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WO1999036330A1 - Ameliorations concernant des conteneurs - Google Patents

Ameliorations concernant des conteneurs Download PDF

Info

Publication number
WO1999036330A1
WO1999036330A1 PCT/SE1999/000026 SE9900026W WO9936330A1 WO 1999036330 A1 WO1999036330 A1 WO 1999036330A1 SE 9900026 W SE9900026 W SE 9900026W WO 9936330 A1 WO9936330 A1 WO 9936330A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxygen
indicator
sterilization
iron
container
Prior art date
Application number
PCT/SE1999/000026
Other languages
English (en)
Inventor
Peter HÖGSTRÖM
Original Assignee
Fresenius Kabi Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE9800101A external-priority patent/SE511776C2/sv
Application filed by Fresenius Kabi Ab filed Critical Fresenius Kabi Ab
Publication of WO1999036330A1 publication Critical patent/WO1999036330A1/fr

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N31/00—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods
    • G01N31/22—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators
    • G01N31/223—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators for investigating presence of specific gases or aerosols
    • G01N31/225—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators for investigating presence of specific gases or aerosols for oxygen, e.g. including dissolved oxygen
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D79/00—Kinds or details of packages, not otherwise provided for
    • B65D79/02—Arrangements or devices for indicating incorrect storage or transport

Definitions

  • the present invention relates to leak detection in containers for oxygen sensitive agents with an oxygen absorber which provides the manufacturer with effective means to discard defect containers immediately after their final sterilization.
  • containers especially suitable for oxygen sensitive parenterally administerable fluids of flexible polymeric materials have been described in detail in the International Patent Application No. PCT/SE97/00590. Principally, these containers comprise a sealed inner, primary container made of a polymeric material which is filled with one or several agents in different chambers. The inner container is filled and sealed in a controlled atmosphere and thereafter enclosed in an outer airtight, flexible and transparent envelope together with an oxygen absorber capable of consuming both residual and penetrating oxygen and an oxygen indicator, whereupon the envelope is finally sealed and subjected to a final sterilization before it is ready to be delivered to the consumers.
  • the outer envelope has a high resistance against penetrating oxygen
  • the inner container is made of material admitting a certain oxygen transfer in order to allow dissolved residual oxygen of the stored parenteral agents to be consumed by the oxygen absorber.
  • Suitable materials for the containers and oxygen absorbers are described in more detail in the mentioned PCT/SE97/00590.
  • An especially suitable oxygen indicator which can be heat sterilized with maintained indicating capacity has been described in the Swedish Patent application No. 9602818-6.
  • the containers described in PCT/SE97/00590 have an unexpectedly advantageous storage capacity and admits notoriously problematic pharmaceutical agents such as lipid emulsions comprising a high amount of oxidation sensitive polyunsaturated fatty acids, to be stored with retained integrity and maintained physical properties for at least 12 months and preferably more at least 24 months, while avoiding migration of undesired substances from the container material.
  • the combination of container materials, the capacity of the deoxidizer and the carefully designed details of the container as well as its manufacturing and filling processes all contribute to the favorable storage results.
  • An object of the present invention is to provide a selection method for discarding defect flexible containers storing oxygen sensitive pharmaceutical articles directly in connection to their production while being able to employ the same constituents of the container as normally intended (i.e. a substantially airtight envelope, oxygen indicator and optionally an oxygen absorber).
  • Another object of the present invention is to use the same oxygen indicator as intended to alert the user of an inappropriate oxygen exposure of the product during long term storage to detect otherwise invisible defects in the oxygen barrier provided by the outer envelope of a container for storing an oxygen sensitive pharmaceutical article, already in connection to their manufacturing process.
  • the present invention is directed to a method of discarding such flexible containers storing an oxygen sensitive article which have defects in the oxygen barrier against the environment already in connection to the final manufacturing step.
  • the containers are intended to comprise an oxygen sensitive article for long term storage and generally consist of an entirely sealed, oxygen barrier forming, substantially airtight, envelope which entirely encloses the article together with an oxygen indicator.
  • an oxygen absorber or deoxidizer usually in the form of an oxygen scavenging composition enclosed in a sachet.
  • the presence of an oxygen absorber is not mandatory to successfully perform the present invention, but many highly sensitive pharmaceutical liquids to be stored would in the absence of an oxygen absorber require laborious oxygen degassing process steps to be adequately protected.
  • the article, the oxygen indicator and an optional oxygen absorber preferably are separate units, but it would be conceivable for the skilled to connect the indicator and/or the absorbent with the article in various manners.
  • the inventive method is principally characterized by the consecutive steps of sterilizing the containers, inspecting the oxygen indicators after the sterilization and discarding the containers in which the indicator has changed its characteristics in a predetermined identifiable manner.
  • the present invention is directed to the use of an oxygen indicator in the detection of defects in an oxygen barrier against the environment provided by a flexible transparent substantially airtight polymeric material in a container suitable for long term storage of an oxygen sensitive pharmaceutical article, entirely enclosed in a sealed outer oxygen barrier forming outer envelope together with an oxygen absorber.
  • the indicator must thereby be capable of alerting the mentioned defects in connection with the final stage of the container manufacture. It is a desire when obtaining an optimal product safety that the finally sealed containers storing the oxygen sensitive article is sterilized by heat or irradiation according to conventional methods as a final step of their manufacture before storage and/or delivery to the consumers.
  • the sterilization is performed by means of high pressure steam, suitably at 121 °C for about 15 minutes.
  • the oxygen indicators utilized in the present invention are capable to withstand all such sterilization methods with maintained reliability of its detection capacity of oxygen.
  • the inspection of the containers is performed after the sterilization process is finalized. If heat sterilizing the containers with steam, the inspection is performed after being brought out from the treatment station and cooled for a suitable time which optionally includes a period during which the container dries.
  • the inspection is performed immediately after the sterilization which normally means from within a couple of minutes after terminating the sterilization, up to several days after the sterilization is finalized. It is an important advantage of the present invention that it admits a flexibility of the inspection time which provides the manufacturers of freedom to allocate resources due to variations in the production.
  • the inspection can be performed visually by readily trained persons or by automatic vision systems which scan the container for predetermined optic changes of the containers. Such systems may easily be conceived by the skilled person without undue development efforts and are not a part of the present invention. It is also necessary that the present invention shall contribute to the detection of even minor defects in the oxygen barrier forming material in order to enable the removal of substantially all containers which potentially will contain damaged articles when arriving at the customer or after long term storage. For this reason defects generated by small holes or perforations of an average diameter size of about 20 ⁇ m in the enveloping substantially airtight material are detectable according to the present invention.
  • the indicators employed in the present invention preferably change color in a visible and predetermined manner when subjected to a certain level of oxygen penetrating through the defective oxygen barrier of the container, in order to facilitate a manual inspection of the container through a transparent barrier forming material.
  • the sterilization method at least temporarily induces an increased reactivity with oxygen and most preferably the heat generated by heat sterilization, such as autoclavation induces an increase in the indicator reaction rate with oxygen.
  • the indicator shall be able to be sensitive enough for oxygen penetrating the container to undergo a change in color, also in the presence of an oxygen scavenging composition in the deoxidizer which competes for the oxygen molecules.
  • a fast reaction with penetrating oxygen is also preferable to be able to inspect the containers immediately or a suitably short time after sterilization process is finished.
  • a further advantage of the present invention is that it readily enables the manufacturer to discard containers wherein the gas volume inadvertently have increased by a hole in the airtight material which may jeopardize that an effective sterilization is performed.
  • the gas volume inadvertently have increased by a hole in the airtight material which may jeopardize that an effective sterilization is performed.
  • For holes larger than about 50 ⁇ m there is a considerable risk that a sufficient amount of air may enter the container that a significant increase in the gas volume inside the container is obtained.
  • there conventional inspection may lead to that defect containers are delivered to the customer.
  • the indicator will respond already in connection with the sterilization, so the manufacturer can remove all such defect containers.
  • a suitable indicator comprises a composition which involves the oxidation of iron (II) to iron (III) with penetrating oxygen. It is preferable that the indicator comprises an agent affecting its reaction rate, suitably an organic acid and more suitably an organic acid having at least two carboxylic groups.
  • the organic acid is an alpha-hydroxy acid.
  • Preferred iron(II) compounds of the indicator are a salt of iron selected from a group of salts consisting of iron(II)sulfates, iron(II)acetate, iron(II)nitrate, iron(II)chloride and iron(II)trifluoroacetate.
  • the indicator comprises an agent containing pyrogallol entities, suitably tannin of natural, synthetic or semi-synthetic origin.
  • the indicator comprises iron(II)sulphate or iron(II)sulphate heptahydrate; tannin; and citric acid or citric acid 1 -hydrate; optionally in combination with a suitable carrier agent.
  • the relative amount of citric acid can be employed to affect its reaction rate. Generally a reduced amount of citric acid leads to a higher reaction rate, whereas increases in iron and tannin concentrations reduces the reaction rate.
  • indicators of this type can be sensitive to light, it may be suitable to keep the container product in darkness or in shelter from direct sunlight if the time period from sterilization to inspection is prolonged.
  • the stored articles principally may be any type of oxygen sensitive article, such as pharmaceuticals, medical devices, food products, electronic articles.
  • the articles preferably are pharmaceutical agents, intended for parenteral administration, in particular intravenous administration, stored in a primary inner container of polymeric material.
  • Such agents can both in the form of fluids and in solid forms, e.g. a lyophilized composition.
  • the stored article is an inner container made of polymeric material filled with at least one oxygen sensitive parenteral nutrient, such as lipid emulsions, amino acid solution and carbohydrate solutions.
  • the inner container is made of flexible, transparent polymeric film material which is not completely airtight and admits oxygen transfer.
  • Such material comprises polyolefins and particularly polypropylene homopolymers and copolymers.
  • a suitable multilayered film material is disclosed in the European Patent 0 228 819 which besides a polypropylene- polyethylene copolymer comprises a thermoplastic elastomer to provide the film with a desired flexibility.
  • the outer envelope, completely sealing the stored article from the environment preferably is made of a substantially airtight material admitting less oxygen transfer than about 0.5 ml per square meter, day and atmosphere, preferably less than 2 ml per square meter after heat sterilization, measured per day and at 25 °C at 60% relative humidity.
  • the envelope materials must be sufficiently transparent so as to enable a simple reading of changed indicator.
  • Such materials are composed of multilayered structures of several layers with complementary features.
  • such materials comprise a metal oxide layer, such as silicon or aluminum oxides and a layer with additional oxygen barrier forming capacity, such as (poly)ethylene vinyl alcohol (EVOH).
  • EVOH polyethylene vinyl alcohol
  • Especially preferred materials for the envelope are further described in the mentioned PCT/SE97/00590.
  • the deoxidizer preferably comprises a solid oxygen scavenging composition containing iron and is of the type which increases its oxygen consumption when the relative humidity increases which rapidly occurs during a heat sterilization by means of high pressure steam.
  • Suitable oxygen absorbers are disclosed in PCT/SE95/00684, DE 42 33 817 and in PCT/SE97/00590. Examples of commercially available oxygen absorbers which have been found suitable with the inventive method are AgelessOFX 50 to 400 from Mitsubishi.
  • the inventive method of discarding defect containers preferably is practiced with assembled containers each comprising a first inner container of polymeric material according to above, filled with one or several oxygen sensitive agents, an oxygen absorber and an oxygen indicator as separate units which are enclosed in an outer airtight envelope and finally sealed in a protected atmosphere which is depleted of environmental oxygen with conventional means.
  • assembled containers each comprising a first inner container of polymeric material according to above, filled with one or several oxygen sensitive agents, an oxygen absorber and an oxygen indicator as separate units which are enclosed in an outer airtight envelope and finally sealed in a protected atmosphere which is depleted of environmental oxygen with conventional means.
  • the space between the envelope and the inner container will only contain low amounts of remaining oxygen.
  • moisture will penetrate the envelope and enter the space between the envelope and the inner container.
  • moisture will be forced out from the inner container to the space with the oxygen absorber and the oxygen indicator.
  • the oxygen consumption of the oxygen absorber will be triggered by the moisture and the heat and start to scavenge remaining dissolved oxygen in the stored fluids of the inner container as well as the oxygen remaining in the space.
  • the envelope contains defects in the oxygen barrier such as a hole or a crack
  • oxygen from the ambient air will enter the container during the steam sterilization.
  • high amounts of oxygen will rush into the container and saturate the oxygen absorber and rapidly lead to a detectable change of the indicator. If the defects are smaller, there is a risk that the oxygen absorber for a considerable time will be able to consume the incoming oxygen to such an extent that the indicator not will change until a time after the product inspection.
  • the indicator will be able increase its reactivity during the heat sterilization so a detectable change of the indicator occurs.
  • Oxygen indicators to be used with the inventive method of discarding defect containers were made according to the following:
  • composition (g/ )
  • the film was converted from reels of 300- 450 widths to a width of 38 mm.
  • the reel of Excel film was placed on the carrier of a filling equipment.
  • the Excel film was printed using a white hot-stamp foil.
  • the film was double-folded and welded along the side and transversally.
  • the glass flask with indicator solution was placed in a nitrogen-protected vessel above the filling station. The nitrogen overpressure was controlled during the filling process.
  • Indicator solution flowed through a tube into the welded film and the transversal welding station welded a strip of indicators separated by welds of 6 mm.
  • the volume of one indicator is approximately 1 ml. Strips of 50 indicators were packaged in airtight overwrap bags of the material disclosed in the Swedish Patent Application 9601348- 7 together with Z-100 oxygen absorbers.
  • a 2500 ml three chamber container having the dimension 420 x 310 mm, made of the material Excel® supplied from McGaw Inc. is used as a primary chamber-container.
  • the three chambers are divided from each other by welded heat seals which are rupturable by the user.
  • the chambers were filled with liquid oxygen sensitive parenteral nutrients and sealed by permanently welded heat seals.
  • the nutrient liquids are degassed with nitrogen gas before filling and the filling is performed in a controlled atmosphere zone with less than about 1 % residual atmospheric oxygen.
  • the primary container is then wrapped in outer airtight envelope made of the material R 1706 from Soplaril SA (multilayered film comprising the layers of polyethylene terephtalate-metal oxide/glue/polypropylene/(poly)ethylene vinylalcohol/polypropylene) together with an oxygen absorber (Ageless FX200 PA from Mitsubishi) and an oxygen indicator made according to Example 1 (Oxalert® developed by Pharmacia & Upjohn AB).
  • the oxygen indicator and the oxygen absorber are placed in the vicinity of the saddle-formed port system of the primary, inner container before permanently sealing the outer envelope.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Physics & Mathematics (AREA)
  • Emergency Medicine (AREA)
  • Biochemistry (AREA)
  • Dispersion Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
  • Packages (AREA)

Abstract

L'invention concerne un procédé fiable permettant de retirer avant envoi aux clients les conteneurs contenant un produit sensible à l'oxygène, dont la barrière à l'oxygène de l'environnement est défectueuse. Les conteneurs contiennent un produit sensible à l'oxygène, ce produit étant entièrement enfermé dans une barrière oxygène étanche formant avec un indicateur d'oxygène une enveloppe sensiblement étanche à l'air. Le procédé consiste généralement à stériliser les conteneurs, inspecter les indicateurs d'oxygène après stérilisation et écarter les conteneurs dont l'indicateur présente des caractéristiques modifiées de façon notable.
PCT/SE1999/000026 1998-01-16 1999-01-13 Ameliorations concernant des conteneurs WO1999036330A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE9800101-9 1998-01-16
SE9800101A SE511776C2 (sv) 1998-01-16 1998-01-16 Metod och användning av syreindikatorer för läckagedetektering vid sterilisering
US7465598P 1998-02-13 1998-02-13
US60/074,655 1998-02-13

Publications (1)

Publication Number Publication Date
WO1999036330A1 true WO1999036330A1 (fr) 1999-07-22

Family

ID=26663190

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1999/000026 WO1999036330A1 (fr) 1998-01-16 1999-01-13 Ameliorations concernant des conteneurs

Country Status (1)

Country Link
WO (1) WO1999036330A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007051860A1 (fr) 2005-11-07 2007-05-10 Fraunhofer-Gesellschaft Zur Foerderung Der Angewandten Forschung E.V. Vernis contenant un desactivateur d’oxygene et/ou un indicateur d’oxygene pour enduction ou collage et produits obtenus a partir de ce vernis
EP3171868B1 (fr) 2014-07-25 2020-09-30 Terumo Kabushiki Kaisha Préparation de solution pour injection d'acétaminophène conditionnée
EP3970731A1 (fr) * 2015-03-10 2022-03-23 Hemanext Inc. Kits jetables de réduction des niveaux d'oxygène, dispositifs et leurs procédés d'utilisation
US11433164B2 (en) 2009-10-12 2022-09-06 Hemanext Inc. System for extended storage of red blood cells and methods of use
US12089589B2 (en) 2009-10-12 2024-09-17 Hemanext Inc. Irradiation of red blood cells and anaerobic storage
US12201584B2 (en) 2015-04-23 2025-01-21 Hemanext Inc. Anaerobic blood storage containers

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2208287A (en) * 1987-07-30 1989-03-22 Roussel Uclaf A package permitting the prolonged storage of nutrient products
WO1993024820A1 (fr) * 1992-06-03 1993-12-09 Valtion Teknillinen Tutkimuskeskus Indicateur de defaut d'etancheite
WO1998003866A1 (fr) * 1996-07-19 1998-01-29 Pharmacia & Upjohn Ab Composition coloree comportant un agent contenant des entites de pyrogallol, un sel de fer (ii) et un acide organique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2208287A (en) * 1987-07-30 1989-03-22 Roussel Uclaf A package permitting the prolonged storage of nutrient products
WO1993024820A1 (fr) * 1992-06-03 1993-12-09 Valtion Teknillinen Tutkimuskeskus Indicateur de defaut d'etancheite
WO1998003866A1 (fr) * 1996-07-19 1998-01-29 Pharmacia & Upjohn Ab Composition coloree comportant un agent contenant des entites de pyrogallol, un sel de fer (ii) et un acide organique

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007051860A1 (fr) 2005-11-07 2007-05-10 Fraunhofer-Gesellschaft Zur Foerderung Der Angewandten Forschung E.V. Vernis contenant un desactivateur d’oxygene et/ou un indicateur d’oxygene pour enduction ou collage et produits obtenus a partir de ce vernis
EP2295476A2 (fr) 2005-11-07 2011-03-16 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Laque dotée d'une fonction d'indicateur d'oxygène pour le revêtement ou le collage et produits ainsi fabriqués
US11433164B2 (en) 2009-10-12 2022-09-06 Hemanext Inc. System for extended storage of red blood cells and methods of use
US12089589B2 (en) 2009-10-12 2024-09-17 Hemanext Inc. Irradiation of red blood cells and anaerobic storage
EP3171868B1 (fr) 2014-07-25 2020-09-30 Terumo Kabushiki Kaisha Préparation de solution pour injection d'acétaminophène conditionnée
EP3970731A1 (fr) * 2015-03-10 2022-03-23 Hemanext Inc. Kits jetables de réduction des niveaux d'oxygène, dispositifs et leurs procédés d'utilisation
US11350626B2 (en) 2015-03-10 2022-06-07 Hemanext Inc. Oxygen reduction disposable kits, devices and methods of use thereof (ORDKit)
US11375709B2 (en) 2015-03-10 2022-07-05 Hemanext Inc. Oxygen reduction disposable kits, devices and methods of use thereof
US11638421B2 (en) 2015-03-10 2023-05-02 Hemanext Inc. Oxygen reduction disposable kits, devices and methods of use thereof
AU2022203076B2 (en) * 2015-03-10 2024-08-08 Hemanext Inc. Oxygen reduction disposable kits, devices and methods of use thereof
US12201584B2 (en) 2015-04-23 2025-01-21 Hemanext Inc. Anaerobic blood storage containers

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