later fill ampoule is not critical and should be understood to include gases, liquids and solids. The material may be a powder, e.g. a powder, cake or tablet. The material may be a fluid such as a liquid, which includes materials that behave like liquids, such as emulsions or suspensions. The material may undergo transformations, such as when a solid dissolves or the solution is dried, which may occur during manufacture or as the final preparation or mixing step just before use. The nature of the content will also be understood to include medical agents in the broad sense, e.g. natural ingredients and body fluids pre-filling or withdrawn into a container, although most often the medical agent is prepared at the factory.

The invention can help solve many of the problems that arise when using sensitive components that are degraded or denatured under mechanical stress, such as high shear forces. High molecular weight compounds of this type can be high molecular weight hormones, e.g. growth hormones or prostaglandins. The invention may also facilitate the resolution of various problems that arise when using a medical agent requiring lyophilization to prepare or prepare just before the infusion, usually mixing two or more ingredients that can all be liquid or solid, e.g. when a lyophilised powder dissolves in a solvent such like hormones or prostaglandins.

The ampoule carrier kit of the invention is intended to facilitate and improve the production and quality of pre-filled ampoules. This carrier can be used for any of the described ampoule types, although the benefits are obtained with ampoules with certain recommended characteristics. Generally, it can be said that the carrier comprises one or several ampoule seats in which there is a channel for axial insertion and radial retention of the ampoule. The term "carrier" as used herein should be understood to mean a device adapted to carry at least one, and preferably several, ampoules and adapted to be operated as a unit in a production plant. The carrier may be monolithic but is preferably an aggregate of ingredients, served as a unit. The carrier may contain ancillary features, i.e. features relating to the carrier as such, e.g. facilitating its handling in the process, such as details adapted to mechanical clamping, turning and transport as well as an assembly facilitating assembly, disassembly and cleaning. Where applicable, the "upper" and "lower" sides of the carrier will be considered to be the side at the front and rear ends of the ampoule inserted into the carrier, respectively.

The carrier includes at least one "seat" for each transferred ampoule, ie, one or preferably several seats adapted for individual ampoules, such as an individual stop and manipulation assembly. Preferably, each seat is adapted to receive only one ampoule.

The seat comprises at least a ampoule passage adapted to allow axial insertion and radial holding of the ampoule. For example, the channel may contain one or more plates or other separating structures to provide radial support for the ampoule at discrete positions along its axis. However, it is recommended that the canal contain a cavity in the sense of a chamber that surrounds the ampoule at a considerable length and most preferably at its entire length. For example, the cavity may be shaped as a "drill" in the monolithic portion of the carrier body.

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The seat can also contain one or more locks, meaning any structure for holding the ampoule in the axial direction. The lock can clamp the ampoule in any part, e.g. intermediate part, and prevent movement in both axial directions. However, it is recommended that the lock act as a stopping surface at the end of the ampoule, thereby preventing the ampoule from moving in one direction. It is recommended that the carrier be provided with two locks, one at each end of the channel, preferably at a distance corresponding to at least one height of the ampoule or as far away as possible.

It is further recommended that at least one, and preferably all, locks be placed in a release manner to allow access for insertion and removal of the ampoule. The seat may further include auxiliary elements such as guidance structures for tools, sealant positioning elements, gas venting channels, etc.

Constructively, the carrier may advantageously be constructed as an intermediate body portion, covering most of the ampoule height and channel length, the upper head portion with e.g. an upper lock and auxiliary details, and the lower foot part with e.g. an lower zipper and possible auxiliary details. The height of the body part can be adjusted to the length of the ampoules to be processed. The body portion may be a frame type structure, e.g. two or more plates with holes forming the channels, the plates being separated by separators and possibly walls to close the frame. This open structure can be light and easily adaptable to different ampoule lengths. However, it is recommended that the body portion be formed as a uniform, preferably monolithic structure, in which the channels are formed as elongated cavities, e.g. bore holes, at least partially open at the upper and lower ends of the carrier body parts. Such a uniform structure facilitates the placement of the cavity surrounding the ampoule. Preferably, the cavity has at least the same height as the length of the ampoule.

It is generally recommended that the length of the channel should at least match the length of the ampoule so that it does not reveal any of its end when machining the carrier, but it is recommended that the channel be longer, in particular at the upper end to at least hold but preferably also surround the sealant in a non-sealing position relative to the ampoule opening, e.g. to press the sealant into the sealing position and preferably also to allow freeze-drying. As is known, the sealant may be in a partially inserted position, as in the case where the steam channels are placed in the sealant or ampoule, but preferably the sealant position is further forward and it rests only on the edge of the hole, and most preferably the sealant position is extended still further forward in a drifting position above and without contact with the ampoule opening, e.g. to allow a good gas connection even in simple ampoule and sealant structures, which is achieved by using a channel to hold the sealant. The width of the channel at the support points for the ampoules is preferably about the same as the largest width of the ampoule, allowing some additional clearance or tolerance. Similarly, the cross-sectional profile of the channel is preferably more or less concurrent with the cross-sectional profile of the ampoule, possibly with some deviation, e.g. to allow the protruding structure to pass, such as an external bypass. It is preferred that the channel has a substantially constant cross-section at least along the height of the ampoule and preferably that the cross-sectional profile or perimeter forms a closed loop. When the channel is longer than the length of the ampoule, it is recommended that also the length of the additional channel has essentially the same width and profile, which allows axial displacement in it. Accordingly, although the sealant may be held in this part of the duct by projections into the channel, it is recommended that the sealant be held by friction with respect to the walls of the channel, and therefore the sealant preferably should have larger dimensions.

The method of application of the carriers results from the given construction description. The variety and flexibility provided allow for numerous production procedures, both conventional and improvements according to the invention. The generally recommended method of application includes the steps of inserting the ampoule into the canal, filling the ampoule with material, sealing the ampoule opening with sealant, and removing the ampoule from the canal.

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An advantage of the ampoule carrier of the present invention is the ability to perform multiple steps on each side of the carrier. The ability to support the ampoules at their ends allows the ampoules to be inserted from one end of the carrier, preferably the top and vertical ends, and to be filled through the same end, preferably without rotating the ampoules or carrier. It is also possible to insert the sealant from the same end, optionally to perform the lyophilization step in the same position, and to carry out the actual sealing step by pressing from the same end of the channel and, if applicable, removing the ampoule by operations opposite to those for inserting the ampoule. These steps can complete the filling operation for a single-chamber ampoule, e.g. bottles, vials or single-chamber syringes. However, the other side of the carrier and the ends of the channels are available for auxiliary or additional steps. For example, when making two or two-chamber pre-filled ampoules without an initial wall separating the chambers, you can first insert an intermediate piston to create two chambers. This can be done from the front or top end of the single-chamber ampoule, or from the other end of the carrier for any sleeve design. After completion of the above-described filling operations for the first chamber, the front sealed ampoules can be turned upside down, preferably with locks located at this end, and a similar filling operation can be carried out from the other end, possibly ending by inserting the rear plunger into the ampoule housing. This procedure of filling from different ends is of particular value when the ingredients cannot be allowed to contact even in trace amounts during manufacture, or when the second component cannot be present in the first set of manufacturing steps, as in the case of pressure sensitive fluid during freeze drying or sterilization. Without such restrictions, the carrier of the invention allows several chambers to be filled from the same end, whether from the first or the other end, which is advantageous in the production of pre-filled multi-chamber ampoules.

It is preferred to use the carrier in procedures that utilize the gas exchange step between the interior of the ampoule and the environment, since it is possible to simultaneously protect the ampoules and provide gas channels. It is also preferred to use the carrier in method steps, including heat transfer, among others due to convenient heat transfer and heat equalizing properties of the carrier. In addition, it is convenient to use the inventive carrier in conjunction with procedures that utilize pressure changes, amongst others because the aforementioned gas channels serve to allow necessary pressure adaptations, and the flexibility of filling allows delaying the introduction of pressure sensitive material, e.g. material that is moving, expanding or condensing at pressure differences, or material that is destroyed under certain pressure or temperature conditions. Sterilization and lyophilization are typical production steps to which these problems relate in connection with medical agents.

The recommended use is to pass gas through tubular-type ampoules, such as sleeves, from one end to the other, which is facilitated by the use of a carrier that has at least partially exposed ends of the ampoule. Preferably, the carrier channels at such a stage are substantially uncovered, e.g. without sealants. The gas may pass through the ampoules for any purpose, such as rinsing, drying, etc., but the recommended application is gas sterilization of the ampoules. The gas may act chemically, but it is recommended to use hot gas, which uses the advantages of heat transfer through the carrier, as described, e.g. as in furnace sterilization with applied hot gas circulation.

Another advantage of the invention is that the sealant can be positioned in a drifting position above the ampoule opening, since this facilitates the guided and protected seal over, for example, a simple axial movement between the sealant and the ampoule, and because it is possible to carry out process steps between putting the sealant into rest position and entering it ampoule hole. Hence, it is preferred to use the carrier of the invention in conjunction with procedures involving any such operation, or generally a sealing step from the rest position of the sealant. A typical example is the freeze-drying stage, in which the sealant can be put in rest position and freeze drying can be carried out followed by entry

190 718 sealant, which last step can easily be carried out inside the lyophilization chamber due to the simple necessary axial movement of the sealing.

It is also recommended to use a support in elastic sealant processes, among others because such sealant can easily be kept in rest position with friction by simple compression, because such sealant itself can be inserted into at least a pre-seal, sufficient for most production stages and because its clogging can be delayed to the stage when the ampoules are released from the carrier. As indicated earlier, the recommended cover type is the sleeve type, running from the front to the back end, which can be applied after any isolated process steps.

The carriers of the invention may be used to achieve any of the aforementioned benefits, regardless of the features of the production installation. For example, carriers can be used to facilitate manual handling of ampoules at various stages, in automated and mechanized installation systems in which manipulation, transport and operations are carried out by designed instrumentation.

The subject of the invention is shown in the embodiments in the drawing, in which Pos. I shows the prior art double-chamber ampoule with an outer sleeve, Fig. 2 - front end of the new ampoule solution, Fig. 3A - 3D - schematic cross-sections through a single sleeve wall, showing different edge shapes of the ampoule sleeve opening in Fig. 2, Fig. .4 - a diagram of the main stages of the production of pre-filled two-chamber ampoules according to Fig. 2, Fig. 5A - top view of the carrier body kit according to the invention, designed for the ampoule according to Fig. 2, Fig. 5B - view from the shorter side of the ampoule carrier body according to Fig. 2, Fig. 5C - view from the long side of the ampoule carrier body according to Fig. 2, Fig. 5D - cross-section through the ampoule carrier according to Fig. 2, Fig. 5E - partial enlargement of a single carrier opening, Fig. 5F - perspective view of the ampoule carrier body according to Fig. 2, Fig. 6A - top view of the upper ampoule carrier koipus lock according to Fig. 2, Fig. 6B - view from the shorter side of the upper system of the ampoule carrier lock according to Fig. 2, Fig. 6C - view from the long side of the upper system of the lock cooperating with the ampoule carrier body from Fig. 2, Fig. 6D - a single lock for the channel column of the ampoule carrier body of Fig. 2, and Fig. 7 - top view of an alternative embodiment of the ampoule carrier body of Fig. 2 having a different channel distribution.

Pos. And there is shown a known two-chamber ampoule, described in U.S. Patent No. 5,435,076, having an outer sleeve 7 of a general type, in a position prior to axial displacement of the sealing portion and sleeve 7 of the ampoule to the position of sealing the opening of the sleeve of the syringe before the lyophilization step. The syringe barrel 1 has a neck 2 with a front opening. In the syringe barrel 1, the piston 3 is inserted to the level corresponding to the bottom of the bypass 4 of the barrel 1, dividing the barrel 1 into the front chamber 5 and the rear chamber 6. The sleeve 1 is surrounded by a sleeve 7 having approximately the same length as the sleeve 1. The front end 8 sleeve 7, corresponds to the neck 2 of the sleeve 1 and goes into the upper part 9, having an external thread for attaching the needle holder, and ending with an internal collar 10. Inside the upper part 9 there is a stop 11 with an outer collar 12. The inner collar 10 of the upper part 7 of the sleeve 1 and the outer collar 12 of the stop 11 are mutually matched in order to eliminate the possibility of moss of the stop 11 forwards relative to the sleeve 1. The stop 11 further comprises a cylindrical part 13, adapted to be sealed into the neck opening 2 of the sleeve 1, wherein the cylindrical part 13 has a cavity 14 closed with a thin needle-pierced membrane. A gap 16 is left between sleeve 7 and sleeve 1 to allow steam to escape from neck opening 2 during freeze-drying. At the rear of the sleeve 7, a fastening assembly 17 is arranged, allowing it to be connected to the actuation assembly and to anchor the sleeve 7 with the end of the sleeve 1. The front chamber 5 is initially filled with a solution 18 which is to be freeze-dried to a dry state. The opening of the sleeve 1 is closed by sliding the sleeve 7 and the stop 11 axially backwards, and into the rear chamber 6 (not shown) solvent is inserted and the rear plunger is inserted to close it, after which the actuating mechanism is attached to the rear end of the ampoule .

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Figure 2 shows the design of the front end of the ampoule 20, wherein in other respects this ampoule 20 may be similar to the design shown in figure 1. The ampoule 20 comprises a stop portion sealing type 21 having a flange 22, a cylindrical portion 23 intended to be inserted into the hole sleeve, cavity 24, cup-shaped upper surface 25, and recess 26 located in front of flange 22. The ampoule further includes a generally cylindrical sleeve 27 and sleeve 28, extending from the front end of the stop 21 to the rear end of the sleeve 27 and having an inner flange 29, cooperating with the flange 22 of the stop 21 and with a recess 26. The cylindrical portion 23 of the stop 21 is inserted into the open front end sleeve 27, bounded by a flat edge. Flange 22 rests on the flat edge of the bore of sleeve 27, but has a diameter larger than the cylindrical sleeve, thereby protruding radially beyond the outer dimensions of sleeve 27 and at least partially overlaps between sleeve 27 and sleeve 28. As also shown, the collar 22 has a larger diameter than the diameter of any retaining structure located above it, so that the retaining surface of the inner collar 29 of the sleeve 28 can rest on the collar during axial rearward movement. The inner collar 29 may contact with collar 22 due to the moss back of the sleeve 28 also after inserting the stop 21 into the hole of the sleeve 27. The recess 26 of the stop 21 interacts with the bulge of the inner collar 29 of the sleeve 28 to form a snap connection that does not prevent the rearward movement of the sleeve 28 relative to the stop 21. The cup-like shape of the upper surface 25 of stop 21, in addition to cavity 24, further reduces the necessary length of acute penetration tools or needles through the central part of the stop 21. The rear parts of the ampoule 20 (not shown) can be made as in Fig. 1, i.e. with an intermediate piston 3 dividing the sleeve 27 into the front chamber and the rear chamber, with the rear piston and the sleeve 28 anchored to the rear end of the sleeve 27, possibly integrally with the rear piston actuating mechanism. The ampoule according to the invention can advantageously be used in the freeze-drying step, in which the stop collar 22 is frictionally held above the opening of the sleeve 27, even without the sleeve 28, and the distance between the sleeve 27 and the sleeve 28 can be left for reasons other than providing a passage for the steam outlet, which was necessary in the state of the art.

Figures 3A to 3D schematically show axial cross-sections through the wall of a single ampoule to illustrate the possibility of using different shapes of the edges of the sleeve opening 27. In Figure 3A the shown edge of the sleeve opening 27 is rectangular in cross-section and forms a straight end of the wall of the ampoule. This shape of the opening edge cannot be easily produced without leaving any burrs and is not optimal in terms of inserting the stop 27 of the stop 21 into the hole, and in addition in terms of safety and endurance of the end 27. 3B shows the edge of the opening of the sleeve 27, having a cross-sectional shape of a droplet, whose droplet sizes are larger than the thickness of the ampoule wall, such that the material of the opening edge extends both inside and outside the nominal diameter of the ampoule wall. This kind of drop shape often results from the contraction of the fluid after partial melting of the edge material, for example when the glass intermediate is cut. Although this type of rounded edge shape is preferred, the protrusion of the material beyond the ampoule wall is not beneficial for the reasons discussed above.

Figure 3C shows the recommended shape of the opening edge, which is only rounded on the inside with a cross-section, while on the other hand there is no material located radially outside the surface of the ampoule wall. The surface of the wall edge of the ampoule opening without protruding material may be outside or inside the ampoule, depending on which problems you want to avoid. FIG. 3D represents the most recommended hole edge profile, which is essentially rounded with a semi-circle without any material protruding beyond the nominal thickness limits of the ampoule. With this design of the ampoule sleeve edge edge profile all the problems discussed above can be avoided. The preferred edge shapes are preferably used around the opening at the front end of the ampoule, but can preferably also be used at other ampoule openings, such as the rear openings of a sleeve-type ampoule.

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Figure 4 schematically illustrates the main steps of the recommended sequence of steps for making pre-filled twin-chamber syringe type ampoules. Several of these steps are carried out inside the sterile zone, shown in dashed lines 40. In the first step 41, the ampoule sleeves are rinsed and siliconized. The sleeves so treated are sterilized by transferring through a sterile furnace, at the exit of which the sleeves enter the sterile zone 40. In the stage of loading the piston 43, an intermediate piston is inserted into the sleeve to form the front and rear chambers therein. In the solution loading step 44, a freeze-dried solution is introduced into the front chamber, which is freeze-dried into the powder in step 45. Then, in step 46, the front end of the sleeve is sealed in situ in the freeze-drying chamber. The solvent for the lyophilized powder is introduced into the back chamber of the sleeve in step 47. At step 48, a rear piston is introduced into the rear end of the sleeve to seal the solvent in the rear chamber. At this point, the preparations contained in the sleeve are sealed to the surroundings, and the pre-filled sleeve may leave the sterile zone 40. In the final assembly step 49, further components such as the sealing cap and rear actuator may be added, preferably by using the sleeve as an intermediate part component as described. All components loaded into the sleeve, namely the intermediate piston and rear piston, as well as the freeze-dried solution and solvent, must enter the sterile zone 40.

In all steps 43 to 48 carried out inside the sterile zone 40, it is recommended to use the ampoule carrier according to the invention. Due to the versatility of the support, it is possible and recommended to use the support in the sterilization furnace of step 42 and in the rinsing and siliconization step 41, although these steps can also be carried out with the ampoules in bulk or blister form. It is recommended to remove the ampoules from the carrier before carrying out the assembly stage 49. It is generally recommended to turn the carrier ampoules upside down between steps 46 and 47. Preferably, this is the only rotation step before removing the ampoules from the carrier. In the case where the ampoules are of the preferred syringe type described, all steps 41 to 46 can preferably be carried out from the upper side of the carrier. It is also possible to delay the application of the sleeve up to step 49 outside the sterile zone, which limits the number of components entering this zone. According to the invention, it is recommended to load the sealing portions into the resting position of the carrier, allowing vapor escape, which preferably takes place between steps 44 and 45. Sealing in situ from step 46 is preferably accomplished by axially moving the loaded sealing portions from the resting position to the sealing overlap at the front opening the sleeve.

Figures 5A to 5E are different views and cross sections of the carrier bodies 50 according to the invention, and Fig. 5F is an enlarged perspective view of the carrier body. The rectangular carrier body 50 is a monolithic portion preferably made of an aluminum block and has an upper or front portion 51 and a lower or rear portion 52. Numerous channels of 53 ampoules are arranged in the form of interlaced 29 columns and 18 rows, resulting in 261 channels. As shown in fig. 5E, channels 53 include a drill hole 531 in the carrier body 50, which is delimited by the inner wall 532 and whose uppermost portion 533 is somewhat tapered to facilitate insertion of the ampoule and sealing portion. In the upper part 51 of the body there are 29 line guide notches 54, each of which passes through the upper parts of all channels in the column and, as best seen in Figs. 5B and 5D, only on part of the depth of the channels. The cutouts 54 act as guiding structures for the upper lock system, which will be further described in connection with Fig. 6, also used as a tool for moving the sealing portions from the rest position to the sealing position. At the upper part 51 of the body there are 18 linear cutouts 55 of the steam lines, each cutout 55 passing through the upper parts of all channels in the row and, as best seen in Fig. 5B and 5D, only for part of the depth of the channels. These cut-outs 55 of the steam lines 55 serve as additional vapor escape routes during freeze-drying when the sealing portion is inserted into the rest position in the upper part of the channel. As shown in Figs. 5D and 5E, for each channel 53 at the bottom part 52 of the carrier, lower locks 56 are used in the form of an arm extending radially inwardly from the surface of the borehole 532 on which arms

190 718 should rest the frame part of the ampoule. As shown in Fig. 5C. the guide notches 54 extend down one of the long sides of the carrier body at the side slots 57 and the trough 58 runs along the same side of the body transversely to the side slots. The longitudinal recesses 59 are used to support media in a mechanized production installation. In use, the ampoules can be inserted from the upper side 51 of the koipus into the channels for seating on the surfaces of the lower locks 56. On the same side of the body, the sealing parts can be inserted into the resting position, designated in the parts of the cut-outs 54 or 55, in which they are attached for fall protection by means of upper locks in the first axial position. The sealing parts can later be brought to the sealing position by moving the upper locks deeper to the second axial position.

Figures 6A to 6C show a top and side view of the arrangement of the upper lock 60 according to the invention for the ampoule carrier of Fig. 5. Fig. 6D shows a single lock 61 for a channel column. As shown in Fig. 6D, the single channel column lock 61 is generally in the form of an L-shaped strip having a longer straight locking portion 62 and a shorter hinge portion 63. The lock 61 further includes end holes 64 and 64 'for connecting several columnar locks 61 in a parallel arrangement and includes an elongated hinge hole 65, allowing some movement along the hinge portion 63 when an axle is positioned in the hinge hole 65. The radius of curvature 66 is centered on the nearest portion of the opening 65, this curvature becoming the straight portion 69 of the hinge portion 63. As shown in Fig. 6A, 6B and 6C, from such 29 individual columnar locks 61 a uniform arrangement of locks is formed, arranged in parallel and held together by bars 67 and 67 ', passing through holes 64 and 64', respectively. The hinge axis 68 passes through the elongated hinge holes 65 of all the locks 61.

The hinged axle 68 is connected to the carrier body 50 of Fig. 5 and fastened to the trough 58 so that each hinge part 63 of the lock column 61 is placed in a respective side slot 57. If each straight locking portion 62 of the column lock 61 is inserted into its respective guide cutouts 54 on the upper part 51 of the carrier 50 of the carrier 50, the entire arrangement of the upper lock 60 can be moved axially with respect to the channels 53 to the extent allowed by the elongated hinge opening 65. In particular, this allows the upper lock system 60 to take the highest position, guided by the guide notches 54, based on the stops 21 in the rest position above the ampoule openings, and the lowest position to which it is brought by pressing the sealing parts into the sealing position ampoule holes. In the uppermost position, the hinge axis 68 is centered with the curvature 66 of the hinge part 63 and the curvature 66 interacts with the lower parts of the side slots 57, (see Fig. 5D) to allow the upper lock system 60 to pivot around the hinge axis 68 from the upper part 51 of the carrier body . In the lowest position, the front part 69 of the hinge part 63 interacts with the bottom parts of the side slots 57 so as to prevent the upper lock system 60 from rotating about the hinge axis 68. Preferably, an assembly (not shown) is used to releasably secure the lock system in this position.

Figure 7 is a top view of another exemplary embodiment of a co-opus carrier 70 ampoule. The carrier body 70 generally has the same features as the exemplary embodiment of the carrier 50 of Fig. 5, but with a slightly different channel system 71. The channels 71 are arranged in ten columns containing ten rows 73, the latter having slightly smaller spacing, which gives generally rectangular distribution. Other columns and rows with straight holes 74 are inserted between each column and row, serving mainly to reduce the weight of the carrier body 70 and to increase the contact surface in stages where a heat exchange process occurs, namely in hot gas sterilization. Channels 71 have the same features as described in connection with Fig. 5E. The upper surface of the carrier kipus 70 guiding the notches 75 for the combined arrangement of the upper lock and pressing similar to the lock 60 of Fig. 6. Carrier body 70 also has transverse venting cutouts 76 providing vapor escape channels during freeze-drying. Cut-outs 75 and 76 extend only to part of the length of the axial channels. Holes 77 facilitate media handling in a mechanized installation. In this exemplary embodiment of carrier koipus 70, no hinges are provided for

190 718 upper lock system. Instead, ten simple columnar straps of zippers were combined to form a plain grille. As in the exemplary embodiment of Figs. 5 and 6, such a grid can be closed by column locks located in the guide notches 75 above the sealing parts in rest position, with the possibility of later axial movement to insert the sealing parts into the ampoule holes. The grid can also be placed in additional notches 78, passing above the holes 74 (to expose the holes 71, e.g. for the stages of the filling procedure and will still be kept within the upper surface limitations of the carrier body 70. A mounting assembly may be used to hold the grid in different positions (not shown).

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Price PLN 4.00