Method for fabricating a sterile ready-pack and a container for such a ready-pack

A method for a single step sterilization of a ready-pack, such as a blister pack, in an autoclave is described. The ready pack includes a container, such as a syringe, filled with a substance. The environment in the autoclave, that is, the temperature, the heating period and, preferably, the pressure is controlled to sterilize simultaneously the ready-pack and its contents by circulating steam in the autoclave. The steam penetrates into the blister pack through a steam-permeable base. The temperature is maintained between about 120.degree. C. to 130.degree. C. for about 15-20 minutes.

TECHNICAL FIELD 
The invention relates to a method for fabricating a sterile ready-pack and 
a container for such a ready-pack with at least one sealed-in, especially 
blister-type container with a filling, especially with a medication, a 
diagnostic means, or the like, especially a syringe, bag, bottle, or other 
medical utility object, whose package, especially a blister pack, has a 
region which is permeable preferably to the diffusion of steam, and for 
the rest is tight, such that the material used for the container is stable 
at least 125.degree. C. (degrees Celsius), preferably at 130.degree. C., 
and such that the sealed, tightly closed pack is exposed to an autoclaving 
process. 
When water is heated in a closed pressure vessel, an over-pressure of 1 bar 
is reached at 121.degree. C. 15 to 20 minutes action of the "confined" 
steam is sufficient to kill all micro-organisms capable of reproduction. 
PRIOR ART 
With a known ready-pack of this kind, the individual parts of the plastic 
syringe are gassed with ethylene oxide in order to sterilize them. Then 
the syringe is assembled under sterile conditions and is filled with the 
previously sterilized fill under aseptic conditions, and is then sealed. 
Then the filled syringe is blistered into a sealed package, which then is 
gassed with ethylene oxide for sterilization. The gas then penetrates 
through porosities in the covering and flushes the syringe from the 
outside. 
With this method, it is expensive to fabricate the filled syringe, since 
this is done under sterile conditions. Also, expensive precautions must be 
taken to prevent ethylene oxide residues or decomposition products from 
finding their way from the gassing process of the syringe and of the 
finished pack into the fill of the syringe and remaining there. 
The U.S. Pat. No. 4,828,797 shows the fabrication of a biological test kid 
sic, but evidently should be "kit"! by means of which the effectiveness 
e.g. of an ethylene oxide sterilization process can be tested. Here, an 
open plastic throw-away syringe in a blister is freed of germs by means of 
a Tyvek (registered trademark) film through sterilization. A test strip is 
here situated in the interior of the syringe, and it changes color if the 
sterilization is adequate, e.g. through ethylene oxide. 
The U.S. Pat. No. 5,033,252 discloses a sterilization method, in which a 
bottle filled with a sterile salt solution is placed into a blister, which 
subsequently is exposed to gassing by ethylene oxide or by confined steam. 
The exterior of the bottle is thus freed of germs. This method presupposes 
that the bottle must be filled completely, without any residual air in its 
interior, and that the bottle must be filled under aseptic conditions. 
This regularly involves an overflow of the fill, in order to assure that 
no air is present in the interior of the bottle. Consequently, the bottle 
itself and its environment must be cleaned after the filling process. In 
conjunction with the aseptic filling process and sealing process, this 
method is very expensive and consequently not very economical. 
The EP 0 227 401 B1 describes a method for the end sterilization of a 
plastic syringe together with its content (liquid) by means of steam and a 
support pressure. This method has already been described for ready-to-use 
syringes made of glass, in detail and with pictures, in Venten & Hoppert, 
Pharm. Ind., Volume 40 (1978), Page 665 ff Point 4. 
EXPLANATION OF THE INVENTION 
The first object of the invention is to simplify the fabrication of a 
sterile ready-pack of the type mentioned in the introduction, and to make 
possible economic and ecologically friendly fabrication with autoclaving 
of the final package. 
The inventive method is specified by the features of claim 1. Advantageous 
designs and modifications are the subject of the subclaims. 
The inventive method accordingly is characterized in that, in a single 
operating step, both the fill is sterilized for at least 15 minutes, 
preferably 20 minutes, at a minimum of 121.degree. C., by means of a 
steam-air mixture rotary method, and the outer surface of the container as 
well as the package are also sterilized. 
According to the invention, it has been recognized that it is especially 
economical to autoclave the ready-pack in one step, so that both the 
inside of the pack (blister), the outside of the closed container, and 
also the fill material (liquid, gel-like, or paste-like medication) are 
sterilized in a single treatment process. 
An especially preferred modification of the inventive method is 
characterized in that several ready-packs are disposed in one packing unit 
(folding box), which has a region that is permeable to steam, and that the 
internal temperature of the liquid, gel-like, or paste-like medication is 
measured in at least one ready-pack, preferably in at least two 
ready-packs, of the entire autoclave charge. 
In an especially advantageous manner, the procedure furthermore can be such 
that, during the entire sterilization cycle, the pressure and the moisture 
content are measured, and the sterilization cycle is regulated in 
dependence on the measured data, such that the pressure preferably can be 
changed at a specifiable rate. 
Since the temperature is measured in the medication (or material) itself, 
the perfect progress of the sterilization cycle can be assured and 
documented directly and without any doubt. If the measured temperature is 
too low, a control mechanism activates a heating device which directly or 
indirectly brings addition heat (steam) into the autoclave chamber. Since 
the pressure and the moisture can be controlled at the same time, it is 
possible to prevent damage of the ready-pack or of the packing unit due to 
pressure differences or due to condensing water. The pressure can be 
changed preferably at a rate of .+-.0.1 bar per 5 minutes. For example, a 
pressure of 3.0 bar is provided as the maximum support pressure during 
cooling. In order to make the reduction of pressure possible, the 
autoclave has an evacuation mechanism which is controlled in accordance 
with the measured data. 
Cardboard, in a preferred folding-box design, is used as the material for 
the packing unit, which contains several ready-packs. This carton 
preferably is perforated at least in part, so that the steam can reach the 
interior of the packing unit without great resistance. For example, a 
paper bag can also be used for the packing unit. From the point of view of 
economy and of the disposal of the ready-pack, it is advantageous to make 
the area that is permeable to steam out of paper. Consequently, no 
disposal problems arise in connection with the cardboard structure of the 
packing unit, since the above materials can readily be recycled. 
In a preferred embodiment, the sterilization by steam takes place on 
filled, blistered syringes packed by tens in folding boxes. The moisture 
of the air-steam mixture is regulated to an optimal, empirically 
determined level at the steam/condensate boundary. This assures rapid heat 
transfer through the preferably perforated folding box and through the 
paper of the ready-pack to the outside of the syringe. The outside of the 
syringe must be heated and wetted in such a way that a temperature of 
121.degree. C. is reached, preferably for 20 minutes, in its fill (liquid, 
gel-like, or paste-like medication). 
The inventive optimization of the steam/condensate range during the 
autoclaving process prevents visual changes (water spots) both on the 
sterile paper of the blister and on the folding box. 
In contrast to the syringe used in the known method, the syringe used in 
accordance with the invention is stable at 125.degree. C. and consequently 
can be sterilized with confined steam. As a result, it becomes possible to 
sterilize the ready-to-go sealed ready-pack thermally. When the ready-pack 
is gassed with ethylene oxide, the sterilization acts only on the exterior 
of the syringe body; in contrast, sterilization by a steam-air mixture can 
also sterilize the interior of the syringe body (container) and its fill. 
As a result, expensive production measures for producing a syringe with a 
sterile fill can be avoided. Furthermore, since no microbicidal gasses 
need to be used for the sterilization, the problem of the residues of such 
gasses no longer exists. 
Furthermore, an aseptic fill process of a liquid, gel-like, or paste-like 
medication is no longer necessary. As is well known, such a process 
involves the risk of microbial contamination, in contrast to a final 
sterilization of the medication in the closed final container. 
It is well known that sterilization by autoclaving at 121.degree. C. for 20 
minutes results in adequate sterilization. However, one must assure, by a 
proper choice of the sterilization time and temperature, that the 
sterilization conditions, namely 121.degree. C. and 20 minutes' duration, 
also prevail in the innermost part of the fill. In view of the unavoidable 
temperature gradient, a core temperature of 121.degree. C. in the fill 
requires a temperature of several degrees Celsius above this for the 
syringe body. This is the reason why the syringe body must have a 
temperature stability that is at least several degrees Celsius higher, 
even though 121.degree. C. is sufficient for sterilization. 
A thermally stable plastic, especially polypropylene or glass, is 
especially suited as a material for the syringe. According to the 
invention, a piston rod can be inserted into the syringe, parts of which 
have a rubber sealing device. 
The inventive method for fabricating a ready-pack with a syringe preferably 
is performed in such a way that an empty syringe, equipped with a 
discharge cone, is held ready with its piston advanced to the discharge 
position, that a dose of the fill is pressed into the ready syringe 
through the discharge cone and thus the piston is pressed back, that the 
discharge cone of the filled syringe is sealed with a sealing cap which 
consists of a flexible material that is stable at least at 121.degree. C., 
preferably of a temperature-stable rubber or plastic, that the filled, 
sealed syringe is placed into a blister-type package, that the blister is 
closed and sealed, that the ready-pack or a packing unit with several 
ready-packs is heated by steam all the way through to 121.degree. C. in 
the autoclave, preferably after previous evacuation, and is maintained 
heated all the way through at 121.degree. C. for at least 20 minutes, and 
that the ready-pack is then cooled slowly, preferably with the 
introduction of a support pressure, and thus is decompressed, and that its 
moisture is completely removed by single or multiple evacuation. 
Another variant of the inventive method is characterized in that a syringe 
without a piston rod is kept ready, whose discharge cylinder is closed by 
means of a closure cap or by an injection needle rigidly connected to the 
syringe and closed with a needle protection cap, or by an applicator, 
which consists of an elastic material that is stable at least at 
121.degree. C., the fill is dosed into the ready syringe from the opening 
for the piston rod, the piston rod is sealingly introduced into the filled 
syringe, the filled, closed syringe is inserted into a blister, the 
blister closure is now sealed, the ready-pack or a packing unit containing 
one or more ready-packs is heated to 121.degree. C. by steam in the 
autoclave, preferably after previous evacuation, and is kept heated at 
121.degree. C. for at least 20 minutes, and the ready-pack is then slowly 
cooled, preferably while a support pressure is introduced, and thus is 
decompressed. 
In a preferred design, the container is placed into the ready-pack or the 
wall of the ready-pack is fitted to the container so that a linear 
expansion or linear displacement, which may sometimes occur due to the 
sterilization (heating) process, is at least partially suppressed by the 
wall of the container. Thus, especially in the case of syringes, the 
piston can be prevented from escaping as a result of the heating of the 
filling and of the residual air bubble. In this connection, the syringe is 
altogether fixed in a ready-pack, preferably in the blister, so that no 
fill can emerge from the syringe. 
A second object of the invention is to design a syringe that is 
advantageously suited for the performance of the inventive method and is 
easily handled during fabrication, filling, and use. 
A syringe designed in accordance with these requirements is one wherein a 
syringe body has a cylindrical fill space, at least enclosed, open toward 
the rear along its entire cross-sectional area and in the front going over 
into a discharge cylinder, a longitudinally extended piston rod is 
disposed coaxial to the fill space, the rear end of said piston rod 
extending out of the fill space and having a handle, the front end of said 
piston rod having a piston which fits into the fill space so that it can 
be moved longitudinally, the piston has at least one piston disk, disposed 
frontally at the piston rod and fitting sealingly in the fill space, a 
closure cap is provided, which can be placed on the discharge cylinder, 
and which preferably can be moved along the discharge channel by a 
specifiable amount, and all parts consist of a material that is stable at 
least at 121.degree. C., preferably a plastic. In a preferred design, 
behind a first piston disk, a second piston disk is present, which fits 
only leadingly into the fill space. 
The two piston disks assure an axial guide of the piston rod both during 
the filling process and during use, without fabrication of the piston rod 
being made more difficult thereby. On the contrary, known pistons, axially 
extended for guidance, require more plastic material than the two piston 
disks provided here. 
The assembled syringe is filled, in one inventive embodiment, through the 
open discharge cone. Dosing is here facilitated if, as is done preferably, 
an inner stop is provided at rear end of the inside wall which surrounds 
the fill space. This stop acts as a rear stop for the second piston disk 
when the piston is in the fill position, and it withstands the fill 
pressure. On the other hand, it can be overcome by the piston if greater 
force is exerted. When the dose intended for the fill has been reached, 
the fill pressure can be reduced, or it can be kept so low in advance that 
it does not overcome the stop. In this fashion, the dosing tolerances of 
the fill can be kept very tight. 
The stop can be a single protrusion or also a number of protrusions 
disposed about the circumference, but preferably the stop is a bead 
concentric with the fill space. 
In a preferred design of the inventive syringe, the piston rod has a 
circumferential seal, especially an O-ring sealing device made of rubber, 
which permanently assures a good seal even after autoclaving. An 
alternative inventive design variant is characterized in that a sealing 
device, which can be elastically deformed in the piston direction, and 
which consists especially of rubber, with at least one circumferential 
sealing lamella, is present frontally before the piston disk. The elastic 
deformability can partially intercept the pressure which builds up in the 
interior during the sterilization process, especially if air bubbles are 
present. 
Advantageous modifications and developments are the subject of the other 
subclaims. 
The features of the claims can be combined with one another in arbitrary 
fashion, except as they obviously exclude one another. 
Further designs and advantages of the invention are elucidated by the 
embodiments specified below. 
The invention as well as advantageous designs and developments thereof are 
described and elucidated in more detail below in terms of the examples 
shown in the drawing. The features found in the description and the 
drawing can be used individually or in groups in arbitrary combination.

WAYS TO IMPLEMENT THE INVENTION 
In the drawing, 1 generally designates the ready-pack. This consists of a 
syringe 3 filled with a fill 2, and a sealed, closed pack 4 for this 
syringe. The syringe 3 consists of the syringe body 5, the piston rod 6, 
and a sealing cap 7. 
The syringe body 5 is cylindrical and extends longitudinally. At its rear, 
it has an opening 10 extending over its entire cross-sectional area. The 
front end of the syringe body goes over into a discharge channel body 8 
with a discharge channel 9, which can be closed by the sealing cap 7, 
which can be attached. The syringe body encloses the fill space 11, which 
is filled with the flowable fill 2, preferably a liquid, gel-like, or 
paste-like medication, and in particular at least translucent but 
preferably even transparent. An oval disk 22, serving as a handle, is 
disposed coaxial to the syringe axis 14, at the rear end of the syringe 
body. 
The piston rod 6 consists of two crossed, flat strips 12, 13. Its rear end 
extends out of the fill space 11, and there it has a pressure disk 15 as a 
handle, attached concentric to the syringe axis 14. Its front end has a 
piston 16, set into the fill space. This piston 16 consists of a first 
piston disk 17, disposed frontally at the piston rod, coaxial to the 
syringe axis 14, and of a second piston disk 18, disposed coaxial to the 
syringe axis 14, at some distance behind the first piston disk 17. 
The first piston disk 17 fits sealingly into the fill space 11, while the 
second piston disk fits only guidingly into the fill space 11. The two 
piston disks 17 and 18 are circular in correspondence with the cross 
section of the fill space 11. The second piston disk 18 can have recesses 
along its circumference. The only important point is that it is shaped so 
as to provide adequate guidance. The fill 2 ends at the first piston disk 
17. 
The reference symbol 19 designates a bead, extending concentrically into 
the fill space 11, and serving as an inner stop for the second piston disk 
18. This bead extends along the rear end at the inside wall of the syringe 
body. It forms a rear stop for the second piston disk 18, and specifically 
in the fill position of the piston 17. This stop withstands a fill 
pressure that is sufficient for filling the syringe through the discharge 
channel 9, but it can be overcome with a greater exertion of force by the 
two piston disks. 
The syringe body 5 consists of plastic or of glass. The sealing cap 7 
consists of rubber. The piston rod 6 consists of plastic, possibly with a 
stopper or an O-ring of rubber. The individual parts are all 
temperature-stable at 125.degree. C., preferably at 130.degree. C. 
The pack 4--also called the blister--consists of a flat base 20 and a hood 
21. The base 20 consists of stable paper, which is permeable to the 
diffusion of steam, but otherwise is tight. The hood 21 consists of 
transparent plastic. The hood and the base are stable at least up to 
121.degree. C., preferably 125.degree. C. The pack is sufficiently stiff, 
so that several ready-packs can be stacked one on top of the other without 
the pack being pressed in. The hood 21 is tightly welded to the base 20. 
The hood 21 is vapor-tight. 
The hood 21 is here designed such that, when the syringe is inserted, its 
frontal wall regions 21.1 and 21.2 lie against the front side of the 
pressure disk 15 and the front side of the sealing cap 7 respectively. In 
this way, the piston rod is prevented from escaping during the 
sterilization process. Heating the fill 2 and/or the air bubbles existing 
in the interior of the syringe body 5 causes a thermal length expansion or 
the build-up of an interior pressure. This could push the piston rod and 
the sealing cap away from the syringe body, so that the fill could exit in 
an undesired manner. According to the invention, this is prevented by the 
length expansion being at least partially prevented by the pack 1,4 itself 
taking up the stress due to the length expansion of the syringe 3. 
Furthermore, the sealing cap 7 is disposed on the cylindrical discharge 
channel body 8 so as to be movable lengthwise to a predetermined extent, 
without the fill being able to exit from the discharge channel 9 when the 
sealing cap 7 moves by this predetermined path. This movability likewise 
counteracts a pressure which builds up in the interior of the syringe body 
5. 
The procedure for fabricating the ready-pack is as follows: 
The syringe, fabricated under clean conditions, is held ready with the 
piston pushed from the front into the syringe body and with the sealing 
cap 7 pulled off. Liquid, gel-like, or paste-like fill material, 
especially a medication or a diagnostic agent, is now pressed through the 
discharge channel 9, and thus the piston rod 6 is pushed rearward. When 
the fill pressure used for this is so low that the stop formed by the bead 
19 cannot be overcome, this fill pressure can be retained until the end; 
otherwise it is lowered shortly before reaching a complete fill to such an 
extent that the stop cannot be overcome. As soon as the second piston disk 
18 contacts the bead 19, the fill process is completed, and the sealing 
cap 7 is attached. 
Then the filled syringe is placed into the fabricated and prepared hood 21. 
Then the base 20 is attached and is welded to the hood along its entire 
circumference (blistering). One or more blisters are packed into folding 
boxes and are sterilized in an autoclave as follows. 
The autoclave is first evacuated to 40 Torr. Then the autoclave chamber is 
heated to 125.degree. C. by injecting steam. The pressure required for 
this is built up so slowly that the diffusion of steam in the intermediate 
space between the syringe and the pack can cause the pressure in the 
interior of the ready-pack to follow to such an extent that the ready-pack 
is not pressed in. The temperature of 125.degree. C. is maintained until 
the sterilization of the fill in the container is complete. The 
temperature in the fill is measured and recorded by measurement sensors. 
In this connection at least two closed containers are always equipped with 
a temperature sensor in one autoclave charge. After sterilization, the 
sterilized material in the chamber is cooled indirectly. To remove 
impermissible residual moisture, the autoclave chamber is evacuated once 
or several times during and after the cooling process. It is then cooled 
to the outside temperature, is vented, and is opened. The cooling process 
takes place slowly, while a support pressure generated by air is 
introduced simultaneously, and in such a way that the pressure can 
equalize in the interior of the ready-pack, without the hood being pressed 
in thereby. 
In the regional longitudinal section shown in FIGS. 4 and 5, what is 
involved is the seal of the piston rod 6 inside the syringe 3. The same 
components bear the same reference symbols and will not be explained 
again. 
The piston rod 34, shown in FIG. 4, has a piston disk 30, which has a 
groove along its circumference, in which is mounted an O-sealing ring 32 
made of rubber. The O-ring 32 assures adequate tightness even after 
autoclaving despite shrinkage of the piston rod itself, which can happen 
occasionally. 
The piston rod 48, shown by way of a cut-out in FIG. 5, has a circular disk 
40, at whose front side a rubber stopper 42 is disposed as a sealing 
device. This rubber stopper has three elastic sealing lamellas 44 
extending lengthwise. The rubber stopper can be elastically deformed in 
the longitudinal direction (arrow 45), so that this property can at least 
partly counteract a pressure which builds up in the interior of the 
syringe 3 during the sterilization process. 
FIG. 6 schematically shows an autoclave 51, into which a packing unit 50 
has been placed for autoclaving. This packing unit 50 contains several 
ready-packs 1 which are equipped with a filled syringe. The packing ring 
50 consists of at least one folding box, which in some areas has a 
perforation 52, as shown schematically in FIG. 6. In at least two 
ready-packs 1.1 in each autoclave charge, a temperature sensor 54 is 
present in the interior of the syringe 3, to measure the temperature of 
the medication filled into the syringe body, during the autoclaving 
process. This temperature sensor 54 delivers a signal to a control unit 
56, which acts on a heating apparatus and a cooling apparatus 64 and, as 
necessary, causes increased heating if the temperature is too low and 
causes the controlled cooling of the autoclave charge after sterilization. 
In a special embodiment, a plurality (e.g. 1,000) folding boxes 50, each 
charge with ten blisters 1, are steam-sterilized in an autoclave 51. The 
temperature is here sensed and controlled (regulated) by means of a 
measurement sensor 54 in two syringes 3, distributed over the 
sterilization material (e.g. on the top and in the middle). Furthermore, a 
pressure sensor 58 and a moisture sensor 60 are present in the autoclave 
51. These likewise deliver their signals to the control device 56. The 
control device 56 acts, as necessary, on an evacuation apparatus 62 in 
dependence on the signals from the pressure sensor 58 and the moisture 
sensor 60. The evacuation apparatus 62 makes it possible to reduce the 
pressure at a specified rate. The moisture content is compared with an 
empirically determined value, said value being determined such that as 
little condensate as possible is produced, and such that so much moisture 
is present in the steam-air mixture that good heat transfer takes place to 
the fill in the container so as to provide fast and perfect sterilization, 
and, on the other hand, as little condensate as possible is formed, so 
that no visual impairments (water spots) appear at the blister and at the 
folding box and so that no residual moisture remains in the pack. 
With this packing unit 50, the ready-pack, the outside of the syringe, and 
the fill in the syringe are sterilized in one step. An expensive, aseptic 
fill process is thus obviated. Furthermore, the inventive method makes it 
possible that the preservatives, frequently used to preserve the fill, are 
not needed, since the sterilization process can assure a sufficiently long 
storage time, without deterioration of the effectiveness of the fill. 
Allergic reactions which could occur from the preservatives thus can be 
avoided. 
The inventive method thus can also be used preferably for filled glass 
syringes or for other medical utility articles, for which sterility is 
required not only for the fill, i.e. the medication itself, but also an 
external sterility, namely preferably in areas of a clinic, in which such 
ready-packs are needed or used intra-operatively, i.e. in operating rooms 
for operations on the open body.