EP0065469A2 - Method for preparation of a liquid to be lyophilized and use of said liquid - Google Patents

Method for preparation of a liquid to be lyophilized and use of said liquid Download PDF

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Publication number
EP0065469A2
EP0065469A2 EP82400943A EP82400943A EP0065469A2 EP 0065469 A2 EP0065469 A2 EP 0065469A2 EP 82400943 A EP82400943 A EP 82400943A EP 82400943 A EP82400943 A EP 82400943A EP 0065469 A2 EP0065469 A2 EP 0065469A2
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EP
European Patent Office
Prior art keywords
liquid
neck
container
pocket
bag
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Legal status (The legal status 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 status listed.)
Granted
Application number
EP82400943A
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German (de)
French (fr)
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EP0065469B1 (en
EP0065469A3 (en
Inventor
Annie Bedout
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Individual
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Individual
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Priority to AT82400943T priority Critical patent/ATE36645T1/en
Publication of EP0065469A2 publication Critical patent/EP0065469A2/en
Publication of EP0065469A3 publication Critical patent/EP0065469A3/en
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Publication of EP0065469B1 publication Critical patent/EP0065469B1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/10—Bag-type containers
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing

Definitions

  • the invention relates to a container for liquid to be lyophilized produced in the form of a flexible bag. It finds application in particular in the medical field, where such a container may contain physiological liquids such as blood plasma, preserved in the lyophilized state.
  • the invention therefore provides a solution of considerable technical interest by allowing lyophilization to be carried out directly in receptacles in the form of flexible bags in which the product can be stored, without transfer, from lyophilization to use, under conditions of complete aseptic.
  • the invention provides a container for liquid to be lyophilized produced in the form of a flexible bag, characterized in that it comprises a rigid neck sealingly passing through the envelope of the flexible bag, largely dimensioned to allow the evacuation of the vapor produced during the lyophilization of a liquid received in the bag.
  • the flexible pouch is produced, most simply, by an envelope made of a flexible plastic material, sterilizable, and preferably transparent, formed of two flat sheets welded to one another around their periphery, except on the one side, at the step of the neck, where they are each welded around half of the neck to surround it completely and ensure sealing.
  • the neck itself will generally also be made of plastic and its rigidity can be obtained for example by giving it a cylindrical shape with sufficiently thick walls or er. providing it with appropriate ribs.
  • an internal passage section with a diameter of at least 10mm, preferably between 20 mm and 60 mm, for a liquid capacity of 100 ml to 2 liters, preferably with a section of the order of 0.001 to 0.05 times the internal surface of the pocket considered flat; the latter ratio is between 0.5% and 2% in the best cases.
  • a similar pocket can also be produced by blowing (of polyolefin or polyurethane resins for example) or by any other process suitable for generating a flexible plastic container with a large neck.
  • means are also provided to allow the bag to be kept in an inflated position, temporarily during the lyophilization operations.
  • These are means which can be described as "mechanical” and which make it possible to separate two opposite walls of the flexible bag from one another and to keep them in this position, horizontally at a distance l one of the other which can be, for example, of the same order of magnitude as the diameter of the rigid neck, is generally between 20 and 60 millimeters.
  • the lyophilization of any liquid is generally carried out in two essential stages.
  • the first consists in freezing the liquid suddenly, at a temperature below minus 30 ° C, and the second consists in extracting the water from the frozen liquid by sublimation by heating it under vacuum.
  • the utility The unity of the temporary spacing means is felt from the first step.
  • the bag containing the liquid to be frozen is placed in the lyophilization installation, in a substantially horizontal position, flat on a surface slightly inclined to the horizontal, or housed in a slightly hollow cavity, so that the liquid meets on one of the two opposite walls, and that the rigid neck is released from the volume of liquid and that the latter nevertheless offers a large free surface.
  • the spacing means make it possible to lift the upper wall above this free surface.
  • the subsequent sublimation step requires only a relatively short treatment time because the water sublimes quickly from this large free surface of the frozen liquid, advantageously kept clear by lifting the upper wall of the bag by means of 'spacing, and the water vapor is easily evacuated through the orifice of the largely dimensioned neck.
  • Particular embodiments of the container according to the invention may comprise on the flexible pocket at least one tab or loop formed outwardly on at least one of the two opposite walls of the pocket.
  • tabs or loops can be designed to cooperate with, for example, a hook provided in the freeze-drying installation for lifting the upper wall of the bag in its center, or with an independent stiffening element capable of being engaged through it and then maintain the top wall of the pocket in a bell shape.
  • the neck can be advantageously closed, after lyophilization, by a plug made of elastic face, in particular in rubber, which can be perforated without breaking the seal by an injection needle.
  • the container may be advantageous to provide the container with inlet and outlet fittings embedded in the plastic, which are ready to be put into service when the lyophilized liquid is reconstituted for use.
  • the neck provided for lyophilization or its stopper are L tiles once performed lyophilization, and to facilitate the storage and handling of filled pouches is often advantageous to élimirer this neck with its stopper by welding and cut walls under the base of the neck.
  • the lyophilized liquid container is intended to receive blood plasma which is introduced in the liquid state before lyophilization, then which undergoes the lyophilization operations therein, is stored there in the lyophilized state, until the reconstitution of L : liquid and its use which is carried out directly from the same container.
  • This container consists of a flexible plastic bag which is shown in plan in Figure 1.
  • the bag is limited by two opposite walls 1 (the upper wall only being visible in the figure) which are made of flexible sheets of material plastic such as polyvinyl chloride, joined to each other according to a welded joint plane 2, according to a substantially rectangular outline.
  • the container On one side of the pocket which can be designated as the upper side, as in the position adopted shown in the figure, the container has a neck 6, constituted by a cylindrical plastic nozzle, which is welded between the two sheets, so that it provides a sealed passage through the joint plane 2.
  • the wall of this cylindrical neck is thick enough to be rigid.
  • the neck 6 is closed on the outside of the container by a conventional closure assembly, of a type commonly used on other containers intended to contain physiological liquids, comprising a cap. of elastic material 8, protected by a metal capsule 7, crimped on an external annular projection 10 of the neck 6.
  • the plug 8 is made for example of rubber, its elasticity making it possible to pass through it by an injection needle without breaking the tight closure this pocket.
  • the protective cap 7 has a tamper-evident tab 9, which is easy to tear to provide access to the stopper.
  • a lumen 3 is formed through the two sheets of plastic material welded together in the joint plane.
  • the figure also shows an example of a loop formed in the center of one of the walls 1 of the pocket, by a tab 4 arranged longitudinally and welded at its ends 5 to the plastic sheet constituting this wall.
  • the bag is first of all filled with plasma to be lyophilized, while it is suspended by the neck 6 in the vertical position of the figure.
  • the neck remaining open the pocket is placed flat on a horizontal support, however slightly inclined to keep the neck 6 out of the liquid volume, just above the free level of the liquid.
  • the latter covers a surface which corresponds substantially to that of the walls 1.
  • the lower wall on which the container is lying in this position is that which does not include the tab 4.
  • an element is engaged which may in particular be a hook provided in the lyophilization installation and which allows the upper wall of the bag to be raised so as to free it from the free level of liquid.
  • the container is brought into this position in the freeze dryer.
  • the liquid plasma is frozen there by sudden cooling to a temperature of minus 40 to minus 80 ° C.
  • the frozen product is reheated to for example 27 ° C. while maintaining a empties the order of 0.2 to 0.1 torr in the freeze dryer. The product is thus freed from the water it contains by sublimation.
  • the pocket is closed by fitting the plug 8 on the neck 6, then crimping the capsule 7.
  • the container as shown can be produced with necks having an internal diameter of 25 mm or 20 to 30 mm in dimensions ranging from 10 cm to 17 cm for the width and. 15 cm to 30 cm for the length. These dimensions are particularly suitable for capacities of between 200 and 500 ml of plasma to be lyophilized. But it is also possible to adapt the container to capacities outside these limits by varying the dimensions of the pocket and those of the neck.
  • the container according to the invention has all the advantages of flexible, flat pockets, compared to rigid bottles. In addition, it even has advantages for lyophilization on them: it is complete and rapid thanks to the large exchange surface offered by the free level of the product when the liquid has been allowed to spread in the coated pocket at dish.
  • the container according to the invention can be produced in many ways compared to the embodiment which has been described and shown.
  • the tab 4 is only one example among the many means which can be used to allow, temporarily during freeze-drying, to separate the two walls of the flexible bag from one another by lifting the upper wall .
  • the leg 4 could be replaced by several analogous legs juxtaposed or by a flexible continuous duct welded transversely to the upper wall, and the cooperating suspension hook could be replaced by a rigid curved metal element or by a U-shaped pin.
  • one of the branches would be linked in this way temporarily to the upper wall while the other would be linked in the same way to the lower wall of the pocket.
  • the container is not used only for lyophilization of physiological liquids but that it can also be used for other liquids, pharmaceutical or food products for example.
  • the pocket is from the outset devoid of the tab 4 of the previous embodiment. It has indeed been found that the best solution for obtaining the necessary spacing during freezing of the upper wall of the bag is to inflate the container beforehand, by injection of an inert gas under pressure.
  • This gas can for example be nitrogen, which is introduced into the pocket in the same way as the liquid, by a filling needle passing through the material cap. elastic.
  • a plug having two positions, one completely closing the neck, the other releasing a gas evacuation duct. It is in this second position that the plug is brought in for the lyophilization operation, so that the vapor is evacuated through the cleared conduit.
  • the container of Figure 2 on the other hand, in addition to the previous one, on the side opposite the neck, has two fittings embedded in the plastic of the walls. These two connections 11 and 12 are intended to serve for the entry of water and the exit of the reconstituted liquid when the latter is used. It is enough to cut off the plastic extensions which cover them to clear the end of each fitting.
  • Each comprises a tube 13 made of rigid plastic, provided with a safety membrane 14 which ensures the sterility of the content until the last moment.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Vaporization, Distillation, Condensation, Sublimation, And Cold Traps (AREA)
  • Drying Of Solid Materials (AREA)

Abstract

1. Method of conditioning and utilization of a liquid involving its lyophilization, wherein : - in order to contain the liquid in the conditioning stage and in the utilization stage, there is employed one and the same container constructed in the form of a flexible bag having a first and a second wall (1) bonded along their external contour (82) so as to form an envelope and a rigid neck (6) which extends through said envelope in leak-tight manner, thus forming an opening of the bag ; - in the conditioning stage : the liquid container is partially filled with liquid, the container is placed in a substantially horizontal position on a support of the lyophilization device in such a manner as to ensure that a first wall and the neck are in contact with said support, the two walls being maintained in relatively spaced relation solely by the neck in the vicinity of this latter, said second wall is lifted in its remaining non-spaced portion so as to ensure that the liquid which rests substantially on said first wall has a free surface which is not in contact with the second wall, the liquid is cooled to freezing point, it is reheated in a vacuum while discharging through the neck the steam extracted by sublimation of the frozen product, the opening of the neck is hermetically sealed-off, said container is stored until direct utilization of the conditioned liquid ; - and in the utilization stage : the liquid is reconstituted by injecting water into the container without impairing leak-tightness, the reconstituted liquid is withdrawn from said container.

Description

L'invention a pour objet un recipient pour liquide à lyophiliser réalisé sous forme c'une poche souple. Elle trouve application notamment dans le domaine médical, où un tel récipient peut contenir des liquides physiologiques tels que le plasma sanguin, conservés l'état lyophilisé.The invention relates to a container for liquid to be lyophilized produced in the form of a flexible bag. It finds application in particular in the medical field, where such a container may contain physiological liquids such as blood plasma, preserved in the lyophilized state.

Il est tout à fait courant de voir utiliser des poches souples, en matière plastique généralement transparente, pour la distribution de liquides physiologiques, par exemple le sang dans les centres de transfusion. Par contre on n'a jamais pu jusqu'à ce jour envisager pour les liquides à lyophiliser d'autre solution que les flacons de verre, avec tous les inconvénients de la fragilité de ce genre de matériau, rigide et cassable.It is quite common to see the use of flexible bags, of generally transparent plastic material, for the distribution of physiological liquids, for example blood in the transfusion centers. On the other hand, it has never been possible to date for liquids to be lyophilized other than glass vials, with all the drawbacks of the fragility of this kind of material, rigid and breakable.

L'invention apporte donc une solution d'un intérêt technique considérable en permettant de réaliser la lyophilisation directement dans des récipients sous forme de poches souples dans'lesquelles le produit peut être conservé, sans transvasement, depuis la lyophilisation jusqu'à l'utilisation, dans des conditions d'aseptie complète.The invention therefore provides a solution of considerable technical interest by allowing lyophilization to be carried out directly in receptacles in the form of flexible bags in which the product can be stored, without transfer, from lyophilization to use, under conditions of complete aseptic.

A cet effet, l'invention propose un récipient pour liquide à lyophiliser réalisé sous forme d'une poche souple, caractérisé en ce qu'il comporte un goulot rigide traversant de manière étanche l'envelcppe de la poche souple, largement dimensionné pour permettre l'évacuation de la vapeur produite lors de la lyophilisation d'un liquide reçu dans la poche.To this end, the invention provides a container for liquid to be lyophilized produced in the form of a flexible bag, characterized in that it comprises a rigid neck sealingly passing through the envelope of the flexible bag, largely dimensioned to allow the evacuation of the vapor produced during the lyophilization of a liquid received in the bag.

En pratique, la poche souple est réalisée, le plus simplement, par une enveloppe en une matière plastique souple, stérilisable, et de préférence transparente, formée de deux feuilles planes soudées l'une à l'autre sur leur pourtour, sauf sur l'un des côtés, à l'endroit du passage du goulot, où elles sont soudées chacune autour de la moitié du goulot pour l'entourer complètement et assurer l'étanchéité. Le goulot lui-même sera en général également en matière plastique et sa rigidité pourra être obtenue par exemple en lui donnant une forme cylindrique à parois suffisamment épaisses ou er. le munissant de nervures apprcpriées. Il aura avantageusemert une section interne de passage d'un diamètre d'au moins 10mm, de préférence compris entre 20 mm et 60 mm, pour une contenance de liquide de 100 ml à 2 litres, avec de préférence une section de l'ordre de 0,001 à 0,05 fois la surface interne de la poche considérée à plat ; ce dernier rapport est compris entre 0,5 % et 2 % dans les meilleurs cas. Toutefois le mode de réalisation ci-dessus n'est pas limitatif. Une poche analogue peut aussi être réalisée par soufflage (de résines de polyoléfines ou polyuréthanes par exemple) ou par tout autre procédé convenant pour engendrer un récipient souple en matière plastique avec un gros goulot.In practice, the flexible pouch is produced, most simply, by an envelope made of a flexible plastic material, sterilizable, and preferably transparent, formed of two flat sheets welded to one another around their periphery, except on the one side, at the step of the neck, where they are each welded around half of the neck to surround it completely and ensure sealing. The neck itself will generally also be made of plastic and its rigidity can be obtained for example by giving it a cylindrical shape with sufficiently thick walls or er. providing it with appropriate ribs. It will advantageously have an internal passage section with a diameter of at least 10mm, preferably between 20 mm and 60 mm, for a liquid capacity of 100 ml to 2 liters, preferably with a section of the order of 0.001 to 0.05 times the internal surface of the pocket considered flat; the latter ratio is between 0.5% and 2% in the best cases. However, the above embodiment is not limiting. A similar pocket can also be produced by blowing (of polyolefin or polyurethane resins for example) or by any other process suitable for generating a flexible plastic container with a large neck.

Selon une autre caractéristique de l'invention, il est prévu en outre des moyens pour permettre de maintenir la poche dans une position gonflée, d'une manière provisoire pendant les opérations de lyophilisation. Il s'agit de moyens que l'on peut qualifier de "mécaniques" et qui permettent d'écarter deux parois opposées de la poche souple l'une de l'autre et de les maintenir dans cette position, horizontalement à une distance l'une de l'autre qui peut être, par exemple, du même ordre de grandeur que le diamètre du goulot rigide, soit généralement comprise entre 20 et 60 millimètres.According to another characteristic of the invention, means are also provided to allow the bag to be kept in an inflated position, temporarily during the lyophilization operations. These are means which can be described as "mechanical" and which make it possible to separate two opposite walls of the flexible bag from one another and to keep them in this position, horizontally at a distance l one of the other which can be, for example, of the same order of magnitude as the diameter of the rigid neck, is generally between 20 and 60 millimeters.

On sait que la lyophilisation d'un liquide quel qu'il soit s'effectue d'une manière générale en deux étapes essentielles. La première consiste à congeler brusquement le liquide, à une température inférieure à moins 30° C, et la seconde consiste à extraire l'eau du liquide congelé par sublimation en le réchauffant sous vide. L'utilité des moyens d'écartement provisoire se fait sentir dès la première étape. La poche contenant le liquide à congeler est placée dans l'installation de lyophilisation, dans une position sensiblement horizontale, à plat sur une surface un peu inclinée sur l'horizontale, ou logée dans une cavité légèrement creuse, de manière que le liquide se réunisse sur l'une des deux parois opposées, et que le goulot rigide soit dégagé du volume de liquide et que ce dernier offre cependant une surface libre importante. Les moyens d'écartement permettent de soulever la paroi supérieure au-dessus de cette surface libre. Cn évite ainsi qu'il y ait adhérence entre cette paroi supérieure de la poche et le liquide congelé. L'étape subséquente de sublimation ne demande qu'un temps de traitement relativement réduit car l'eau se sublime rapidement à partir de cette surface libre importante du liquide congelé, avantageusement maintenu dégagé par soulèvement de la paroi supérieure de la poche par les moyens d'écartement, et la vapeur d'eau s'évacue facilement par l'orifice du goulot largement dimensionné.It is known that the lyophilization of any liquid is generally carried out in two essential stages. The first consists in freezing the liquid suddenly, at a temperature below minus 30 ° C, and the second consists in extracting the water from the frozen liquid by sublimation by heating it under vacuum. The utility The unity of the temporary spacing means is felt from the first step. The bag containing the liquid to be frozen is placed in the lyophilization installation, in a substantially horizontal position, flat on a surface slightly inclined to the horizontal, or housed in a slightly hollow cavity, so that the liquid meets on one of the two opposite walls, and that the rigid neck is released from the volume of liquid and that the latter nevertheless offers a large free surface. The spacing means make it possible to lift the upper wall above this free surface. This prevents adhesion between this upper wall of the bag and the frozen liquid. The subsequent sublimation step requires only a relatively short treatment time because the water sublimes quickly from this large free surface of the frozen liquid, advantageously kept clear by lifting the upper wall of the bag by means of 'spacing, and the water vapor is easily evacuated through the orifice of the largely dimensioned neck.

Des formes de réalisation particulière du récipient selon l'invention peuvent comporter sur la poche souple au moins une patte ou boucle for-née extérieurement sur l'une au moins des deux parois opposées de la poche. De telles pattes ou boucles peuvent être conçues pour coopérer avec, par exemple, un crochet prévu dans l'installation de lyophilisation pour soulever la paroi supérieurede la poche en son centre, ou avec un élément de rigidification indépendant susceptible d'être engagé à travers elle et de maintenir alors la paroi supérieure de la poche dans une forme en cloche.Particular embodiments of the container according to the invention may comprise on the flexible pocket at least one tab or loop formed outwardly on at least one of the two opposite walls of the pocket. Such tabs or loops can be designed to cooperate with, for example, a hook provided in the freeze-drying installation for lifting the upper wall of the bag in its center, or with an independent stiffening element capable of being engaged through it and then maintain the top wall of the pocket in a bell shape.

En liaison avec le domaine d'application privilégié de l'invention, qui exige que le produit lyophilisé soit conservé stérile, le goulot peut être avantageusement fermé, après la lyophilisation, par un bouchon en matière élastique, en caoutchouc notamment, perforable sans rompre l'étanchéité par un aiguille d'injection.In connection with the preferred field of application of the invention, which requires that the lyophilized product be kept sterile, the neck can be advantageously closed, after lyophilization, by a plug made of elastic face, in particular in rubber, which can be perforated without breaking the seal by an injection needle.

Dans d'autres formes de réalisation du récipient selon l'invention, on peut se dispenser de prévoir des moyens mécaniques d'écartement des parois, en dehors du goulot rigide, qui assurent déjà un écartement à cette extrémité. L'écartement des parois lors de la congélation peLt alors s'effectuer par gonflement de la poche par du gaz inerte sous pression, lequel peut être introduit par une aiguille de remplissage à travers le bouchon.In other embodiments of the container according to the invention, it is possible to dispense with the provision of mechanical means for spacing the walls, apart from the rigid neck, which already provide a spacing at this end. The separation of the walls during freezing can then be carried out by swelling of the bag with inert gas under pressure, which can be introduced by a filling needle through the plug.

Par ailleurs, il peut être avantageux de munir le récipient de raccords d'entrée et de sortie noyés dans la matière plastique, qui sont prêts à être mis en service lorsque le liquide lyophilisé est reconstitué pour être utilisé. Dans ce cas ni le goulot prévu pour la lyophilisation ni son bouchon ne sont Ltiles une fois la lyophilisation réalisée, et pour faciliter la conservation et la manipulation des poches remplies il est souvent avantageux d'élimirer ce goulot avec son bouchon par soudage et coupure des parois sous la base du goulot.Furthermore, it may be advantageous to provide the container with inlet and outlet fittings embedded in the plastic, which are ready to be put into service when the lyophilized liquid is reconstituted for use. In this case or the neck provided for lyophilization or its stopper are L tiles once performed lyophilization, and to facilitate the storage and handling of filled pouches is often advantageous to élimirer this neck with its stopper by welding and cut walls under the base of the neck.

L'invention sera rraintenant décrite plus en détail, dans certaines de ses formes de réalisation, En se référant en particulier aux figures 1 et 2 jointes qui représentent un récipient selon l'invention dans des modes de réalisation particuliers nullemert limitatifs.The invention will be restrictive described in more detail, in some of its embodiments, With particular reference to Figures 1 and 2 attached which represent a container according to the invention in particular embodiments nullemert limiting.

Le récipient à liquide lyophilisé est destiné à recevoir du plasma sanguin qui est introduit à l'état liquide avant lyophilisation, puis qui y subit les opérations de lyophilisation, y est conservé à l'état lyophilisé, jusqu'à la reconstitution dL: liquide et son utilisation qui s'effectue directement à partir du même récipient.The lyophilized liquid container is intended to receive blood plasma which is introduced in the liquid state before lyophilization, then which undergoes the lyophilization operations therein, is stored there in the lyophilized state, until the reconstitution of L : liquid and its use which is carried out directly from the same container.

Ce récipient est constitué par une poche souple en matière plastique qui est représentée en plan sur la figure 1. La poche est limitée par deux parois opposées 1 ( la paroi supérieure seule étant visible sur la figure) qui sont réalisées par des feuilles souples en matière plastique telle que le chlorure de polyvinyle, réunies l'une à l'autre selon un plan de joint soudé 2, selon un contour sensiblement rectangulaire.This container consists of a flexible plastic bag which is shown in plan in Figure 1. The bag is limited by two opposite walls 1 (the upper wall only being visible in the figure) which are made of flexible sheets of material plastic such as polyvinyl chloride, joined to each other according to a welded joint plane 2, according to a substantially rectangular outline.

Sur un côté de la poche que l'on peut désigner comme étant le côté supérieur, comme dans la position adoptée sur la figure, le récipient comporte un goulot 6, constitué par un ajutage cylindrique en matière plastique, qui est soudé entre les deux feuilles, de telle sorte qu'il ménage un passage étanche à travers le plan de joint 2. La paroi de ce goulot cylindrique est suffisammert épaisse pour qu'il soit rigide. Pour permettre la conservation en milieu stérile du produit lyophilisé, le goulot 6 est fermé à l'extérieur du récipient par un ensemble de fermeture classique, d'un type couramment utilisé sur d'autres récipients destinés à contenir des liquides physiologiques, comportant un bouchon de matière élastique 8, protégé par une capsule métallique 7, sertie sur une saillie annulaire extérieure 10 du goulot 6. Le bouchon 8 est réalisé par exemple en caoutchouc, son élasticité permettant de le traverser par une aiguille d'injection sans rompre la fermeture étanche ce la poche. La capsule de protection 7 comporte une languette d'inviolabilité 9, facile à déchirer pour dégager un accès au bouchon.On one side of the pocket which can be designated as the upper side, as in the position adopted shown in the figure, the container has a neck 6, constituted by a cylindrical plastic nozzle, which is welded between the two sheets, so that it provides a sealed passage through the joint plane 2. The wall of this cylindrical neck is thick enough to be rigid. To allow the lyophilized product to be stored in a sterile environment, the neck 6 is closed on the outside of the container by a conventional closure assembly, of a type commonly used on other containers intended to contain physiological liquids, comprising a cap. of elastic material 8, protected by a metal capsule 7, crimped on an external annular projection 10 of the neck 6. The plug 8 is made for example of rubber, its elasticity making it possible to pass through it by an injection needle without breaking the tight closure this pocket. The protective cap 7 has a tamper-evident tab 9, which is easy to tear to provide access to the stopper.

A l'opposé du goulot 6, sur le côté inférieur de la poche telle que représentée, une lumière 3 est méra- gée à travers les deux feuilles de matière plastique soudées ensemble dans le plan de joint.Opposite the neck 6, on the lower side of the pocket as shown, a lumen 3 is formed through the two sheets of plastic material welded together in the joint plane.

Enfin la figure montre aussi un exemple de boucle formée au centre de l'une des parois 1 de la poche, par une patte 4 disposée longitudinalement et soudée en ses extrémités 5 à la feuille de matière plastique constituant cette paroi.Finally, the figure also shows an example of a loop formed in the center of one of the walls 1 of the pocket, by a tab 4 arranged longitudinally and welded at its ends 5 to the plastic sheet constituting this wall.

Pour réaliser la lyophilisation dans un récipient tel que celui qui vient d'être décrit, on remplit tout d'abord la poche partiellement de plasma à lyophiliser, alors qu'elle est suspendue par le goulot 6 dans la position verticale de la figure. Le goulot restant ouvert, la poche est placée à plat sur un support horizontal, toutefois légèrement incliné pour maintenir le goulot 6 hors du volume liquide, juste au-dessus du niveau libre du liquide. Ce dernier couvre une surface qui correspond sensiblement à celle des parois 1. La paroi inférieure sur laquelle est couché le récipient dans cette position est celle qui ne comporte pas la patte 4. Dans cette patte on engage un élément qui peut être notamment un crochet prévu dans l'installation de lyophilisation et qui permet de soulever la paroi supérieure de la poche de manière à la dégager du niveau libre de liquide.To perform lyophilization in a container such as that which has just been described, the bag is first of all filled with plasma to be lyophilized, while it is suspended by the neck 6 in the vertical position of the figure. The neck remaining open, the pocket is placed flat on a horizontal support, however slightly inclined to keep the neck 6 out of the liquid volume, just above the free level of the liquid. The latter covers a surface which corresponds substantially to that of the walls 1. The lower wall on which the container is lying in this position is that which does not include the tab 4. In this tab, an element is engaged which may in particular be a hook provided in the lyophilization installation and which allows the upper wall of the bag to be raised so as to free it from the free level of liquid.

Le récipient est amené dans cette position dans le lyophilisateur. Dans une première étape le plasma liquide y est congelé par un refroidissement brusque à une température de moins 40 à moins 80° C. Cans une seconde étape le produit congelé est réchauffé jusqu'à par exemple 27° C tandis que l'on maintient un vide l'ordre de 0,2 à 0,1 torr dans le lyophilisateur. Le produit est ainsi débarrassé de l'eau qu'il contient par sublimation. Une fois l'opération terminée la poche est fermée par mise en place du bouchon 8 sur le goulot 6, puis sertissage de la capsule 7.The container is brought into this position in the freeze dryer. In a first step the liquid plasma is frozen there by sudden cooling to a temperature of minus 40 to minus 80 ° C. In a second step the frozen product is reheated to for example 27 ° C. while maintaining a empties the order of 0.2 to 0.1 torr in the freeze dryer. The product is thus freed from the water it contains by sublimation. Once the operation is complete, the pocket is closed by fitting the plug 8 on the neck 6, then crimping the capsule 7.

Quand arrive le moment d'utiliser le produit conservé dans le récipient à l'état lyophilisé, il convient tout d'abord de reconstituer le plasma liquide. A cet effet on introduit dans la poche une quantité d'eau équivalente à celle qui a été évacuée par sublimation. Ceci s'effectue dans des conditions aseptiques par injection au moyen d'une aiguille que l'on pique à travers le bouchon 8 après retrait de la languette d'inviolabilité 9. Pour utiliser le liquide reconstitué on peut introduire de la même manière une aiguille de prélèvement à travers le bouchon 8. Pour faciliter l'écoulement du liquide il est bien pratique de faire emploi de la lumière 3 pour suspendre la poche souple en position renversée, le bouchon en bas.When the time comes to use the product stored in the container in a lyophilized state, it is first necessary to reconstitute the liquid plasma. To this end, an amount of water equivalent to that which has been removed by sublimation is introduced into the pocket. This is carried out under aseptic conditions by injection using a needle which is pricked through the plug 8 after removal of the tamper-evident tab 9. To use the reconstituted liquid, a needle can be introduced in the same way. sampling through the plug 8. To facilitate the flow of the liquid it is very practical to use the light 3 to suspend the flexible bag in the inverted position, the plug at the bottom.

Pour donner un exemple dimensionnel, le récipient tel que représenté peut être réalisé avec des goulots ayant un diamètre intérieur de 25 mm ou 20 à 30 mm en des dimensions allant de 10 cm à 17 cm pour la largeur et de. 15 cm à 30 cm pour la longueur. Ces dimensions conviennent particulièrement bien à des contenances comprises entre 200 et 500 ml de plasma à lyophiliser. Mais l'on peut aussi adapter le récipient à des contenances hors de ces limites en variant les dimensions de la poche et celles du goulot.To give a dimensional example, the container as shown can be produced with necks having an internal diameter of 25 mm or 20 to 30 mm in dimensions ranging from 10 cm to 17 cm for the width and. 15 cm to 30 cm for the length. These dimensions are particularly suitable for capacities of between 200 and 500 ml of plasma to be lyophilized. But it is also possible to adapt the container to capacities outside these limits by varying the dimensions of the pocket and those of the neck.

Le récipient selon l'invention présente tous les avantages des poches souples, plates, par rapport aux flacons rigides. En outre il présente même sur eux des avantages pour la lyophilisation : celle-ci est complète et rapide grâce à la grande surface d'échange offerte par le niveau libre du produit lorsqu'on a laissé le liquide s'étaler dans la poche couchée à plat.The container according to the invention has all the advantages of flexible, flat pockets, compared to rigid bottles. In addition, it even has advantages for lyophilization on them: it is complete and rapid thanks to the large exchange surface offered by the free level of the product when the liquid has been allowed to spread in the coated pocket at dish.

Tout en conservant ses avantages, le récipient selon l'invention peut être réalisé sous de nombreuses variintes par rapport au mode de réalisation qui a été décrit et représenté. En particulier le patte 4 ne constitue qu'un exemple parmi les nombreux moyens auxquels on peut faire appel pour permettre, provisoirement pendant la lyophilisation, d'écarter les deux parois de la poche souple l'une de l'autre en soulevant la paroi supérieure. Dans d'autres cas, on pourrait remplacer la patte 4 par plusieurs pattes analogues juxtaposées ou par un conduit continu souple soudé transversalement sur la paroi supérieure, et remplacer le crochet de suspension coopérant par un élément métallique rigide courbe ou par une épingle en U dont l'une des branches serait liée de cette manière provisoirement à la paroi supérieure tandis que l'autre serait liée de la même manière à la paroi inférieure de la poche. On peut même utiliser une poche dépourvue de toute patte ou boucle ou anneau analogue, si l'on dispose par exemple d'une installation de lyophilisation équipée d'un système de ventouse permettant de soulever la paroi supérieure de la poche à l'écart de la surface support sur laquelle elle est posée par sa surface inférieure.While retaining its advantages, the container according to the invention can be produced in many ways compared to the embodiment which has been described and shown. In particular the tab 4 is only one example among the many means which can be used to allow, temporarily during freeze-drying, to separate the two walls of the flexible bag from one another by lifting the upper wall . In other cases, the leg 4 could be replaced by several analogous legs juxtaposed or by a flexible continuous duct welded transversely to the upper wall, and the cooperating suspension hook could be replaced by a rigid curved metal element or by a U-shaped pin. one of the branches would be linked in this way temporarily to the upper wall while the other would be linked in the same way to the lower wall of the pocket. One can even use a pocket devoid of any tab or loop or similar ring, if one has for example a lyophilization installation equipped with a suction cup system to lift the upper wall of the pocket away from the support surface on which it is placed by its lower surface.

Il est évident aussi que le récipient n'a pas pour seul usage la lyophilisation de liquides physiologiques mais qu'il peut aussi bien être utilisé pour d'autres liquides, des produits pharmaceutiques ou alimentaires par exemple.It is also obvious that the container is not used only for lyophilization of physiological liquids but that it can also be used for other liquids, pharmaceutical or food products for example.

Des variantes de réalisation du récipient selon l'invention seront maintenant signalées en se référant à la figure 2 et en liaison avec une autre forme de mise en oeuvre du procédé.Variant embodiments of the container according to the invention will now be indicated with reference to FIG. 2 and in conjunction with another embodiment of the method.

On remarquera tout d'abord que dans ce cas, lorsque la poche est représentée une fois remplie et après lyophilisation du liquide de remplissage, le goulot 6 de la figure 1 a été éliminé en même temps que son bouchon et sa capsule éventuelle. Ceci est réalisé d'une manière en soi connue par soudure étanche des deux parois entre elles, par hautre fréquence ou laser, it coupure le long de la soudure. On obtiert ainsi une poche remplie, de forme extra-plate, qui facilite le stockage du sang lyophilisé.It will be noted first of all that in this case, when the bag is shown once filled and after freeze-drying of the filling liquid, the neck 6 of FIG. 1 has been removed at the same time as its cap and its possible capsule. This is achieved in a manner known per se by sealing the two walls together, by high frequency or laser, it cuts along the weld. This produces a filled pocket, of extra-flat shape, which facilitates the storage of lyophilized blood.

De plus, la poche est dès l'origine dépourvue de la patte 4 du mode de réalisation précédent. On a trouvé en effet que la meilleure solution pour obtenir lors de la congélation l'écartement nécessaire de la paroi supérieure de la poche était de gonfler le récipient auparavant, par injection d'un gaz inerte sous pression. Ce gaz peut être par exemple de l'azote, qui est introduit dans la poche de la même manière que le liquide, par une aiguille de remplissage traversant le bouchon en matière élastique. Il est en outre avantageux d'utiliser un bouchon présentant deux positions, l'une obturant complètement le goulot, l'autre dégageant un conduit d'évacuation des gaz. C'est dans cette seconde position que le bouchon est amené pour l'opération de lyophilisation, de sorte que la vapeur s'évacue par le conduit dégagé.In addition, the pocket is from the outset devoid of the tab 4 of the previous embodiment. It has indeed been found that the best solution for obtaining the necessary spacing during freezing of the upper wall of the bag is to inflate the container beforehand, by injection of an inert gas under pressure. This gas can for example be nitrogen, which is introduced into the pocket in the same way as the liquid, by a filling needle passing through the material cap. elastic. It is also advantageous to use a plug having two positions, one completely closing the neck, the other releasing a gas evacuation duct. It is in this second position that the plug is brought in for the lyophilization operation, so that the vapor is evacuated through the cleared conduit.

Le récipient de la figure 2 comporte par contre en plus du précédent, du côté opposé au goulot, deux raccords noyésdans la matière plastique des parois. Ces deux raccords 11 et 12 sont destinés à servir pour l'entrée de l'eau et la sortie du liquide reconstitué au moment de l'utilisation de ce dernier. Il suffit de section- rer les prolongements de matière plastique qui les envelcp- pert pour dégager l'extrémité de chaque raccord. Chacun comporte un tube 13 en matière plastique rigide, muni d'une membrane de sécurité 14 qui assure jusqu'au dernier moment la stérilité du contenu.The container of Figure 2, on the other hand, in addition to the previous one, on the side opposite the neck, has two fittings embedded in the plastic of the walls. These two connections 11 and 12 are intended to serve for the entry of water and the exit of the reconstituted liquid when the latter is used. It is enough to cut off the plastic extensions which cover them to clear the end of each fitting. Each comprises a tube 13 made of rigid plastic, provided with a safety membrane 14 which ensures the sterility of the content until the last moment.

Claims (10)

1. Récipient pour liquide à lyophiliser réalisé sous forme d'une poche souple, caractérisé en ce qu'il comporte un goulot rigide (6) traversant de manière étanche l'enveloppe de la poche souple, largement dimensionné pour permettre l'évacuation de la vapeur produite lors de la lyophilisation d'un liquide reçu dans la poche.1. Container for liquid to be lyophilized produced in the form of a flexible pocket, characterized in that it comprises a rigid neck (6) sealingly passing through the envelope of the flexible pocket, largely dimensioned to allow the evacuation of the vapor produced during lyophilization of a liquid received in the bag. 2. Récipient selon la revendication 1, caractérisé en ce qu'il comporte en outre des moyens (4) d'écartement provisoire de deux parois (1) opposées de la poche.2. Container according to claim 1, characterized in that it further comprises means (4) for temporary spacing of two walls (1) opposite the pocket. 3. Récipient selon la revendication 1, caractérisé en ce qu'il comporte un bouchon (8) de fermeture dudit goulot, en matériau élastique, perforable par une aiguille de remplissage et/ou de prélèvemert.3. Container according to claim 1, characterized in that it comprises a plug (8) for closing said neck, of elastic material, perforable by a filling and / or sampling needle. 4. Récipient selcn la revendication 1, 2, ou 3, caractérisé en ce qu'il comporte en outre des raccords (11, 12) d'entrée et de scrtie de liquide, noyés dans l'enveloppe de la poche souple.4. Container according to claim 1, 2, or 3, characterized in that it further comprises fittings (11, 12) for inlet and liquid scrtie, embedded in the envelope of the flexible bag. 5. Récipient selon l'une quelconque des revendications 1 à 4, caractérisé en ce qu'il comporte deux parois opposées formées par des feuilles de matière plastique souple soudées EnsEmble suivant le contour extérieur de la poche et enveloppant entre elles ledit goulot (6; extérieurement.5. Container according to any one of claims 1 to 4, characterized in that it comprises two opposite walls formed by sheets of flexible plastic material welded EnsEmble along the outer contour of the pocket and enclosing between them said neck (6; outwardly. 6. Récipient selon l'une quelconque des revendications 1 à 5, caractérisé en ce qu'il comporte un bouchon de fermeture du goulot (6) présentant une position secondaire dégageant un conduit d'évacuation de la vapeur.6. Container according to any one of claims 1 to 5, characterized in that it comprises a closure cap for the neck (6) having a secondary position releasing a steam evacuation duct. 7. Procédé d'utilisation du récipient selon l'une quelconque des revendications 1 à 6, caractérisé en ce que l'on remplit partiellement la poche d'un liquide à lyophiliser , on dispose la poche couchée sur une paroi inférieure sur un support, on soulève la paroi supérieure opposée pour l'écarter du niveau libre de liquide étalé sur la paroi inférieure, on refroidit le liquide jusqu'à le congeler, on réchauffe sous vide le produit congelé et l'on évacue par le goulot la vapeur d'eau extraite par sublimation du produit congelé, on conserve----ainsi le produit lyophilisé dans la poche , puis pour l'utiliser, on reconstitue le liquide en injectant de l'eau dans la poche.et l'on prélève le liquide reconstitué.7. A method of using the container according to any one of claims 1 to 6, characterized in that the bag is partially filled with a liquid to be lyophilized, the bag lying on a lower wall is placed on a support, the opposite upper wall is lifted to separate it from the free level of liquid spread on the lower wall, the liquid is cooled until it is frozen, the frozen product is heated under vacuum and the steam is evacuated through the neck water extracted by sublimation from the frozen product, ---- the freeze-dried product is stored in the pocket, then to use it, the liquid is reconstituted by injecting water into the pocket. and the reconstituted liquid is taken out . 8. Procédé selon la revendication 7, caractérisé en ce que le produit lyophilisé est conservé dans la poche après avoir fermé le goulot par son bouchon et en ce que l'on reconstitute le liquide en injectant de l'eau dans la poche par une aiguille introduite à travers ledit bouchon et l'on prélève de la même manière le liquide reconstitué.8. Method according to claim 7, characterized in that the lyophilized product is kept in the pocket after closing the neck with its cap and in that the liquid is reconstituted by injecting water into the pocket with a needle introduced through said plug and the reconstituted liquid is removed in the same way. 9. Procédé selon la revendication 7, caractérisé en ce qu'après la lyophilisation on sectionne le goulot du reste de la poche contenant le produit lyophilisé et fermé de manière étanche, la poche comportant des raccords d'entrée et de sortie pour la reconstitution du liquide et le prélèvement du liquide reconstitué.9. Method according to claim 7, characterized in that after lyophilization, the neck of the rest of the bag containing the lyophilized product is closed and sealed, the bag comprising inlet and outlet fittings for reconstituting the liquid and the withdrawal of the reconstituted liquid. 10. Procédé suivant la revendication 7, 8 ou 9, caractérisé en ce que ledit liquide est un liquide physiologique tel que du plasma sanguin.10. The method of claim 7, 8 or 9, characterized in that said liquid is a physiological liquid such as blood plasma.
EP82400943A 1981-05-20 1982-05-19 Method for preparation of a liquid to be lyophilized and use of said liquid Expired EP0065469B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT82400943T ATE36645T1 (en) 1981-05-20 1982-05-19 METHOD OF FREEZE DRYING OF LIQUIDS AND ITS APPLICATION.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8110069 1981-05-20
FR8110069A FR2506264A1 (en) 1981-05-20 1981-05-20 FLEXIBLE POUCH CONTAINER FOR LYOPHILIZING LIQUID AND METHOD OF USE

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EP0065469A2 true EP0065469A2 (en) 1982-11-24
EP0065469A3 EP0065469A3 (en) 1983-06-22
EP0065469B1 EP0065469B1 (en) 1988-08-24

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AT (1) ATE36645T1 (en)
DE (1) DE3278928D1 (en)
FR (1) FR2506264A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0426475A1 (en) * 1989-11-01 1991-05-08 Cryopharm Corporation Blood bag for lyophilization and method of use
DE4405965A1 (en) * 1994-02-24 1995-08-31 Bernd Hansen Infusion container with two connections
US5871110A (en) * 1996-09-13 1999-02-16 Grimard; Jean-Pierre Transfer assembly for a medicament container having a splashless valve
US5925029A (en) * 1997-09-25 1999-07-20 Becton, Dickinson And Company Method and apparatus for fixing a connector assembly onto a vial with a crimp cap
US6003566A (en) * 1998-02-26 1999-12-21 Becton Dickinson And Company Vial transferset and method
US6090093A (en) * 1997-09-25 2000-07-18 Becton Dickinson And Company Connector assembly for a vial having a flexible collar
US6213994B1 (en) 1997-09-25 2001-04-10 Becton Dickinson France, S.A. Method and apparatus for fixing a connector assembly onto a vial
GB2361709A (en) * 2000-04-26 2001-10-31 Moorlodge Biotech Ventures Ltd Vessel for transporting micro organisms

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US6382442B1 (en) 1998-04-20 2002-05-07 Becton Dickinson And Company Plastic closure for vials and other medical containers
US6681946B1 (en) 1998-02-26 2004-01-27 Becton, Dickinson And Company Resealable medical transfer set
US6378714B1 (en) 1998-04-20 2002-04-30 Becton Dickinson And Company Transferset for vials and other medical containers

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US2642866A (en) * 1951-02-03 1953-06-23 Arthur F Smith Blood container and method of making the same
GB730148A (en) * 1953-08-04 1955-05-18 Armour & Co Improvements in or relating to closures for lyophilization containers
CH323689A (en) * 1953-07-31 1957-08-15 Antoine Rieutord Louis Marie Process for controlling the desiccation of a vacuum body and device for implementing this process
FR2281276A1 (en) * 1974-08-06 1976-03-05 Behringwerke Ag METHOD OF MANUFACTURING A CONTAINER FOR LYOPHILIZED MATERIAL FIRM UNDER STERILE CONDITIONS
GB1428373A (en) * 1972-06-12 1976-03-17 Smith & Nephew Res Containers
FR2284842A1 (en) * 1974-09-11 1976-04-09 Nestle Sa IMPROVEMENT PROVIDES LYOPHILIZATION OF SOLID, LIQUID OR PASTE PRODUCTS
FR2456674A1 (en) * 1979-05-18 1980-12-12 Terumo Corp PLASTIC CONTAINER FOR MEDICAL LIQUID

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US2642866A (en) * 1951-02-03 1953-06-23 Arthur F Smith Blood container and method of making the same
CH323689A (en) * 1953-07-31 1957-08-15 Antoine Rieutord Louis Marie Process for controlling the desiccation of a vacuum body and device for implementing this process
GB730148A (en) * 1953-08-04 1955-05-18 Armour & Co Improvements in or relating to closures for lyophilization containers
GB1428373A (en) * 1972-06-12 1976-03-17 Smith & Nephew Res Containers
FR2281276A1 (en) * 1974-08-06 1976-03-05 Behringwerke Ag METHOD OF MANUFACTURING A CONTAINER FOR LYOPHILIZED MATERIAL FIRM UNDER STERILE CONDITIONS
FR2284842A1 (en) * 1974-09-11 1976-04-09 Nestle Sa IMPROVEMENT PROVIDES LYOPHILIZATION OF SOLID, LIQUID OR PASTE PRODUCTS
FR2456674A1 (en) * 1979-05-18 1980-12-12 Terumo Corp PLASTIC CONTAINER FOR MEDICAL LIQUID

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0426475A1 (en) * 1989-11-01 1991-05-08 Cryopharm Corporation Blood bag for lyophilization and method of use
DE4405965A1 (en) * 1994-02-24 1995-08-31 Bernd Hansen Infusion container with two connections
US5520677A (en) * 1994-02-24 1996-05-28 Hansen; Bernd Infusion container with two connections
US5871110A (en) * 1996-09-13 1999-02-16 Grimard; Jean-Pierre Transfer assembly for a medicament container having a splashless valve
US5925029A (en) * 1997-09-25 1999-07-20 Becton, Dickinson And Company Method and apparatus for fixing a connector assembly onto a vial with a crimp cap
US6090093A (en) * 1997-09-25 2000-07-18 Becton Dickinson And Company Connector assembly for a vial having a flexible collar
US6213994B1 (en) 1997-09-25 2001-04-10 Becton Dickinson France, S.A. Method and apparatus for fixing a connector assembly onto a vial
US6003566A (en) * 1998-02-26 1999-12-21 Becton Dickinson And Company Vial transferset and method
GB2361709A (en) * 2000-04-26 2001-10-31 Moorlodge Biotech Ventures Ltd Vessel for transporting micro organisms

Also Published As

Publication number Publication date
ATE36645T1 (en) 1988-09-15
DE3278928D1 (en) 1988-09-29
EP0065469B1 (en) 1988-08-24
FR2506264A1 (en) 1982-11-26
EP0065469A3 (en) 1983-06-22
FR2506264B1 (en) 1985-01-04

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