WO2014187779A1 - Method for sterilizing the surface of a prefilled syringe - Google Patents

Method for sterilizing the surface of a prefilled syringe Download PDF

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Publication number
WO2014187779A1
WO2014187779A1 PCT/EP2014/060248 EP2014060248W WO2014187779A1 WO 2014187779 A1 WO2014187779 A1 WO 2014187779A1 EP 2014060248 W EP2014060248 W EP 2014060248W WO 2014187779 A1 WO2014187779 A1 WO 2014187779A1
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WIPO (PCT)
Prior art keywords
functional packaging
sterilization
primary container
drug
materials
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PCT/EP2014/060248
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German (de)
French (fr)
Inventor
Andreas Kalitzki
Heiko Kranz
Original Assignee
Bayer Pharma Aktiengesellschaft
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Publication of WO2014187779A1 publication Critical patent/WO2014187779A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
    • A61L2/0094—Gaseous substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/20—Gaseous substances, e.g. vapours
    • A61L2/206—Ethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/20—Gaseous substances, e.g. vapours
    • A61L2/208—Hydrogen peroxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/002—Packages specially adapted therefor, e.g. for syringes or needles, kits for diabetics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B55/00—Preserving, protecting or purifying packages or package contents in association with packaging
    • B65B55/02—Sterilising, e.g. of complete packages
    • B65B55/04—Sterilising wrappers or receptacles prior to, or during, packaging
    • B65B55/10—Sterilising wrappers or receptacles prior to, or during, packaging by liquids or gases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
    • A61L2202/10—Apparatus features
    • A61L2202/18—Aseptic storing means
    • A61L2202/181—Flexible packaging means, e.g. permeable membranes, paper
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
    • A61L2202/20—Targets to be treated
    • A61L2202/21—Pharmaceuticals, e.g. medicaments, artificial body parts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/001—Apparatus specially adapted for cleaning or sterilising syringes or needles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B2220/00—Specific aspects of the packaging operation
    • B65B2220/16—Packaging contents into primary and secondary packaging

Definitions

  • the invention relates to a protein syringe in a Sterilbarrieresystem for sterilization with a gas, further the surface sterilization of a protein syringe with hydrogen peroxide or ethylene oxide, and a measuring method for process control of surface sterilization (a blistered syringe) with hydrogen peroxide or ethylene oxide.
  • the present invention enables the surface sterilization of a primary container incl. Maintaining this sterility at least over the life.
  • the primary container is introduced into a functional packaging.
  • the functional packaging enables sterilization and maintains sterility at least over the life of the product.
  • the functional packaging is developed according to ISO 1 1607-1 and -2.
  • the functional packaging completely encloses the primary container and may consist of one or two or more materials which are firmly connected or closed against each other, eg sealed. At least one of the materials is permeable to gases, particularly sterilization gases (such as hydrogen peroxide or ethylene oxide). On the other hand, this material is germ-impermeable.
  • gases particularly sterilization gases (such as hydrogen peroxide or ethylene oxide).
  • this material is germ-impermeable.
  • Such a gas-permeable but germ-impermeable material may be, for example: polyethylene flow (PE flow, for example, trademark Tyvek) or paper or modifications of the aforementioned materials.
  • biological indicators can be introduced, which are spore-coated carrier.
  • the functional packaging may be a flexible package (pouch) or a rigid package (blister).
  • the primary container is contained in a functional packaging (as described above) which allows external sterilization of the primary container and ensures sterility at least over its lifetime.
  • the primary container may be, for example, prefilled syringes (glass or plastic, see ISO 1 1040-4, ISO 1 1040-6) or cartridges (see ISO 13926-1), which are then packaged secondarily in the functional packaging.
  • the primary container is suitable for medicinal products, including biological medicinal products (eg aflibercept (Eylea) or ranibizumab (Lucentis)) and medical devices.
  • the surface sterilization of the primary container in the functional packaging is carried out with a suitable sterilization method, typically by means of vaporous hydrogen peroxide or ethylene oxide.
  • a suitable sterilization method typically by means of vaporous hydrogen peroxide or ethylene oxide.
  • vapor or hydrogen peroxide or ethylene oxide sterilization also allows for the external sterilization of primary packaging (e.g., pre-filled syringes) with temperature sensitive drugs, e.g. biological drug molecules (especially aflibercept (Eylea) and ranibizumab (Lucentis)), using gentle sterilization conditions, since the method at low temperatures of 15- 40 ° C, especially at 17 ° C-30 ° C, preferably at 20-25 ° C and low pressures can be performed.
  • the functional packaging may have a shape that ensures that the primary container remains in position and also prevents pressure fluctuations, e.g. B. during transport by air or sterilization, flexible components, such. B. the plug of the syringe, move.
  • the subject of this invention is a process for surface sterilization with vaporous hydrogen peroxide or ethylene oxide of a primary container, which
  • (B) has been incorporated into a functional packaging made up of one or more materials, of which at least one of the materials is permeable to gases.
  • the process is characterized in that it is carried out at low temperatures of 15-40 ° C.
  • Pre-filled syringes sterilized by ethylene oxide or hydrogen peroxide have a germ-free outer surface.
  • the process can achieve a Sterility Assurance Level (SAL) of at least 10 "6 , especially 10 " 9, preferably O "12 or higher.
  • SAL Sterility Assurance Level
  • the described containers are delimited by a sterile outer surface of the primary container.
  • the sterility of the primary container is ensured by a validated sterilization process with a 12-log germ reduction.
  • the success of the sterilization process is unequivocally proven in the process by biological indicators, which are introduced into the sterilization chamber or the functional packaging before the sterilization process, for example.
  • the biological indicators are spore-coated carriers such as Geobacillus stearothermophilusis or Bacillus subtilis, which are proven to be suitable for sterilization with gases such as ethylene oxide and hydrogen peroxide.
  • the bioindicators used eg, as a disk or ribbon type from Mesa Labs or bioindicators from Skan
  • the bioindicators are introduced into the secondary packaging in such a way that the spore-loaded part is free during sterilization and from the gas on all sides is introduced into the functional packaging.
  • the bioindicators can be fixed to the functional packaging.
  • the primary container consists of a cylindrical body made of glass or plastic (e.g., cycloolefin or polypropylene).
  • the cylindrical body has an internal volume of 0.3 ml to 1 ml.
  • the cylindrical part may be formed as a Luer cone at the front end.
  • the cylindrical part may be flanged at the rear end.
  • the cylindrical part can be coated with a lubricant.
  • the cylindrical part can be printed with a scale or a dose mark.
  • the primary container is sealed at the front end (for drug delivery) with a closure that is (but not necessarily complete) made of an elastomer (such as butyl or polyisoprene) or a
  • Thermoplastic elastomer exists.
  • This closure may include other features such as a security lock or a luer lock adapter.
  • the primary tank is sealed at the rear end with a closure that is (but not necessarily complete) made of an elastomer (such as butyl, polyisoprene or polyisobutylene) or a thermoplastic elastomer.
  • This rear seal may be wholly or partly coated, e.g.
  • the rear end seal may be constructed of several materials, such as e.g. a plastic core with thread and a softer shell.
  • a linkage may be fitted in the seal at the rear end (eg via a thread or other fitting connection). However, the linkage can also be introduced without a fixed connection for sealing at the rear end. By means of this linkage, the seal can be moved and the syringe drained via the front end.
  • This flange can be made of plastic.
  • Figure 1 a shows an example of a primary container.
  • Figure 1 b shows an example of a primary container in a functional
  • FIG. 1 c shows a biological indicator introduced into the functional packaging.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Anesthesiology (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Mechanical Engineering (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Abstract

The invention relates to a protein injection syringe in a sterilization barrier system for a sterilization process using a gas, to the sterilization of the surface of a protein injection syringe using hydrogen peroxide or ethylene oxide, and to measurement methods for controlling a surface sterilization process (of a blister-packed syringe) using hydrogen peroxide or ethylene oxide.

Description

Verfahren zur Oberflächensterilisation einer Fertigspritze  Process for surface sterilization of a pre-filled syringe
Die Erfindung betrifft eine Proteinspritze in einem Sterilbarrieresystem zur Sterilisation mit einem Gas, weiterhin die Oberflächensterilisation einer Proteinspritze mit Wasserstoffperoxid oder Ethylenoxid, sowie eine Messmethode zur Prozesskontrolle einer Oberflächensterilisation (einer verblisterten Spritze) mit Wasserstoffperoxid oder Ethylenoxid. The invention relates to a protein syringe in a Sterilbarrieresystem for sterilization with a gas, further the surface sterilization of a protein syringe with hydrogen peroxide or ethylene oxide, and a measuring method for process control of surface sterilization (a blistered syringe) with hydrogen peroxide or ethylene oxide.
Die vorliegende Erfindung ermöglicht die Oberflächensterilisation eines Primärbehälters incl. der Wahrung dieser Sterilität mindestens über die Lebensdauer. Hierbei wird der Primärbehälter in ein funktionales Packmittel eingebracht. The present invention enables the surface sterilization of a primary container incl. Maintaining this sterility at least over the life. Here, the primary container is introduced into a functional packaging.
Das funktionale Packmittel ermöglicht eine Sterilisation und wahrt die Sterilität mindestens über die Lebensdauer des Produktes. Das funktionale Packmittel wird gemäß ISO 1 1607-1 und -2 entwickelt. Das funktionale Packmittel umschließt den Primärbehälter vollständig und kann aus ein oder zwei oder mehreren Materialien bestehen, die gegeneinander fest verbunden bzw. verschlossen werden, z.B. gesiegelt sind. Mindestens eines der Materialien ist durchlässig für Gase, insbesondere Sterilisationsgase (wie Wasserstoffperoxid oder Ethylenoxid). Andererseits ist dieses Material keimundurchlässig. Ein solches gasdurchlässiges aber keimundurchlässiges Material kann z.B.: Polyethylen-Fließ (PE-Fließ z.B. Handelsmarke Tyvek) oder Papier bzw. Abwandlungen von zuvor genannten Materialien sein. In das funktionale Packmittel können biologische Indikatoren eingebracht werden, die mit Sporen beschichtete Träger sind. Als Sporen können z.B. Sporen von Geobacillus stearothermophilusis oder Bacillus subtilis mit einer Beladungspopulation von mindestens 1 x 106 Sporen verwendet werden. Das funktionale Packmittel kann eine flexible Verpackung (Pouch) oder eine steife Verpackung (Blister) darstellen. Der Primärbehälter befindet sich in einem funktionalen Packmittel (wie oben beschrieben), das eine äußerliche Sterilisation des Primärbehälters ermöglicht und die Sterilität mindestens über die Lebensdauer sicherstellt. Beim Primärbehälter kann es sich z.B. um Fertigspritzen (Glas oder Kunststoff, siehe ISO 1 1040-4, ISO 1 1040-6) oder Karpulen (siehe ISO 13926-1 ) handeln, die anschließend in der funktionalen Verpackung sekundär verpackt wird. Der Primärbehälter ist geeignet für Arzneimittel, auch biologische Arzneimittel (z.B. Aflibercept (Eylea) oder Ranibizumab (Lucentis)) und Medizinprodukte. The functional packaging enables sterilization and maintains sterility at least over the life of the product. The functional packaging is developed according to ISO 1 1607-1 and -2. The functional packaging completely encloses the primary container and may consist of one or two or more materials which are firmly connected or closed against each other, eg sealed. At least one of the materials is permeable to gases, particularly sterilization gases (such as hydrogen peroxide or ethylene oxide). On the other hand, this material is germ-impermeable. Such a gas-permeable but germ-impermeable material may be, for example: polyethylene flow (PE flow, for example, trademark Tyvek) or paper or modifications of the aforementioned materials. In the functional packaging biological indicators can be introduced, which are spore-coated carrier. For example, spores of Geobacillus stearothermophilusis or Bacillus subtilis with a loading population of at least 1 × 10 6 spores can be used as spores. The functional packaging may be a flexible package (pouch) or a rigid package (blister). The primary container is contained in a functional packaging (as described above) which allows external sterilization of the primary container and ensures sterility at least over its lifetime. The primary container may be, for example, prefilled syringes (glass or plastic, see ISO 1 1040-4, ISO 1 1040-6) or cartridges (see ISO 13926-1), which are then packaged secondarily in the functional packaging. The primary container is suitable for medicinal products, including biological medicinal products (eg aflibercept (Eylea) or ranibizumab (Lucentis)) and medical devices.
Die Oberflächensterilisation des Primärbehälters im funktionalen Packmittel erfolgt mit einer geeigneten Sterilisationsmethode, typischerweise mittels dampfförmigem Wasserstoffperoxid oder Ethylenoxid. Verglichen mit alternativen Sterilisationsverfahren (wie Hitze oder Strahlung), ermöglicht die Sterilisation mit dampfförmigem Wasserstoffperoxid oder Ethlylenoxid auch die äußerliche Sterilisation von Primärpackmitteln (z.B. vorgefüllten Spritzen) mit temperatursensiblen Arzneimitteln, wie z.B. biologischen Wirkstoffmolekülen (insbesondere Aflibercept (Eylea) und Ranibizumab (Lucentis)), unter Anwendung von schonenden Sterilisationsbedingungen, da die Verfahren bei niedrigen Temperaturen von 15- 40°C, insbesondere bei 17°C-30°C, vorzugsweise bei 20-25°C und geringen Drücken durchgeführt werden können. The surface sterilization of the primary container in the functional packaging is carried out with a suitable sterilization method, typically by means of vaporous hydrogen peroxide or ethylene oxide. Compared to alternative sterilization methods (such as heat or radiation), vapor or hydrogen peroxide or ethylene oxide sterilization also allows for the external sterilization of primary packaging (e.g., pre-filled syringes) with temperature sensitive drugs, e.g. biological drug molecules (especially aflibercept (Eylea) and ranibizumab (Lucentis)), using gentle sterilization conditions, since the method at low temperatures of 15- 40 ° C, especially at 17 ° C-30 ° C, preferably at 20-25 ° C and low pressures can be performed.
Das funktionale Packmittel kann eine Form haben, die sicherstellt, dass der Primärbehälter in seiner Position verbleibt und die auch verhindert, dass bei Druckschwankungen, z. B. während des Transportes mit dem Flugzeug oder bei der Sterilisationen, flexible Komponenten, wie z. B. der Stopfen der Spritze, sich verschieben. The functional packaging may have a shape that ensures that the primary container remains in position and also prevents pressure fluctuations, e.g. B. during transport by air or sterilization, flexible components, such. B. the plug of the syringe, move.
Gegenstand dieser Erfindung ist ein Verfahren zur Oberflächensterilisation mit dampfförmigen Wasserstoffperoxid oder Ethylenoxid eines Primärbehälters, welcherThe subject of this invention is a process for surface sterilization with vaporous hydrogen peroxide or ethylene oxide of a primary container, which
(a) ein Arzneimittel enthält und (a) contains a medicinal product and
(b) in ein funktionales Packmittel eingebracht worden ist, das aus einem oder mehreren Materialien aufgebaut ist, wovon mindestens eines der Materialien für Gase durchlässig ist. Das Verfahren ist dadurch gekennzeichnet, dass es bei niedrigen Temperaturen von 15-40 °C durchgeführt wird. (B) has been incorporated into a functional packaging made up of one or more materials, of which at least one of the materials is permeable to gases. The process is characterized in that it is carried out at low temperatures of 15-40 ° C.
Fertigspritzen, die mittels Ethylenoxid oder Wasserstoffperoxid sterilisiert wurden, weisen eine keimfreie äußere Oberfläche auf. Mit dem Prozess kann ein Sterility Assurance Level (SAL) von mindestens 10"6 erreicht werden, insbesondere 10"9 vorzugsweisel O"12 oder höher. Pre-filled syringes sterilized by ethylene oxide or hydrogen peroxide have a germ-free outer surface. The process can achieve a Sterility Assurance Level (SAL) of at least 10 "6 , especially 10 " 9, preferably O "12 or higher.
Von den bisher bekannten Primärbehältnissen (z.B. vorgefüllten Fertigspritzen) grenzen sich die beschriebenen Behälter (Primärbehälter in einem funktionalen Packmittel, äußerlich sterilisiert) in dieser Erfindung durch eine sterile äußere Oberfläche des Primärbehältnisses ab. Of the heretofore known primary containers (e.g., pre-filled prefilled syringes), the described containers (primary containers in a functional packaging, externally sterilized) in this invention are delimited by a sterile outer surface of the primary container.
Der Sterilität des Primärbehältnisses wird über einen validierten Sterilisationsprozess mit einer 12-log Keimreduktion gewährleistet. The sterility of the primary container is ensured by a validated sterilization process with a 12-log germ reduction.
Bedingt durch die keimfreie Außenoberfläche des Primärbehälters bieten selbige eine erhöhte Sicherheit zur Vermeidung von Infektionen, insbesondere für die Injektion von Arzneimitteln ins Auge (ophthalmologische Anwendungen). Während einer Injektion des Arzneimittels ist die Gefahr einer bakteriellen Kontamination reduziert. Due to the germ-free outer surface of the primary container selbige offer increased safety to prevent infections, especially for the injection of drugs in the eye (ophthalmic applications). During an injection of the drug, the risk of bacterial contamination is reduced.
Der Sterilisationserfolg wird im Prozess zweifelsfrei durch biologische Indikatoren nachgewiesen, die z.B. vor dem Sterilisationsprozesses in die Sterilisationskammer oder die funktionale Verpackung eingebracht werden. Bei den biologischen Indikatoren handelt es sich um Sporen beschichtete Träger wie z.B. Geobacillus stearothermophilusis oder bacillus subtilis, die nachweislich für die Sterilisation mit Gasen wie z.B. Ethylenoxid und Wasserstoffperoxid geeignet sind. Die verwendeten Bioindikatoren (z.B. Ausführung als Disk oder Ribbon Type der Fa. Mesa Labs oder Bioindikatoren der Fa. Skan) haben eine Beladung mit einer Sporenpopulation von mindestens 1 x 106. Im beschriebenen Prozess werden die Bioindikatoren derart in die Sekundärverpackung eingebracht, dass der sporenbeladene Teil während der Sterilisation frei und von allen Seiten vom Gas erreichbar in die funktionale Verpackung eingebracht wird. Beispielsweise können die Bioindikatoren dabei am funktionalen Packmittel fixiert werden. The success of the sterilization process is unequivocally proven in the process by biological indicators, which are introduced into the sterilization chamber or the functional packaging before the sterilization process, for example. The biological indicators are spore-coated carriers such as Geobacillus stearothermophilusis or Bacillus subtilis, which are proven to be suitable for sterilization with gases such as ethylene oxide and hydrogen peroxide. The bioindicators used (eg, as a disk or ribbon type from Mesa Labs or bioindicators from Skan) have a loading with a spore population of at least 1 × 10 6 . In the described process, the bioindicators are introduced into the secondary packaging in such a way that the spore-loaded part is free during sterilization and from the gas on all sides is introduced into the functional packaging. For example, the bioindicators can be fixed to the functional packaging.
Die funktionale Verpackung in Zusammenhang mit den angewandten Sterilisationsverfahren (wie Ethylenoxid oder Wasserstoffperoxid) und der Nachweismethode bezüglich des Sterilisationserfolges ermöglichen: The functional packaging in connection with the applied sterilization processes (such as ethylene oxide or hydrogen peroxide) and the detection method with respect to the sterilization success enable:
• eine Oberflächensterilisation eines Primärbehälters, insbesondere Fertigspritzen, mit einen SAL Level von 10"6 und somit eine erhöhte Sicherheit insbesondere für die Injektion von Arzneimitteln ins Auge (ophthalmologische Anwendungen). • a surface sterilization of a primary container, in particular pre-filled syringes, with a SAL level of 10 "6 and thus an increased safety especially for the injection of drugs into the eye (ophthalmological applications).
• schonende Sterilisationsbedingungen und somit die Sterilisation von Behältern mit biologischen Wirkstoffmolekülen.  • Gentle sterilization conditions and thus the sterilization of containers with biological active agent molecules.
• eine zweifelsfreie Prozesskontrolle und ein Nachweis des Sterilisationserfolges durch die Nutzung von Bioindikatoren mit der beschriebenen Gebrauchsweise.  • a clear process control and proof of sterilization success through the use of bioindicators as described.
Aufbau der Spritze: Structure of the syringe:
• Der Primärbehälter besteht aus einem zylindrischen Körper, welcher aus Glas oder Kunststoff (z.B. Cycloolefin oder Polypropylen) besteht.  The primary container consists of a cylindrical body made of glass or plastic (e.g., cycloolefin or polypropylene).
o Der zylindrische Körper hat ein Innenvolumen von 0,3 ml bis 1 ml.  o The cylindrical body has an internal volume of 0.3 ml to 1 ml.
o Der zylindrische Teil kann am vorderen Ende als Luer Konus ausgeformt sein.  o The cylindrical part may be formed as a Luer cone at the front end.
o Der zylindrische Teil kann am hinteren Ende mit einem Flansch versehen sein.  o The cylindrical part may be flanged at the rear end.
o Der zylindrische Teil kann mit einem Gleitmittel beschichtet sein.  o The cylindrical part can be coated with a lubricant.
o Der zylindrische Teil kann mit einer Skalierung oder einer Dosismarkierung bedruckt sein.  o The cylindrical part can be printed with a scale or a dose mark.
• Der Primärbehälter ist am vorderen Ende (zum Medikamentenaustritt) mit einem Verschluss abgedichtet, der (zur Abdichtung aber nicht zwangsläufing komplett) aus einem Elastomer (wie Butyl- oder Polyisopren) oder einem • The primary container is sealed at the front end (for drug delivery) with a closure that is (but not necessarily complete) made of an elastomer (such as butyl or polyisoprene) or a
Thermoplastischen Elastomer besteht. Thermoplastic elastomer exists.
o Dieser Verschluss kann weitere Funktionen beinhalten, wie einem Sicherheitsverschluss oder einen Luer-Lock-Adapter. • Der Primärbehälter ist am hinteren Ende mit einem Verschluss abgedichtet, der (zur Abdichtung aber nicht zwangsläufig komplett) aus einem Elastomer (wie Butyl-, Polyisopren oder Polyisobutylen) oder einem Thermoplastischen Elastomer besteht. o This closure may include other features such as a security lock or a luer lock adapter. • The primary tank is sealed at the rear end with a closure that is (but not necessarily complete) made of an elastomer (such as butyl, polyisoprene or polyisobutylene) or a thermoplastic elastomer.
o Diese hintere Abdichtung kann ganz oder teils beschichtet sein, z.B. mit o This rear seal may be wholly or partly coated, e.g. With
Polytetrafluorethylen oder Silikonöl, um die Eigenschaften zu optimieren. Polytetrafluoroethylene or silicone oil to optimize the properties.
o Die Abdichtung am hinteren Ende kann aus mehreren Materialien aufgebaut sein, wie z.B. einem Kunststoff kern mit Gewinde und einer weicheren Hülle.  o The rear end seal may be constructed of several materials, such as e.g. a plastic core with thread and a softer shell.
• In die Abdichtung am hinteren Ende kann ein Gestänge angebracht sein (z.B über ein Gewinde oder eine andere Passverbindung). Das Gestänge kann aber auch ohne feste Verbindung zur Abdichtung am hinteren Ende eingebracht sein. Mittels dieses Gestänges kann die Abdichtung bewegt und die Spritze über das vordere Ende entleert werden.  • A linkage may be fitted in the seal at the rear end (eg via a thread or other fitting connection). However, the linkage can also be introduced without a fixed connection for sealing at the rear end. By means of this linkage, the seal can be moved and the syringe drained via the front end.
• Am hinteren Ende kann ein zusätzlicher Flansch aufgesetzt werden, der eine bessere Handhabung ermöglicht. Dieser Flansch kann aus Kunststoff bestehen. Figuren  • At the rear end, an additional flange can be placed for better handling. This flange can be made of plastic. characters
Figur 1 a zeigt ein Beispiel für einen Primärbehälter. Figure 1 a shows an example of a primary container.
Figur 1 b zeigt ein Beispiel für einen Primärbehälter in einer funktionalen  Figure 1 b shows an example of a primary container in a functional
Verpackung.  Packaging.
Figur 1 c zeigt einen in die funktionale Verpackung eingebrachten biologischen Indikator. FIG. 1 c shows a biological indicator introduced into the functional packaging.

Claims

Patentansprüche claims
Verfahren zur Oberflächensterilisation mit dampfförmigen Wasserstoffperoxid oder Ethylenoxid eines ein Arzneimittel enthaltenden Primärbehälters, wobei der Primärbehälter in ein funktionales Packmittel eingebracht worden ist, das aus einem oder mehreren Materialien aufgebaut ist, wovon mindestens eines der Materialien für Gase durchlässig ist, dadurch gekennzeichnet, dass das Verfahren bei niedrigen Temperaturen von 15-40 °C durchgeführt wird. A process for surface sterilization with vaporous hydrogen peroxide or ethylene oxide of a primary container containing a drug, the primary container having been incorporated into a functional packaging made up of one or more materials, at least one of which materials is permeable to gases, characterized in that the method at low temperatures of 15-40 ° C is performed.
Verfahren nach Anspruch 1 , wobei das Arzneimittel Aflibercept oder The method of claim 1, wherein the drug is aflibercept or
Ranibizumab ist.  Ranibizumab is.
Verfahren nach Anspruch 1 , wobei das Arzneimittel Aflibercept ist. Verfahren nach Ansprüchen 1 -3, wobei die Temperatur 17-30 °C beträgt. Verfahren nach Anspruch 4, wobei die Temperatur 20-25 °C beträgt. The method of claim 1, wherein the drug is aflibercept. Process according to claims 1-3, wherein the temperature is 17-30 ° C. The method of claim 4, wherein the temperature is 20-25 ° C.
Verfahren nach einem der vorangehenden Ansprüche, wobei das für Gase durchlässige Material ausgewählt ist aus der Gruppe bestehend aus, The method of any one of the preceding claims, wherein the gas permeable material is selected from the group consisting of
Polyethylen-Fließ (z.B. Handelsmarke Tyvek) oder Papier, bzw.  Polyethylene flow (e.g., Tyvek trademark) or paper, or
Abwandlungen von den zuvor genannten Materialien.  Modifications of the aforementioned materials.
Verfahren nach einem der vorhergehenden Ansprüche, dadurch Method according to one of the preceding claims, characterized
gekennzeichnet, dass der Primärbehälter eine Fertigspritze ist.  characterized in that the primary container is a pre-filled syringe.
Verfahren zum Nachweis des Sterilisationserfolges erzielt durch ein Verfahren gemäß der vorhergehenden Ansprüche, wobei biologische Indikatoren, die mit Sporen beschichtete Träger sind, vor dem Sterilisationsprozess in den funktionalen Sekundärbehälter eingebracht werden. A method of detecting sterilization success achieved by a method according to the preceding claims, wherein biological indicators, which are spore-coated carriers, are introduced into the functional secondary container prior to the sterilization process.
Verfahren gemäß Anspruch 8, wobei es sich bei den Sporen um Geobacillus stearothermophilusis oder Bacillus subtilis handelt. The method of claim 8, wherein the spores are Geobacillus stearothermophilusis or Bacillus subtilis.
10. Verfahren gemäß Ansprüchen 8 oder 9, wobei die Bioindikatoren eine Beladung mit einer Sporenpopulation von mindestens 1 x 106 haben. 10. The method according to claims 8 or 9, wherein the bioindicators have a loading with a spore population of at least 1 x 10 6 .
1 1 .Verfahren gemäß Anspruch 1 , wobei es sich bei den verwendeten Gasen um Ethylenoxid oder Wasserstoffperoxid handelt. 11. The process according to claim 1, wherein the gases used are ethylene oxide or hydrogen peroxide.
12. Funktionales Packmittel, dass 12. Functional packaging that
a. aus einem oder mehreren Materialien aufgebaut ist, wovon mindestens eines der Materialien für Gase durchlässig ist und die gegeneinander fest verbunden bzw. verschlossen sind und dass  a. is constructed of one or more materials, of which at least one of the materials is permeable to gases and which are firmly connected or closed against each other and that
b. einen mit einem Arzneimittel gefüllten Primärbehälter enthält und  b. contains a primary container filled with a drug and
diesen vollständig umschließt,  completely enclosing it,
dadurch gekennzeichnet, dass das funktionale Packmittel eine  characterized in that the functional packaging means a
Oberflächensterilisation des Primärbehälters bei niedrigen Temperaturen von 15-40 °C ermöglicht.  Surface sterilization of the primary container at low temperatures of 15-40 ° C allows.
13. Funktionales Packmittel gemäß Anspruch 12, wobei es sich bei den 13. Functional packaging according to claim 12, wherein it is in the
verwendeten Gasen um Ethylenoxid oder Wasserstoffperoxid handelt.  used gases to ethylene oxide or hydrogen peroxide.
14. Funktionales Packmittel nach Anspruch 12, wobei das Arzneimittel Aflibercept oder Ranibizumab ist 14. Functional packaging according to claim 12, wherein the drug is aflibercept or ranibizumab
15. Funktionales Packmittel nach Anspruch 12, wobei das Arzneimittel Aflibercept ist. 15. Functional packaging according to claim 12, wherein the drug is aflibercept.
16. Funktionales Packmittel nach Ansprüchen 12-15, wobei die Temperatur 17-30 °C beträgt. 16. Functional packaging according to claims 12-15, wherein the temperature is 17-30 ° C.
17. Funktionales Packmittel nach Anspruch 16, wobei die Temperatur 20-25 °C beträgt. 17. Functional packaging according to claim 16, wherein the temperature is 20-25 ° C.
18. Funktionales Packmittel nach einem der Ansprüche 12 - 17, wobei das für Gase durchlässige Material ausgewählt ist aus der Gruppe bestehend aus Polyethylen-Fließ (z.B. Handelsmarke Tyvek) oder Papier, bzw. Abwandlungen von den zuvor genannten Materialien. 18. Functional packaging means according to any one of claims 12-17, wherein the gas-permeable material is selected from the group consisting of Polyethylene flow (eg trademark Tyvek) or paper, or modifications of the aforementioned materials.
19. Funktionales Packmittel nach einem der Ansprüche 12 - 18, dadurch gekennzeichnet, dass der Primärbehälter eine Fertigspritze ist. 19. Functional packaging according to one of claims 12 - 18, characterized in that the primary container is a pre-filled syringe.
PCT/EP2014/060248 2013-05-24 2014-05-19 Method for sterilizing the surface of a prefilled syringe WO2014187779A1 (en)

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EP4202055A1 (en) 2021-12-21 2023-06-28 Bayer Aktiengesellschaft Enzyme indicators for the process control of sterilization processes

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WO2022259217A1 (en) 2021-06-11 2022-12-15 Cilag Gmbh International Gas sterilizable syringes having apertures covered by gas permeable barriers for enabling ingress and egress of sterilization gases while preventing leakage of flowable materials
EP4202055A1 (en) 2021-12-21 2023-06-28 Bayer Aktiengesellschaft Enzyme indicators for the process control of sterilization processes
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