WO2002080990A1

WO2002080990A1 - Apparatus for sterile transfer

Info

Publication number: WO2002080990A1
Application number: PCT/GB2002/001491
Authority: WO
Inventors: Brian Bergin; Philip Templeton; Douglas Thorogood
Original assignee: Individual
Current assignee: Individual
Priority date: 2001-04-07
Filing date: 2002-04-05
Publication date: 2002-10-17
Anticipated expiration: 2003-10-07
Also published as: GB0108850D0

Abstract

An apparatus for sterile transfer of an article between a sterile container (11) and a sterile enclosure (23), said apparatus comprising the sterile enclosure having a first opening (21) provided with a first closure (24), the container having a second opening (12) provided with a second closure (13) and interconnection means (19) for connection of said enclosure to said container, whereby said connection results in formation of a chamber (31) defined, at least in part, by said interconnection means and said first and second closures, said chamber being provided with means (27) for entry of fluid thereto such that the chamber can be sterilised using a suitable fluid medium, opening of the first and second closures then providing a pathway for said sterile transfer.

Description

APPARATUS FOR STERILE TRANSFER

The present invention relates to an apparatus for sterile transfer of an

article and a method of using said apparatus.

Maintenance of sterile conditions is of vital importance in the

manufacture and/or processing of a number of products, including, for

example, bulk and finished pharmaceuticals, medical devices,

biotechnological products, radiopharmaceuticals and foodstuffs. In such

cases, the sterility of both the manufacturing/processing environment and

also any equipment and materials for use therein must be maintained to

safeguard against product contamination.

Typically, an aseptic process will be carried out in a sterile clean

area, such as a traditional clean-room or an isolator. Whilst it may be

possible to create and maintain a sterile environment within the clean area,

difficulties arise where items are required to be transferred into or out of the

clean area. For example, it is frequently necessary for pre-sterilised raw

materials, components or equipment for use in a process to be transferred

into the clean area. Thus, the problem of allowing the transfer of items into

and/or out of the clean area whilst maintaining sterile integrity must be

addressed.

In order to facilitate such transfer of items between two separate

sterile environments, specialised mating ports have been developed.

Typically a closable port is provided in an appropriate part of an outer wall of the clean area. A corresponding closable port is provided in a further

sterile container, the two ports being engageable to form an airtight seal.

Commonly, silicon gaskets are used around each port to ensure that airtight

sealing is achieved, and a mechanical locking mechanism is employed to

bring the corresponding gaskets into mating engagement. Once mated, the

ports can be opened to enable transfer of items between the previously

separate sterile environments.

However, whilst the use of mating ports of the type described above

undoubtedly helps to reduce the risk of biological contamination of a sterile

processing area, there are problems associated with their use. The presence

of the gaskets, used to form an airtight seal between the respective ports, t presents a problem in that the exposed perimeter of each gasket is not

sterile. Contaminants present on the surface of the gaskets can be

transferred into the clean area as the ports engage and the seal is formed.

The risk of contamination is relatively low, and mating ports of this kind may

be acceptable for some purposes, these ports providing a useful means of

transfer in particular when the frequency of transfer is relatively low, for

instance once per day or once per week. However, as the frequency of

transfer increases, the significance of the risk of contamination increases

considerably. For example, many modern processes will require 4 transfers

per hour into a clean area, which will greatly increase the chances of sterility

being breached. Mating ports of the kind described above are capable of providing

sterility assurance levels of 10^"3 on the basis of finished product. This may

be measured by carrying out so-called 'media-fill' control experiments in

which transfer and processing steps are performed using aliquots of suitable

cell growth media, which are subsequently incubated at 37 °C. Any viable

biological contaminants entering the clean area during transfer via the mating

port will be revealed by colony growth in the media.

However, the results of such a control experiment cannot provide a

definitive level of sterility assurance, since the mechanical sealing of the

mating port is carried out by a human operator, and is not therefore

reproducible. In other words, once the transfer has been carried out and the

transferred item has been introduced into the sterile process, no assurance

can be provided as to the level of sterility that has been maintained during

the transfer.

The inability to provide a means of true aseptic transfer, and the lack

of proper sterility assurance, mean that mating ports of this kind are

unsuitable for use in certain processes, for example pharmaceutical

production processes where a sterility assurance level of 10^~6 (i.e. a

reduction by a factor of 10^~6 of viable contaminants) is desirable.

As a consequence, more advanced sterile port transfer systems have

been developed, which allow improved sterility assurance levels to be

attained. These systems use radiation to sterilise the interface between ports provided in separate sterile enclosures prior to mating as described

previously. This is an effective means of achieving a greater level of sterility

assurance as compared to the more basic mating ports of the kind described

above.

An irradiation source, such as a UV lamp, may be incorporated into a

closure of the port provided in a clean area, whereby when mating

engagement of that port and the port provided in the further, separate sterile

environment has taken place, the lamp can be activated to irradiate

previously exposed surfaces.

This type of transfer port does not depend upon a human operator to

ensure sterile integrity of a transfer. A greater level of sterility assurance can

be attained, and this can be measured accurately and reliably. Typically,

sterility assurance is measured by adding a so-called 'bio-burden' to the

exposed surfaces that will form part of the seal between the ports upon their

engagement, said bio-burden providing an artificially high level of

contaminant microorganisms. The ability of the irradiation device to kill the

contaminant cells is then assessed. A return to sterility following irradiation

of the bio-burden provides evidence that the irradiation device is working

effectively and it can be concluded that the said device will destroy the

quantity of viable contamination routinely present at the interface of the two

sterile enclosures.

There are significant problems associated with this type of sterile transfer port, however. A first problem is that the size of the port is limited

due to the need to utilise irradiation sources for sterilisation, these being

expensive to manufacture, operate and maintain. This size limitation

restricts the type of items that can be transferred to relatively small items,

and thus certain larger items cannot be transferred. Moreover, the rate of

transfer through the port is also limited by the size limitation of the port.

Any attempt to increase the size of such ports would necessarily

require larger and more expensive irradiation sources. However, irradiation

sources of the type used in these ports emit heat energy, this emission

reducing the efficiency of sterilisation thereby. As the size of the irradiation

source is increased, the amount of heat emission increases accordingly. In

order to utilise a larger irradiation source without a reduction in sterilising

efficiency therefore, a supplementary cooling system would have to be

provided. This would significantly increase the cost of manufacture,

operation and maintenance of the transfer port.

The irradiation sources themselves are expensive and have finite life-

spans, and therefore require regular replacement at significant expense.

Often, the irradiation source will be incorporated into a sealed unit to provide

a closure for the port and a complete unit will need to be obtained in order

to replace a spent irradiation source. This further increases the maintenance

costs.

The present invention has been made from a consideration of the aforementioned problems.

According to a first aspect of the present invention there is provided

an apparatus for sterile transfer of an article between a sterile container and

a sterile enclosure, said apparatus comprising a sterile enclosure having a

first opening provided with a first closure, a container having a second

opening provided with a second closure and interconnection means for

connection of said enclosure to said container, whereby said connection

results in formation of a chamber defined, at least in part, by said

interconnection means and said first and second closures, said chamber

being provided with means for entry of fluid thereto such that the chamber

can be sterilised using a suitable fluid medium, opening of the first and

second closures then providing a pathway for said sterile transfer.

The apparatus of the present invention is advantageous in that it

allows the sterile transfer of much larger materials and equipment than is

possible using currently available sterile transfer systems, these being limited

by the size of their irradiation sources as hereinbefore described. Improved

rate of sterile transfer relative to said currently available systems is also

achieved.

Moreover, the cost of manufacture, operation and maintenance of the

apparatus of the present invention is significantly reduced relative to the

currently available sterile transfer systems without any compromise in the

level of sterility assurance that can be obtained. The sterility assurance provided by the apparatus of the present invention is equal to or greater than

that of the currently available systems as hereinbefore described.

With regard to the sterile enclosure, this may comprise any contained

environment sterilised in any suitable manner. Typically however, this will

be a clean-room or isolator.

The first closure may take any suitable form, but preferably comprises

a door and a means of forming a seal. The door may be hinged. The means

of forming a seal may comprise an expandable seal or a gasket.

With regard to the interconnection means, this may take any suitable

form. Preferably however, said interconnection means comprises first and

second interengageable elements, said first element being attached or

attachable to the sterile enclosure and said second element being attached

or attachable to the container. Most preferably, the first and second

interengageable elements comprise support structures surrounding the first

and second openings respectively, said structures being adapted for

interengagement of one another, and having means for forming a seal

between one another upon said interengagement. Preferably, the means of

forming a seal is an expandable seal mechanism or a gasket.

In a preferred embodiment of the invention, the interconnection means

comprises first and second interengageable elements adapted so as to have

complementary 'male' and 'female' configurations, whereby interengagement

thereof is facilitated. Advantageously, the element having the 'male' configuration will comprise a collar of rigid material. The said material may

be a plastics material, such as polypropylene or polythene and may be

moulded into a suitable shape. In a particularly preferred embodiment of the

invention, the second element is adapted so as to have the 'male'

configuration.

Preferably, the interconnection means is operable to lock the sterile

enclosure and sterile container into a fixed position, thereby preventing

accidental displacement of the container which might compromise the sterile

integrity of either the enclosure or the container.

Preferably also, a mechanical locking device is further provided to

facilitate connection of the sterile enclosure and sterile container by the

interconnection means.

A sensor device may be provided to detect formation of a seal upon

connection of the sterile enclosure and sterile container by the

interconnection means to form the chamber. This sensor device may

function to initiate a sequence of steps to seal and sterilise the chamber.

The sensor device may function to prevent said initiation if it is detected that

an effective seal has not been formed.

With regard to the sterile container, this may take any suitable form,

and may be adapted according to the nature of the article or articles to be

contained. Preferably, said container comprises a heat resistant container.

Preferably also, at least a portion of the container is fabricated from a porous material having a pore size of less than 0.2μm. These properties allow the

interior of a sealed container and any contents thereof to be pre-sterilised by

heat sterilisation using steam, or by gas sterilisation using ethylene oxide,

since the said porous material will permit the passage of gas or vapour but

not of microorganisms.

Most preferably, pre-sterilisation of the interior of the container and

any contents thereof is achieved by irradiation, using gamma radiation or

electron beam.

In a preferred embodiment of the invention, the container comprises

a bag, and ideally a collapsable bag. The bag may be fixed to the

interconnection means. Preferably the bag is fixed to a collar having 'male'

configuration. The bag may comprise a bag having two or more separate

layers to reduce the likelihood of the bag being breached.

The second closure may take any suitable form. Preferably however,

said second closure is formed from a non-porous material. The second

closure may be provided in a pre-assembled arrangement with the second

element of the preferred interconnection means, this arrangement being

attachable to the container.

Preferably, the container will be re-usable, allowing refilling and further

sterilisation, thus providing a relatively inexpensive sterile transfer system.

Preferably, the means for entry of fluid into the chamber comprises an

inlet pipe. In a preferred embodiment of the invention, the means for entry of fluid into the chamber is integral to the interconnection means, and is

most preferably integral to the first element of the preferred interconnection

means. The chamber may be further provided with a means for exit of fluid

from the chamber, said means preferably being an outlet pipe. Preferably

also, the means for exit of fluid from the chamber is integral to the

interconnection means, most preferably to said first element thereof.

Sterilisation of the chamber may be achieved by generating and

feeding into said chamber via the means of entry of fluid thereto sterilisation

media, either alone or in combination, selected from sterilising vapours,

liquids or gases including hydrogen peroxide, steam, ethylene oxide, formalin,

peracetic acid, isopropyl alcohol or any known phenolic or chlorinated

disinfectant.

Most preferably, sterilisation of the chamber is achieved using

vaporised hydrogen peroxide.

Sterilising fluids as described above may be generated by any known

means. Conveniently, the fluid used to sterilise the chamber may be the

same fluid used to sterilise the interior of the sterile enclosure, thereby

allowing a common supply of sterilisation fluid to be used to sterilise both

the enclosure and the chamber.

According to a second aspect of the present invention there is

provided an apparatus for the sterile transfer of an article between a sterile

chamber and a sterile enclosure, said sterile enclosure having a first opening provided with a first closure, said apparatus comprising a container having

a second opening provided with a second closure and interconnection means

for connection of said enclosure to said container, whereby said connection

results in formation of a chamber defined, at least in part, by said

interconnection means and said first and second closures, said chamber

being provided with means for entry of fluid thereto such that the chamber

can be sterilised using a suitable fluid medium, opening of the first and

second closures then providing a pathway for said sterile transfer.

It will therefore be appreciated that an apparatus of the invention may

be used to effect sterile transfer between a container and a pre-existing

sterile enclosure.

According to a third aspect of the present invention there is provided

a method for sterile transfer of an article between a sterile container and a

sterile enclosure, said container and enclosure each having an opening

provided with a respective closure, said method comprising the steps of

connecting the container to the enclosure using an interconnection means to

form a chamber defined, at least in part, by said interconnection means and

the said closures, said chamber being provided with a means for entry of

fluid thereto, introducing a suitable sterilisation fluid into the chamber via

said means for entry so as to sterilise the chamber, opening said closures,

and transferring said article as required.

Sterilisation fluid may be introduced into the chamber at a flow rate of between 0.5 and 12 g/min. Preferably, said sterilisation fluid leaves the

chamber at a similar rate, whereby sterilisation fluid is made to flow through

the chamber. This ensures that thorough sterilisation of the chamber is

achieved.

The invention will now be described further by way of example only

and with reference to the accompanying drawings, in which:

Fig. 1 is a diagrammatic cross-section of one form of apparatus

of the present invention;

Fig. 2 is a diagrammatic cross-section of the collar of the

apparatus as shown in Fig. 1 ; and

Fig. 3 is a diagrammatic perspective sectional view of the

apparatus of Fig. 1.

With reference to the drawings, an apparatus 10 has a container 1 1 ,

this being a collapsible bag, preferably having porous structure with a pore

size of less than 0.2μm. The container 1 1 has an opening 12, the opening

12 being sealed in an airtight manner by a film 13 of a non-porous plastics

material. The container 1 1 is attached to a collar 14 adjacent to the opening

12, the collar 14 being made from a rigid plastics material. The collar 14

comprises upper 16 and lower 17 sections releasably joined to form an

airtight seal 18. The upper section 16 of the collar 14 forms a support

structure surrounding the opening 12 and is sealed by the film 13. The

lower section 17 of the collar 14 is attached to the container 1 1. The interior of the container 1 1 , and any article contained therein, has

been pre-sterilised, preferably by irradiation of the container 1 1 .

The container 1 1 may conveniently be supported by a pallet 20. The

container 1 1 may have a volume of approximately 1 m³ to enable it to be

positioned on a standard pallet for easy storage.

The collar 14, and more specifically the upper section 16 of the collar

14, is engageable with a corresponding support structure 1 9 formed around

an opening 21 in a wall 22 of a sterile enclosure 23, the support structure

1 9 projecting from an external surface of the enclosure 23. The collar 14

and corresponding support structure 19 are formed into respective

complementary 'male' and 'female' configurations, such that the support

structure 1 9 accommodates a portion of the collar 14 to facilitate their

interengagement.

The support structure 1 9 is provided with inlet 27 and outlet 28 pipes

through which fluid, usually in the form of a gas or vapour, can flow. The

support structure 1 9 is also provided with

an expandable seal 29 which is expandable to form an airtight seal with the

upper section 1 6 of the collar 14.

A hinged door 24 is provided to close the opening 21 in the wall 22

of the sterile enclosure 23, the door 24 being sealable using an expandable

seal 26 provided around the peripheral edge of the door 24. The seal 26 is

preferably expanded by inflation to provide an airtight seal. In Fig. 3, the door 24 is shown in the open position.

In use, the container 1 1 is positioned adjacent the enclosure 23 as

shown in Fig. 1 , with the upper section 16 of the collar 14 accommodated

by the support structure 1 9. The seal 29 provided in the support structure

1 9 is expanded, preferably by inflation, so as to engage the surface of the

upper section 16 of the collar 14, forming an airtight seal and locking the

respective positions of the container 1 1 and enclosure 23.

A chamber 31 is thereby formed, the film 13, door 24 and support

structure 1 9 forming the boundaries thereof.

Sterilising fluid, this most preferably being vaporised hydrogen

peroxide, is then pumped into the chamber 31 via the inlet pipe 27 using a

suitable gas pump. Conveniently, the pump may be a pump also used to pre-

sterilise the enclosure 23. The sterilising fluid exits the chamber 31 via the

outlet pipe 28, such that said sterilising fluid flows through the chamber 31 .

After an appropriate period of time has elapsed to allow the

sterilisation fluid to sterilise the surfaces defining the chamber 31 , the supply

of sterilising fluid is stopped and residuals are removed from the chamber.

The door 24 is then opened from within the enclosure 23 and the film 13 is

pierced or peeled back to provide a pathway for sterile transfer of an article

from the container 1 1 into the enclosure 23.

The door is subsequently re-closed and then re-sealed using the seal

26, prior to release of the collar 14 from engagement with the support structure 19 by contraction of the seal 29.

Thus, the apparatus 10 allows sterile transfer of an article into the

sterile enclosure 23 from the container 1 1 , with a high level of sterility

assurance.

The container 1 1 may be recycled by re-filling and re-sealing before

further sterilisation. Said re-sealing may be achieved by detachment of the

upper 16 and lower 17 sections of the collar 14 and attachment of a fresh

upper section 16 sealed by an intact film 13, thus providing a sealed

container unit for sterilisation.

It is of course to be understood that the invention is not intended to

be restricted to the details of the above embodiment which are described by

way of example only.

Claims

1 . An apparatus for sterile transfer of an article between a sterile

container and a sterile enclosure, said apparatus comprising a sterile

enclosure having a first opening provided with a first closure, a

container having a second opening provided with a second closure

and interconnection means for connection of said enclosure to said

container, whereby said connection results in formation of a chamber

defined, at least in part, by said interconnection means and said first

and second closures, said chamber being provided with means for

entry of fluid thereto such that the chamber can be sterilised using a

suitable fluid medium, opening of the first and second closures then

providing a pathway for said sterile transfer.

2. An apparatus according to claim 1 , wherein said sterile enclosure is

selected from a clean-room and an isolator.

3. An apparatus according to either of claims 1 or 2, wherein said first

closure comprises a door and a means of forming a seal.

4. An apparatus according to claim 3, wherein said means of forming a

seal is selected from an expandable seal and a gasket.

5. An apparatus according to any of claims 1 to 4, wherein said

interconnection means comprises first and second interengageable

elements, said first element being attached or attachable to said

sterile endosure and said second element being attached or

attachable to said container.

6. An apparatus according to claim 5, wherein said first and second

interengageable elements comprise support structures surrounding

said first and second openings respectively, said structures being

adapted for interengagement of one another, and having means of

forming a seal between one another upon said interengagement.

7. An apparatus according to claim 6, wherein said first and second

interengageable elements are adapted so as to have complementary

'male' and 'female' configurations, whereby interengagement thereof

is facilitated.

8. An apparatus according to claim 7, wherein said second

interengageable element is adapted so as to have the 'male'

configuration.

9. An apparatus according to any of claims 6 to 8, wherein said means

of forming a seal is selected from an expandable seal or a gasket.

10. An apparatus according to any of claims 1 to 9, wherein said

interconnection means is operable to lock the sterile enclosure and

sterile container into a fixed position.

1 1. An apparatus according to any of claims 1 to 10, wherein said

apparatus further comprises a mechanical locking device operable to

facilitate connection of said sterile enclosure and sterile container by

said interconnection means.

12. An apparatus according to any of claims 1 to 1 1 , wherein a sensor

device is provided to detect formation of a seal upon connection of said sterile enclosure and sterile container by said interconnection

means to form said chamber.

13. An apparatus according to any of claim 1 to 1 2, wherein said sterile

container is heat resistant.

14. An apparatus according to any of claims 1 to 13, wherein at least a

portion of said sterile container is fabricated from a porous material

having a pore size of less than 0.2μm.

1 5. An apparatus according to any of claims 1 to 14, wherein said sterile

container comprises a collapsible bag.

1 6. An apparatus according to any of claims 1 to 1 5, wherein said

second closure is formed from a non-porous material.

17. An apparatus according to any of claims 1 to 1 6, wherein said

means for entry of fluid into said chamber comprises an outlet pipe

integral to said interconnection means.

1 8. An apparatus according to any of claims 1 to 1 7, wherein said

apparatus is further provided with an outlet pipe for exit of fluid from

said chamber.

1 9. An apparatus according to claim 1 8, wherein said outlet pipe is

integral to said interconnection means.

20. An apparatus according to any of claims 1 to 19, wherein

sterilisation of said chamber is achieved using a fluid medium

selected from one or more of the following sterilising vapours, liquids

and gases: hydrogen peroxide, steam, ethylene oxide, formalin, peracetic acid, isopropyl, alcohol and phenolic and chlorinated

disinfectants.

21 . An apparatus according to claim 20, wherein sterilisation of said

chamber is achieved using vaporised hydrogen peroxide.

22. An apparatus according to any of claims 1 to 21 , wherein the same

fluid is used to sterilise said chamber and said sterile enclosure.

23. An apparatus for the sterile transfer of an article between a sterile

chamber and a sterile enclosure, said sterile enclosure having a first

opening provided with a first closure, said apparatus comprising a

container having a second opening provided with a second closure

and interconnection means for connection of said enclosure to said

container, whereby said connection results in formation of a chamber

defined, at least in part, by said interconnection means and said first

and second closures, said chamber being provided with means for

entry of fluid thereto such that the chamber can be sterilised using a

suitable fluid medium, opening of the first and second closures then

providing a pathway for said sterile transfer.

24. A method for sterile transfer of an article between a sterile container

and a sterile enclosure, said container and enclosure each having an

opening provided with a respective closure, said method

comprising the steps of connecting the container to the enclosure

using an interconnection means to form a chamber defined, at least

in part, by said interconnection means and the said closures, said chamber being provided with a means for entry of fluid thereto,

introducing a suitable sterilisation fluid into the chamber via said

means for entry so as to sterilise the chamber, opening said closures,

and transferring said article as required.

25. A method according to claim 24, wherein sterilisation fluid is

introduced into said chamber at a flow rate of between 0.5 and

12g/min.

26. A method according to either of claims 24 or 25, wherein said

sterilisation fluid leaves said chamber at a similar flow rate to that at

which it is introduced into said chamber.