WO1998019715A1

WO1998019715A1 - Method for producing a pre-filled sterile syringe

Info

Publication number: WO1998019715A1
Application number: PCT/EP1997/006258
Authority: WO
Inventors: Frank Schnegotzki
Original assignee: Schering Aktiengesellschaft
Priority date: 1996-11-05
Filing date: 1997-11-05
Publication date: 1998-05-14
Also published as: DE19647694C1; AU5321098A

Abstract

The invention relates to a method for producing a pre-filled sterile syringe. The syringe comprises a syringe body (1) having a proximal (2) and a distal end (3), a syringe outflow piece (4) on the distal end (3), a closure (5), a stopper (11) and a fluid medium and a gas medium, the fluid medium being a contrast agent. The method comprises the following steps: the syringe body (1), the closure (5) and the stopper (11) are prepared. The syringe is brought to a vacuum chamber and vacuum is built up. The syringe is subsequently filled through the proximal end (2) and the stopper is also introduced through the proximal end (2). Thereafter, the vacuum chamber is once again brough back to normal pressure. The syringe is sterilized in a sterilizing chamber under auxiliary pressure after filling.

Description

Method of making a prefilled, sterile syringe

The invention relates to a method for producing prefilled syringes which are terminally sterilized. The focus here is in particular on the problem-free insertion of the plunger into the syringe body. These syringes are preferably provided for the use of injectable diagnostic agents, in particular contrast media, which are injected, for example, into blood vessels, organs, organ parts, cavities and other vessels or which have an imaging effect there. The international application claims the filing of the German patent application DE 196 47 694 with the filing date of November 5, 1996.

Publication EP 0 227 401 describes a method for producing a filled, terminally sterilized plastic syringe. The syringe has a cylinder with a distal end with a syringe outlet. The syringe outlet piece is sealed by a closure. After filling, the syringe is closed with a flexible rubber stopper that is slidable in the cylinder. The process begins with removing debris or other contaminants from the closure and the plunger. Microbial contaminants on the cap and piston are destroyed. The cylinder is washed with a variety of water jets to remove pyrogens and waste particles. Then silicone oil is applied to the inner wall of the syringe. Then the closure is placed on the syringe outlet piece. The contrast medium is filled into the syringe through the proximal end of the syringe. The syringe is then closed with the stopper. Inserting the stopper involves evacuating air from the cylinders using a vacuum system so that the stopper can be inserted into the proximal end of the cylinder with a selected amount of inert gas above the level of the liquid content. A description of how the vacuum system works is not disclosed in the publication. This assembled and filled syringe is sterilized in an autoclave. In addition to the usual autoclave pressure, an additional support pressure is generated in the autoclave. As a result, the pressure on the outer surface of the syringe becomes equal to or greater than the pressure on the inner surface of the syringe. From the publication by Venten and Hoppert (E Venten and J Hoppert (1978) Pharm Ind Vol 40, No. 6, pages 665 to 671), a terminal sterilization of prefilled syringe vials is known. The syringe vials, which have a stopper at the proximal end, become distal Filled by the rolled edge The rolled edge is then sealed by a sealing washer, with a crimp cap fixing the sealing washer on the rolled edge (M Junga (1973) Pharm Ind Vol 35, No. 11 a, pages 824 to 829) The pre-filled syringe vials then transferred to an autoclave, which can be regulated with regard to the temperature and the pressure, so that the sealing disk does not detach itself from the spray ampoule, a nozzle pressure is generated in the autoclave. The nozzle pressure is built up by an additional gas. This makes it possible to reduce the pressure on the inside to keep the sealing washer approximately equal to the pressure on the outside of the sealing washer. This also causes a movement of the already used Avoiding pistons As a result of the good regulation, it is even possible to sterilize two-chamber vials filled with two solutions in a terminal manner, without an inadmissible stopper movement or sealing disc leakage

EP 0 553 926 describes a terminal sterilization process for prefilled syringes, in which no autoclave is used, but only a pressure-resistant stenciling chamber is used. The distally or proximally filled syringe is introduced into this plunger chamber. The chamber is heated by means of heating gas This heating gas also ensures a pressure that is intended to compensate for the pressure rise in the syringe.To avoid evaporation of liquid that can penetrate through plastic, water vapor may also be introduced in addition to the heating gas.It is represented in the property right that the same safety with regard to sterilization occurs, as can be achieved with an autoclave

WO 95/12482 describes a method for producing prefilled plastic syringes that are filled with a contrast agent. The syringes consist of a cylinder, a syringe outlet piece at the distal end, which is prepared for a cannula attachment. Furthermore, the syringe comprises a stopper that slides in the cylinder can He seals the proximal end of the syringe The syringe has been manufactured using a process that leads to pyrogen-free objects. There are also no more particles. The syringe is filled through the proximal end, and the syringe outlet piece is sealed with a closure. The filled syringe is then with that Plug closed The particle status of the premises corresponds to the conditions of class 100 After the syringe parts come out of the mold, they are blown off with gas to remove particles. The syringe is then washed. The syringe is then sterilized so that the syringe can be processed, stored or can be transported

The stopper, the syringes described above, usually consists of an elastic rubber material. This stopper is pushed into the interior of the pre-filled body. For this purpose, it is necessary that a compression device specially made for this purpose compresses the stopper with respect to the cylinder wall. In the case of elastic rubber material, this provides not a problem in addition to this very flexible rubber material, plugs are also suitable which have a modulus of elasticity which is significantly larger than the modulus of elasticity of rubber

It is the task of offering a method for producing a terminal-sterilized syringe, which is pre-filled with a medium and is closed after filling, the medium being permanently in the syringe without sacrificing quality. In particular, the residual air quantity in the syringe is said to be so be in such a way that a disability does not occur during the stabilization and the application. The stopper should have a higher modulus of elasticity than conventional rubber stoppers

The first three alternative forms of the solution differ only in the point in time at which the negative pressure is created. A partial evacuation before filling the medium is preferred

The object is achieved by a method for producing a prefilled, sterile syringe made of glass or plastic or a mixture of glass and plastic, furthermore a glass syringe with an associated plastic film and a plastic syringe with an associated glass coating, which includes Syringe a cylindrical tip body with a closable proximal and a closable distal end a syringe outlet piece at the distal end a closure sealing the syringe outlet piece, a stopper which is slidable in the syringe body, the stopper being movable by a plunger, and a fluid and a gaseous medium, the fluid medium being a liquid, a solution, a

A suspension or an emulsion, the method comprising the following steps:

Providing the syringe body which is free of germs, pyrogens and / or endotoxins and is low in particles, - providing the closure which is free of germs, pyrogens and / or endotoxins and is low in particles,

Providing the stopper, which is free from germs, pyrogens and / or endotoxins and is low in particles, application of a lubricant, - creating a negative pressure, the negative pressure being built up in a setting tube (17) which lies sealingly against the syringe body (1), which is connected to a vacuum system and which can be sealed by the stopper (11) at its end pointing away from the syringe,

Sealing the distal end through the closure of the syringe outlet piece

Filling the syringe through the proximal end, sealing the proximal end by inserting the stopper into the syringe body,

Depressurization and thermal sterilization in a sterilization chamber.

An alternative embodiment consists of a method for producing a prefilled, sterile syringe made of glass or plastic or a mixture of glass and plastic, furthermore a glass syringe with an associated plastic film and a plastic syringe with an associated glass coating, the syringe comprising a cylindrical syringe body with a closable proximal and a closable distal end, a syringe outlet piece at the distal end, a closure sealing the syringe outlet piece, a stopper which is slidable in the syringe body, the stopper being movable by a plunger, and a fluid and a gaseous medium, the fluid medium being a liquid, a solution, a

A suspension or an emulsion, the method comprising the following steps:

Provision of the stopper which is free from germs, pyrogens and / or endotoxins and is low in particles, application of a lubricant, sealing of the distal end by the closure of the syringe outlet piece

Creation of a negative pressure, the negative pressure being built up in a setting tube (17) which lies sealingly against the syringe body (1), which is connected to a negative pressure system and which can be sealed by the stopper (11) at its end pointing away from the syringe the syringe through the proximal end sealing the proximal end by inserting the stopper into the syringe body,

Depressurization and thermal sterilization in a sterilization chamber.

A third embodiment consists in a method for producing a prefilled, sterile syringe made of glass or plastic or a mixture of

Glass and plastic, still a glass syringe with an associated

Plastic film and a plastic syringe with a glass coating connected to it, the syringe comprising a cylindrical syringe body with a closable proximal and a closable distal end, a syringe outlet piece at the distal end, a closure sealing the syringe outlet piece, a stopper which is slidable in the syringe body, the stopper being movable by a plunger, and a fluid and a gaseous medium, the fluid medium being a liquid, a solution, a

A suspension or an emulsion, the method comprising the following steps:

Filling the syringe through the proximal end creating a negative pressure, the negative pressure being built up in a setting tube (17) which lies sealingly against the syringe body (1), which is connected to a negative pressure system and which is connected by the stopper (11) to the latter Syringe groundbreaking end is sealable

- Seal the proximal end by inserting the plug into

^~ the syringe body,

Depressurization and thermal sterilization in a sterilization chamber.

This process only requires small cavities to be evacuated, which means that the forces that occur are also lower. It is also advantageous that the partial vacuum reinforces the seal between the setting tube and the syringe body.

Another method is that the setting tube comprises a filling opening with which the syringe can be filled.

The methods according to the invention are advantageous for all stopper shapes and stopper materials. Through this procedure, the residual air in the filled syringe kept to a minimum. This has considerable advantages both for terminal sterilization and for later application. Air residues are always a hindrance when a syringe content is to be injected into a patient. Residual air in a syringe with thermal sterilization always leads to an increased pressure, the sum of which consists of the partial pressure which is attributable to the water vapor and a gas partial pressure which is brought about by the residual volume of the gas in the syringe.

Syringe plugs can be made of very different materials. In the case of small volumes, the aforementioned rubber-elastic stoppers are preferred. However, if larger pressures are applied to the stopper during application, undesirable deformations of the rubber-elastic stopper may occur. Therefore, plugs made of a less elastic material are preferred. More preferred are plugs which have a relatively inelastic, plate-shaped core, made of a plastic material with a coating of rubber-elastic material. Such plugs can be designed in several pieces. The solid core consists of a cylindrical disc, which sits in a rubber-elastic plug hollowed out on the inside. The rubber-elastic part has a relatively thin wall thickness, which guarantees a tight fit of the stopper against the inner wall of the syringe. However, it is disadvantageous that, as is usually the case, compression devices for rubber stoppers can no longer be used. Either the applied compression pressures are no longer sufficient, or the stoppers are no longer reversible.

The term syringe includes the terms cartridge (large-volume syringe with a volume of at least 100 ml), ampoule syringes, disposable syringes, disposable syringe ampoules, disposable syringes, injection ampoules, spray ampoules, ready-to-use ampoules, cylindrical ampoules and immediate syringes.

Glass syringes and plastic syringes are described in detail in the M. Junga publication. A mixture of glass and plastic is shown in WO 96/00098 (filing date June 23, 1995).

Plastics are described in detail in Römpp-Chemie-Lexikon, edited by Jürgen Falbe and Manfred Regitz, 9th edition, Stuttgart, 1990 on pages 2398 ff. COC, TPXPP, PC and polymethylpentene (COC = cycloolefin copolymer) are preferred. These plastics are especially for use with pre-filled, terminally sterilized syringes because their high melting point of at least 130 ° C allows steam sterilization according to the standard procedure at 121 ° C. In addition, the optical properties are sufficient for a medicinal book-compliant, visual inspection.

The terms proximal and distal are defined from the perspective of the treating doctor. At the distal end is the syringe outlet piece, to which, for example, the cannula or a hose leading to a cannula is connected. At the proximal end is the stopper that pushes the medium through the distal end during application. The plug can be moved manually or mechanically. The term stopper also includes pistons. For the manual actuation of the syringe, it is helpful for the operating personnel if the syringe carries finger holders at the proximal end. The finger holders usually have at least one surface as an abutment for the index and middle fingers, the surface of the finger holder being essentially perpendicular to the axis of the syringe barrel. Various models are known for mechanical pump devices. A syringe then preferably carries one or more device holders at the preferably proximal end. Such a mechanical pump is described particularly well in publication EP 0 584 531 (filing date July 21, 1993). Mixed forms of finger holder and device holder are also possible.

The syringes are usually rotationally symmetrical, only the finger holder and device holder and sometimes also the syringe outlet piece deviate from the symmetry. So the syringe outlet piece can be arranged eccentrically. The Luer lock is particularly preferred since it is only used when contrast agents are applied when mechanical pump devices are used. Even with manual application, the Luer Lock and the tubing connected to it prevent unintentional movements of the doctor from being transmitted directly to the cannula. The simple Luer approach and the record approach are also known. The proximal and distal ends of the syringes must be closable. The distal end is sealed by a closure which can be placed on the syringe outlet piece. In this protective right, the syringe outlet piece covers the ceiling of the syringe barrel. The syringe outlet piece further comprises a tube leading to the needle or the hose, an end piece which is in contact with the needle or the hose and a threaded cylinder on the inside, the cylinder surrounding the end piece. there and carries a thread for a Luer lock, for example. The syringe outlet piece can be single-story or multi-story. The ceiling can be flat or pyramid-shaped. Mixed forms are also conceivable. The stopper closes the proximal end of the syringe. It must be slidable in the cylinder and must keep the medium away from the environment. It should be as little permeable to gases and liquids as possible. Temperature fluctuations must also be able to be absorbed without malfunction. The stopper is usually not provided with its own stamp when the syringe is mechanically emptied. This is not mandatory. Rather, a plunger, which is part of the pump device, engages in a closure inside the stopper, so that movement of the stopper is possible without any problems (see publication EP 0 584 531). The plug can be made of a material that is less elastic than the usual rubber material, especially for mechanical application. Such plugs are necessary because the pressure which is caused by the pump devices leads to a deformation of the otherwise usual rubber material. The otherwise usual rubber material evades the occurring loads, there are undesired leaks between the rubber plug and

Syringe inner wall. Such errors can seriously endanger the entire form of application. The volume and also the pressure occurring are no longer clearly defined. This method is particularly preferred for stoppers which are no longer formed in one piece. Such plugs have a cylindrical disk made of a relatively little elastic material and a sealing part put over it, which is made of, for example, a rubber-elastic material. When using this two-part plug or a plug with a similar little elastic function there is a difficulty in compressing the rubber plug with conventional compression devices. This leaves an undesired residual volume of air in the syringe. This air can no longer easily escape when the plug is inserted into the syringe body.

A method for producing a prefilled, sterile syringe is preferred, the syringe being filled in a steam atmosphere. A method for producing a prefilled, sterile syringe is more preferred, the vapor being hotter than the fluid medium, in particular the liquid. Most preferred is a method for producing a prefilled, sterile syringe, in which the difference between normal pressure and the negative pressure has a value of 800 to 970 mbar, the steam having a temperature of 20 to 70 ° C and wherein the fluid medium has a .Temperature of 20 to 70 ° C.

Working in a steam atmosphere has the particular advantage that when the steam cools, it condenses and there is therefore a small residual volume of gas between the liquid and the stopper in the filled syringe. The residual air content can be minimized by a clever choice of negative pressure and temperature difference between steam and fluid medium.

A method for producing a prefilled, sterile syringe is preferred, the sterilization chamber being an autoclave or sterilizer, with steam, hot air and / or a microwave. Such sterilization chambers are described in detail in the cited prior art. The additional support pressure that can be built up in the sterilization chamber is of particular interest. A method for producing a prefilled, sterile syringe is most preferred, wherein a support pressure is built up by a gas in the sterilization chamber, the pressure on the outer surface of the syringe being equal to, greater than or less than the pressure on the inner surface of the syringe.

The medium in the filled syringe is a mixture of a fluid medium and at least one gas. The medium can be a liquid, a solution, a suspension or an emulsion. These manifestations are in W. Schröter et al., (1987) Chemie; Facts and Laws, 14th edition, Leipzig described on pages 23 ff. A fluid medium which is a contrast medium is preferred. Sterile and pure production processes are described in DAB 1996 or Ph. EUR.

Lubricants are used so that the plug can be moved within the cylinder without great effort. Preferred is silicone oil, which has the following property: viscosity of at least 1000 cSt; Quality: Medical grade.

So that the plug does not move inside the cylinder during sterilization, it can be advantageous if the plug is fixed during sterilization. This allows a pressure difference to be built up between the volume in the syringe and the volume around the syringe. Such a fixation of the stopper in the French pateritcript is published in detail with the cation number 2,258,866, which was submitted on January 30, 1974.

Examples:

The stages of the method according to the invention are exemplified in the

Drawing shown. The drawing includes the following figures: Figure 1 shows an unfilled syringe.

Figure 2 shows an unfilled syringe in a vacuum chamber

FIG. 3 shows a filled syringe in a vacuum chamber

Figure 4 shows a filled syringe in a vacuum chamber, the

Plug is about to be used. Figure 5 shows a filled syringe into which the stopper is inserted and which is still in the vacuum chamber.

Figure 6 shows a fully filled syringe.

Figure 7 shows a syringe before filling.

FIG. 8 shows a filled syringe. FIG. 9 shows a syringe with a seat tube attached and a stopper in the

Riser.

Figure 10 shows a syringe with a set tube and a stopper in the proximal end of the syringe.

FIG. 1 shows a syringe according to the invention with a cylindrical syringe body 1 which has a closable proximal end 2 and a closable distal end 3. A syringe outlet piece 4 is arranged at the distal end. It is sealed by a closure 5, which is preferably a tip-cap. There is a device holder 6 at the proximal end. Such a syringe has previously undergone several process steps. The syringe body, closure and stopper have been cleaned or were made under sterile conditions. High temperatures when processing the plastic ensure that even pyrogens are no longer detectable. The three parts are thus freed of germs, produced without pyrogens and without endotoxins. Furthermore, they are preferably low in particles and even free of particles. In addition, a lubricant has already been applied.

The syringe from FIG. 1 is then transferred to a vacuum chamber 7 shown in FIG. This vacuum space seals the space in which the syringe is arranged in a gas-tight manner. A valve 8 is used to selectively extract gas from the vacuum chamber, or gas can also be conducted into the vacuum chamber. At the stage shown in FIG. there, the interior of the vacuum chamber is evacuated. A pressure of 100 mbar is built up.

A further stage of the filling process is shown in FIG. Through an additional valve 9, liquid is filled into the lumen of the syringe 1. The filling continues until the level designated 10 is reached. Above this level there is a gas space which has a pressure of approximately 100 mbar.

FIG. 4 shows the step of the filling process in which the stopper 11 is transferred into the lumen of the syringe 1. The plug 11 consists of a pyramid-shaped core 12 and a rubber-elastic jacket 13 which is open towards the proximal end. Through this opening of the rubber-elastic jacket 13, the relatively firm and rigid core 12 can be inserted into the jacket. The plug 11 is now inserted through the proximal end 2 of the syringe 1. The pressure is then increased from 100 mbar to a normal pressure atmosphere, as a result of which the stopper 11 migrates further into the syringe, so that there is only a small residual volume between the stopper 11 and the surface of the liquid, as can be seen from FIG.

Figure 6 then shows a filled syringe, which is now outside the vacuum chamber.

It is advantageous not to feed the vacuum chamber continuously, but to provide the syringes in batches, in order to then fill them under vacuum and to provide them with the stopper.

FIGS. 7 to 10 show the preferred embodiment, different stages of the filling being shown.

FIG. 7 shows a syringe body 1 which is not filled with medium and whose proximal end 2 points upwards. The device holder 6 points in the horizontal direction. The syringe outlet piece 4 is sealed with a closure 5. The distal end 3 rests in a lifting device 16. FIG. 8 shows a syringe according to FIG. 7 which is filled with medium which forms an interface between liquid and air at level 10. Above the proximal end 2 there is a filler neck 14, from which the contrast medium flows during filling. The filling process is to be controlled via a filling valve 15.

FIG. 9 shows the syringe body 1 which is meanwhile filled with contrast medium and which rests with its distal end 3 on a lifting device 16. The lifting device 16 moves the syringe body 1 in the direction of a setting tube 17, which consists of a setting tube cylinder 18. It (18) has an inside diameter in the lower riser tube area 19 which essentially corresponds to the inside diameter of the syringe body 1. The setting tube has an O-ring 22 on the downward-facing cylinder edge, which lies sealingly against the edge of the syringe body 1. The riser cylinder 18 has a riser outlet 24 which is connected to a vacuum system by means of a riser valve 25.

In the lower riser pipe area 19 is the plug 11, which rests with its rubber beads on the jacket 13 sealingly against the inner edge of the riser pipe. The plug 11 is transferred into its position by a holder 26, which fixes reversibly in the core 12, and held there.

The syringe body 1 is positioned under the setting tube 17 by means of the lifting device 16, so that the axis of the setting tube 17 coincides with the axis of the syringe body 1. Then the moves

Lifting device 16 in the direction of the setting tube 17 until the O-ring 22 touches the edge of the syringe body 1. As a result, a cavity is formed, which is formed by the syringe body 1, the setting tube 17 and the plug 11, which is located in the setting tube. Then the setting tube valve 25 is opened so that the cavity is connected to the vacuum system. The cavity is partially evacuated. The stopper 11 is fixed in position by the holder 26. The evacuated cavity causes the setting tube 17 to press even more against the edge of the syringe body 1 via the O-ring 22. This ensures the sealing.

FIG. 10 shows the last stage when inserting the stopper 11 into the syringe body 1. The stopper is located in the proximal end 2 of the syringe body 1, a part of the stopper 11 being immersed in the contrast medium. The setting tube 17 is still in sealing contact with the syringe body. The holder 26 has released the core 12 of the plug. The plug 11 is now in the syringe body 1, the residual volume of gas corresponding to the residual gas which is achieved in other filling processes.

Reference symbol list:

1 syringe body

2 proximal ends

3 distal ends

4 syringe outlet piece

5 closure

6 device holder

7 vacuum chamber

8 valve

9 additional valve

10 level

11 plugs

12 core

13 coat

14 filler neck

15 filling valve

16 lifting device

17 riser

18 cylinders

19 lower riser area

22 O-ring

24 riser outlet

25 riser valve

26 bracket

Claims

claims

1. A method for producing a prefilled, sterile syringe made of glass or plastic or a mixture of glass and plastic, furthermore a glass syringe with an associated plastic film and a plastic syringe with an associated glass coating, the syringe comprising a cylindrical syringe body (1) a closable proximal (2) and a closable distal end (3), a syringe outlet piece (4) at the distal end (3), a closure (5) sealing the syringe outlet piece (4), a stopper (11) which is located in the syringe body ( 1) is slidable, the plug (11) being movable by a plunger, and a fluid and a gaseous medium, the fluid medium being a liquid, a solution, a suspension or an emulsion, the method comprising the following steps:

Providing the syringe body (1) which is free from germs, pyrogenes and / or endotoxins and is low in particles,

Providing the closure which is free from germs, pyrogens and / or endotoxins and is low in particles,

Providing the stopper (11) which is free from germs, pyrogens and / or endotoxins and is low in particles, - application of a lubricant,

Creation of a negative pressure, the negative pressure being built up in a setting tube (17) which lies sealingly against the syringe body (1), which is connected to a negative pressure system and which can be sealed by the stopper (11) at its end pointing away from the syringe the distal end (3) through the closure (5) of the syringe outlet piece (4),

Filling the syringe through the proximal end (2) - sealing the proximal end (2) by inserting the stopper

(11) into the syringe body (1),

Depressurization and thermal sterilization in a sterilization chamber.

2. A method for producing a prefilled, sterile syringe made of glass or plastic or a mixture of glass and plastic, further a glass syringe with an associated plastic film and a plastic syringe with an associated glass coating, the syringe comprising a cylindrical syringe body (1) a closable proximal (2) and a closable distal end (3), a syringe outlet piece (4) at the distal end (3), a closure sealing the syringe outlet piece (4), a stopper (11) which slides in the syringe body (1) the plug (11) can be moved by a plunger, and a fluid and a gaseous medium, the fluid medium being a liquid, a solution, a

A suspension or an emulsion, the method comprising the following steps:

Providing the syringe body (1) which is free of germs, pyrogens and / or endotoxins and is low in particles, - providing the closure which is free of germs, pyrogens and / or endotoxins and is low in particles,

Providing the stopper (11), which is free of germs, pyrogens and / or endotoxins and is low in particles, application of a lubricant, - sealing the distal end (3) by the closure (5) of the

Syringe outlet piece (4), creating a negative pressure, the negative pressure being built up in a setting tube (17) which lies sealingly against the syringe body (1), which is connected to a negative pressure system and which, through the plug (11), points away from the syringe Is sealable at the end,

(11) into the syringe body (1),

Depressurization and thermal sterilization in a sterilization chamber.

3. A process for the production of a prefilled, sterile syringe made of glass or plastic or a mixture of glass and plastic, furthermore a glass syringe with an associated plastic film and a plastic syringe with an associated glass coating, the syringe comprising a cylindrical syringe body (1) with a closable proximal (2) and a closable distal end (3), a syringe outlet piece (4) at the distal end (3), a closure (5) sealing the syringe outlet piece (4), a stopper (11) which is located in the syringe body (1 ) is slidable, the plug (11) being movable by a plunger, and a fluid and a gaseous medium, the fluid medium being a liquid, a solution, a

A suspension or an emulsion, the method comprising the following steps:

Syringe outlet piece (4),

Filling the syringe through the proximal end (2) creating a negative pressure, the negative pressure being built up in a setting tube (17) which lies sealingly against the syringe body (1), which is connected to a negative pressure system and which is connected to it by the stopper (11) the end pointing away from the syringe can be sealed, sealing the proximal end (2) by inserting the stopper (11) into the syringe body (1),

Depressurization and thermal sterilization in a sterilization chamber.

4. A method for producing a prefilled, sterile syringe according to one of the preceding claims, wherein the setting tube (17) comprises a filling opening with which the syringe can be filled.

5. A method for producing a prefilled, sterile syringe according to any one of the preceding claims, wherein the syringe is filled in a steam atmosphere.

6. A method of making a prefilled, sterile syringe according to claim 5, wherein the vapor is hotter than the fluid medium.

7. The method for producing a prefilled, sterile syringe according to claim 6, wherein the difference between normal pressure and the negative pressure has a value of 800 to 970 mbar, the steam having a temperature of 20 to 70 ° C and wherein the fluid medium Has temperature of 20 to 70 ° C.

8. A method for producing a prefilled, sterile syringe according to one of the preceding claims, wherein the sterilization chamber is an autoclave or

Sterilizer, with steam, hot air and / or microwave.

9. A method for producing a pre-filled, sterile syringe according to one of the preceding claims, wherein a support pressure is built up by a gas in the sterilization chamber, the pressure on the outer surface of the syringe being equal to, greater than or less than the pressure on the inner surface of the syringe .

10. A method of making a prefilled, sterile syringe according to any one of the preceding claims, the syringes comprising: cartridges,

Ampoule syringes, disposable syringes, disposable syringe ampoules, disposable syringe ampoules, disposable syringes, injection ampoules, spray ampoules, ready-to-use ampoules, cylindrical ampoules or immediate syringes.

11. A method for producing a prefilled, sterile syringe according to one of the preceding claims, wherein the plastic of the polyolefins from the group COC, TPX, polymethylpentene and PP.

12. A method for producing a prefilled, sterile syringe according to one of the preceding claims, wherein the syringe has a Luer lock at the distal end.

13. A method for producing a prefilled, sterile syringe according to one of the preceding claims, wherein the medium in the filled syringe is a mixture of a fluid medium and at least one gas.

14. A method for producing a prefilled, sterile syringe according to claim 13, wherein the medium is a liquid, a solution, a

Suspension or an emulsion.

15. A method of making a prefilled, sterile syringe according to claim 14, wherein the medium is a contrast agent.

16. A method for producing a pre-filled, sterile syringe according to one of the preceding claims, wherein the stopper (11) is fixed during sterilization.