WO1997044068A1

WO1997044068A1 - Method of terminally sterilizing filled syringes

Info

Publication number: WO1997044068A1
Application number: PCT/EP1997/002641
Authority: WO
Inventors: Johannes Tack; Thomas Schurreit; Jörg ZÜRCHER
Original assignee: Schering Ag
Priority date: 1996-05-23
Filing date: 1997-05-23
Publication date: 1997-11-27
Also published as: AU2960297A; EP0901380A1; JP2000510740A; DE19622283A1

Abstract

The invention concerns a method of producing a pre-filled sterile syringe. The syringe comprises a syringe body with a proximal end and a distal end, a syringe-outlet part at the distal end, a seal, a stopper, a fluid medium and a gaseous medium, the fluid medium being a liquid. The method comprises the following steps: preparing the syringe body, seal and stopper which is/are free from germs and/or endotoxins and low in particles; a lubricant is applied; the proximal end is sealed by inserting the stopper into the syringe body; the syringe is filled through the distal end; the syringe outlet part is sealed with the seal; the syringe is sterilized in a sterilizing chamber; the syringe is then packaged and the package container is then sterilized once again.

Description

Process for the terminal sterilization of filled syringes

The invention relates to a method for the terminal sterilization of filled syringes. In particular, the focus is on a pyrogen-free and germ-free surface of the syringes. These syringes are preferably provided for the use of injectable diagnostics, 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 patent specification AT-E 68 979 describes a method for producing a filled, terminally sterilized syringe. The syringe is made of plastic. The syringe has a barrel 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 contamination on the closure and the 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. The closure is then 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. 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.

A terminal sterilization of prefilled syringe vials is known from the publication by Venten and Hoppert (E. VENTEN and J. HOPPERT (1978) Pharm. Ind. Vol. 40, No. 6, pages 665 to 671). The spray ampoules, which have a stopper at the proximal end, are filled distally through the rolled rim. The rolled edge is then sealed by a sealing washer, whereby a flanged cap fixes the sealing washer on the rolled edge. (M. JUNGA (1973) Pharm. Ind. Vol. 35, No. 11 a, pages 824 to 829) The prefilled syringe vials are then transferred to an autoclave. This autoclave can be regulated in terms of temperature and pressure. So that the sealing washer a support pressure is generated in the autoclave. The support pressure is built up by an additional gas. This makes it possible to keep the pressure on the inside of the sealing disk approximately equal to the pressure on the outside of the sealing disk. This also avoids movement of the plunger used. to be sterilized terminally without an inadmissible plug movement or sealing disk leakage occurring

Finnish patent application FI 93 0405 describes a method for the periodic sterilization of a prefilled plastic syringe or glass syringe, the syringe containing a contrast agent. The syringe consists of a syringe barrel which has a syringe outlet piece at the distal end Venten and Hoppert form described The syringes have an open proximal end which can be closed by a stopper which is slidable in the syringe. The stopper is connected with a stamp

When the syringe or syringe ampoule is filled, the stopper is first inserted into the proximal end of the syringe or syringe ampoule and then filled through the distal end. The distal end is then sealed by a closure. In the case of the tip ampoules, a sealing washer is fixed to the rolled edge with a brothel cap. The syringes or syringe ampoules are then sterilized, using a support pressure. The pressure on the outer surface of the syringe is therefore less than that Pressure held on the inside surface of the syringe or spray ampoule. With the spray ampoules, the pressure in the autoclave is the same, greater or less than the pressure in the spray ampoule.

WO 95/12418 describes a terminal stencilization process for prefilled syringes, in which no autoclave is used, but only a pressure-resistant sterilization chamber is used. The distally or proximally filled syringe is introduced into this sterilization 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 increase in the syringe. In order to avoid evaporation of liquid that penetrates through the plastic, water vapor is also introduced in addition to the heating gas. It is described in the protection law that the same safety as in an autoclaving should be achieved 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 hub. The syringe further includes a stopper that can slide in the barrel. It seals the proximal end of the syringe. The syringe is made using a process that results in pyrogen-free objects. There are also no more particles. The syringe is filled through the proximal end, the syringe outlet piece being sealed with a closure. The filled syringe is closed with the stopper. 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 in order to remove particles. The syringe is then washed. The syringe is then sterilized, so that the syringe can optionally be further processed, stored or transported.

The task is to offer a syringe which is pre-filled with a medium, the medium being permanently in the syringe without any loss of quality. Particularly high demands are to be placed on safety with regard to sterility and low particle content inside and outside the syringe.

The object is achieved by a manufacturing method 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 oil 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 , wherein the fluid medium is a liquid, a solution, a suspension or an emulsion, the method comprising the following steps: Providing the syringe body which is free from germs, pyrogens 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 which is free from germs, pyrogens and / or endotoxins and is low in particles, applying a lubricant,

Sealing the proximal end by inserting the stopper into the syringe body and filling the syringe through the distal end and closing the syringe outlet piece with the closure or welding the syringe outlet piece, or alternatively

Sealing the distal end by sealing or welding the syringe outlet piece and filling the syringe through the proximal end and sealing the proximal end by inserting the

Plugging into the syringe body, thermal sterilization in a sterilization chamber, in particular an autoclave or sterilizer with steam, hot air and / or microwave, - if appropriate, build-up of a nozzle pressure by a gas in the

Steπlisationskammer, wherein the pressure on the outer surface of the syringe is equal to, greater or less than the pressure on the inner surface of the syringe

Packaging the sterilized syringe in a container, in particular a secondary packaging and

Sterilizing the packaged syringe with a substance that permeates at least parts of the container, in particular the secondary packaging

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 syringe ampoules, disposable syringes, injection ampoules syringe ampoules, ready-to-use ampoules, cylindrical ampoules, double-chamber syringes, two-chamber syringes, two-chamber syringes Disposable syringe and immediate syringe

Glass syringes and plastic syringes are detailed in the publication by Junga (M JUNGA (1973) Pharm Ind Vol 35 No. 11a pages 824 to 829) A mixture of glass and plastic is described in WO 96/00098 (filing date 23 6 1995)

Plastics are shown in detail in Rompp - Chemie - Lexikon, published by Jurgen FALBE and Manfred REGITZ, 9th edition Stuttgart, 1990 on pages 2398 ff. COC, PP and polymethylpentene [COC = cycloolefin copolymer with the brand name CZ (manufacturer Nihon Zeon) are preferred and TOPAS (manufacturer Mitsui Chemicals and Hoechst)] These plastics are particularly suitable for use with pre-filled, terminally sterilized syringes because their high melting point (at least 130 ° C) allows steam stagnation (standard procedure 121 ° C) the optical properties are sufficient for a medical one-hundred percent inspection

The terms proximal and distal are defined from the point of view of the attending physician. At the distal end there is the syringe outlet piece, to which, for example, the cannula or a hose leading to a channel is connected. At the proximal end there is the stopper that passes the medium through the The distal end prints during application. The movement of the stopper can take place manually or mechanically. The expression stopper also includes pistons. For the manual actuation of the syringe, it is helpful for the operating personnel if the syringe carries finger holders on the proximal end the finger holders usually have at least one surface as an abutment for the index finger and middle finger, the surface of the finger holder being essentially perpendicular to the axis of the syringe barrel. Different models are known for mechanical pumping devices. A syringe then preferably carries one or more device holders on the two Such a mechanical pump is particularly well described in EP 0 584 531 (Reilly et al. filing date 21 07 1993). Mixed forms of finger holder and device holder are also possible

The syringes are usually rotationally symmetrical, only the finger mounts and device mounts and sometimes also the syringe outlet piece deviate from the symmetry. The syringe outlet piece can be arranged eccentrically. The Luer lock is particularly preferred because it is used exclusively when contrast agents are applied then comes into play when mechanical pumping devices are used. Also in the manual application cation, the Luer lock and the tubing connected to it prevent unintentional movements of the doctor from being transmitted directly to the cannula. Furthermore, the simple Luer approach and also the record approach are known.

It is also possible to weld the syringe outlet piece and thereby seal it. It is then advantageous that a syringe outlet piece has a predetermined breaking point, which allows the syringe outlet piece to be opened easily before use.

The proximal and the distal end of the syringe 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 comprises the top of the syringe barrel. Furthermore, the syringe outlet piece comprises a tube which leads 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 and carrying a thread for a Luer lock, for example. It can

Syringe outlet piece can be in one piece or in several pieces. The ceiling can be curved, 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 reliably retain the medium from the environment as little permeability as possible for gases and liquids Even temperature fluctuations must be absorbed without malfunction. Usually, the stopper is not provided with its own stamp during the mechanical emptying of the syringes. Instead, a stopper, which is part of the pumping device, engages in a closure inside the stopper, so that movement of the stopper is possible without problems (cf. EP 0 584 531)

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 on pages 23 and following

Preferred is a fluid medium, which is a contrast agent. These are the following contrast agents with the generic names Ami- dotrizoic acid, gadopentetic acid, gadobutrol, gadolinium EOB-DTPA, lopamidol, lopromid, lotrolan and lotroxinic acid.

A syringe must be cleaned of foreign objects. Foreign bodies are all the particles that are not made of the material of the syringe and the medium and the detached fragments of the syringe.

Pyrogens are substances that, as fragments of bacteria, provoke an immune response in humans. In particular, they are lipopolysaccharides.

Sterile and pure production processes are in JJAB 1996 or Ph.Eur. described.

Publications on sterilizing and reducing the number of bacteria are listed in the following sources:

K.H. WALLHÄUSSER (1990) The microbial purity of pharmaceutical raw materials and pharmaceuticals, Pharma Technologie, Vol 11, No. 4, pages 2 - 9; H. SEYFARTH (1990) Critical comments on the hygiene requirements of the EC guidelines for good manufacturing practice for pharmaceuticals,

Pharma Technologie, Vol 11, No. 4, pages 10 - 19; W. Hecker and R. MEIER (1990) Determination of the number of airborne bacteria in the production area using newer devices, Pharma Technologie, Vol 11, No. 4, pages 20 - 28; G. SPICHER (1990) Possibilities and Limits of Sterilization Using

Gases and ionizing radiation in comparison with the classic sterilization processes, Pharma Technologie, Vol 11, No. 4, pages 50 - 56;

Treatment with ethylene oxide, propan-3-olide and diethyl dicarbonate, hydrogen peroxide and an ozone / steam mixture are known as chemical sterilization processes. Such procedures are described in:

G. SPICHER (1990) Possibilities and Limits of Sterilization with Gases and Ionizing Radiations in Comparison with the Classic Sterilization Process, Pharma Technologie, Vol 11, No. 4, pages 50 -

56; H. HÖRATH (1990) Legal framework for sterilization with ethylene oxide and formaldehyde, Pharma Technologie, Vol 11, No. 4, pages 57 - 64;

J. SCHUSTER (1990) The practice of operational ethylene oxide sterilization and attempts to optimize it, Pharma Technologie, Vol 11, Nr

4, pages 65-71;

M. MARCZINOWSKI (1990) Practical implementation of formaldehyde sterilization, Pharma Technologie, Vol 11, No. 4, pages 72 - 76;

The process with hydrogen peroxide is particularly preferred.

Sterilization with high-energy radiation is also possible. Gamma rays and X-rays are known. Neutron rays, beta rays and alpha rays are also used

Lubricants are used so that the plug can be moved within the cylinder without great effort. Silicone oil is preferred, which has the following properties: viscosity at least 1000 cSt; Quality: medical grade

After the syringe has been partially assembled, it may be possible to clean the syringe again of foreign bodies. Foreign bodies are all the particles that are not made from the material of the syringe and the medium and that are broken fragments of the syringe. Sterilization methods are particularly suitable " Radiation sterilization or chemical sterilization processes

Treatment with ethylene oxide, propan-3-olide and diethyl dicarbonate, hydrogen peroxide and an ozone / steam mixture are known as chemical sterilization processes

Sterilization with high-energy radiation is also possible. Gamma rays and X-rays are known here

If necessary, the parts of the syringe are sterile packed in bacteria-proof but gas-permeable film or aluminum. The sterilization is carried out with the aid of thermal and / or chemical sterilization, with gamma rays or X-rays, neutron rays or Beta rays or a mixture of the aforementioned rays, treatment with hydrogen peroxide or ozone / steam mixture is preferred

The syringe body is then filled through the distal or proximal end, with either the stopper or the closure sealing the opposite end. The filling opening is then closed by the closure or the stopper

The distal end is closed with a closure or by welding the distal end. When welding, the distal end has a predetermined breaking point proximal to the welding. As a result, the distal end can be opened without problems after the welding

In the next step, the syringe or cartridge is thermally sterilized in the autoclave or sterilizer with hot air or using a microwave

So that the stopper does not move within the cylinder, it is advantageous if the stopper is fixed during stenciling

If necessary, it is possible to build up a nozzle pressure in the sterilization chamber of the autoclave or the sterile chamber by means of a gas in the sterilization chamber, the pressure on the outer surface of the syringe being greater than or less than the pressure on the inner surface of the syringe pressure is to be defined as the pressure which corresponds to the sum of the partial pressures in the control room minus the partial pressure of the steam

It is advantageous if the stopper is readjusted after sterilization. This ensures that the stopper is in an optimal position. Sometimes the friction between stopper and cylinder is so great that the stopper is set in the stable position that there is no pressure difference between the inside and outside of the syringe does not take place independently

At this point, an optical check is advantageous. This ensures that particles that are in the syringe are found. Syringes with particles must be discarded

It is particularly important to pack the sterilized syringe in a container and to sterilize the filled container. This process can take place in a control room. This step is particularly advantageous because there is only security to offer the treating doctor an injection that is also sterile on the outside. In this way the risk of contamination can be reduced. This advantage also applies to the syringes to be mechanically emptied, since the doctor touches the syringe here too. The syringes to be emptied mechanically are often used in sterile operating rooms. Only sterile or disinfected materials may be brought into these rooms. Thus, a syringe to be mechanically emptied must also be sterile on the outside.

It is also advantageous that the filled and terminally filled syringe is packaged in sterile plastic film and / or aluminum film under optionally aseptic conditions. It is advantageous here that the syringe is packed in possibly sterile blisters, where aseptic conditions may prevail. The syringe lying in the container is then externally sterilized again by treating the syringe with ethylene oxide, propan-3-olide and / or diethyl dicarbonate. Furthermore, hydrogen peroxide and a

Ozone / vapor mixture known.

A preferred embodiment is shown below by way of example. A syringe according to the invention is shown in FIG. 1 as a perspective drawing.

A sectional drawing of the syringe is shown in FIG. FIG. 3 shows a flow chart in which the process of manufacture, sterilization, filling and terminal sterilization is shown.

1 and 2 show a plastic syringe 100, which consists of a syringe body 1 with a syringe barrel 2. The syringe 100 has a proximal end 3, which is closed by a stopper 4. The stopper has a pyramid-shaped distal stopper part 5 and a cylindrical proximal stopper part 6, which lies sealingly against the inner wall of the syringe barrel 2. The contact between the proximal stopper part 6 and the inner wall of the cylinder takes place via a plurality of rubber beads 7. Device holders 8, which consist of a device holder ring 9 and two device holder projections 10 and 10 ^′, are arranged on the proximal end of the device cylinder Clamping the syringe in a mechanical pumping device. At the distal end 11 of the syringe there is a pyramid-shaped syringe outlet piece 12, which comprises a tube 13 and an end piece 14. The pyramid-shaped distal stopper part 5 fits complementarily into the pyramid-shaped syringe outlet piece 12. The conically tapering tube 13 is arranged centrally from the syringe outlet piece 12 that ends in the tail 14. This end piece 14 is surrounded by a cylinder 15 which carries a thread 16 for a Luer lock on the inside. The end piece 14 can be closed either by a tip closure part in the form of a tip cap or by a syringe closure part with a Luer lock. The syringe closure part is in not shown in the drawing

A flow chart is shown in FIG

51414AWOM1XX00-P 21 5 1997

Claims

claims

1. Manufacturing process 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 with a closable proxi - Paint 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 is a liquid, a solution, a suspension or an emulsion, the method comprising the following steps - providing the syringe body which is free from germs, pyrogens 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 which is free from germs, pyrogens and / or endotoxins and is low in particles,

Applying a lubricant,

Sealing the proximal end by inserting the plug into the syringe body and filling the syringe through the distal end and closing the syringe outlet piece with the closure or welding the syringe outlet piece, or alternatively

Sealing the distal end by closing or welding the syringe outlet piece and filling the syringe through the proximal end and sealing the proximal end by inserting the stopper into the syringe body, thermal sterilizing in a stenciling chamber, packaging the sterilized syringe in a container and Sterilizing the packaged syringe with a substance that permeates at least parts of the container

2. Manufacturing method according to claim 1, wherein the stencilization chamber is an autoclave or sterilizer, with steam, hot air and / or microwave

3 Manufacturing method according to one of the preceding claims, wherein a support pressure is built up by a gas in the stencilization chamber, wherein the pressure on the outer surface of the syringe is equal to, greater than or less than the pressure on the inner surface of the syringe

4 Manufacturing method according to one of the preceding claims, wherein the syringes comprise cartridges, ampoule syringes, disposable syringes, disposable syringe ampoules, disposable syringe ampoules, disposable syringes, injection ampoules, syringe ampoules, ready-to-use ampoules, cylindrical ampoules, double-chamber syringe ampoules, two-chamber syringes, two-chamber syringe ampoules - Single or instant syringes

5 Manufacturing method according to one of the preceding claims, wherein the plastic of the polyolefins from the group COC polymethylpentene and PP

6. The manufacturing method according to claim 1, wherein the syringe has a luer lock at the distal end

7 manufacturing method according to any one of the preceding claims, wherein the

Medium in the filled syringe is a mixture of a fluid medium and at least one gas

8. The production method according to claim 7, wherein the medium is a liquid, a solution, a suspension or an emulsion

9 Manufacturing method according to claim 8, wherein the medium is a contrast medium

10 manufacturing method according to claim 9, wherein the contrast medium comprises a substance or a mixture from the group of the following substances: amidotπzoic acid, gadopentetic acid, gadobutrol, gadolinium EOB-DTPA, lopamidol, lopromide, lotrolan and lotroxin acid

11. The manufacturing method according to any one of the preceding claims, wherein the gas sterilization process comprises treatment with ethylene oxide, propan-3-olide and diethyl dicarbonate, furthermore hydrogen peroxide and an ozone / steam mixture.

12. The production method according to claim 11, wherein the treatment comprises hydrogen peroxide.

13. The production method according to one of the preceding claims, wherein the stopper is fixed during sterilization.

14. Manufacturing method according to one of the preceding claims, wherein the stopper is readjusted after sterilization.

15, manufacturing method according to one of the preceding claims, wherein the filled and terminally filled syringe is packaged in sterile plastic film and / or aluminum foil under optionally aseptic conditions.

16. The manufacturing method according to claim 15, wherein the syringe, which is in the container, is again sterilized externally by treating the syringe with ethylene oxide, propan-3-olide, hydrogen peroxide, an ozone / steam mixture and / or diethyl dicarbonate. Are also known.