CZ20001043A3 - Ampoules filled in advance and apparatus for producing them - Google Patents

Abstract

A syringe ampoule consists of a container (1) s front and rear faces that define each other axis. The container (1) has a substantially constant cross section between front and rear, at least the front face ends through the hole. It further comprises a seal formed by a stopper (21), attached to the front face and sealing the aperture, at least from one piston (3) slidably and sealed arranged in the container (1), and a sleeve (7) extending at least along a portion of the container (1). The sleeve (7) has a front section and a rear section with a front section the part is connected to the seal formed by the stopper (21). Container (1) has a front face terminated by an edge surrounding the opening, wherein the edge has an outer circumference that is substantially the same as the outer circumference of the container (1). The invention further relates to a process producing a filled ampoule and units to perform this production method.

Description

Technical field

BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to a syringe vial comprising a container with a front face and a rear face defining an axis therebetween, the container having a substantially constant cross section between the front and rear faces, at least the front face ending in an opening from the seal attached to the front face. and sealing the opening, at least one piston slidably and sealingly disposed in the container, and a sleeve extending at least along a portion of the container, the sleeve having a front portion and a rear portion, wherein the front portion is attached to the seal. The invention further relates to a method and compositions for making pre-filled ampoules.

Background Art

Ampoules pre-filled with different components are produced for various purposes. In particular, the present invention relates to articles of this kind, for those applications which are particularly demanding. A representative example consists of pre-filled ampoules for medical examinations or for medical applications that are subject to stringent requirements, in particular their integrity, tightness, sterility, purity, amount, stiffness, etc. The ampoules may be fully breakable ampoules, sealed containers, etc. There are still increasing demands for

more complex ampoules. For example, syringe syringes increase the importance of piston and seal friction and limit the choice of front face seal. In addition, two- or multi-chamber vials require openable seals between the chambers, for mixing, or for reliable sequential delivery. Although the present invention has a more general utility value, it will mainly be described by these desired uses.

Every requirement for quality and tolerance of the product is transferred to production problems. In general, many components and manufacturing operations require immediate control. As such, the components may constitute a source of contamination when particles of glass, rubber or aluminum are released from the vials, seals and shutters, respectively. Most operations must be carried out in a clean or even sterile area, with the exception of some initial or end operations. The use of human operators in a sterile environment is difficult and a fully mechanized alternative becomes complex when the number of relevant operations and components increases. Bulk handling is simple but tends to increase the problems associated with damage, destruction, or particle release. On the other hand, individual handling complicates machinery and reduces capacity. The use of cartridges or carriers for multiple components is merely an exchange of extremes. When the ampoules are to contain a lyophilized compound, further limitations of the equipment used occur, as operations such as ampoule closure must be performed within a closed lyophilization (freeze-drying) chamber and should provide for example steam transfer and uniform heat exchange and be compatible with the necessary appropriate temperature and pressure changes. Syringe ampoules usually have limited access to their inner space, because • 0 00 · 0 00 · 0 · 00

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The apertures are mainly adapted to the pistons and to attach the needle, and the temperature and pressure changes may displace the retracted piston. Furthermore, multi-chamber vials increase labor and may require rotation and bilateral access, and additional features such as bypass structures make handling difficult.

A typical two-chamber syringe and method of automatic manufacture of such a pre-filled syringe are disclosed in Neue Verpackung, No. 3, 1988. Str. 5052; Drugs Made in Germany, Vol. 30, pp. 136-140 (1987);

Pharm.Ind. 46, No. 10 (1984) pp. 1045-1048 and Pharm.Ind. 46,

No. 3 (1984), pp. 317-318. The syringe ampoule is a two-chamber device with a front opening as for a vial, a needle attachment, a two-piston, and an external bypass for mixing the lyophilized powder in the anterior chamber and a dilution fluid in the posterior chamber. The described method comprises two washing and siliconing operations (silicon surface saturation), inserting multiple containers into support paths, sterilizing, introducing the middle piston through the rear face of the container, rotating the paths to the inverted position, feeding the powder solution through the front opening, freeze-drying to dry powder, closing the front opening during the presence of the powder in the freeze-drying chamber, rotating the tracks, bringing the diluent liquid through the rear end of the container, inserting the rear piston, removing the product from the tracks, and final inspection and packaging. This known method exhibits most of the general problems outlined above. It is highly limited to specific manufactured products, for example, when a special sealing system is required, and containers based on the outer bypass structure in the tracks.

A general problem with prior art devices is the limited consideration of combining manufacturing simplicity and construction. U.S. Pat. No. 5,453,076 discloses a double chamber syringe design with reduced attachment and holding structure requirements on its own ampoule, still with features that facilitate manufacture. In the illustrated embodiments, the central receptacle is surrounded by a sleeve extending from the aperture to the rear face of the receptacle, making it unnecessary for any and all fastening structures on the receptacle itself. At the opening, the sleeve acts to provide a seal in the sealing position and eliminates the need for a separate closure. A finger holder, a piston or a feed mechanism may be attached to the sleeve portion at the rear face. Despite the simplicity of the container, the seal and sleeve can be joined into one closure member, allowing sealing by simple axial movement, also in a freeze-drying chamber. Whenever this collar is present in the manufacturing process, it also protects the central container and, for example, in case of damage, reduces the dispersion of the container fragments to other products or to the manufacturing plant itself. However, there is still room for improvement, especially for adaptation to highly automated manufacturing methods.

Therefore, there is a need for both the vial design and the vial filling methods and associated devices to better meet the high requirements for the production of pre-filled vials.

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SUMMARY OF THE INVENTION

The main object of the present invention is to provide a system of vial designs, manufacturing methods, and manufacturing devices that better meet the requirements and avoid the problems described. A more specific goal is to offer a system whose components are all simplified compared to the prior art. Another aim is to offer a system that is easily adaptable to product changes. Yet another object is to provide a system that is suitable for use in highly automated manufacturing. Yet another object is to provide a system that is suitable for use with lyophilization operations. A further object is to provide a system that is suitable for the manufacture of syringe ampoules, and in particular two or multi-chamber ampoules. Yet another goal is to create a system that allows for more reliable production, resulting in fewer malfunctions and better repeatability.

These objectives are achieved in accordance with the characteristics indicated in the appended claims.

The invention can be applied to the already described improved type of syringe device having a collar around the central container. According to the invention, such a device can be further simplified by using a container which has substantially the diameter of its front opening the same as its overall diameter, allowing for example the use of a straight cylinder. This construction further facilitates the front opening filling operation, but above all allows the piston to be inserted through the front opening and not just the rear opening, which can be used to reduce the necessary manufacturing steps, and facilitates the construction of the apparatus, since multiple steps can be performed from the same

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6 maintained within the diameter of the container, further on the side. This design also facilitates the use of a seal or plug for the front opening extending from the diameter and through the container diameter. This feature will allow this product to center the seal and align the outer sleeve, and the same manufacturing feature will allow the seal to be retained and maintained in the device cavity, which is adapted to the container diameter, and which in turn can be used to eliminate the use of the sleeve when handling the seal. it creates a looser construction of the sleeve, for example relative to the distance of the container from the sleeve, and allows the sleeve to be removed from the sterile manufacturing area and allows independent inspection of the container container blank. The use of a container with an edge of the front opening surrounded by the edge material, the nominal inner and the outer increases these advantages. Furthermore, this feature provides general advantages in handling bulk containers or in the individual handling of containers, such as higher accuracy and greatly reduced risk of product damage and particulate release. Seals and plugs can be attached by mechanical means to the aperture, more easily and without risk of knocking, also in the absence of a sleeve as a seal handling means, and manufactured plugs as such may be less complex, and with a smaller cavity forming portions in the container. The invention further provides an ampoule carrier, providing substantially general advantages in the manufacture of pre-filled ampoules. The carrier can be used in most handling operations by reducing bulk container handling and the corresponding risk of container damage. The carrier is provided with one or more individual vial channels. The channels formed as cavities in the carrier body and substantially surrounding the vial provide protection and containment, similar to known sockets. It has been found that this cavity helps in

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- uniform heat conduction and radiation protection, of particular importance in freeze-drying processes. If desired, the cavity can be made to radially support the ampoule at its substantial length, and this structure can be made, for example, by spacers or otherwise, to accommodate vials of varying length or width, thereby providing valuable multi-purpose. While not limited to any special ampoule shape, this construction preferably cooperates with ampoules of generally described cylindrical shape. A channel made in a length greater than that of the vial may be used to maintain the seal in a floating and still protected position above the vial, but centered with the vial opening, for later individually centered and axially guided displacement to the closed position to select individual values for lyophilization ( freeze-drying), to allow the first vapor passage through the seal and later on the dust chamber closure located on the spot. With the use of a slightly larger size seal, with a vial type with a cylindrical container as described, these advantages can be achieved by maintaining the possibilities of introducing the vial into the channel from the abutment side of the seal carrier, without additional guiding structures. Upper and lower locking surfaces extending into the channel may be used to limit axial displacement of the ampoule. The surface separation of at least the height of the vial allows the vial to remain between the surfaces. The first advantage of this feature is that the ampoule faces are used for axial mounting, making any auxiliary structures such as flanges, recesses, container neck openings, bypass construction, etc., superfluous, and thus make the carrier compatible with most of the custom designs described herein. ampoules. A further advantage is that all forces acting on the vial during its manufacture, such as insertion, filling, insertion, sealing and removal, are preferably absorbed in the axial fefefefefe fefe • fe · fefe fe fe · · Fefe • fe fe • fefe

-8 direction, thereby greatly reducing the risk of damage to the ampoule and contamination of the factory. The releasable locking may still make both sides of the workflow channel accessible, both for direct manufacturing operations but also for indirect operations such as ampoule testing and weighing, creating substantial flexibility in use, particularly in combination with a rotatable carrier arrangement, factory plant values for types of multiple ampoules or multiple chambers in ampoules. The sliding locking surfaces may be supplemented by stop surfaces fixed to each channel to further reduce the risk of inadvertent compression or reduction of excessive forces, which is important, for example, when precise dimensional or support tolerances cannot be guaranteed.

Other objects and advantages of the present invention will become apparent from the following detailed description.

Detailed description

As indicated in the introduction, the described syringe can be used for a variety of purposes, within and outside the medical field, and for any type of formulation, such as chemicals, chemical compounds or mixtures, in any container and when used for any purpose. For the reasons outlined, this system has some special values in relation to the delivery device of the medical devices, where design constraints are more stringent than most other uses.

The principles of the present invention may be applied to ampoule devices or systems in wide scope. It is possible to use the principles of this invention for the manufacture of ampoules per se,

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ie empty ampoules, for example for later filling or for use as mixing or preparation chambers, but it is preferred to use the present invention in connection with pre-filled ampoules and the method of their manufacture, ie including filling operations. The type of material pre-filled or additionally filled into the vials is not critical and is understood to include gases, liquids, or solids. The material may be a powder, such as a powder, cake or tablet. The material may be a fluid medium such as a liquid, including materials that act as liquids, such as emulsions or suspensions. The material may be subjected to a transformation wherein, for example, the solid is dissolved or the solution is dried, which may occur during manufacture or as a final preparation or mixing operation, immediately prior to use. It is to be understood that the nature of the therapeutic compositions includes therapeutic agents in a broad sense, and includes, for example, natural ingredients and body fluids, pre-filled or introduced into the container, even when the therapeutic agents are most often manufactured by the factory. The invention can assist in solving special problems in connection with sensitive chemical compounds that are susceptible to degradation or denaturation by mechanical forces such as high shear forces. Chemical compounds of this type can be high molecular weight compounds, high molecular weight hormones such as growth hormones or prostaglandins hormones. The invention may also assist in solving special problems in connection with medically required lyophilization steps, in production or preparation steps, immediately prior to infusion, typically for mixing two or more components which may all be liquid or may contain solids such as lyophilized powder in a solvent such as hormones or prostaglandins.

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-10Ampulka

The term "ampoule should be understood in a broad sense, and it should be generally understood that it includes a portion of the container and at least one aperture for access to its interior. Although otherwise indicated, the aperture should be considered to define an ampoule axis that is perpendicular and centered with the aperture surface, in a free exposition is parallel and centered with a hypothetical flow through the entire aperture. The direction along this axis through this hole from the inside and inside the container should be considered a forward direction and a reverse direction, respectively. When the vial is provided with two or more apertures, then the at least one aperture or reference aperture will be the aperture to be sealed in the process, and if the vial contains two or more such apertures to be sealed, the aperture will be the aperture for the final aperture. a use for passing a pre-filled material from the inside of the vial through the opening to the outside. The distance between the foremost and rearmost face of the vial will be considered the height or length of the vial. The positioning and directional provisions will be given according to the stated relationships, unless otherwise specified.

The container has at least one opening through which the contents of the container may pass during use of the ampoule, either from inside the container to the environment, for example, to deliver the medicament to the patient, or to the container, in the case of body fluid intake or during preparatory steps such as filling, mixing or dissolving in container. The container may have a plurality of apertures, in particular a front and a rear aperture, in the tube-type container. The same opening or the same openings may be used for both manufacturing and feeding connections, or different openings may be used, e.g.

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9 99 through a second opening which can be closed by a releasable or breakable seal.

The physical structure of the opening may require adjustment for this purpose. The plunger end of the syringe vial may require an aperture to accommodate the plunger, with the possibility of an end structure for engagement with the finger holder, as well as a plunger or feed mechanism. The other end, as well as the container opening, may require an arrangement to seal the seal. For this purpose, some kind of body attachment may be provided for the closure means, for example, protruding or recessed structures for engagement with additionally shaped closure portions. These structures can be placed on the inside of the hole, on the outside of the hole, or on both parts. Although threaded or bayonet-type designs are acceptable, it is preferred to provide engagement with simple axial relative displacement between the container and the closure, without requiring substantial angular movements. Such constructions may include flanges, grooves, undercuts, etc., continuous or intermittent, positioned around the aperture, including a conventional vial type, with an aperture, aperture portions, and collar. Several such structures may be used, for example axially displaced, for example to assist in positioning the closure portions in an open position allowing gas exchange, and in a closed position, although other arrangements are preferably used for this purpose, as will be explained. For similar purposes, as will be explained, there are advantages in using a straight tube shape hole, without the aforementioned designs, which can be closed by inserting a simple pin-shaped seal or plug, or any kind of closure such as a flat engaging seal in combination with the aforementioned sleeve mounting.

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It is clear that the ampoule in general is compatible with different embodiments of the aperture, as well as with different embodiments of the closure, including known conventional types, such as resilient seals with or without a lid, for permanent sealing or for a permeable or breakable configuration.

The container portion may assume a variety of shapes, such as any kind of tube, container, flexible bag, vial, capsule, cartridge, hemisphere, syringe body, and the like.

There are some advantages in using containers that are rigid, at least at their aperture, but preferably generally rigid, such as vials, rigid tubes, or syringe bodies. Further, there are some advantages when using roughly symmetrical container portions that are at least partially symmetrical with a constant cross section about a symmetry axis, such as vial bodies or cylindrical containers, with the aperture axis and container axis being substantially parallel, and most preferably they are essentially coaxial. Even more preferred is the use of the same cross-sectional profile for both the container and the aperture, providing elongated ampoules of substantially uniform shape from front to back face, for example, cylindrical, with or without closed back end, as in a vial. Conventional container materials such as plastics or, preferably, glass may be used. The container may have an integral or folded structure such that it includes an outer shell or any other multi-part structure for closure, attachment, protection, etc., and unless otherwise stated, it will be understood that "the container includes any auxiliary portion.

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The ampoule may be a single container, a vial or a bag, but the invention is of particular importance in connection with more advanced type ampoules, and this type of ampoule is particularly complex and is usually in the form of a cartridge forming part of a syringe vial in a delivery system that may be further developed in the case of multi-chamber cartridges. For this purpose, the cartridge may generally comprise a container with a front face and a rear face defining a general cartridge axis, a preparation outlet arranged at the front portion, and at least one sliding wall disposed at the rear portion, where displacement of the wall causes the prepared fabric moves forward or ejects with this output. The shape of the container and the sliding wall must be matched to each other. The container may have a substantially constant internal cross section, with a similarly constant container axis, between the front and rear portions generally forming the tube-shaped container, and most preferably is of the conventional cylindrical type, representing a substantially cylindrical container. The sliding wall then preferably has a substantially constant shape, although it may form a resilient body sealed to the inner surface of the container, and in particular the piston type.

Double-chamber or multi-chamber types of cassettes are known, for example, for requiring mixing of two or more components or precursors prior to administration. The components are held apart by one or more intermediate walls of various known designs, wherein the walls divide the container into a plurality of chambers, which are sometimes spaced parallel to the axis of the cassette, but most often are located in a folded configuration along this axis. Unification of components can occur by breaking, penetrating or opening a valve structure in the middle walls, for example, by inserting a pin or needle through the front of the cassette, through or near the rear of the cassette • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-14 sliding walls or at the outer part of the cassette (compare, for example, with WO 93/02720). In another known construction, the middle wall or middle wall is or is of the plunger type, and the flow connection between the chambers is achieved by moving the plunger to the bypass section, wherein the inner wall has one or more enlarged sections or repeated circumferential grooves and facets allowing bypassing of the rear chamber content to the front the chamber by moving the rear sliding wall (compare, for example, US 4,968,200 or WO 93/20868 and WO 95/11051). The last type of bypass is preferred because it permits the construction of a vial of substantially constant cross-section. The chambers may contain gas, liquids or solids. Usually at least one liquid is present. In pharmaceutical uses, there are more often two chambers, and usually contain one liquid and one solid where the substance dissolves and converts during the mixing operation.

As a conventional measure in the prior art, the described vials, cartridges or syringes can be adapted to be connected to a supply line. The feed line may be an infusion channel or any conduit, such as a tube or catheter, a needle or cannula, or a needle-free system based on injection of a gas or gas-driven liquid or gun. The conduit will be connectable to the interior of the container, particularly through the aperture in the ampoule, by attaching it to an openable, breakable or permeable seal.

A preferred embodiment of a syringe vial

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While the system of the invention includes manufacturing methods and means beneficial to all of the described types of vials, the system also includes one type of vial that has a special value in this system. As indicated in the preamble, a preferred type of syringe consists of a container with a front face and a rear face defining an axis therebetween, the container having a substantially constant cross-section between the front and rear faces, at least the front face ending in the opening from the seal attached to the front face and sealing the aperture, at least one piston slidably and sealingly disposed in the receptacle, and a sleeve extending at least along a portion of the receptacle, the receptacle having a front portion and a rear portion, wherein the front portion is attached to the seal.

In such a device, when a substantially constant cross-section is desired, small deviations in the example of the fastening structures on the front and rear faces or the middle bypass structure cannot be excluded, although it is preferable to make such deviations as small as possible, e.g. to a minimum diameter of less than 2 mm, preferably less than 1 mm, more preferably less than 0.5 mm, and most preferably substantially zero. As used herein, the term "diameter" does not imply a restriction on the circular cross-section, but will generally mean opposing points on the outer circumference of the non-circular profiles. It is still preferred that the container cross-section is substantially circular, which is essentially a circular container shape. The container may preferably be a two-chamber or multi-chamber type, with at least one built-in bypass arrangement. In the foregoing examples of bypass arrangement, the use of such arrangements is preferred,

• fefefefefeefefefefefefeefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefe an example of the construction of divided facets and grooves. Similarly, it is preferred that the cross-sectional area between the front and rear faces be substantially constant, since any deviation makes the container stronger or weaker than needed, such that the arrangement where

Therefore, it is also preferred to omit connecting structures, ducts, bypass cutouts, and so on, or are kept to a minimum extent, for example, so that cross-sectional variations at any point along the axial length of the container are maintained at less than 20%, more preferably less than 10% and most preferably less than 5%.

Also, it is preferred that the opening has substantially the same cross-sectional profile as the container, so that the aperture substantially constitutes a continuation or termination of the container, and the aperture edge roughly corresponds to the cross section of the container perpendicular to its axis. Also, it is preferred that a portion of the opening is included in the above conditions of constant cross-sectional area determined for the container as a whole. This overall edge shape does not preclude the shape of the actual end of the edge, for example when viewed in an axial cross-section, to a suitable shape for this purpose. For example, it is common to make the edges smooth, to avoid the risk of rupture, loosening of particles, cuts, deformation of the stopper, etc. A rounded shape is preferred for the inner or outer portion of the edge of the edge, and in particular for both portions where this rounding can be achieved by grinding. but in the case of meltable materials it is preferably carried out by heating. However, the melting may cause the molten material to shrink into a drop shape, seen in an axial cross section where the diameter of the largest drops exceeds the material thickness before heating, ie a partial drop is larger than the semicircle. When used on • 9 • · *

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- a current container, the edge may extend into the interior of the container and / or over the outside of the container. It is advantageous, for example, to shape the edge so as to maintain a uniform outer portion of the container and to facilitate handling, so that substantially all of the edge material is maintained within the outer diameter of the container. Similarly, it is advantageous to form an edge shape such that substantially all of the edge material is kept out of the inner diameter of the receptacle, facilitating access to the opening during manufacture, for example when filling or retracting the piston or seal. This also facilitates the construction of the seal, since a less pronounced bevel angle and length is required for any component coming into the bore, which in turn facilitates engagement and reduces dead and covered spaces in the sealed chamber.

To put it simply, it is advantageous if the curvature of the edge corresponds to about half a circle or is somewhat smaller. According to a preferred method of producing a smooth and still narrow edge, the container blank is heated around the desired edge profile and the two parts are separated by axial pull, while the heated edges are still hot, while heating can be maintained. The heating can be carried out by conventional means such as flame, but preferably is carried out by laser, in particular by carbon dioxide laser on glass, for the narrowest area of heating and better overall control, or by a combination of heating methods. This method of heating and tensile separation is known per se for other uses, and is disclosed, for example, in WO 86/05172, US 4,682,003 and DE 44 44 547. Although the aperture may be provided with other structures such as cutouts or the channels on the inner surface of the container, close to the opening, to allow gas to be exchanged with the environment, such as freeze-drying, also with the gasket retracted, it is preferred to use other methods and means to do this close to • ·

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The hole is substantially uniform, for example for simplicity and better sealing properties. In particular, the above considerations are suitable for an opening that is to be at least partially temporarily closed or sealed, particularly a front opening of the syringe vial, ie, on the outlet preparation side, but may also preferably be applied to the rear opening normally used for affecting the rear piston.

The seal used to seal the front opening may be of any kind described. It may have already formed an opening for fluid communication with the interior of the container and / or the already connected conduit or fittings for this conduit. However, it is preferred to use a seal to form a complete seal for later opening or connection for the pipe, in particular any seal suitable for penetration. Furthermore, it is advantageous to use a seal that can be brought from a leak-free position into a sealing contact with the opening by a simple axial displacement. The seal may be of a type that creates a seal by axial pressure against the edge of the opening, for example with a surface or flange portion corresponding to the edge, but it is preferable to use a sealing plug, one part of which is inserted into the opening and forms a seal by radial contact or pressure against the interior of the container, with and in particular in combination with a flange portion for axial contact with the rim. The portion inserted into the container may be generally cylindrical, and may in the usual manner have a central cavity, cut-out or recess, to increase flexibility or reduce the length required to penetrate the needle or other kind of blade. The intermediate stopper may preferably have a slanted shape to assist in self-guiding the lower edge of the stopper in a radial direction relative to the axis when inserted into the opening. The bevelled portion may advantageously be limited to the lower permeable portion of the plug, with the angle

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In particular, as large as possible is avoided between the axis and the lower surface, in order to avoid dead spaces due to the necessary guidance. Independently of the choice of seal type, e.g. flat, flange and / or plug type, it is preferred that at least a portion of the gasket, hereinafter referred to as "flange portion, be widened in a radial direction, ie perpendicular to its axis when the gasket is installed, which is larger than the outer diameter of the container. It is preferred that this portion has at least a larger container diameter at the opening, which, among other things, creates radial access to this portion at the opening, which preferably engages the sleeve, at least at the opening. It is preferred that the flange portion of the seal is also larger than the largest container diameter when the container is not completely uniform, as in the above example, which then makes the diameter of the flange the largest diameter of the container and seal unit, which increases the above benefits. Such an extension also allows the seal to be held by friction or otherwise, without contact with the container, in a channel of the same diameter as the outer diameter of the container, thereby facilitating automatic displacement of the seal from the rest position in such a channel above the container to the sealing position, in contact with the opening in the container . A channel of this diameter also allows the container to be moved or retracted over the resting position for the seal. If the channel diameter is significantly greater than the largest container diameter, it is preferred that the seal flange is larger than the channel diameter. The degree of expansion "greater than the diameter of the container at the aperture, its larger diameter, or the diameter of the channel, respectively, should be adapted for the intended purpose, and may depend on the tension of the desired handle and the flexibility or material of the seal, etc. For example, to hold the seal in the channel, the diameter should be functionally adapted to generate sufficient friction to maintain it during the method execution operations, but not to prevent its axial displacement during sealing

operation. Typically, the degree of expansion may be at least 0.05 mm, more preferably at least 0.1 mm, and most preferably at least 0.2 mm greater than the respective diameter. It may also be kept less than 10 mm, more preferably less than 5 mm, and more preferably less than 2 mm compared to the respective diameter. It is sufficient for the flange to have a predetermined extension at least somewhere around its periphery, for example at at least two opposing positions, preferably at least three or more points, more preferably symmetrically distributed around the periphery for better centering, and most preferably substantially around your entire circuit. While such an enlarged portion may be compressible enough to be inserted into the aperture, it is preferred that the flange be designed to be positioned in its sealing position outside the container, and most preferably in a flat portion intended to axially contact the aperture edge . Sealing parts, increasingly remote from the opening edge, are not critical. However, this axially distal face should in particular be designed to engage with the sleeve to prevent axial displacement of the seal out of the opening when the sleeve is in the locking position, and in particular should also be consistent with the purpose of allowing axial re-displacement the sleeve to said locking position when the seal is installed. For this purpose, the seal preferably has a contact surface, at least with a surface component that is perpendicular to the axis on which the sleeve can abut, for example a flat flange-like contact surface against which the sleeve flange can be positioned. Otherwise, the distal end of the seal may have a conventional shape, for example a central portion exposed to the penetration, preferably in the form of a concave dish, to reduce the necessary length of the penetration. The described seal is preferably made of a resilient material such as conventional rubber or elastomeric materials. Is possible, • ·

If desired, the seal typically does not need to be supplemented with a conventional closure to hold the resilient seal, since the sleeve described herein preferably performs this function.

The vial contains at least one piston, axially displaceable in the vial, and acts as a pump, for example, when sucking material into the vial and / or displacing its contents from the vial, the latter being particularly used with pre-filled syringes. In the case of a double chamber, there may be arranged a device and an additional piston which divides the first chamber, between the rear piston and the front opening of the container, on the front and rear chambers. In this case, a bypass may be provided, as described, positioned either centrally along the container to allow overflow from the back chamber to the front chamber, for example, to mix or dissolve, or located close to the opening, first to allow the contents of the front chamber to be displaced and then expelling the back chamber contents by bypassing the center piston. Such additional structures can be divided into three or more chambers. The piston may be of a conventional type, made of a resilient material, similar to the seal material, and is typically cylindrical in shape.

As used herein, the term "sleeve" means any structure that bridges the front and rear faces of the container. The main objective of the sleeve is to maintain the seal against forward displacement relative to the container, whereby the sleeve should both clamp the seal for this purpose and be attached to the container so as to prevent at least its forward displacement with respect to the container. This attachment to the container is preferably provided at the rear of the container, and can be performed laterally by means of an adhesive or a special one

A clamping structure, such as a flange or recess in the container, but preference is given to attaching the sleeve to the container using the rear face of the container as a stop surface for the forward movement of the sleeve, wherein the principle allows the use of a smooth tube type container without any clamping structures. The connection may be made, for example, by a structure that forms a part, or is attached to a sleeve that extends radially inwardly from a main portion of the sleeve for contact with the rear face, for example, a rear flange on the sleeve or a rear plate or piston holder to which the rear sleeve portion is attached . Similarly, at the rear end of the sleeve, the seal may be clamped by the side means, but is preferably clamped in the axial direction by contact between the front face of the seal. as previously described, and between the backward facing surface of the sleeve, such as the rear surface of the sleeve flange, extending radially inwardly from the main axial portion of the sleeve. Clearly, in these preferred configurations, the forces between the sleeve and the container are completely axial in both the container and the main sleeve portion. The main part of the sleeve, ie the part outside of the outer part of the container, extending between the front and rear faces, can form any spacer, such as a single rod or arm, two or more such arms, distributed around the perimeter of the container in a crimp type design, or one or several tube parts. However, it is preferred, for example, for reasons of protection, that the sleeve extends substantially around the entire container so as to surround the container having, for example, a tube shape. The sleeve may be a single internal structure, but is preferably made of at least two parts, for mounting, for example, from a separate front or rear portion, or two portions of flange tubes, to engage the front and rear faces of the receptacle where the portions are in the middle position. Auxiliary constructions may advantageously be arranged on the sleeve.

Rather than on a container, such as a clamping structure, a guide structure, a plunger and handle structure, a dispensing mechanism, and a needle attachment structure, for example, to accommodate a combined cartridge-type cartridge and sleeve for manual or mechanized and automated control and control in the feed device. In the radial direction, the sleeve may be in contact with the container, but it is generally preferred that a certain distance be maintained between the components for reasons of tolerance and safety. The actual distance depends on the shape of the container, for example if it is provided with an external bypass, but for preferred containers of substantially uniform cross-section, this distance is preferably small, for example less than 2 mm, more preferably less than 1 mm, and v most preferably less than 0.5 mm. The seal, which has a slightly larger radial dimension, as described hereinbefore, may be of benefit with the additional advantage of centering, guiding and aligning the sleeve with the container.

The described syringe ampoule construction, in addition to providing extremely simple and smooth container shapes, has a beneficial manufacturing advantage in its wide front opening. This feature may, for example, be used to introduce the piston through the leading edge rather than the rear face of the canister, which may be further utilized to perform several steps of the manufacturing process from the same side of the canister, e.g. multiple chambers, for example, to facilitate machine construction, omission of rotation steps, and leaving the second container face for attachment, testing, or other filling operation. In combination with the explained additional features, additional manufacturing advantages are achieved, as already indicated.

The invention for a pre-filled purpose

-24 Ampoule carrier

The vial carrier is formed to facilitate and improve the manufacture and quality of the vials. The carrier can be used for any of the described type of ampoules, although the advantages of using the vials with the preferred features are achieved. In general, the carrier consists of one or more ampoule seats, where the seat forms a channel for axial insertion, but radially engages the ampoule.

As used herein, the term "carrier" refers to a device that is suitable for supporting or storing at least one, and in particular a plurality of, ampoules, and is desirable to be treated as a unit in a manufacturing plant. The carrier may be monolithic, but it is preferred that it form an aggregate of the individual parts considered as a unit. The carrier may comprise auxiliary features, ie, features relating to the carrier as such, for example, facilitating its handling in the manufacturing process, such as individual parts suitable for mechanical gripping, turning and transporting, as well as means for facilitating assembly, disassembly and cleaning. By using the term " upper and " lower side of the carrier, it will be meant the side at the front and rear ends of the vial when inserted into the carrier.

The carrier will comprise at least one "seat" for each stored vial, ie one or more of several saddles, and it will be understood that it will include any individual portion on the carrier adapted for the individual vials, such as the vial.

-25 individual means for holding and handling. Preferably, each seat is adapted to accommodate only one vial.

The saddle comprises at least one vial channel, which means any technical feature adapted to allow axial insertion or translation but radial retention of the vial. For example, the channel may include one or more pads or other spacers forming a radial support of the vial at separate locations along its axis. However, the channel is more preferably formed by a "cavity, in the sense of a chamber surrounding the vial over a substantial portion of its length, and most preferably over its entire length. For example, the cavity may be formed as a "hole in the monolithic portion of the carrier body."

The seat may also be provided with one or more locking means, meaning any structure for holding the vial in the axial direction. The locking means may clamp the vial in any part, for example, in the middle portion, and prevent displacement in both axial directions. In particular, the locking means acts as a stop surface at the vial face, thereby preventing the vial from sliding in one direction. The seat is preferably provided with two locking means, one at each end of the channel, in particular at a distance of at least the height of the vial, but with the possibility of a greater distance. Furthermore, it is preferred that at least one, and in particular all of the locking means, are releasably arranged to allow access to the ampoule and to insert and withdraw the ampoule.

* '- 0 0 · · · »

000 00 »· ♦ ··

The seat may be provided with additional auxiliary individual parts, such as guiding structures for tools, positioning for seals, ventilation ducts for gases, and so on.

Structurally, the carrier may preferably be arranged as an intermediate body portion surrounding a larger portion of the vial height and channel length, such as an upper portion, for example, with an upper locking device and auxiliary individual portions, and as a lower, heel portion, e.g. individual parts. The height of the body portion may be adapted to the length of the ampoules being processed. The body portion may be of the frame type or of the frame structure, for example in the form of two or more plates with holes forming channels where the plates are separated by spacer means and possible walls for closing the frame. Such an open structure can be lightweight and easily adaptable to varying ampoule lengths. However, it is preferred that this body part is formed as a unitary structure, in particular monolithic, in which the channels are formed as longitudinal cavities, for example as bores, at least partially open at the upper and lower ends of this part of the carrier body. Such a uniform structure facilitates the arrangement of the cavity surrounding the vial, which is advantageous for reasons that have been determined in the preamble, the cavity preferably having the same height as the vial length.

Generally, it is preferred that the length of the channel at least corresponds to the length of the ampoule so that, for example, it does not expose any end thereof when handling the carrier, but it is preferred that the channel is longer, especially at the upper end, at least for holding, but especially also for sealing the seal in the leak. position relative to the vial opening, for example, as a preparation for pushing the seal into the sealing position, and in particular for

- 27 allowing freeze-drying. As is known per se, the sealing position may be in a partially retracted position with respect to the opening when the steam channels are arranged in the seal or in the vial, but in a more preferred embodiment the sealing position is further forward and only remains at the opening edge, but most preferably the embodiment is a sealing position even longer in front, in a floating position above and without contact with the vial opening, for example allowing a good gas connection even with a simple vial design and seal, which is easily achieved by using a seal retaining channel. In particular, the width of the channel at the support points for the vials is about the same as the largest vial width, allowing some additional clearance or tolerance. Similarly, the cross-sectional profile of the channel is particularly approximately equal to the cross-sectional profile of the vial, with the possibility of some variation, for example allowing a projecting structure such as an external bypass to pass if present. It is preferred that the channel has a substantially constant cross section at least along the height of the vial, and in particular that the cross-sectional profile or circumference forms a closed loop. When the channel is longer than the length of the vial, it is preferred that the length of the additional channel also has substantially the same width and the same profile, allowing axial displacement of the vial in the channel. Therefore, although the seal may be held in this portion of the channel by interfering with the channel, it is preferred that the seal be maintained by friction against the channel walls where the seal may have a larger dimension as described herein.

A locking means for limiting axial displacement acting on the rear face of the ampoule, as described, forms a surface extending into a portion of the canal fitted with the ampoule to such an extent as to support one end portion of the ampoule. The locking means should also be attached • • ♦ ···

·· ·· · · · · · · · · · · · · · · ·

The carrier, for example, at its top or bottom or at the top or bottom end of the channel. The attachment may be permanent, such as when the locking means is part of the carrier, or otherwise attached to the carrier. For example, a permanent locking means may be used at one end of the channel when the ampoule is retracted and withdrawn by the other end, which should be sufficient if all of the manufacturing steps can be performed from one side, and there is no need to rotate the carrier to the inverted position. The releasable locking means can be used as a permanent locking means, but provides greater flexibility, and can be used to block the side of the ampoule feed channel and, when such two locking means are used, both sides of the channel are accessible for manufacturing steps or for inserting and withdrawing ampoules. The releasable locking means may be attached by any type of attachment, for example, for complete removal or detachment. While the releasable locking means may be designed as a series of individually releasable structures, one for each ampoule channel, it is preferred that a single locking structure be used to block several, and in particular all, channels such as a plate or grid, the attachment of which to the carrier blocks all individual channels. The exact type of remaining area may vary. The locking surface can completely close the end of the channel to which it is attached, for example by a plate or multiple plug construction, but it is preferred that the entire area only partially covers the opening of the channel, thereby allowing access to the ampoule with the locking means installed. Advantageously, the locking means may partially cover the channel such that the channel means may be partially closed. with this uncovered part, a tool could be inserted to axially lift or push the vial away from the locking means. In the case of a vial type vial,

This can be accomplished through almost any uncovered portion, but in the case of a tube-type vial, for example a cylindrical container, at least a portion of the edge may be required to be exposed, for example by using a circular bar-shaped locking surface over the end of the channel or flange. covering only a portion of the container edge. In the case where the vial has an opening in the locking means, whether the front or rear opening of the container, it is also preferred that the opening be accessible and, in particular, completely accessible, for example for insertion of the piston or seal, which again may require that the locking means only cover its edge or part.

It is preferable to provide the seats with at least one locking means, for example at the lower end of the channel on which the vial rests when performing operations at the other end of the channel, for example at the upper end, for example operations such as retracting the piston, filling, retracting the floating seal, lyophilizing (freeze-drying) and final seal. It may also be desirable to provide the upper end with locking means, for example, to allow operations at the lower end or at the lower end, after operations at the upper end, wherein operations at the lower end may require retention of the vial or rotation of the carrier to an inverted position, e.g. filling the chamber or retracting the piston.

In all operations, according to the examples, separate tools, other than blocking structures, such as conventional press pins for insertion or displacement of the piston, gaskets or the vials themselves, may be used, and filling nozzles may be used to perform filling operations. Such individual tools for each channel may advantageously be arranged on a common support for joint manipulation, means or means.

-30 without pressure-equalizing means. However, it is preferred that the locking means also be used for at least one manufacturing step. For this purpose, the locking structure can advantageously be combined with the other auxiliary individual parts at the respective end of the channel. As described, they may be configured to retain the seal at the opening of the vial, which may then be pushed into engagement with the opening. Here, a locking means can be advantageously arranged on the upper part of the seal when pressed into engagement. Further, it is preferred to use the same structure to compress the seal into engagement and to act as a blocking means for the channel. In particular, the compression movement with the blocking structure may be guided, for example, by recesses in the carrier body, and these recesses may also act to limit the backward movement of the structure, against the desired movement to engage the seal, so as not to damage the actual ampoules, but these recesses may additionally used as vapor channels in the lyophilization or sterilization step. Similar guide structures may be provided at the lower end, if alternatively, engagement with the seal is performed by compressing the vial from below towards the seal using a lower locking means, under which the seal may be kept static, using an upper locking means or plate. For combined purposes, the locking means may have the same tooling design as mentioned but with the preferred shape for both purposes. The long "knives" or "rigid strips" locking structure placed by their edge or narrower edge towards the end of the channel, and thus by its wide surface positioned axially and bridging opposite several channels in a row, have been found to be suitable for the combined purpose, inter alia, of maintaining partial access to channels, easy axial guidance in longitudinal recesses along surfaces ♦ »····

-31carriers where. these recesses are preferably provided in each channel, with a choice of connection with the ventilation passages, with simple release and clamping, with the possibility of being housed inside the carrier body, etc. Although the recesses for guiding such locking structures may fulfill several purposes, both movement limitation and gas passage, it is possible to use different recesses for such purposes, such as elongated recesses for blocking structures and other gas passage recesses, such as holes or elongated recesses extending parallel, or preferably at an angle to the initially mentioned recesses, such as perpendicularly.

Method of use

The method of using carriers should be apparent from the given description of the structure, logically for each feature and step, according to the examples. The versatility and flexibility provided by the established characteristics allows for a variety of manufacturing schemes to be carried out, both in conventional manufacturing methods and in improved methods of the invention. In general, the preferred method of use includes the steps of inserting the vial into the channel, filling the material into the vial, sealing the vial opening with the seal, and removing the vial from the channel.

An advantage of the invention is the possibility of carrying out a series of steps from each side of the carrier. The possibility of supporting the vials at their faces allows the vials to be inserted from one end of the carrier, preferably from the upper and erect ends, and to perform filling with the same end, preferably without any rotation of the vials or carrier. It is also possible to insert gaskets from the same end,

99

9 9 9

9 9 9

9 9 9

9 9 9

99 * 99 * 9

To optionally perform a lyophilization step in the same position, and perform a real compression step from the same end of the channel and, if applicable, withdraw the vial by backward movement against the insertion step of the vial. These steps can terminate single-chamber vial type filling operations, such as single chamber vials, vials or syringes. The second side of the carrier and the second side of the channel are still available for additional or additional steps. For example, when a pre-filled two-chamber or multi-chamber device is produced, without the initial compartment for separating the cells, the middle piston may first be inserted to form the two chambers. This can be done from the front or top end, as already described for a single-shell device, if the vial has a previously described preferred construction, or from the other side of the carrier, in the case of any container construction. Upon completion of the above-described filling operations for the first chamber, the vial sealed from the front may be turned to an inverted position, in particular with the locking means installed at said end, and a similar filling operation from the other end may be performed, with the possibility of retracting the rear piston, in the case of a syringe vial. This method of filling from different ends is of particular importance when the individual components must not come into contact during production, even to a small extent, or when the first component must not be present in the first set of steps, such as the lyophilization or sterilization step of pressure sensitive liquids. Without such limitations, the invention allows the filling of several chambers from the same end, regardless of which end, where this is also of importance in the manufacture of pre-filled multi-chamber ampoules.

It is preferred to use the carrier in methods including a gas exchange step between the interior of the vial and the surrounding medium between the vials.

Another is because it allows both the protection of the vials and the arrangement of the gas channels. It is also desirable to use the present invention in conjunction with process steps including heat transfer, inter alia, due to the appropriate properties of the heat carrier and heat equalizer. Furthermore, it is desirable to use the present invention in conjunction with methods involving varying the pressure, inter alia because the aforementioned gas passages serve to allow the desired pressure adjustment, and because the filling flexibility allows for postponing the delivery of the pressure-sensitive material, e.g. condensing due to differences in pressure or material that degrades under certain pressure or temperature conditions. Typical manufacturing steps involving such treatment-related problems are sterilization and lyophilization.

A preferred use is when passing gas through a tube type tube, such as containers, from one end to the other end, which is facilitated by selecting a carrier where the vial fronts are at least partially exposed. In such a step, the carrier channels are preferably substantially uncovered, e.g. The gas may pass through the vials for any purpose, such as washing, drying, etc., but a preferred use is for gas sterilization of the vials. The gas can act chemically, but it is preferable to use hot gas, taking advantage of the heat conduction in the carrier as described, for example, in a hot gas circulating apparatus.

Another advantage of the present invention is the choice of leaving the seal in floating position above the vial opening, inter alia because it facilitates guided and protected engagement of the seal, for example by simple axial movement between the seal and the vial, and <

»· To · ¹ ► · · '• to » <

• to · · · · · to · <

Because it is possible to perform a method step between introducing the seal in the rest position and engaging it in the opening of the vial. Therefore, it is advantageous to use the invention in conjunction with methods comprising any such operation or generally a sealing step from a resting seal position. A typical example is the freeze-drying step, where the seal can be inserted into a rest position and freeze-drying can be performed, followed by a seal engagement, where this last step can be easily performed in the lyophilization chamber due to the simple axial movement of the seal.

It is also advantageous to use the carrier in a sealing method with a resilient seal, inter alia because such a seal can be easily maintained in a rest position by friction, at light pressure, since such a seal alone can easily be brought into a pre-seal that is sufficient for most manufacturing steps, and since any closure closure can be postponed to any later stage, from the carrier. As previously the type of closure has a sleeve type which, when the vials have been released, is preferred to be passed from the front to the rear face, for example, after any separate step in the method.

Carriers can be used to achieve any of the above advantages, regardless of the characteristics of the manufacturing plant. For example, the carriers may be used to facilitate manual handling of the vials in the various steps thereof. The carriers can also be advantageously used in automated and mechanized manufacturing plants where handling, transportation and processing are carried out by means of a marked machine in which the simplicity and flexibility of the carrier can be optimally utilized.

• »this · · · · · · · · · · · · · · · · ·

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

For the stated reasons, the products produced by the method according to the system of the invention have advantages as such and form part of the system.

List of drawings in the drawing

BRIEF DESCRIPTION OF THE DRAWINGS The invention will now be explained in more detail with reference to the invention, wherein FIG. 1 shows a dual-chamber cartridge with an external sleeve according to the prior art.

Figure 2 shows a front face of an alternative cassette construction according to the invention.

FIGS. 3A-3D show various cross-sectional shapes of the aperture described in the present invention in a cross-section of a single container.

FIG. 4 is a schematic representation of the main steps of a method for producing pre-filled dual-chamber cartridges.

Figures 5A-5F are plan view, short side view, long side view, sectional view, partial magnification, and perspective view of the ampoule carrier of the invention.

FIGS. 6A-6C are top and side elevational views of the ampoule carrier of FIG. 5; FIG. 6D illustrates a single channel column locking means; FIG.

· Fcfcfc · • · fcfcfc · · · · · · · · · · · · · · · · · · · · · · fc * · · · · · · · · · · fcfcfc ·

Figure 7 is a top plan view of an alternative vial carrier with a different channel distribution.

EXAMPLES OF THE INVENTION

FIG. 1 shows a double chamber cassette having an external sleeve of the general type disclosed in U.S. Pat. No. 5,435,076, which is incorporated herein by reference. The figure shows the relationship between the components before the seal and the sleeve have been axially displaced into the seal connection with the container opening, and before the lyophilization step is performed. The syringe container 1 has a neck 2 with a front opening. A piston 3 is inserted into the container 7 towards the rear of the bypass 4, and divides the container 1 into the front chamber 5 and the rear chamber.

6. The container 1 is surrounded by a sleeve 7 having approximately the same length as the container 7. The front end 8 of the sleeve 7 corresponds to the neck 2 of the container 1 and extends further into the threaded portion 9 provided with external threads for connecting the needle holder and ends with the inner flange 10. Inside the threaded portion 9 there is a plug 11, with an outer flange 12. the sleeves 7 and the outer flange 12 of the plug 11 are mutually adapted to prevent the forward movement of the plug 11 relative to the sleeve

Further, the stopper 11 is provided with a roughly cylindrical portion 13 intended to be sealed into the aperture of the receptacle 3, and the cavity 14 in this portion forming the thin membrane 15 is intended to penetrate the needle. A space 16 is formed between the sleeve 7 and the container 1, allowing the steam to escape from the opening during lyophilization. The fastening means 17 provided on the sleeve 7 allow attachment to the actuating means and anchoring of the sleeve 7 behind the end of the receptacle 7. The front chamber 5 is first filled with the solution 18 to be lyophilized into?

• • 0 0 0 0 0 « • • 0 0 0 0 0 • • 0 0 9 0 · 0 0 • 0 0 0 0 0 0 0 0 0 0 * 0 0 ·

-37 dry state. The opening of the container 1 is then closed by axially shifting the sleeve 2 ^and Finally, (not shown), the rear chamber 6 is filled with solvent, the rear piston is inserted to close the rear chamber 6, and the operating mechanism is attached to the rear end of the cartridge unit.

FIG. 2 shows a preferred alternative design of the front face of the cartridge, wherein the cassette may in other respects be similar to that shown in FIG. 1. The cassette is generally designated by the reference numeral 20 and includes a gasket 21 having a flange 22, a roughly cylindrical portion 23 for insertion into the receptacle opening, cavity 24 in the cylindrical portion 23, top surface 25, cup-shaped recess and recess 26 in the front portion of the flange 22. The cassette 20 further comprises a generally cylindrical receptacle 27 and a sleeve 28 extending from the front end of the plug 21 to the rear face of the cylindrical container 27 and the inner flange 29, to engage the flange 22 and the recess 26 of the stopper 21. The cylindrical portion 23 of the stopper 21 is inserted into the front face of the container 27, whose opening simply forms the end of the cylindrical container 27 and in this embodiment forms a flat fringe. The flange 22 rests on the flat edge of the container opening 27 but has a larger diameter than the cylindrical container 27 so that it extends radially over the outer dimensions of the container 27, and at least partially into the space between the container 27 and the sleeve 28. As further shown, the flange 22 has a larger diameter than any part of the stopper 21 in front of it, so that the flange 22 can abut by the axial backward movement of the retention surface. The inner flange 29 of the sleeve 28 is intended to provide a retention surface for abutment against the flange 22 of the plug 21, and it is clear that the inner flange 29 may come into contact with the flange 22 by retracting the sleeve 28, also after inserting the plug 21 into the opening. The recess 26 of the stopper 21 engages with the innermost protruding shape of the inner flange 29 ·· · · · · · · · · · · ·

The upper surface 25 of the cup-shaped plug 21, in addition to the cavity 24, further limits the necessary penetration length, for example, for the blade or needle through the central portion of the plug 21. Rear the portions of the cassette 20 (not shown) may be indicated as in Figure 1, ie the middle piston dividing the container into the front chamber and the rear chamber, the bypass arrangement, the rear piston and the sleeve anchorage to the rear face of the container, with integral connection to the control mechanism structure rear piston. According to the principles of the present invention, this construction can be advantageously used in the lyophilization step, wherein the flange 22 of the plug 21 is maintained by friction above the opening of the container 27. This may be done without the presence of the sleeve 28, and the space between the container 27 and the sleeve 28 may be provided for further considerations than the formation of a steam channel as required in the prior art.

FIGS. 3A-3D show various cross-sectional shapes of the aperture described in the present invention in a cross-section of a single container. The edge of Fig. 3A has a rectangular cross-section and forms a straight end of the ampoule wall. This edge shape is not easy to produce without debris, and is not optimal due to the plug insertion, safety and strength. Fig. 3B shows a droplet-shaped edge, wherein the droplet dimensions in the lateral direction relative to the ampoule axis are greater than the ampoule wall thickness, so that the edge material exceeds the nominal ampoule diameters, both in and out. The teardrop shape is often the result of shrinkage of the liquid material after partial melting of the edge, for example when aligning or cutting the glass blank. Even though the rounded shape, as such, is beneficial, there is no reason to describe it.

A teardrop-shaped material outside the nominal wall thickness of the ampoule. Fig. 3C shows a preferred edge shape which is still rounded but on one side of the cross-section where no material outside the nominal surface of the ampoule wall is present on the left side of the figure. The wall surface without protruding material may be provided on the outside of the vial or on the inside of the vial, depending on where the problems described are to be eliminated. FIG. 3D shows an even more advantageous edge profile which is substantially round-shaped, where no material exceeds the nominal wall thickness on either side. This problem can eliminate all the problems described. An advantage is most important for roughly cylindrical vials and when the aperture has approximately the same diameter as the inner diameter of the cylindrical vial. In particular, these preferred edge shapes are used around the aperture at the front of the vial, but may also be advantageously used at the other vial apertures, such as the back of the vial type vial. In the figures, the dashed face surfaces of the wall below the marginal area are indicated.

FIG. 4 is a schematic representation of the order of the main steps of a preferred method of making a pre-filled two-chamber syringe cartridge. Some steps are performed in the sterile region 40, indicated by dashed lines. In the first step 41, the syringe containers are washed and the silicon surface is saturated. The containers thus processed are transported through the sterilization device 42, at the exit of which they enter the sterile region 40. At the insertion step 43, the middle piston is inserted into the container for separating the front and rear compartments.

-40fe · ······ fefe · fefe · f · f · f · f · f · f · · · · · · · · ·· · · · · Fefe · fefe · ·

In the filling step 44, the solution to be lyophilized is charged into the front chamber and the solution is lyophilized in step 45. In the next step 46, the front face of the container is sealed in place in the lyophilization chamber. The solvent for the lyophilized (frozen) powder is fed into the back chamber at the next filling step 47. At the next feed step 48, the rear piston is inserted into the rear face of the canister to seal the solvent in the back chamber. Formulations in the container are now sealed against the environment and the pre-filled container may leave the sterile region 40. In the final assembly step 49, other components, such as the seal cap and the rear actuator, may be added as an auxiliary component as described. It is clear that all components and components supplied to the container, especially the intermediate piston and the rear piston, as well as the solution and solvent, must be fed into the sterile region 40 under sterile conditions.

In the above method, it is preferable to use the vial carrier of the invention, in all steps 43 to 48, carried out within the sterile region 40. Due to the versatility of the carrier, it is also possible and advantageous to use the carrier in step 42 in a sterilization device, and the carrier can also be used in the first step 41, where the syringe containers are washed and their siliconized surface, although these steps may also be performed with bulk vials or in a blister pack. In general, it is preferable to take the ampoules out of the carrier prior to performing the assembly step 49. It is also generally preferred to turn the carrier ampoules into an inverted position between steps 46 and 47, and preferably this is the only rotation step until the vial is removed from the support. If the preferred syringe vials are described, all steps up to and including step 46 may be performed from the top side. 000000 00 ·· · 0 0 · 0 0 · ··· · * • 0 0 0 0 0 ······ • 0 0 · 0000

000000 «0 · * * *

-41 carriers. It is also possible to postpone the assembly of the seal until the assembly step 49 is outside the sterile area, limiting the number of components supplied to the area. According to the invention, it is possible and advantageous to bring the seal into the rest position of the carrier, allowing for the escape of steam, which is in particular carried out between steps 44 and 45. Step 4 6 for sealing directly in place, in particular by axially moving the gaskets supplied from the rest position to the sealing with the front opening of the container.

FIGS. 5A-5E show various views, in cross-section and on an enlarged scale, of the body of the vial carrier according to the invention. FIG. 5F is a perspective view of a vial carrier body in a slightly enlarged scale. Roughly, the rectangular carrier body 50 is a monolithic part, especially made of an aluminum block, and has an upper or front side 51 and a lower or rear side 52. Numerous vial channels 53 are arranged in the form of 29 columns and 18 rows interspersed with an arrangement for creating 261 channels. As best seen in FIG. 5E, the channels comprise a hole 531 in the carrier body 50, wherein the hole 531 is delimited by an inner wall 532 and a uppermost portion 533 that is slightly conical to facilitate insertion of the vial and seal. On the upper side 51 of the body 50 there are 29 linear guide slots 54, all of which extend through the upper portions of all the channels in the columns, and as best seen in FIGS. The cutouts 54 act as a guide structure for the upper locking arrangement as further described in FIG. 6, and are also used to move the seal from the rest position to the sealing position. Similarly, 18 linear slits forming vapor channels 55 are arranged on top 51 of body 50, all of which pass through the upper portions of all channels in rows, as best seen in FIGS.

-42 partial depth of channels. These steam ducts 55 serve as additional conduits to escape the steam during lyophilization when the seal is pushed into the rest position at the top of the duct. As best seen in FIGS. 5D and 5E, for each channel 53, lower locking means are provided on the lower side 52 of the body block 50, in the form of a shoulder 56 extending radially inwardly from the inner wall 532 of the hole 531, where the shoulder 56 is intended for storing the vial flange. As best seen in FIG. 5C, the guide slots 54 extend downwardly in one of the longer sides of the carrier body 50, in the side slots 57, and the groove 58 extends along the same side of the body transversely to said side slots 57, all in order to support the combined locking tools and compression seals. The longitudinal recesses 59 are configured to handle the carriers in the mechanized manufacturing plant. In use, the vials can be pushed from the top 51 of the body 50 into the channels 53 to receive the lower locking shoulder 56. The seals can be inserted from the same side of the body to a rest position located in the portions 54 or 55 of the channels, and secured against being pulled up by the upper locking means in the first axial position, and may be further brought into the sealing position by moving the upper locking means to the lower second position.

FIGS. 6A-6C are top and side elevational views of the upper ampoule locking arrangement 60 of FIG. 5, and FIG. 5F is about the same scale. FIG. 6D illustrates a single channel column locking means 61. As best seen in FIG. 6D, a single channel column locking means is generally formed as an "L" strip having a longer straight locking portion 62 and a shorter hinge portion 63.

9

9

9 * »· 9 9 9 9

999 999 99 9 9 9 9 9

The channel column means 43 further comprises holes 64 and 64 ^from to couple several locking means 61 into a parallel arrangement, and an elongate suspension recess 65 allowing a certain movement along the hinge portion 63 when the axis is positioned in the hinge recess 65. The radius of curvature 66 has a center at the nearest portion of the hinge recess 65, and the curvature goes straight 6A, 6B and 6C, a unit locking arrangement is provided from the column locking means 61, parallel to and held by the rods 67 and 67 &apos;, which extend through the holes 64 and 64, respectively. '. The hinge axis 68 extends through the elongate hinge recess 65 of all the locking means 61 for the columns.

In combination with the carrier body of FIG. 5, the hinge axis 68 is positioned and preferably mounted in the groove 58 such that each hinge portion 63 of the locking means 61 is disposed in corresponding side slots 57. If each straight locking portion 62 of the locking means 61 inserted into the corresponding guide slot 54 on the upper side 51 of the body 50, the entire locking arrangement 60 can be displaced axially with respect to the channels 53 to the extent allowed by the elongate suspension recess 65. This in particular allows the locking arrangement 60 to occupy the uppermost position while still being is guided by guide slots 54, and supports the stoppers in a rest position above the vial openings, and the lowest position where the sliding to this position causes the seal to be compressed into a sealing connection with the vial openings. In the uppermost position, the hinge axis 68 is centered with the curvature 66 of the hinge portion 63 and the curvature 66 engages the lower portions of the side slots 57, compare to Figure 5D, to allow the locking arrangement 60 to pivot about the hinge axis 68, away from the top 51 of the body 50 .

-44 ·· · · · · · · · · · · · · · · · · ·

At its lowest position, the straight portion 69 of the hinge portion 63 engages the lower portions of the side slots 57 to prevent rotation of the locking arrangement 60 about the hinge axis 68, with means (not shown) for releasably securing the locking arrangement 60 in this position.

Fig. 7 is a top plan view of another embodiment of the vial support body 70 of the present invention. The carrier body generally has the same features as the embodiment of Figure 5 but has a somewhat different channel layout. The channels 71 are arranged in columns of ten rows 73 which have slightly smaller spacings resulting in a generally rectangular plan view. Additional columns and other rows with smooth holes 74 are inserted between each column and row, mainly to reduce the weight of the carrier and to increase the interface in the heat exchange step, especially hot gas sterilization. The channels 71 have the same structure as described in FIG. 5E. The upper surface of the carrier body 70 has similarly guided cutouts 75, for a combined upper locking and compression arrangement similar to Figure 6. The carrier body also has transverse ventilation slits 76 providing a vapor escape path during lyophilization. The notches 75 and 76 penetrate only to a portion of the axial length of the channel. Holes 77 form an auxiliary handling structure in a mechanized manufacturing plant.

In this embodiment, no hinge is provided for the upper locking arrangement. Instead, ten straight bar locking strips are connected to a smooth grid. As in the embodiment of FIGS. 5 and 6, the lattice may be positioned with the locking means for the columns in the guide slits 75 above the seals in the rest position for lateral axial movement to engage the seals with the vial openings. However, the lattice can also be placed in additional cut-outs 78, passing through the ů · * to to ♦ ♦ · · · * * * * * *

MN this hole 74 for exposing holes 71, for example, to a filling process step, and the grid will still be held within the upper surface of the carrier body. The grating may be provided with clamping means (not shown) to hold the grille at different positions.

The invention is not limited to the embodiments described, but may be varied within the scope of the claims.

patent claims /

\ T

A syringe ampule consisting of a container with a front face and a rear face defining an axis therebetween, the container having a substantially constant cross-section between the front and rear faces, wherein at least the front face terminates in an opening from a gasket attached thereto. to the front face and sealing the aperture, at least one of the pistons slidably and sealingly disposed in the container, and of the sleeve (extending at least along a portion of the container, the sleeve having / front and rear portions where the front portion is attached to the seal, characterized by characterized in that the container has a front end terminated by an edge surrounding the opening, wherein the edge m ¹ an outer circumference which is substantially the same as the outer periphery of the container.

/

\ T

2. An ampoule according to claim 1, characterized by \ t

that ^from the container is substantially cylindrical, and the outer periphery of the edge and / or container is substantially circular. \ T

Claims (85)

PATENT CLAIMS A vial for syringes, comprising a receptacle having a front face and a rear face defining an axis therebetween, wherein the receptacle has a substantially constant cross-section between the front face and the rear face, wherein at least the front face ends with an aperture; a sealing bore, from at least one piston slidably and sealed disposed in the container, and from a sleeve extending along at least a portion of the container, the sleeve having a front portion and a rear portion, the front portion being attached to the seal; a front face terminated by an edge surrounding the opening, the edge having an outer periphery that is substantially the same as the outer periphery of the container. The vial of claim 1, wherein the container is substantially cylindrical, and wherein the outer periphery of the rim and the container is substantially circular. -46 · to · ♦ toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto Ampoule according to claim 1, characterized in that the cross-section of the container is constant, with a deviation of less than 2 mm, preferably less than 1 mm and most preferably less than 0.5 mm, measured from maximum to minimum external diameter or generally between opposite points on the outer circumference. The vial of claim 1, wherein the seal at least partially exceeds the outer diameter of the front face and the outer diameter of the container. The vial of claim 1, wherein the container is of a two or multi-chamber type comprising at least one mixing arrangement between the chambers. The ampoule of claim 5, wherein the mixing arrangement is a leaking section for the plunger substantially distributed around the periphery of the container. The vial of claim 1, wherein the container has a rear face terminated by a rear edge surrounding the rear opening, the rear edge having an outer periphery that is substantially the same as the outer periphery of the container. »* · · · · · · · -4ΊS. The vial of claim 1 or 7, wherein the rim is rounded. The vial of claim 1 or 7, wherein the entire edge material is substantially maintained within the outer periphery of the container. The vial of claim 1 or 7, wherein the entire material of the rim is substantially maintained outside of the inner periphery of the container. The vial of claim 1, wherein the seal has a portion penetrating into the opening and having radial contact with the inner surface of the container. The vial of claim 1, wherein the seal has a flange portion whose extension is greater than the circumference of the container at the aperture and / or greater than the largest circumference of the container. The ampoule of claim 12, wherein the extension is at least 0.05 mm, more preferably at least 0.1 mm, and most preferably at least 0.2 mm larger, but less than 10 mm. mm, more preferably less than 5 mm, and most preferably less than 2 mm. 9 44 44 44 4 * 4 4 4 · 4 4 4 4 4 4 4 4 * 4 4 4 4 4 4 4 4 4 » 4 4 4 4 4 • • 4,444 4 »* -4814. The ampoule of claim 12, wherein the flange extends substantially around its entire circumference. 15. The vial of claim 1, wherein the seal is resilient. The vial of claim 1, wherein the sleeve is secured to the container. The vial of claim 16, wherein the attachment is to the rear of the container. The vial of claim 16, wherein the attachment comprises at least one structure extending radially inwardly beyond the rear face of the container. The vial of claim 1, wherein the front portion of the sleeve is attached to the seal by at least one structure extending radially inwardly in front of the portion of the seal. The ampoule of claim 1, wherein the sleeve comprises auxiliary structures selected from the group consisting of clamping structures guiding 99 9999 9 9 -49 needle construction, or 0 · · 99 · 9 · 9 4 . 4 9 4 9 9 9 9 9 constructions, dosing mechanism constructions, combinations thereof. plunger structures and handles, attachment A method of manufacturing a pre-filled syringe vial, comprising a container with a front face and a rear face which define an axis therebetween, wherein the container has a substantially constant cross-section between the front and rear face, wherein at least the front face ends with an aperture to a front face and a sealing bore, at least one piston slidably and sealed disposed in the container, and a sleeve extending along at least a portion of the container, the sleeve having a front portion and a rear portion, the front portion being attached to the seal, comprising following the steps of first inserting the piston through the aperture in the front face at a distance from the aperture into sealing engagement with the inner portion of the container to form a chamber between the piston and the aperture, filling the chamber with the material and then sealing the aperture with the seal. 22. The method of claim 21, wherein a lyophilization step is performed prior to the sealing step. The method of claim 21, wherein the lyophilization step comprises the step of sliding a portion of the seal into the opening and contacting the portion with the inner surface of the opening. 9 9 9 · · · fefe fe 9 9 · fefe fefe · fefe fe ·· · ♦ -5024. Method according to claim 21 or 23, characterized in that after the sealing step the sleeve is attached to the seal. 25. The method of claim 24, wherein the sleeve is attached to the rear face of the container. 26. The method of claim 21, wherein a second piston is inserted through the rear opening of the container. A method according to claim 21, characterized in that a back-filling filling operation is performed before the second piston is inserted. A pre-filled syringe ampoule, characterized in that it is manufactured by the method of claims 21 to 28. An ampoule carrier unit for use in the manufacture of pre-filled ampoules, comprising at least one ampoule, and a carrier provided with one or more ampoule seats, wherein the seat forms a channel for axial insertion but radial retention of the ampoule, the ampoule consisting of a receptacle with a front or an upper face and a rear face or a bottom face defining a vial axis therebetween defining radial directions perpendicular to this axis and defining the vial height, and further comprising a receptacle opening, at least at the front face, denoted by 0 0 00 00 · ♦ 0 0 0 0 · 1 · 0 0 0 0 0 0 0 000 00000 0 0 0 0 0 0 0 00 · ·· ·· Characterized in that the channel is formed as a cavity, wherein the walls of the cavity have at least the same height along the vial axis as the height of the vial, and that the walls of the cavity are substantially continuous about said axis and along said height. The unit of claim 29, wherein the vial container is a container selected from the group consisting of a tube, container, bag, vial, holster, dome, syringe container, and combinations thereof. The unit of claim 30, wherein the container is at least partially symmetrical, with a constant cross section, along an axis of symmetry. 32. Unit by claim 31, confess č u j í c í s e t x m that the container has Tube shape. 33. Unit by of Claim 29 X J X c i s e t x m that ampoule consists of a container injection syringes, having front and rear apertures. 34. t X The unit of claim 33, m that the ampoule is basically ..... cylindrical.  of 3 1 c i s e 35. The unit of claim 33, confess her c i s e t X wherein the container is a two-chamber or a multi - chamber -52to · · · toto · toto toto toto toto toto toto to to to to to to to to to to to to to to to to to to to to to Of the type provided with at least one valve or bypass arrangement. Unit according to claim 29, characterized in that the cavity is formed as a bore in a part of the carrier body, in particular in a monolithic part of the carrier body. The unit of claim 29, wherein the width of the channel is approximately equal to the largest width of the vial. 38. The unit of claim 29, wherein the channel cross-sectional profile is approximately equal to that of the vial. The unit of claim 29, wherein the channel has a length at least corresponding to the length of the vial. The unit of claim 39, wherein the channel is longer than the vial. 41. The unit of claim 40, having a seal disposed in the channel at the front face of the vial. -53 • 0 00 · 0 · 0 0 0 0 φ 0 000 000 · φ 000 00 00 00 · 0 0 0 000 0000 000 000 ·· · ·· · 42. The unit of claim 41, wherein the seal is held in the channel by friction. 43. The unit of claim 29, wherein the seat comprises at least one locking means attached to the carrier and configured to limit the axial displacement of the vial. The unit of claim 43, wherein the blocking means has a surface extending into the channel at the front and / or rear face of the vial. 45. The unit of claim 44, wherein the channel cross section is only partially covered by said blocking surface. 46. The unit of claim 45, wherein the face of the vial face is only partially covered by a blocking surface. 47. The unit of claim 43, wherein the single locking structure provides locking surfaces for more than one seat. Fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfc -5448. A unit according to claim 47, characterized in that the blocking surface is provided with at least one rod or one belt bridging more than one channel. 49. Unit according to claim 43; z n a č u j and c í s e that blocking means Yippee releasably attached to the carrier. 50. Unit according to claim 43; z n a č u j and c í s e in that the seat consists of two locking means having a pitch at least equal to the height of the vial. 51. The unit of claim 50, wherein the pitch is greater than the height of the vial. 52. The unit of claim 51, wherein the vial and the seal are disposed between the locking means. 53. The unit of claim 29, wherein the unit is provided with a tool disposed axially displaceably with respect to at least one channel and having a portion for introduction into the channel. -55 • 0 ·· · · 9 9 9 · 9 9 9 9 9 9 · 9 9 9 9 9 9 9 9 9 999 999 99 99 99 99 54. The unit of claim 53, wherein the tool is disposed at least at the upper end of the carrier. 55. The unit of claim 53, wherein the tool is used as a locking device. 56. The unit of claim 53, wherein the tool has a plurality of portions for introduction into a plurality of channels by axial displacement. 57. Unit according to of Claim 53 has a guide structure learning s e feed that : Tools. carrier for axial 58. Unit according to of Claim 57 č u .mu.Ci s e in that each channel is provided with separate guide structures. 59. The unit of claim 57, wherein the guide structures are provided with a stop surface for axially moving the tool toward the channel. 60. The unit of claim 57, wherein the guide structures consist of recesses in the carrier body. -56 • this this ···································· · ** A unit according to claim 60, characterized in that ....... 62. The unit of claim 29, wherein the carrier is provided with ventilation troughs at least between the front face of the vial and the outer portion of the carrier. 63. The unit of claim 62, wherein said grooves are formed as recesses in the carrier body. 64. A vial carrier unit for use in the manufacture of pre-filled vials, comprising at least one vial, and a carrier provided with one or more vial seats, wherein the seat forms a channel for axial insertion but radial retention of the vial, the vial consisting of a vial with a front or an upper face and a rear face or a bottom face defining a vial axis therebetween defining radial directions perpendicular to said axis and defining a vial height, and further comprising a receptacle opening, at least at the front face, characterized in that the channel length is greater than the height of the vial, and that the portion of the channel downstream of the vial comprises an inner surface distributed around the circumference of the channel. -57 • · 0 0 0 0 0 0 0 • 00 0 · 0 00 * · · 0 0 65. The unit of claim 64, wherein said surface has a generally tubular shape, at least in the axial portion. 66. The unit of claim 64, wherein said surface has substantially the same cross-sectional profile as the vial portion of the channel. 67. The unit of claim 64 wherein said surface is provided with a seal. 68. The unit of claim 67, wherein the seal is held to this surface by friction. 69. The unit of claim 67, wherein the seal is located above the front opening of the vial. 70. The unit of claim 64, wherein the carrier has a plurality of channels, and wherein each channel has said inner surface. A unit according to claim 64, characterized in that it comprises the features set forth in claims 29 to 63. «3» »·· -58 • · 4 * A · 9 9 9 99 99 9 9 9 9 9 9 9 9 9 99 99 72. A vial carrier unit for use in the manufacture of pre-filled vials, comprising at least one vial, and a carrier provided with one or more vial seats, wherein the seat forms a channel for axial insertion but radial retention of the vial, the vial consisting of a vial with a front or an upper face and a rear face or a bottom face defining a vial axis therebetween defining radial directions perpendicular to said axis and defining a vial height, and further comprising a receptacle opening at least on the front face, characterized in that it consists of a lower locking surface attached to the channel and extending at least partially into the channel, from an upper blocking surface attached to the channel and extending at least partially into the channel, from the upper blocking surface and from the lower blocking surface axially spaced at a pitch corresponding at least to the vial height and at least low a locking means and an upper locking means releasably connected to the channel. A unit according to claim 72, characterized in that the lower locking means and / or the upper locking means are axially displaceably attached to the channel. A unit according to claim 72, characterized in that it comprises the features set forth in claims 29 to 63. 75. A vial carrier unit for use in the manufacture of pre-filled vials, comprising at least one vial, and a carrier provided with one or more vial seats, wherein the seat forms a channel for axial insertion but radial. Holding the vial, the vial consisting of a container with a front or upper face and a rear or a lower face defining a vial axis therebetween defining radial directions perpendicular to this axis and defining a vial height, and further comprising a vial opening at least on the front face characterized in that it comprises a plurality of seats arranged in a carrier, a lower locking surface attached to each channel and extending at least partially into the channel, an upper locking surface attached to each channel and extending at least partially into the channel, at least one lower a blocking means and an upper blocking means releasably connected to the channel from the guide structures for at least said blocking means arranged on the channel support. releasable for everyone The unit of claim 75, wherein the at least one locking means is axially displaceable relative to the channel. 77. The unit of claim 76, wherein the guide structures are provided with at least one stop surface limiting the axial displacement of the sliding upper or lower locking means toward the channel. A unit according to claim 75, characterized in that it comprises the features set forth in claims 29 to 63. • · · · -6079. A method for producing pre-filled ampoules using an ampoule carrier unit comprising at least one ampoule and a carrier having one or more ampoule seats, wherein the seat forms a channel for axial insertion but radial holding of the ampoule, wherein the ampoule consists of a container with a front or top a face and a back or a bottom face defining a vial axis therebetween defining radial directions perpendicular to this axis and defining a vial height, and further comprising a receptacle opening, at least on the front face, comprising the steps of: inserting the ampoule into the channel, filling the ampoule with the material, then sealing the opening of the ampoule with a seal and finally removing the ampoule from the channel. 80. The method of claim 79, wherein the vial is retracted at the first end of the channel and further, at the same end of the channel, an additional operation is selected from the group of steps consisting of inserting the plunger into the vial. inserting the seal into the channel, removing the ampoule from the channel, and a combination of these steps. 81. The method of claim 80, wherein the first end is held up during the insertion and filling steps. 82. The method of claim 80, wherein the first end is an upper end of the carrier. -6183. The method of claim 1, wherein the evaporation step 80, characterized by a lyophilization step. 84. The method of claim 80, wherein the second end of the channel is selected from said set of steps. additional network step, 85. The method of claim 84 wherein the carrier is rotated to the inverted position prior to performing the additional step. 86. The method of claim 79, wherein an interchange step selected from the group consisting of gas exchange, heat exchange, pressure exchange, and combinations thereof is performed between the inner portion of the vial and the outer portion of the carrier. 87. The method of claim 86, wherein the exchange step comprises a sterilization and / or lyophilization step. 88. The method of claim 79, wherein the vial has a front opening and a rear opening wherein gas is passed through the vial. -6289. 8. The method of claim 87 wherein the gas is hot sterilizing gas. 90. The method of claim 79, wherein the step of sliding the seal into the channel into a rest position in a non-sealing relationship to the vial opening is performed. 91. The method of claim 90, wherein a lyophilization step is performed after insertion of the seal. « 92. The method of claim 90, wherein the seal in the channel is moved from the rest position to the sealing engagement with the vial opening. 93. The method of claim 90, wherein the seal is held in a rest position by friction between the seal and the inner wall of the channel. 94. The method of claim 92, wherein the seal is secured by a closure. F 95. The method of claim 94 wherein an ampoule is removed from the carrier prior to the attachment step. ·· ♦ ··· • · • · · · • · • · • · ··· ··· * 63- • · · · · · • · · ·; í i ···· · · í I i • · · · · · · · '4 44 ·· 96. Ampoule, characterized manufactured according to claims 79 to 95. is that it is 97. An ampoule consisting of containers with front and rear facing each other defines the axis where the container has a substantially constant cross-section between the front and rear faces, at least the front face ending with a rounded edge opening, characterized in that substantially all of the edge material is maintained within the outer perimeter of the container, and / or outside the inner perimeter of the container, a portion of the container opening, close to the rim. 98. The vial of claim 97, wherein the rear face of the container has a rear opening with a rounded edge having a predetermined material distribution. 99. The vial of claim 97, wherein at least one opening is provided with a seal. 100. The ampoule of claim 97, wherein the receptacle is provided with a bypass arrangement or a piston or combinations thereof. 101. A method for manufacturing an ampoule comprising a container with a front face and a rear face that define an axis therebetween, wherein at least the front face terminates in a rounded edge opening wherein substantially all of the edge material is maintained at the edge. • 0 0 00 0 0 0 0 0 • · • 0 000 0 · ·· 0 0 · · · 0 0 0 0 0 0 0 0 0 · 0 0 0 0 · 0 0 0 0 0 0 0 0 · ♦ · -64- outside circuit containers or outside from internal circuit containers circuit concerning parts hole cans, close to Margins v y z n and more c í with E t í m that warms up the tubular material blank for the container around the perimeter, and the portions separated by axial pull while the heated perimeter is still hot. 102. The method of claim 101, wherein the heating is performed by a laser.