U.S. patent application number 11/427430 was filed with the patent office on 2007-03-01 for method for sterilizing lumen devices.
Invention is credited to Tralance O. Addy, Jon M. Jacobs, Paul T. Jacobs, Szu-Min Lin.
Application Number | 20070048177 11/427430 |
Document ID | / |
Family ID | 23866815 |
Filed Date | 2007-03-01 |
United States Patent
Application |
20070048177 |
Kind Code |
A1 |
Lin; Szu-Min ; et
al. |
March 1, 2007 |
METHOD FOR STERILIZING LUMEN DEVICES
Abstract
A method, according to the present invention provides for
sterilizing an interior of a lumen of an article. The method
comprises the steps of: contacting the interior of the lumen with a
liquid comprising hydrogen peroxide; heating the article; and
exposing the article to sub-atmosphere pressure sufficient to
vaporize the hydrogen peroxide within the lumen and for a time
period sufficient to effect sterilization of the interior of the
lumen. Preferably, the liquid comprises a condensed vapor.
Inventors: |
Lin; Szu-Min; (Irvine,
CA) ; Jacobs; Paul T.; (Bicknell, UT) ; Addy;
Tralance O.; (Coto de Caza, CA) ; Jacobs; Jon M.;
(Pasco, CA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
23866815 |
Appl. No.: |
11/427430 |
Filed: |
June 29, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10284987 |
Oct 31, 2002 |
|
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|
11427430 |
Jun 29, 2006 |
|
|
|
09470244 |
Dec 22, 1999 |
6495100 |
|
|
10284987 |
Oct 31, 2002 |
|
|
|
09105280 |
Jun 26, 1998 |
6068817 |
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09470244 |
Dec 22, 1999 |
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|
08833375 |
Apr 4, 1997 |
5961921 |
|
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09105280 |
Jun 26, 1998 |
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08628965 |
Apr 4, 1996 |
6030579 |
|
|
08833375 |
Apr 4, 1997 |
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Current U.S.
Class: |
422/33 ;
422/28 |
Current CPC
Class: |
A61L 2/208 20130101;
A61L 2/16 20130101; A61L 2202/24 20130101; A61L 2202/122 20130101;
A61L 2202/14 20130101; A61L 2/14 20130101 |
Class at
Publication: |
422/033 ;
422/028 |
International
Class: |
A61L 2/20 20060101
A61L002/20 |
Claims
1. A method for sterilizing an interior of a lumen of an article,
comprising: contacting the interior of the lumen with a liquid
comprising hydrogen peroxide; heating the article; and exposing the
article to sub-atmospheric pressure sufficient to vaporize the
hydrogen peroxide within the lumen and for a time period sufficient
to effect sterilization of the interior of the lumen.
2. A method according to claim 1, wherein the liquid comprises a
condensed vapor.
3. A method according to claim 1, wherein the contacting step
comprises delivery via one or more methods selected from the group
consisting of injection, static soak, liquid flow, aerosol spray,
condensation and physical placement.
4. A method according to claim 1, wherein the lumen is at least 27
cm in length and has an internal diameter of no more than 3 mm.
5. A method according to claim 1, wherein the article is heated to
at least 28.degree. C.
6. A method according to claim 5, wherein the article is heated to
at least 40.degree. C.
7. A method according to claim 6, wherein the article is heated to
at least 45.degree. C.
8. A method according to claim 1, wherein the heating is conducted
at atmospheric pressure.
9. A method according to claim 1, wherein the heating is conducted
at reduced pressure.
10. A method according to claim 1, wherein the heating comprises
application of electromagnetic energy to an environment about the
article.
11. A method according to claim 1, further comprising the step of
exposing the article to a plasma.
12. A method according to claim 1, wherein the exposing step
comprises exposing the article to pressure less than the vapor
pressure of hydrogen peroxide.
13. A method according to claim 1, wherein the sub-atmospheric
pressure is between 0 and 100 torr.
14. A method according to claim 13, wherein the sub-atmospheric
pressure is above 30 torr.
15. A method according to claim 14, wherein the sub-atmospheric
pressure is above 50 torr.
16. A method according to claim 1, wherein the interior of the
lumen represents a diffusion restriction which is at least as
diffusion restricted as a lumen 27 cm in length and having an
internal diameter of 3 mm.
Description
[0001] This application is a continuation of application Ser. No.
10/284,987, filed Oct. 31, 2002 which is a continuation of
application Ser. No. 09/470,244, filed Dec. 22, 1999, now U.S. Pat.
No. 6,495,100, which is a continuation-in-part of application Ser.
No. 09/105,280(filed Jun. 26. 1998, now U.S. Pat. No. 6,068,817,
which is a divisional of application Ser. No. 08/833,375, filed
Apr. 4, 1997, now U.S. Pat. No. 5,961,921, which is a
continuation-in-part of application Ser. No. 08/628,965, filed Apr.
4 1996, now U.S. Pat. No. 6,030,579, each of which are hereby
incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to an apparatus and a method for
sterilizing devices in a container using a source of vaporizable
germicide and negative pressure and more particularly, to methods
which include the step of contacting the articles or the container
containing the articles with a vaporizable germicide prior to
exposure to negative pressure or negative pressure combined with
plasma.
[0004] 2. Description of the Related Art
[0005] Medical instruments have traditionally been sterilized using
either heat, such as is provided by steam, or a chemical, such as
formaldehyde or ethylene oxide in the gas or vapor state. Each of
these methods has drawbacks. Many medical devices, such as
fiberoptic devices, endoscopes, power tools, etc. are sensitive to
heat, moisture, or both. Formaldehyde and ethylene oxide are both
toxic gases that pose a potential hazard to healthcare worker.
Problems with ethylene oxide are particularly severe, because its
use requires long aeration times to remove the gas from articles
that have been sterilized. This makes the sterilization cycle time
undesirably long.
[0006] Sterilization using liquid hydrogen peroxide solution has
been found to require high concentration of sterilant, extended
exposure time and/or elevated temperatures. However, sterilization
using hydrogen peroxide vapor has been shown to have some
advantages over other chemical sterilization processes (see, e.g.,
U.S. Pat. Nos. 4,169,123 and 4,169,124). The combination of
hydrogen peroxide with a plasma provides certain additional
advantages, as disclosed in U.S. Pat. No. 4,643,876, issued Feb.
17, 1987 to Jacobs et al., U.S. Pat. No. 4,756,882, issued Jul. 12,
1988 also to Jacobs et al. discloses the use of hydrogen peroxide
vapor, generated from an aqueous solution of hydrogen peroxide, as
a precursor of the reactive species generated by a plasma
generator. The combination of hydrogen peroxide vapor diffusing
into close proximity with the article to be sterilized and plasma
acts to sterilize the articles, even within closed packages.
Further, these methods of combining hydrogen peroxide vapor with a
plasma, while useful in "open" systems, have been found to be
inadequate to effect sterilization in articles having
diffusion-restricted areas, since the methods are dependent upon
diffusion of the sterilant vapor into close proximity with the
article before sterilization can be achieved. Thus, these methods
have been found to require high concentrations of sterilant,
extended exposure time and/or elevated temperatures when used on
long, narrow lumens. For example, lumens longer than 27 cm and/or
having an internal diameter of less than 0.3 cm have been
particularly difficult to sterilize. Thus, no simple, safe,
effective method of sterilizing smaller lumens exists in the prior
art.
[0007] The sterilization of articles containing
diffusion-restricted areas, such as tong narrow lumens, therefore
presents a special challenge. Methods that use hydrogen peroxide
vapor that has been generated from an aqueous solution of hydrogen
peroxide have certain disadvantages, because: [0008] 1. Water has a
higher vapor pressure than hydrogen peroxide and will vaporize
faster than hydrogen peroxide from an aqueous solution. [0009] 2.
Water has a lower molecular weight than hydrogen peroxide and will
diffuse faster than hydrogen peroxide in the vapor state.
[0010] Because of this, when an aqueous solution of hydrogen
peroxide is vaporized in the area surrounding the items to be
sterilized, the water reaches the items first and in higher
concentration. The water vapor therefore becomes a barrier to the
penetration of hydrogen peroxide vapor into diffusion restricted
areas, such as small crevices and long narrow lumens. One cannot
solve the problem by removing water from the aqueous solution and
using more concentrated hydrogen peroxide, since, among other
reasons, concentrated solutions of hydrogen peroxide greater than
65% by weight can be hazardous due to the oxidizing nature
thereof.
[0011] U.S. Pat. No. 4,952,370 to Cummings et al. discloses a
sterilization process wherein aqueous hydrogen peroxide vapor is
first condensed on the article to be sterilized, and then a source
of vacuum is applied to the sterilization chamber to evaporate the
water and hydrogen peroxide from the article. This method is
suitable to sterilize surfaces, however, it is ineffective at
rapidly sterilizing diffusion-restricted areas, such as those found
in lumened devices, since it too depends on the diffusion of the
hydrogen peroxide vapor into the lumen to effect sterilization.
[0012] U.S. Pat. No. 4,943,414, entitled "Method for Vapor
Sterilization of Articles Having Lumens," and issued to Jacobs et
al., discloses a process in which a vessel containing a small
amount of a vaporizable liquid sterilant solution is attached to a
lumen, and the sterilant vaporizes and flows directly into the
lumen of the article as the pressure is reduced during the
sterilization cycle. This system has the advantage that the water
and hydrogen peroxide vapor are pulled through the lumen by the
pressure differential that exists, increasing the sterilization
rate for lumens, but it has the disadvantage that the vessel needs
to be attached to each lumen to be sterilized. In addition, water
is vaporized faster and precedes the hydrogen peroxide vapor into
the lumen.
[0013] In U.S. Pat. No. 5,492,672, there is disclosed a process for
sterilizing narrow lumens. This process uses a multicomponent
sterilant vapor and requires successive alternating periods of flow
of sterilant vapor and discontinuance of such flow. A complex
apparatus is used to accomplish the method. Because flow through of
vapor is used, closed end lumens are not readily sterilized in the
process.
[0014] Thus, there remains a need for a simple and effective method
of vapor sterilization of articles having areas where diffusion of
these vapors is restricted, such as long, narrow lumens.
SUMMARY OF THE INVENTION
[0015] A method, according to the present invention provides for
sterilizing an interior of a lumen of an article. The method
comprises the steps of contacting the interior of the lumen with a
liquid comprising hydrogen peroxide; heating the article; and
exposing the article to sub-atmospheric pressure sufficient to
vaporize the hydrogen peroxide within the lumen and for a time
period sufficient to effect sterilization of the interior of the
lumen. Preferably, the liquid comprises a condensed vapor.
[0016] The contacting step can comprise delivery via Objection,
static soak, liquid flow, aerosol spray, condensation, physical
placement or a combination thereof.
[0017] The method is particularly suited for lumen of at least 27
cm in length and having an internal diameter of no more than 3 mm,
or for lumens which are as diffusion restricted as such lumen.
[0018] Preferably, the article is heated to at least 28.degree. C.,
and more preferably to at least 40.degree. C. or 45.degree. C.
[0019] In one aspect of the invention, the heating is conducted at
atmospheric pressure. In another aspect of the invention, the
heating is conducted at reduced pressure, below atmospheric
pressure.
[0020] In one aspect of the invention the heating comprises
application of electromagnetic energy to an environment about the
article.
[0021] Preferably, the method further comprises the step of
exposing the article to a plasma.
[0022] Preferably, the exposing step comprises exposing, the
article to pressure less than the vapor pressure of hydrogen
peroxide.
[0023] In one aspect of the invention, the sub-atmospheric pressure
is between 0 and 100 torr. In an aspect of the invention the
pressure is above 30 torr or even above 50 torr.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 is a cross-sectional illustration of a lumen
containing an inoculated stainless steel blade placed within a
glass tube having; only a narrow opening to create a
diffusion-restricted environment for testing the sterilization
method of the present invention.
[0025] FIG. 2 is a cross-sectional illustration of an inoculated
stainless steel blade placed directly within a glass tube having
only a narrow opening to create an alternate diffusion restricted
environment for testing the sterilization method of the present
invention.
[0026] FIG. 3 is a cross-sectional illustration of an inoculated
stainless steel blade placed directly within a glass tube having a
filter placed at its narrow opening to create an alternate
diffusion-restricted environment for testing the sterilization
method of the present invention.
[0027] FIG. 4 is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by a container
having a limited diffusion port (communication port consisting of
tubing).
[0028] FIG. 5A is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by a container
having a limited diffusion port (communication port consisting of
tubing or the lumen device) and a tubing connector to connect a
lumen device to the communication port of the container.
[0029] FIG. 5B is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by a container
having a limited diffusion port (communication port consisting of
tubing or the lumen device) and an enclosure connector to connect a
lumen device to the communication port of the container.
[0030] FIG. 6 is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by a container
having a limited diffusion port and an enclosure connector to
connect a lumen device to the window.
[0031] FIG. 7A is a schematic diagram of a round diffusion
restricted port.
[0032] FIG. 7B is a schematic diagram of an oval diffusion
restricted port.
[0033] FIG. 7C is a schematic diagram of a rectangular diffusion
restricted port.
[0034] FIG. 7D is a schematic diagram of a round diffusion
restricted port covered and/or filled with a filter.
[0035] FIG. 8 is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by a container
with a substantially vertical tube with a filter as a limited
diffusion port.
[0036] FIG. 9 is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by a container
with a substantially horizontal tube with filter as a limited
diffusion port.
[0037] FIG. 10 is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by a container
with a hole on the container as a limited diffusion port, where the
lid of the container is thicker in the area of the hole than in the
remainder of the lid.
[0038] FIG. 11 is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by a container
having a hole as a limited diffusion port, where the lid has an
even thickness.
[0039] FIG. 12 is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by a container
having an open channel in the handle of the container with a gas
permeable and microorganism impermeable filter covering the channel
as a limited diffusion port.
[0040] FIG. 13 is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by an
attachable/detachable container having a diffusion restricted port
with a gas permeable and microorganism impermeable filter and a
valve and a second port with a valve.
[0041] FIG. 14 is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by an
attachable/detachable container having two ports with valves.
[0042] FIG. 15 is a cross-sectional illustration of a connector
with O-rings for connecting an attachable/detachable container to a
source of vacuum, source of fluid, and or other feedthrough.
[0043] FIG. 16 is an cross-sectional illustration of an alternative
embodiment of a connector for connecting an attachable/detachable
container to a source of vacuum, source of fluid, and/or other
feedthrough, where the connector allows attachment of one or two
ports.
[0044] FIG. 17 is a cross-sectional illustration of an
attachable/detachable container with a port with a gas permeable
and microorganism impermeable filter attached to the connector of
FIG. 15.
[0045] FIG. 18 is a cross-sectional illustration of an
attachable/detachable container with a valve attached to the
connector of FIG. 15, where the valve on the attachable/detachable
container acts as the diffusion-restricted port.
[0046] FIG. 19 is a cross-sectional illustration of an
attachable/detachable container with a valve and a gas permeable
and microorganism impermeable filter attached to the connector of
FIG. 15, where the valve and/or the filter on the
attachable/detachable container act as the diffusion-restricted
port.
[0047] FIG. 20 is a cross-sectional illustration of an
attachable/detachable container with a gas permeable and
microorganism impermeable filter attached to the connector of FIG.
15, where the filter on the container and/or the valve on the
container act as the diffusion-restricted port.
[0048] FIG. 21 is a cross-sectional illustration of an
attachable/detachable container with two ports, one port with a
valve and a gas permeable and microorganism impermeable filter and
the second port with a septum, where the septum is punctured by a
needlelike device connected to a vacuum source.
[0049] FIG. 22 is a cross-sectional illustration of an
attachable/detachable container attached to a connector, where the
port on the container has a gas permeable and microorganism
impermeable filter and where the diffusion restriction in the
container is due to a combination of the container and the
connector.
[0050] FIG. 23 is a cross-sectional illustration of an
attachable/detachable container with two ports attached to the
connector of FIG. 16, where one port on the attachable/detachable
container has a gas permeable and microorganism impermeable filter
and a valve and a second port has a valve.
[0051] FIG. 24 is a cross-sectional illustration of an
attachable/detachable container with two ports with valves attached
to the connector of FIG. 16.
[0052] FIG. 25 is a cross-sectional illustration of an
attachable/detachable container with two ports, where one port has
a hinged valve and the second port has a hinged valve and a gas
permeable and microorganism impermeable filter.
[0053] FIG. 26 is a cross-sectional illustration of a connector for
connecting attachable/detachable containers with at least one port
with a hinged valve to one or two sources of vacuum, fluid, or
other feedthrough.
[0054] FIG. 27 is a cross-sectional illustration of the
attachable/detachable container of FIG. 25 attached to the
connector of FIG. 26.
[0055] FIG. 28 is a cross-sectional illustration of a container
with a gas permeable and microorganism impermeable window nested
inside an attachable/detachable container with a valve.
[0056] FIG. 29 is a cross-sectional illustration of a container
with a substantially horizontal entry exit port and a gas permeable
and microorganism impermeable filter nested inside an
attachable/detachable container with a diffusion restricted port
with a hinged valve and a gas permeable and microorganism
impermeable filter.
[0057] FIG. 30 is a cross-sectional illustration of a pouch
containing a pair of scissors nested inside an
attachable/detachable container with a valve.
[0058] FIG. 31 is a cross-sectional illustration of a container
with a gas permeable and microorganism impermeable window and a
port with a hinged valve nested inside an attachable/detachable
container with a hinged valve.
[0059] FIG. 32A a cross-sectional illustration of a connector for
connecting containers with hinged valves to a source of vacuum,
fluid, or other feedthrough, where the connector has a stop
limiting movement of the container.
[0060] FIG. 32B is a cross-sectional illustration of a connector
for connecting nested attachable/detachable containers to a source
of vacuum, fluid, or other feedthrough.
[0061] FIG. 32C is a cross-sectional illustration of a connector
for connecting nested attachable/detachable containers to a source
of vacuum, fluid, or other feedthrough, where the connector has an
opening between the O-rings.
[0062] FIG. 33A is a cross-sectional illustration of the nested
containers of FIG. 31 attached to the connector of FIG. 32B, where
the connector extends through only one of the two hinged
valves.
[0063] FIG. 33B is a cross-sectional illustration of the nested
containers of FIG. 31 attached to the connector of FIG. 32B, where
the connector extends through both of the two hinged valves.
[0064] FIG. 34A is a schematic diagram of a system for sterilizing
a single attachable/detachable container.
[0065] FIG. 34B is a schematic diagram of a system for sterilizing
two attachable/detachable containers.
[0066] FIG. 34C is a schematic diagram of a system for sterilizing
four attachable/detachable containers.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0067] Sterilizing the inside of lumened devices has always posed a
challenge to sterilization systems. Achieving rapid sterilization
of lumened devices or other diffusion restricted articles at low
temperatures and low concentrations of sterilant represents an even
greater challenge. In the present invention, the shortcomings of
the prior art sterilization systems are overcome by pre-treating or
contacting articles to be sterilized with a source of peroxide
prior to exposure to a vacuum, or optionally, plasma.
Alternatively, a diffusion-restricted environment containing
articles to be sterilized can be contacted with a source of
peroxide prior to exposure to a vacuum. The source of peroxide
comprises a liquid or condensed vapor in the case wherein an
article is contacted. In the case wherein a diffusion-restricted
environment is contacted, the source of peroxide additionally
comprises a solid. The liquid comprises aqueous solutions of
hydrogen peroxide or peracetic acid. The solid comprises a urea
peroxide complex, or sodium pyrophosphate peroxide complex or like
peroxide complex. The vapor comprises hydrogen peroxide or
peracetic acid vapor. The preferred method of the present invention
utilizes aqueous hydrogen peroxide as the source of peroxide to
contact an article to be sterilized. The methods of the present
invention provide for the rapid sterilization of lumened and
non-lumened articles under conditions that will not damage the
articles nor leave toxic residues on the sterile articles.
[0068] In the method of the present invention, the source of the
peroxide is delivered into direct contact with the article to be
sterilized or with the diffusion-restricted environment containing
the article to be sterilized. In the case of a lumened device, the
source of peroxide may be delivered directly into the lumen. In the
case of an article having all area where diffusion of vapor is
restricted, the source of peroxide may be delivered to the interior
of the diffusion restricted area. For articles which are not
diffusion-restricted, the source of peroxide can be introduced
anywhere into the diffusion-restricted environment. The source of
peroxide is delivered into the lumen or into contact with the
article to be sterilized or into contact with the
diffusion-restricted environment containing the article to be
sterilized through means such as direct delivery or physical
placement, a static soaking process, a liquid flow-through process,
by aerosol spray or by condensation of a vapor. Physical placement
also includes placement of a reservoir containing the source of
peroxide. In the preferred method of the present invention, the
aqueous solutions of hydrogen peroxide can be relatively dilute,
e.g., as low as 1-6% or lower by weight, since sterilization is not
achieved through contact with the hydrogen peroxide solution, but
rather, is achieved at low temperatures and in short periods of
time upon exposure to hydrogen peroxide vapor under vacuum or
vacuum combined with plasma. The method of the present invention is
particularly effective with articles having inaccessible or
hard-to-reach places. Such articles include long, narrow lumens,
hinges, mated surface, and other articles having spaces where
diffusion of vapors is restricted.
[0069] The general operation of one embodiment of a preferred
method of the present invention, which is useful for sterilizing
the inside of long, narrow lumens, is as follows: [0070] 1. The
lumen to be sterilized is contacted with a source of peroxide. The
source of peroxide can be physically delivered as a small amount
directly into the lumen, or by static soaking, liquid flow-through,
aerosol spray or condensation of a vapor. [0071] 2. The lumen to be
sterilized is placed within a chamber, and the chamber is sealed
and evacuated. (The source of peroxide can also be delivered to the
inside of the article after placing the article in the chamber.)
[0072] 3. The lumen is exposed to the vacuum for a period of time
and at a temperature sufficient to effect sterilization. [0073] 4.
The sterile lumen is removed from chamber.
[0074] In an alternative embodiment of the method of the present
invention, a similar method is used to sterilize both the inside
and outside of an article. In this alternative embodiments the
article to be sterilized is placed in a diffusion-restricted
environment. The diffusion-restricted environment can be a rigid
container or flexible pouch having at least one communication port.
The communication port can be an exit tube, a hole, or a channel.
In this embodiment, the communication port is preferably
diffusion-restricted. Alternatively, it is not necessary that the
communication port be diffusion-restricted so long as diffusion of
sterilant vapor is limited by the article to be sterilized, such as
the case wherein sterilant vapor must flow through a limited
diffusion area or lumen of an article to be sterilized. This
depends upon the configuration of the container. The exit tube may
be constructed from a variety of materials, such as glass, metals
and plastics and may include a filter. The filter may be sufficient
to prevent entry of bacteria from the environment into the
container. The source of peroxide is introduced to the inside of
the article. The source of peroxide can be introduced either before
or after placing the article in the diffusion-restricted
environment. The diffusion-restricted environment containing the
article to be sterilized is then placed in the chamber, exposed to
vacuum and removed as in steps 2 through 4 above.
[0075] In an alternative embodiment of the present invention, the
device to be sterilized is placed in a diffusion restricted
container which can be attached and detached from a source of
vacuum. The source of vacuum can be a vacuum chamber or may be a
source of vacuum not connected to a vacuum chamber.
[0076] The general operation of an alternative embodiment of the
method of the present invention, which is also useful for
sterilizing the inside of long narrow diffusion-restricted lumens,
is as follows: [0077] 1. The article to be sterilized is placed in
a diffusion-restricted environment such as a container, said
container comprising at least one communication port comprising an
exit tube or air and vapor permeable window; and [0078] 2. The
diffusion-restricted environment is contacted with a source of
peroxide, steps 1. and 2. being performed in either order; followed
by [0079] 3. The diffusion-restricted environment is exposed to
negative pressure for a time period sufficient to effect complete
sterilization of said article.
[0080] The communication port is preferably connected through a
connector to the article, so that sterilant vapor may flow through
the article and out of the container. In this embodiment, the
communication port comprising an exit tube or air aid vapor
permeable window is also preferably diffusion-restricted.
Alternatively, it is not necessary that the communication port, in
particular an air and vapor permeable window, be a limited
diffusion port so long as diffusion of sterilant vapor is limited
by the article to be sterilized, such as the case wherein sterilant
vapor must flow through a limited diffusion area or lumen of an
article to be sterilized. This depends upon the configuration of
the container. The exit tube may be constructed from a variety of
materials, such as glass, metals and plastics and may include a
filter. The filter may be sufficient to prevent entry of bacteria
from the environment into the container. The air and vapor
permeable window may be constructed from permeable materials such
as Tyvek.
[0081] In yet another alternative embodiment of the present
invention which pertains to all of the above methods, the article
to be sterilized is exposed to a vacuum followed by low temperature
plasma for a time sufficient to effect sterilization. When used in
the present specification and claims, the term "plasma" is intended
to include any portion of the gas or vapor that contains electrons,
ions, free radicals, dissociated and/or excited atoms or molecules
produced as a result of an applied electric field, including any
accompanying radiation that might be produced. The applied field
may cover a broad frequency range; however, a radio frequency or
microwaves are commonly used.
[0082] The sterilization methods of the present invention can also
be used with plasmas generated by the method disclosed in the
previously mentioned U.S. Pat. No. 4,643,876. Alternatively, the
methods of the present invention may be used with plasmas described
in U.S. Pat. No. 5,115,166 or 5,087,418, in which the article to be
sterilized is located in a chamber that is separated from the
plasma source.
[0083] The present invention provides several advantages over
earlier vapor sterilization systems, such as, (1) the rapid
sterilization of lumened devices and diffusion restricted articles
can be rapidly achieved at low temperatures; (2) the use of
concentrated, potentially hazardous, solutions of anti-microbials
is avoided; (3) the need to attach a special vessel to deliver
sterilant vapors into long, narrow lumens is eliminated; (4) no
toxic residues remain; (5) since the product is dry at the end of
the process, sterile storage of these articles can be achieved; (6)
closed end lumens can be sterilized; and (7) the process can be
repeated as desired without undue effects. The method of the
present invention therefore provides for a highly efficient,
nonhazardous, and relatively inexpensive method of
sterilization.
[0084] To determine the efficacy of the preferred sterilization
method of the present invention, preliminary tests were first
performed to evaluate the effect of dilute hydrogen peroxide
solutions on contaminated surfaces in an open, non-diffusion
restricted environment. These tests are described below in Example
1.
EXAMPLE 1
[0085] To evaluate the sterilization efficacy of dilute hydrogen
peroxide solution alone, a biological challenge consisting of
2.5.times.10.sup.6 Bacillus stearothermophilus spores on a
stainless steel scalpel blade was used. Inoculated blades were
submerged in 40 ml of hydrogen peroxide solution in a 100 ml
beaker. Four different concentrations of hydrogen peroxide solution
were used: 3%, 6%, 9% and 12% by weight. The blades were allowed to
soak in the peroxide solutions for various time periods. The blades
were then removed from the solution and tested for sterility. The
results of this testing are listed in Table 1 as a ratio of the
number of inoculated blades which remain contaminated after
treatment over the number of inoculated blades tested.
TABLE-US-00001 TABLE 1 Effect of H.sub.2O.sub.2 Concentration and
Soak Times on Sporicidal Activity of H.sub.2O.sub.2 Solution
Concentration of H.sub.2O.sub.2 Solution Soak Time 3% 6% 9% 12% 1
min 4/4 4/4 4/4 4/4 5 min 4/4 4/4 4/4 4/4 30 min 4/4 4/4 4/4 4/4 60
min 4/4 4/4 4/4 4/4 90 min N/D* 4/4 2/4 0/4 120 min N/D 4/4 N/D N/D
*N/D = not determined
[0086] Complete sterilization was not effected until after the
blades had been soaked in 12% hydrogen peroxide solution for at
least 90 minutes. Moreover, none of the blades tested were
sterilized after 2 hours in 6% hydrogen peroxide solution. It is
clear from these data that contact with dilute hydrogen peroxide
solution alone is ineffective at providing sterilization, unless
extended soak times and concentrated solutions are used.
[0087] Testing was next performed to evaluate the effect on the
sterilization of long, narrow lumens of a pretreatment step in
which the lumens to be sterilized are exposed to hydrogen peroxide
solution prior to exposure to a vacuum. The testing evaluated the
efficacy of hydrogen peroxide vapor sterilization inside the
lumens. The testing is detailed below in Example 2.
EXAMPLE 2
[0088] A biological challenge consisting of 1.9.times.10.sup.6 B.
stearothermophilus spores on a stainless steel scalpel blade was
used. Some inoculated blades were pretreated with a solution of
aqueous hydrogen peroxide. Other inoculated blades, designated
control blades, did not receive pretreatment with hydrogen
peroxide. The pretreatment consisted of 5 minutes of static soaking
in peroxide solution. The pre-treated blades were blotted dry, and
each blade was then placed inside a stainless steel lumen, 3 mm
internal diameter (ID).times.50 cm length. The lumen had a center
piece of 1.3 cm ID and 5 cm length. The pre-treated blade was
placed inside this center piece, and additional hydrogen peroxide
solution was added into the center piece in various amounts.
Control blades were handled identically, except that they did not
receive pretreatment with hydrogen peroxide solution. The lumens
were placed in a vacuum chamber, and the chamber was evacuated to 1
Torr and held there for 15 minutes, during which time the
temperature increased from approximately 23.degree. C. to
approximately 28.degree. C. Following exposure to the vacuum, the
chamber was vented and the blades were removed from the chamber and
tested for sterility. The results were as follows: TABLE-US-00002
TABLE 2 Effect of Pretreatment and Hydrogen Peroxide Concentration
on Sterilization of the Interior of Lumens Additional peroxide
added Blades not pre-treated Blades pre-treated in into the center
piece with peroxide peroxide solution (A) With 1% hydrogen peroxide
solution and vacuum 10 .mu.L + + 20 .mu.L + + 30 .mu.L + + 40 .mu.L
+ + 50 .mu.L + + 100 .mu.L + - 150 .mu.L + - 200 .mu.L - - 250
.mu.L - - (B) With 3% hydrogen peroxide solution and vacuum 10
.mu.L - - 20 .mu.L - - 30 .mu.L - - 40 .mu.L - - 50 .mu.L - - 100
.mu.L - - 150 .mu.L - - 200 .mu.L - - 250 .mu.L - - (C) With 6%
hydrogen peroxide solution and vacuum 10 .mu.L - - 20 .mu.L - - 30
.mu.L - - 40 .mu.L - - 50 .mu.L - -
[0089] As seen from these results, sterilization can be effected
using relatively dilute solutions of peroxide and exposure to
negative pressure. When the vacuum was applied, the peroxide added
to the center piece of the lumen was vaporized and contacted the
blade, which was sufficient to effect sterilization. It can be seen
from these data that the pre-treatment increases effectiveness, but
that pre-treatment is unnecessary as long as the peroxide diffuses
from the inside to the outside,
[0090] Sterilization inside various lumen sizes after pretreatment
with peroxide was compared with sterilization inside the lumens
without the pretreatment step. This testing is detailed in Example
3.
EXAMPLE 3
[0091] A biological challenge consisting of 1.9.times.10.sup.6 B.
stearothermophilus spores on a stainless steel scalpel blade was
used. Test A in Table 3 below consisted of the inoculated blades
being pretreated with a solution of 3% aqueous hydrogen peroxide.
The pretreatment consisted of 5 minutes of static soaking in the
peroxide solution. The pretreated blades were blotted dry, then
placed into the center piece of a stainless steel lumen which
varied in size, together with 10 .mu.l of 3% hydrogen peroxide
solution. The center piece was 1.3 cm ID and 5 cm length. Test B in
Table 3 below consisted of identically inoculated control blades
which did not receive pretreatment with hydrogen peroxide. Each
inoculated control blade was placed directly into the center piece
of a stainless steel lumen together with 10 .mu.l of 3% hydrogen
peroxide solution. The center piece had dimensions identical to
those in Test A. Lumens of various dimensions were used to evaluate
the effect on sterilization of lumen internal diameter and length.
The lumens were placed in a vacuum chamber, and the chamber was
evacuated to 1 Torr for 15 minutes. During this 15 minutes of the
sterilization cycle, the temperature increased from approximately
23.degree. C. to approximately 28.degree. C. Following exposure to
the vacuum, the chamber was vented and the blades were removed from
the chamber and tested for sterility. The results are reported in
Table 3, where "L/D Ratio" indicates the ratio of length to
internal diameter. TABLE-US-00003 TABLE 3 Effect of Pretreatment
With Dilute Hydrogen Peroxide in Various Sized Lumens SS lumen size
L/D Ratio Test A Test B 1 mm .times. 50 cm 500 - - 1 mm .times. 40
cm 400 - - 1 mm .times. 27 cm 270 - - 1 mm .times. 15 cm 150 - - 3
mm .times. 50 cm 1662/3 - - 3 mm .times. 40 cm 1331/3 - - 3 mm
.times. 27 cm 90 - + 3 mm .times. 15 cm 50 + + 6 mm .times. 50 cm
831/3 - - 6 mm .times. 40 cm 662/3 - - 6 mm .times. 27 cm 45 + + 6
mm .times. 15 cm 25 + +
[0092] All lumens having a L/D ratio greater than 50 which were
tested under the conditions of Test A of Example 3 were
sufficiently diffusion-restricted to be sterilized in this system.
Thus, it is believed that other lumens having an L/D ratio greater
than 50 should also provide a sufficient level of
diffusion-restriction for sterilization in accordance with the
present invention. This testing shows that, in direct contrast to
prior art methods, sterility through diffusion of hydrogen peroxide
vapor from inside the article to outside the article is easier to
achieve in longer, narrower lumens than in shorter, wider lumens.
This is believed to be due to the larger lumens allowing too much
of the hydrogen peroxide vapor to diffuse out of the inside of the
lumen during the sterilization process. Thus, the vapor does not
contact the internal surfaces for a period of time sufficient or at
a concentration sufficient to effect sterilization.
[0093] As discussed above, prior art methods of hydrogen peroxide
vapor sterilization of lumens are generally limited to use on
relatively short and wide lumens. In contrast to these prior art
methods, the method of the present invention is effective on the
interior of long, narrow lumens, including those longer than 27 cm
in length and/or having an internal diameter of less than 3 mm.
[0094] To determine whether the ability of the sterilant vapor to
diffuse within the system is a critical factor in achieving
sterility, additional testing was performed to compare diffusion
restricted and open, non-diffusion restricted systems. A
non-diffusion restricted system is one in which the diffusion of
vapors in and around the article is not restricted by narrow
openings, long, narrow lumens, or the like. As used herein,
"diffusion-restricted" refers to any one or more of the following
properties: (1) the ability of an article placed within the
sterilization system of the present invention to retain 0.17 mg/L
or more hydrogen peroxide solution after one hour at 40.degree. C.
and 10 torr, (2) having the same or more diffusion restriction than
provided by a single entry/exit port of 9 mm or less in internal
diameter and 1 cm or greater in length; (3) having the same or more
diffusion restriction than provided by a lumen 27 cm in length and
having an internal diameter of 3 mm; (4) having the same or more
diffusion restriction than provided by a lumen having a ratio of
length to internal diameter greater than 50; (5) the ability of an
article placed within the sterilization system of the present
invention to retain 17% or more of the hydrogen peroxide solution
placed therein after one hour at 40.degree. C. and 10 torr; or (6)
being sufficiently diffusion-restricted to completely sterilize a
stainless steel blade within a 2.2 cm by 60 cm glass tube having a
rubber stopper with a 1 mm by 50 cm stainless steel exit tube
therein at a vacuum of 10 torr for one hour at 40.degree. C. in
accordance with the present invention. It is acknowledged that
characteristics (1) and (5) will vary depending on the initial
concentration of hydrogen peroxide placed into the article;
however, this can be readily determined by one having ordinary
skill in the art.
[0095] As discussed in the Background of the Invention, articles
having diffusion restricted areas are difficult to sterilize using
known methods of hydrogen peroxide vapor sterilization, since these
methods are dependent upon the diffusion of peroxide vapors from
outside the article to the interior of the article. Testing
performed to evaluate the importance of sterilant vapor diffusion
is described in Example 4.
EXAMPLE 4
[0096] Hydrogen peroxide vapor sterilization was tested in both
open and diffusion restricted systems. The open system consisted of
stainless steel lumens having internal diameters of 1, 3, and 6 mm,
and lengths of 15, 27, 40 and 50 cm. Stainless steel scalpel blades
were inoculated with 1.9.times.10.sup.6 B. stearothermophilus
spores, and the blades placed in the center piece of the lumen
together with 10 .mu.l of 3% hydrogen peroxide solution. The
dimensions of the center piece were 1.3 cm ID, 5 cm length and 6.6
cc volume.
[0097] The diffusion restricted system is illustrated in FIG. 1.
Identically inoculated scalpel blades 5 were placed within the
center pieces 10 of lumens 15 having dimensions identical to those
described above. Ten .mu.l of 3% hydrogen peroxide solution was
also added to the center piece 10 of the lumen 15. The lumen 15 was
then placed within a 2.2 cm.times.60 cm glass tube 20. The tube 20
was closed at one end, and the open end was plugged with a rubber
stopper 25 having a 1 mm.times.10 cm stainless steel tube 30
inserted through the stopper 25. Thus, gases entering or exiting
the glass tube 20 could pass only through this 1 mmn.times.10 cm
opening.
[0098] The open lumen system and the diffusion restricted system
were placed inside a vacuum chamber. The chamber was evacuated to 1
Torr pressure and held there for 15 minutes, during which time the
temperature increased from approximately 23.degree. C. to
approximately 28.degree. C. The chamber was then vented, and the
blades removed from the lumens and tested for sterility. The
results are as follows: TABLE-US-00004 TABLE 4 Hydrogen Peroxide
Vapor Sterilization in Open and Diffusion Restricted Systems
Peroxide System amount Length 1 mm ID 3 mm ID 6 mm ID Open 10 .mu.L
of 3% 50 cm - - - 40 cm - - - 27 cm - + + 15 cm - + + Diffusion 10
.mu.L of 3% 50 cm - - - Restricted 40 cm - - - Environment 27 cm -
- - 15 cm - - -
[0099] Under the test conditions of Example 4, sterilization was
not achieved in the shorter, wider lumens in the open system
without pre-treatment with hydrogen peroxide. Pre-treatment, and
other test conditions, such as higher peroxide concentration or
longer treatment time, would likely allow sterilization of the 27
cm.times.3 mm lumen, which has an L/D ratio greater than 50. In the
diffusion restricted system, the blades were sterilized in all
sizes of lumens, using a 3% hydrogen peroxide solution.
[0100] These results indicate that providing a source of hydrogen
peroxide within a diffusion restricted environment allows for
complete sterilization within the system. It is the restriction of
vapor diffusion in the system, not the length or internal diameter
of the lumen per se that determines the efficacy of the hydrogen
peroxide vapor sterilization. Again, however, these data show that,
unlike the prior art methods of hydrogen peroxide vapor
sterilization of lumens, the method of the present invention is
effective even on non-diffusion-restricted articles when placed
into a diffusion-restricted environment.
[0101] To further test the idea that restriction of the diffusion
of vapor in a system affects the ability to sterilize the system,
the following experiment was performed.
EXAMPLE 5
[0102] A stainless steel scalpel blade 5 was placed within a 2.2
cm.times.60 cm glass tube 20 which was closed at one end, as
illustrated in FIG. 2. Each blade 5 had been inoculated with
1.9.times.10.sup.6 B. stearothermophilus spores. For some of the
testing, the glass tube 20 was left open at one end, providing an
open system. To create a diffusion restricted environment, the open
end of the glass tube 20 was sealed with a rubber stopper 25 having
a 1 mm.times.10 cm stainless steel tube 30 through its center. In
both the open and diffusion restricted systems, hydrogen peroxide
solution at a concentration of either 3% or 6% was added to the
glass tube 20 in amounts of 50, 100, 150 or 200 .mu.l, together
with the inoculated blade 5. The tube 20 was placed in a vacuum
chamber, and the chamber evacuated to 1 Torr for 15 minutes, during
which time the temperature increased from approximately 23.degree.
C. to approximately 28.degree. C. The diffusion restricted system
only was also tested at 1 Torr for 30 minutes, during which time
the temperature increased from approximately 23.degree. C. to
approximately 33.degree. C. The vacuum chamber was then vented, and
the blades 5 removed from the tube 20 and tested for sterility. The
results are listed in Table 5 below. TABLE-US-00005 TABLE 5
Hydrogen Peroxide Vapor Sterilization in Open and Diffusion
Restricted Systems 50 .mu.L 100 .mu.L 150 .mu.L 200 .mu.L Open
System, 15 minutes vacuum at 1 Torr: 3% peroxide + + + + 6%
peroxide + + + + Diffusion Restricted System, 15 minutes vacuum at
1 Torr: 3% peroxide + - - - 6% peroxide - - - - Diffusion
Restricted System, 30 minutes vacuum at 1 Torr: 3% peroxide - - -
-
[0103] These results show that the addition of hydrogen peroxide
solution, followed by exposure to vacuum, is ineffective for
achieving rapid sterilization in an open system. Identical
treatment in a diffusion restricted system, by comparison, results
in complete sterilization, except at the very weakest concentration
of hydrogen peroxide solution in an amount of only 50 .mu.l.
Sterilization can be effected, however, by increasing the exposure
to the vacuum.
[0104] Thus, the method of the present invention, wherein small
amounts of hydrogen peroxide solution are delivered to the article
to be sterilized prior to exposure to a vacuum, is an effective
method of sterilization. The method does not depend on the
diffusion of sterilant vapor into the article being sterilized.
Rather, the hydrogen peroxide vapor is created by the vacuum within
the system. This vapor is prevented from leaving the system too
quickly, because the diffusion of the sterilant vapor from the
inside of the article to the outside of the article is slowed. In a
diffusion restricted environment, the vapor therefore contacts the
article to be sterilized for a period of time sufficient to effect
complete sterilization. In addition, unlike the prior art methods
where the water in the peroxide solution is vaporized first and
becomes a barrier to the penetration of the peroxide vapor, the
method of the present invention removes any water from the system
first, thereby concentrating the hydrogen peroxide vapor remaining
in the system. More importantly, in the preferred method of the
present invention, the diffusion of vapor is from the inside to
outside rather than outside to inside as in the prior art. As a
result, diffusion-restriction in the present invention serves to
increase the effectiveness of sterilization rather than to decrease
the effectiveness, as in the prior art.
[0105] To determine the effect of various pressures on a diffusion
restricted sterilization system, the following experiment was
performed.
EXAMPLE 6
[0106] A stainless steel scalpel blade 5 was placed within a 2.2
cm.times.60 cm glass tube 20 which was closed at one end, as shown
in FIG. 2. Each blade 5 had been inoculated with 1.9.times.10.sup.6
B. stearothermophilus spores. To create a diffusion restricted
environment, the open end of the glass tube 20 was sealed with a
rubber stopper 25 having a 1 mm.times.10 cm stainless steel tube 30
through its center. Hydrogen peroxide solution at a concentration
of 3% was added to the glass tube 20 in amounts of 50, 100, 150 or
200 .mu.l, together with the inoculated blade 5. The tube 20 was
placed in a vacuum chamber, and subjected to various pressures for
15 minutes, during which time the temperature increased from
approximately 23.degree. C. to approximately 28.degree. C. In a
further experiment to determine the effect of increased temperature
on the system, the tube 20 was first heated to 45.degree. C., then
subjected to 50 Torr pressure for 15 minutes. The results were as
follows. TABLE-US-00006 TABLE 6 Effect of Temperature and Pressure
on a Diffusion Restricted System 50 .mu.L 100 .mu.L 150 .mu.L 200
.mu.L 15 minutes vacuum with 3% hydrogen peroxide solution: 1 torr
pressure + - - - 5 torr pressure - - - - 10 torr pressure - - - -
15 torr pressure - - - - 20 torr pressure - - - - 25 torr pressure
- - - - 30 torr pressure + + + + 35 torr pressure + + + + 40 torr
pressure + + + + 45 torr pressure + + + + 50 torr pressure + + + +
15 minutes vacuum with 3% hydrogen peroxide at 45.degree. C.: 50
torr pressure - - - -
[0107] These data show that sterilization can be achieved in
diffusion restricted environments at pressures up to about 25 Torr
at 28.degree. C. At pressures of 30 Torr and higher, sterilization
was not achieved; this is believed to be due to the fact that the
vapor pressure of hydrogen peroxide at 28.degree. C. is
approximately 28 Torr. Thus, at higher pressures, the liquid
hydrogen peroxide inside the glass tube was not vaporizing. This
was confirmed by the testing done at 50 Torr pressure at 45.degree.
C., wherein sterilization was achieved. The vapor pressure of
hydrogen peroxide is increased at 45.degree. C., thus, the hydrogen
peroxide was vaporized at 50 Torr, effectively sterilizing the
blade placed inside the tube.
[0108] Accordingly, in order to achieve sterilization using the
method of the present invention employing an aqueous solution of
hydrogen peroxide, the temperature and pressure within the vacuum
chamber should be such that vaporization of the aqueous hydrogen
peroxide solution is achieved, i.e. the system should preferably be
operated below the vapor pressure of the hydrogen peroxide. The
pressure needs to be below the vapor pressure of hydrogen peroxide,
such that the hydrogen peroxide solution present in the system is
vaporized and diffuses from the interior of the diffusion
restricted environment to the outside. Alternatively, the hydrogen
peroxide can be vaporized locally where the system remains above
the vapor pressure by introducing energy to the site of the
peroxide, such as through microwaves, radio waves, or other energy
sources.
[0109] To further determine the effect of varying the pressure and
the temperature in the diffusion restricted system described in
Example 6, the following experiments were performed.
EXAMPLE 7
[0110] A stainless steel scalpel blade 5 was placed within a 2.2
cm.times.60 cm glass tube 20 which was closed at one end, as
illustrated in FIG. 2. Each blade 5 had been inoculated with
1.9.times.10.sup.6 B. stearothermophilus spores. To create a
diffusion restricted environment, the open end of the glass tube 20
was sealed with a rubber stopper 25 having a 1 mm.times.10 cm
stainless steel tube 30 through its center. Hydrogen peroxide
solution at a concentration of 3% was added to the glass tube 20 in
amounts of 50, 100, 150 or 200 .mu.l together with the inoculated
blade 5. The tube 20 was placed in a vacuum chamber, and the
chamber evacuated to 5 Torr. To vary the pressure within the
chamber, the valve to the vacuum pump was closed, such that the
pressure within the chamber rose from 5 Torr to 6.15 Torr after 15
minutes, during which time the temperature increased from
approximately 23.degree. C. to approximately 28.degree. C. In a
second test, the tube 20 was placed in the chamber and the chamber
was evacuated to 50 Torr. The temperature of the glass tube 20 was
increased to 45.degree. C. after the evacuation of the chamber was
complete. The tube 20 was treated for 15 minutes. The results of
these tests are reported below. TABLE-US-00007 TABLE 7 Effect of
Varying Temperature and Pressure on Diffusion Restricted
Sterilization System 50 .mu.L 100 .mu.L 150 .mu.L 200 .mu.L
Pressure increased from 5 Torr to 6.15 Torr: Efficacy Results - - -
- Temperature of the tube increased to 45.degree. C.: Efficacy
Results - - - -
[0111] These results show that maintaining a constant pressure or
temperature is not required in the diffusion restricted environment
to effect sterilization. Under the conditions tested, the hydrogen
peroxide is vaporized and kept in contact with the device to be
sterilized for a time sufficient to effect complete
sterilization.
[0112] The preferred method of the present invention relies on the
delivery of liquid hydrogen peroxide to the article to be
sterilized prior to vacuum or plasma treatment. The following
testing was performed to determine the effect of the location of
the delivery of the hydrogen peroxide within the diffusion
restricted environment.
EXAMPLE 8
[0113] A stainless steel scalpel blade 5 was inoculated with
1.9.times.10.sup.6 B. stearothermophilus spores, and the blade 5
placed in the center piece 10 of a lumen 15 as illustrated in FIG.
1. The dimensions of the center piece 10 were 1.3 cm ID, 5 cm
length and 6.6 cc volume, while the lumen itself varied in size,
having an ID of 1, 3 or 6 mm, and a length of 15, 27, 40 or 50 cm.
The lumen 15 was placed within a 2.2 cm.times.60 cm glass tube 20.
The tube 20 was closed at one end, and the open end was plugged
with a rubber stopper 25 having a 1 mm.times.10 cm stainless steel
tube 30 placed through the stopper 25. Thus, gases entering or
exiting the glass tube 20 could pass only through this 1
mm.times.10 cm opening. 10 .mu.l of 3% hydrogen peroxide solution
was placed inside the lumen 15, or 100 .mu.l of 3% hydrogen
peroxide solution was placed inside the glass tube 20, but outside
the stainless steel lumen 15. The glass tube 20 was then placed in
a vacuum chamber, which was sealed and evacuated to 1 Torr for 15
minutes, during which time the temperature increased from
approximately 23.degree. C. to approximately 29.degree. C. Results
of this testing are as follows. TABLE-US-00008 TABLE 8 Effect of
Hydrogen Peroxide Solution Placed Outside Inner Lumen Peroxide
amount Length 1 mm ID 3 mm ID 6 mm ID 10 .mu.L of 3% 50 cm - - - in
lumen 40 cm - - - 27 cm - - - 15 cm - - - 100 .mu.L of 3% 50 cm + +
+ in glass tube 40 cm + + + 27 cm + + + 15 cm + + -
[0114] These data show that, under the test conditions of Example
8, sterilization did not occur within the inner lumen when the
hydrogen peroxide solution was placed outside the lumen in a
diffusion restricted environment, but that complete sterilization
was effected when the hydrogen peroxide solution was placed inside
all of the lumens in a diffusion restricted environment. When the
hydrogen peroxide vapor must diffuse from outside to inside, the
sterilant vapor cannot enter the inner lumen in a diffusion
restricted environment unless the lumen is sufficiently large.
Thus, when the hydrogen peroxide solution was placed outside the
lumen, only the shortest, widest lumens allowed sufficient vapor
penetration to allow sterilization inside the lumen. These data
confirm that prior art methods which require diffusion of sterilant
vapor from outside the article to the interior article cannot
achieve sterilization in diffusion restricted environments under
these conditions. In contrast, under the same conditions except
where the hydrogen peroxide was placed inside the article, allowing
hydrogen peroxide to diffuse from inside to outside, complete
sterilization occurred with much lower amounts of hydrogen
peroxide.
[0115] The method of the present invention is therefore useful in
environments where diffusion of the sterilant vapor is limited. To
evaluate the effect of changes in the amount of diffusion
restriction within a diffusion restricted environment, the
following testing was performed.
EXAMPLE 9
[0116] A stainless steel scalpel blade 5 was inoculated with
1.9.times.10.sup.6 B. stearothermophilus spores, and placed in a
2.2 cm.times.60 cm glass tube 20 as illustrated in FIG. 2. The tube
20 was closed at one end, and the open end was plugged with a
rubber stopper 25. Stainless steel tubing 30 of various dimensions
was inserted through the stopper 25. Thus, gases entering or
exiting the glass tube 20 could pass only through the opening in
the tubing 30, which varied from 1 mm to 6 mm in diameter. Three
percent hydrogen peroxide solution in volumes ranging from 50 .mu.L
to 200 .mu.L was also placed inside the glass tube 20. The glass
tube 20 was then placed in a vacuum chamber, which was sealed and
evacuated to 5 Torr for 15 minutes, during which time the
temperature increased from approximately 23.degree. C. to
approximately 28.degree. C. In addition, three lumens were tested
at 10 Torr for 15 minutes with 3% hydrogen peroxide. The results of
this testing are listed below in Table 9. TABLE-US-00009 TABLE 9
Effects of Tubing Dimension and Vacuum Pressure on Sterilization SS
tubing 50 .mu.L 100 .mu.L 150 .mu.L 200 .mu.L 15 minutes vacuum at
5 Torr with 3% hydrogen peroxide 1 mm .times. 10 cm - - - - 1 mm
.times. 5 cm - - - - 1 mm .times. 2.5 cm + - - - 3 mm .times. 10 cm
- - - - 3 mm .times. 5 cm - - - - 3 mm .times. 2.5 cm + - - - 6 mm
.times. 10 cm - - - - 6 mm .times. 5 cm + - - - 6 mm .times. 2.5 cm
+ - - - 15 minutes vacuum at 10 Torr with 3% hydrogen peroxide 1 mm
.times. 2.5 cm - 3 mm .times. 2.5 cm - 6 mm .times. 2.5 cm -
[0117] Complete sterilization was achieved in the majority of the
environments tested. Sterilization could not be achieved at 5 torr
using the shortest length of stainless steel tubing and only 50
.mu.l hydrogen peroxide solution. Greater volumes of hydrogen
peroxide must be used in these systems.
[0118] These data also confirm that the vacuum pressure affects
sterilization efficacy, since the container with the shortest and
widest exit tube could provide sterilization at 10 Torr, but not at
5 Torr. At too low pressures (such as pressures below 5 Torr in the
conditions tested) however, it appears that the hydrogen peroxide
vapor is pulled from the interior of the article being sterilized
too quickly, resulting in an insufficient amount of hydrogen
peroxide vapor being allowed to contact the interior of the device
to effect sterilization. It would appear that although a pressure
of 5 torr produces acceptable results, a pressure of approximately
10 Torr is better under the conditions tested.
[0119] The method of the present invention has been shown to be
effective in diffusion restricted environments of metal and glass.
To evaluate whether the method is effective in diffusion restricted
environments formed of other materials, the experiments described
in Examples 10 and 11 were performed.
EXAMPLE 10
[0120] For this testing, a diffusion restricted system was tested.
1.2.times.10.sup.6 B. stearothermophilus spores were inoculated
onto non-woven polypropylene pieces. As illustrated in FIG. 1, the
inoculated pieces 5 were placed inside the center piece 10 of a
plastic lumen 15, together with 10 .mu.l of 3% hydrogen peroxide
solution. The center piece 10 was made of Teflon.TM. and had
dimensions of 1.3 cm.times.5 cm. The lumen 15 varied from 1 mm to 6
mm ID, and 15 cm to 50 cm in length. Teflon.TM. was used for the 1
mm lumen, polyethylene was used for the 3 mm and 6 mm lumen. The
lumen 15 was then placed within a 2.2 cm.times.60 cm glass tube 20.
The glass tube 20 was closed on one end, and the open end was
sealed with a rubber stopper 25 having a 1 mm.times.10 cm piece of
PTFE tubing 30 through it. The glass tube 20 was placed in the
vacuum chamber and treated for 15 minutes at 1 Torr, during which
time the temperature increased from approximately 23.degree. C. to
approximately 28.degree. C. The results of this testing are set
forth below. TABLE-US-00010 TABLE 10A Sterilization in Diffusion
Restricted Systems Using Plastic Lumens System Pressure Length 1 mm
ID 3 mm ID 6 mm ID Diffusion 1 torr 50 cm - - - Restricted 40 cm -
- - System 27 cm - - - 15 cm - - -
[0121] Sterilization in diffusion restricted environments can be
effected in both short, wide lumens and long, narrow lumens,
regardless of whether metal or plastic is used to form the lumens.
Thus, the method of the present invention is an effective
sterilization method for diffusion restricted articles, and can be
used on a wide variety of such articles, regardless of their
composition.
[0122] To further confirm this, 2.1.times.10.sup.6 B.
stearothermophilus spores were inoculated on stainless steel
blades, and 1.2.times.10.sup.6 B. stearothermophilus spores were
inoculated onto non-woven polypropylene pieces. As shown in FIG. 2,
the blades 5 or non-woven polypropylene pieces 5 were placed inside
a 2.2 cm.times.60 cm glass tube 20 together with 50 .mu.l of 3%
hydrogen peroxide solution. One end of the tube was closed, and the
open end was sealed with a rubber stopper 25 having either a 1
mm.times.10 cm stainless steel tube 30 therein, or a 1 mm.times.10
cm piece of Teflon.TM. tubing 30 therein. The glass tube 20 was
placed inside a vacuum chamber and treated for 15 minutes at 5
Torr, during which time the temperature increased from
approximately 23.degree. C. to approximately 28.degree. C. The
results are as follows. TABLE-US-00011 TABLE 10B Effect of Metal
and Plastic on Sterilization in a Diffusion Restricted System SS
tubing Teflon tubing Metal blade - - Polypropylene - -
[0123] Thus, all four combinations of metal and plastic provide for
effective hydrogen peroxide vapor sterilization in a diffusion
restricted environment. This testing confirms that the method of
the present invention is an effective sterilization method for
diffusion restricted articles, and can be used on a wide variety of
such articles, regardless of the materials used to form them.
[0124] Further testing was next performed to evaluate the effect of
various temperatures and pressures on the sterilization of a
diffusion restricted system. The testing is described below.
EXAMPLE 11
[0125] Stainless steel blades were inoculated with
2.1.times.10.sup.6 B. stearothermophilus spores. The blades 5 were
placed inside a 2.2 cm.times.60 cm glass tube 20 as illustrated in
FIG. 2, along with various amounts of 3% hydrogen peroxide
solution. The glass tube 20 was placed in a vacuum chamber and
subjected to different pressures and different temperatures for
various periods of time. During the sterilization cycles reported
in Table 11A, the temperature increased from approximately
23.degree. C. to the temperatures indicated. In the experiments
reported in Table 11B, the chamber was heated to approximately
45.degree. C. In an alternative embodiment, rather than heating the
chamber, the temperature of the peroxide solution itself call be
heated. In the experiments reported in Table 11C, the temperature
increased from approximately 23.degree. C. to approximately
28.degree. C. during the 15 minute period of exposure to vacuum.
TABLE-US-00012 TABLE 11A Effect of Time and Volume of Peroxide on
Sterilization in a Diffusion Restricted Environment At 5 Torr
pressure: 5 min. (approx. 10 min. 15 min. 24.degree. C.) (approx.
26.degree. C.) (approx. 28.degree. C.) 50 .mu.L of 3% peroxide - -
- 100 .mu.L of 3% peroxide - - - 150 .mu.L of 3% peroxide + - - 200
.mu.L of 3% peroxide + - -
[0126] TABLE-US-00013 TABLE 11B Effect of Elevated Chamber
Temperature and Volume of Peroxide on Sterilization in a Diffusion
Restricted Environment Chamber at approximately 45.degree. C.: 5
min. 150 .mu.L of 3% peroxide - 200 .mu.L of 3% peroxide -
[0127] TABLE-US-00014 TABLE 11C Effect of Pressure and Volume of
Peroxide on Sterilization in a Diffusion Restricted Environment
With 15 minutes exposure time: Approx. 28.degree. C. 1 torr 5 torr
10 torr 20 .mu.L of 3% peroxide N/D + - 50 .mu.L of 3% peroxide + -
- 100 .mu.L of 3% peroxide - - -
[0128] Under the test conditions of Example 11, large volumes of
hydrogen peroxide solution were ineffective at achieving
sterilization when vacuum was applied for only very short periods
of time. This is believed to be at least partially because water
vaporizes more quickly than hydrogen peroxide. Thus, the water
present in the aqueous solution will vaporize first, and more time
is needed to vaporize the hydrogen peroxide. This also explains why
the larger volumes of hydrogen peroxide solution were effective at
achieving sterilization at higher temperatures; the vaporization of
the hydrogen peroxide occurs sooner at higher temperatures. Thus,
when more water is present in the system, either higher
temperatures or more time is required to achieve sterilization.
[0129] Again, it would appear from these data that slightly higher
pressures, i.e. 10 Torr, achieve more effective sterilization under
these conditions. This is believed to be because at higher
pressures, more hydrogen peroxide vapor is retained inside the
system. At too low a pressure, the hydrogen peroxide vapor is
pulled out of the system too quickly.
[0130] In order to evaluate a putative minimum concentration of
peroxide in the liquid/vacuum system in a diffusion-restricted
container, Example 12 was carried out.
EXAMPLE 12
[0131] Various concentrations of peroxide were used in a system
substantially as described in connection with FIG. 2. In this
system, the exit tube 35 was a stainless steel tube having a length
of 50 cm and an internal diameter of 1 mm. A stainless steel blade
inoculated with 1.9.times.10.sup.6 spores of B. stearothermophilus
was placed within the container which was a 2.2 cm.times.60 cm
glass tube. Various amounts of 3% hydrogen peroxide were introduced
into the container. The container was placed in a vacuum chamber of
173 liters, and the pressure reduced to 10 Torr for a period of one
hour, during which time the temperature increased from
approximately 23.degree. C. to approximately 40.degree. C.
Sporicidal activity was evaluated at each concentration of
peroxide. In addition, the amount of peroxide remaining in the
container after the sterilization process was evaluated by standard
titration techniques, whereby the peroxide was reacted with
potassium iodide and titrated with sodium thiosulfate. Results are
shown in Table 12 where "N/D" indicates not determined.
TABLE-US-00015 TABLE 12 Amount of Peroxide Sporicidal Remaining in
Glass Tube Activity Peroxide 0.5 mg/L liquid + N/D 0.6 mg/L liquid
+ N/D 0.7 mg/L liquid + N/D 0.8 mg/L liquid + N/D 0.9 mg/L liquid +
N/D 1.0 mg/L liquid - 0.17 mg/L
[0132] The results reported in Table 12 indicate that 1.0 mg/L of
3% liquid peroxide were required in the system tested to effect
sterilization. Further, under the conditions tested, a
concentration of 0.17 mg/L of peroxide remaining in the system was
sufficient to provide complete sterilization. These data also show
that the glass tube used in these experiments provided a sufficient
level of diffusion restriction to retain 17% of the hydrogen
peroxide placed therein.
[0133] We further investigated the effects of length and internal
diameter of the exit tube used in a system similar to that of
Example 12. This testing is shown in Example 13.
EXAMPLE 13
[0134] A system similar to that described above in connection with
Example 12, with the exception that 15 minutes of vacuum rather
than one hour was used. Thus, the temperature increased only to
about 28.degree. C. In this testing, the size of the exit tube 35
was varied, as well as the volume of 3% peroxide solution. The
results are reported below in Table 13. TABLE-US-00016 TABLE 13 50
.mu.l 100 .mu.l 150 .mu.l 200 .mu.l Open without tubing + + + + 6
mm ID .times. 1 cm length + - - - 9 mm ID .times. 1 cm length + - -
- 13 mm ID .times. 1 cm length + + + +
[0135] The results show that provided sufficient peroxide is
present, the diffusion-restriction provided by a single entry/exit
port of 9 mm or less in internal diameter, or 1 cm or greater in
length is sufficient to effect sterilization.
[0136] To further evaluate the effect on sterilization efficacy of
changes in the amount of restriction of vapor diffusion in the
system, the following testing was performed.
EXAMPLE 14
[0137] A stainless steel blade was inoculated with
2.1.times.10.sup.6 B. stearothermophilus spores. The blade 5 was
placed inside a 2.2 cm.times.60 cm glass tube 20 as shown in FIG.
3, together with various amounts of 3% hydrogen peroxide solution.
One end of the tube was closed, and the open end was sealed with a
rubber stopper 25 having a syringe filter 35 inserted therein. The
glass tube 20 was placed inside a vacuum chamber and treated for 15
minutes at 5 Torr, during which time the temperature increased from
approximately 23.degree. C. to approximately 29.degree. C. As a
control, identically inoculated blades were placed inside 2.2
cm.times.60 cm glass tubes. The open end of the tubes was left
open, no stopper or syringe filter was used. Thus, the diffusion of
vapor from the interior of the tube was not restricted.
[0138] Various syringe filters having various pore sizes were
tested, including, MFS PTFE 25 mm syringe filters with a 0.2 .mu.m
membrane filter and a 0.5 .mu.m membrane filter; a Nalgene PTFE 50
mm syringe filter with a 0.2 .mu.m membrane filter and a 0.45 .mu.m
membrane filter; a Whatman Anotop.TM. 10 Plus sterile syringe
filter with a 0.02 .mu.m membrane filter and a 0.1 .mu.m membrane
filter; and finally, a Gelman Acrodisc.quadrature. CR PTFE syringe
filter with a 0.2 .mu.m, 0.45 .mu.m, and a 1.0 .mu.m membrane. The
results are as follows. TABLE-US-00017 TABLE 14 Sporicidal Activity
of H.sub.2O.sub.2 Solution with Vacuum in a Container Having a
Syringe Filter 15 minutes vacuum and 3% hydrogen peroxide: 50 .mu.L
100 .mu.L 150 .mu.L 200 .mu.L (a) Without syringe filter and
stopper: 5 Torr + + + + 10 Torr + + + + (b) With MFS.quadrature.
PTFE 25 mm syringe filter: (1) 0.2 .mu.m membrane filter 5 Torr + -
- - 10 Torr - - - - (2) 0.5 .mu.m membrane filter 5 Torr + - - - 10
Torr - - - - (3) With 2 MFS .TM. filters together at 5 Torr
pressure Two 0.2 .mu.m filters - Two 0.5 .mu.m filters - (c) With
Nalgene .TM. PTFE 50 mm syringe filter: (1) 0.2 .mu.m membrane
filter 5 Torr - - - - 10 Torr - - - - (2) 0.45 .mu.m membrane
filter 5 Torr - - - - 10 Torr - - - - (d) With Whatman Anotop .TM.
10 Plus syringe filter: (1) 0.02 .mu.m membrane filter 5 Torr - -
10 Torr - - (2) 0.1 .mu.m membrane filter 5 Torr - - 10 Torr - -
(e) With Gelman Acrodisc .TM. CR PTFE syringe filter: (1) 0.2 .mu.m
membrane filter 5 Torr + - 10 Torr - - (2) 0.45 .mu.m membrane
filter 5 Torr + - 10 Torr - - (3) 1.0 .mu.m membrane filter 5 Torr
+ - 10 Torr - -
[0139] As is apparent from these results, certain brands of filters
do not create a sufficiently diffusion restricted environment at 5
Torr pressure when only 50 .mu.L of hydrogen peroxide solution is
placed in the system. Other brands of filters did provide
sufficient diffusion restriction; these brands of filters had
either longer lumens or smaller filter pore size. Using larger
volumes of peroxide solution, 10 Torr pressure, or serial filters
enhances the efficacy of the sterilization system. This is
important, as filters, including ones made of Tyvek.TM., are often
used in packaging of sterile articles to prevent re-contamination
with bacteria. These filters generally have a pore size of 1 .mu.m
or less, or in the case of Tyvek.TM., create a tortuous path which
bacteria cannot cross. In the present invention, filters can be
used in combination with other packaging means to create a
diffusion restricted environment to effect sterilization, and the
sterile article can remain inside the packaging during storage
prior to use; the filter will prevent re-contamination of the
sterile article.
[0140] FIG. 4 is a cross-sectional illustration of one embodiment
of a diffusion restricted environment represented by a container
having a limited diffusion port or communication port consisting of
tubing. This communication port 30 may have an air permeable
microorganism barrier such as a filter in order to maintain a
sterility of the devices 15 and 40 in the container 20 after the
container 20 is removed from the vacuum source. The non-lumen
device 40 and the exterior of the lumen device 15 can be sterilized
with the peroxide vapor generated from the source of peroxide
within the container 20. In one method of efficiently sterilizing
the interior of the lumen device 15, the peroxide vapor needs to be
generated within the lumen device 15. Therefore, the lumen device
15 needs to be pre-treated with liquid peroxide.
[0141] FIGS. 5-6 illustrate other embodiments of the present
invention employing other packaging means to create a
diffusion-restricted environment to effect sterilization. Another
approach can be used to sterilize the interior of lumen device 15
without pre-treating the interior of lumen device 15 with the
source of peroxide. In order to flow the peroxide vapor generated
inside container 20 through the interior of lumen device 15, a
connector can be used to connect the lumen device 15 to the
communication port 30 of the container 20. FIGS. 5A and 5B
illustrate this approach. FIG. 5A is a cross-sectional illustration
of one embodiment of a diffusion restricted environment represented
by a container 20 having a limited diffusion port or communication
port 30, consisting of tubing, and a tubing connector 45 to connect
a lumen device 15 to the communication port 30 of the container 20.
FIG. 5B is a cross-sectional illustration of one embodiment of a
diffusion restricted environment represented by a container 20
having a limited diffusion port (communication port 30 consisting
of tubing) and an enclosure connector 50 to connect a lumen device
15 to the communication port 30 of the container 20. The enclosure
connector 50 has an interface 51 between the container 20 and the
enclosure connector 50. This interface 51 can be constructed in
several different ways so as to allow a portion of the lumen device
15 to be inserted into the connector enclosure 50, while
maintaining an air and vapor pressure seal between parts 15 and 50.
One way to achieve this is with a camera shutter approach employing
an iris diaphragm, such as a precision iris diaphragm from Edmund
Scientific. An optional spring can be used to insure the closure of
the shutter. Another way to achieve an acceptable interface is to
employ two plates, wherein the area between the two plates has a
compressible material, such as a rubber material. The lumen device
15 can be placed between the two plates and the two plates moved
together to form a gas and vapor impermeable seal around the lumen
device 15. Optionally, a porous material like a sponge or air
permeable material may be utilized for the compressible material.
In this case, some vapor sterilant can diffuse between the
compressible material and the lumen device. However, most of the
sterilant vapor is forced to diffuse through the lumen device. Yet
another way to achieve an acceptable interface is to employ a hole
or horizontal opening for one or more lumen devices 15, said hole
or opening being a gas or liquid inflatable port. Thus, the
connector can be a tubing adapter 45 which can be attached to the
lumen device 15 or an enclosure 50 which contains a portion of the
lumen device 15. Since one of the openings of the lumen device 15
is connected to the communication port 30 with the connector 45 or
50, the vaporized peroxide has to be evacuated through the lumen
device 15. Tubing connector 45 can be constructed of any materials
such as silicone, Teflon, etc. which meet the thermal, pressure,
gas and vapor compatibility requirements of the system. These same
considerations apply to materials utilized for other parts
illustrated herein. Note that the limited diffusion port can be
created by either the communication port 30 or the lumen device
15.
[0142] FIG. 6 illustrates another possible arrangement. FIG. 6 is a
cross-sectional illustration of one embodiment of a diffusion
restricted environment represented by a container 20 having a
communication port 30 consisting of a window with an air permeable
barrier and an enclosure connector 50 to connect a lumen device 15
to the window 30. In this embodiment, the lumen device 15 is
connected to the connector 50 and is used as the device to create
the diffusion restricted area in the container 20. Therefore, the
communication port 30 in FIGS. 4, 5A and 5B can be replaced with an
air permeable window 30 if desired. This porous window 30 allows
the diffusion of air and vapor, but prevents microorganisms from
outside from contaminating the sterilized instruments 15 or 40 in
the container or pouch 20. Under the reduced pressure environment,
the peroxide vapor is first generated in the container or pouch 20
and then diffuses through the lumen device 15 into the connector
50. The entire connector 50 can be made of air permeable material.
FIG. 6 additionally illustrates how the reduced pressure is to be
achieved. This is achieved via a port 55 in the vacuum chamber 65,
said port being connected to a vacuum pump 60 to produce the
reduced pressure environment. In order to test whether other
sterilants can also be used to effect sterilization in diffusion
restricted environments, the following testing was performed.
EXAMPLE 15
[0143] A stainless steel blade was inoculated with
1.9.times.10.sup.6 B. stearothermophilus spores. The blade 5 was
placed inside a 2.2 cm.times.60 cm glass tube 20 as shown in FIG.
2, along with various amounts of 4.74% peracetic acid solution
(Solvay Interox Ltd., Warrington, England). The glass tube 20 was
placed in a vacuum chamber and subjected to 5 Torr pressure for 15
minutes, during which time the temperature increased from
approximately 23.degree. C. to approximately 28.degree. C. The
results of this testing is shown below. TABLE-US-00018 TABLE 15
Sterilization With Peracetic Acid in a Diffusion Restricted System
50 .mu.L 100 .mu.L 150 .mu.L 200 .mu.L Efficacy Results - - - -
[0144] These results show that peracetic acid, in which hydrogen
peroxide coexists, can also be used in the sterilization method of
the present invention.
[0145] It was discovered that by delivering small amounts of
hydrogen peroxide solution to an article to be sterilized prior to
exposure to vacuum, sterilization could be effected at lower
temperatures and in short periods of time. The following testing
was performed to evaluate different methods of delivering hydrogen
peroxide solution to the article to be sterilized. Further, the
efficacy of vacuum treatment and plasma treatment following
pretreatment with aqueous hydrogen peroxide were compared. The
testing is described in Example 16 below.
EXAMPLE 16
[0146] In a first series of tests, stainless steel blades were
inoculated with 2.5.times.10.sup.6 B. stearothermophilus spores.
The blades were placed in the expanded center piece of a 3
mm.times.50 cm stainless steel lumen. The lumen was placed in a
1000 ml beaker containing 800 ml of hydrogen peroxide solution. The
lumen was soaked for 5 minutes in 3% hydrogen peroxide solution.
The number of surviving organisms following this initial soak was
determined. The lumens were removed from the hydrogen peroxide
solution and the outside blotted dry with paper towels. The inside
of the lumens were dried by placing one end of the lumen into a
flask and blowing with a three second burst of compressed air. The
lumens were shaken, and the blowing and shaking repeated until no
more solution was blown out. Subsequently, the lumen was placed in
a sterilization chamber and exposed to either a vacuum of 0.5 Torr
for 15 minutes, or plasma for 15 minutes at 0.5 Torr. After 15
minutes of vacuum, the temperature increased from approximately
23.degree. C. to approximately 28.degree. C. The results are set
forth below in Table 16A. TABLE-US-00019 TABLE 16A Effect of
H.sub.2O.sub.2 Solution Soak on Sporicidal Activity in Stainless
Steel Lumens Prior to Either a Plasma or a Vacuum Treatment Number
of Surviving Sterility Test Results Conc. H.sub.2O.sub.2 (%)
Organisms After Soak Soak + Soak + Soak Time 5 min Soaking Alone
Alone Vacuum Plasma 3.0 8.2 .times. 10.sup.5 4/4 0/4 0/4
[0147] A five minute soak in 3% hydrogen peroxide solution was an
effective means for delivering the hydrogen peroxide into the lumen
prior to vacuum or plasma treatment. As noted before, treatment
with hydrogen peroxide solution only is ineffective to achieve
sterilization using dilute solutions and short soak times. Delivery
of hydrogen peroxide solution via static soaking is at least as
effective a way to deliver the hydrogen peroxide as depositing
small volumes directly into the lumen of the device.
[0148] Flow-through delivery of hydrogen peroxide was tested next.
Here, stainless steel blades were inoculated with
2.5.times.10.sup.6 B. stearothermophilus spores. The blades were
placed in the expanded center piece of a 3 mm.times.50 cm stainless
steel lumen. Hydrogen peroxide solution at 3% concentration was
delivered to the lumen at a flow rate of 0.1 L/min, using a
peristaltic pump. The lumen was dried as described above. Following
pretreatment with hydrogen peroxide solutions the lumen was then
placed in a sterilization chamber and exposed to either a vacuum of
0.5 Torr for 15 minutes, or plasma for 15 minutes at 0.5 Torr. The
results are set forth below in Table 16B. TABLE-US-00020 TABLE 16B
Effects of Flow-Through Delivery of H.sub.2O.sub.2 Solution on
Sporicidal Activity Prior to Either a Vacuum or a Plasma Treatment
in Stainless Steel Lumens Sterility Conc. H.sub.2O.sub.2 Number of
Surviving Test Results (%) Organisms after Flow Flow + Flow + 5 min
flow Alone Vacuum Plasma 3 6.2 .times. 10.sup.5 0/4 0/4
[0149] Delivery of the hydrogen peroxide solution via constant flow
is also an effective way to deliver hydrogen peroxide to the
system.
[0150] Finally, the effect of delivery of hydrogen peroxide by
aerosol spray was tested. Stainless steel blades were inoculated
with 2.5.times.10.sup.6 B. stearothermophilus spores. The
inoculated blades were placed in the expanded center piece of a 3
mm.times.50 cm stainless steel lumen. Three percent hydrogen
peroxide solution was delivered to the lumen via a 3 second aerosol
spray. Aerosol spray rate was determined to be 0.04 L/min. After a
5 minute wait following pretreatment with hydrogen peroxide, the
lumen was dried as described above and the lumen was then placed in
a sterilization chamber and exposed to either a vacuum of 0.5 Torr
for 15 minutes, or plasma for 15 minutes at 0.5 Torr. The results
are set forth below in Table 16C. TABLE-US-00021 TABLE 16C Effects
of Aerosol Delivery of H.sub.2O.sub.2 Solution on Sporicidal
Activity Prior to Either a Vacuum or a Plasma Treatment in Metal
Lumens Number of Surviving Sterility Test Results Conc.
H.sub.2O.sub.2 Organisms after Aerosol + Aerosol + (%) Aerosol
Alone Vacuum Plasma 3 7.4 .times. 10.sup.5 0/4 0/4
[0151] Flow-through of hydrogen peroxide as either a liquid
solution or aerosol can also be achieved by introducing increased
pressure at the delivery end or decreased pressure at the exit end
of the device to be treated.
[0152] It is evident from the data in Tables 16A-16C that all three
methods of delivering hydrogen peroxide solution to the article to
be sterilized provided for effective sterilization. Thus, it
appears that a number of different methods of delivery can be used,
as long as the hydrogen peroxide solution is present in the system
prior to exposure to vacuum or plasma.
[0153] Finally, the efficacy of pretreatment with hydrogen peroxide
prior to a sterilization cycle which combines exposure to hydrogen
peroxide vapor, vacuum, and plasma was evaluated. The testing was
as follows.
EXAMPLE 17
[0154] Stainless steel blades were inoculated with
2.5.times.10.sup.6 B. stearothermophilus spores. The blades were
soaked in 3% hydrogen peroxide solution for either 1 or 5 minutes.
The blades were then placed in the expanded center piece of a 3
mm.times.50 cm stainless steel lumen. The lumen was then placed in
a sterilization chamber which was evacuated to approximately 0.5
Torr. The sterilization cycle consisted of 15 minutes of hydrogen
peroxide vapor diffusion with a minimum of 6 mg/L hydrogen
peroxide, followed by 15 minutes of plasma at 400 watts. Following
the plasma treatment, the chamber was vented and the blades tested
for sterility. The results are shown below. TABLE-US-00022 TABLE 17
Effects of H.sub.2O.sub.2 Solution Soak on Sporicidal Activity in
Stainless Steel Lumens Prior to a Hydrogen Peroxide Vapor and
Plasma Cycle Sterility Test Results Conc. H.sub.2O.sub.2 Soak Time
Soak Alone Soak + Cycle 3% 1 min 4/4 0/4 5 min 4/4 0/4
[0155] Processing the lumens in a hydrogen peroxide vapor and
plasma cycle alone left an average of 30 surviving organisms per
blade. Pre-treating the blades by soaking in 3% hydrogen peroxide
solution for 5 minutes alone left an average of 8.2.times.10.sup.5
surviving organisms per blade. Thus, under these particular test
conditions, a combination of hydrogen peroxide vapor exposure and
plasma exposure, which has been found to be effective for many
articles, was ineffective in a diffusion restricted environment.
However, by pre-treating the article to be sterilized with dilute
hydrogen peroxide solution prior to exposure to hydrogen peroxide
vapor and plasma, complete sterilization can be achieved.
Alternative Forms of Diffusion-Restricted Container
[0156] The Figures below illustrate various alternative embodiments
of diffusion-restricted containers which can be used in embodiments
of the method of the invention. In an embodiment of the method of
the invention, an article to be sterilized is placed into a
diffusion-restricted container, a liquid solution comprising a
vaporizable germicide is placed inside the diffusion restricted
container or onto the article which is to be sterilized, and the
diffusion restricted container with the enclosed article is exposed
to vacuum to vaporize the germicide, sterilizing the article.
Optionally, the article may be exposed to plasma.
[0157] In another embodiment of the method of the invention, the
article to be sterilized comprises a diffusion-restricted area such
as a lumen, hinge, or mated surface. In the alternative embodiment
of the method of the invention, a liquid solution comprising a
vaporizable germicide is placed inside the diffusion-restricted
area before the diffusion restricted container with the enclosed
article is exposed to vacuum to vaporize the germicide. By placing
the germicide into the diffusion-restricted area of the article,
both the interior and the exterior of the diffusion-restricted
article can be sterilized.
[0158] Although a wide range of vaporizable germicides may be
utilized in the method, hydrogen peroxide, and peracetic acid are
exemplary vaporizable germicides for use in the methods of the
present invention. It is to be understood that, although the
vaporizable germicide may be described as "peroxide", the methods
and apparatus are not limited to hydrogen peroxide and peracetic
acid but are applicable to a wide range of vaporizable germicides
including, but not limited to, hydrogen peroxide, peracetic acid,
or glutaraldehyde.
[0159] Further, although the containers are described as
diffusion-restricted containers, the diffusion restriction need not
necessarily occur in the container. The diffusion restriction may
occur elsewhere in the system between the container and the source
of vacuum.
[0160] Although the communication ports 3)0 which have been
described thus far have been either exit tubes or windows, and the
shapes of the communication ports 30 in the Figures have been
round, the communication ports 30 or entry/exit ports are not
limited to exit tubes, windows, or a circular shape. Other
embodiments of communication ports 30 or entry/exit ports are given
in the Figures below.
[0161] FIGS. 7A-7D show various shapes of communication ports 30 or
entry/exit ports which are suitable for use in embodiments of the
invention. Any of the embodiments of the communication ports 30 can
have these shapes. Further, the shapes shown in FIGS. 7A-7D are
illustrative only. Other shapes are also suitable for embodiments
of communication ports 30 for use in the embodiments of the
invention.
[0162] FIG. 7A shows a communication port 30 having a circular
shape. FIG. 7B shows a communication port 30 having an oval shape.
The communication port 30 of FIG. 7C has a rectangular shape with
rounded corners. The communication port 30 of FIG. 7D is round but
is covered anchor filled with a filter 72.
[0163] The shapes of communication ports 30 of entry/exit ports
shown in FIGS. 7A-7D are suitable shapes for any of the embodiments
of entry/exit ports. The shapes are suitable for both the
embodiments of communication port 30 which have been described thus
far such as exit tubes or windows and for the embodiments of
entry/exit ports described below. For example, the exit tubes in
the previous Examples were round exit tubes. Exit tubes with cross
sections having an oval shape as shown in FIG. 7B are equally
suitable to exit tubes having the round shape of FIG. 7A.
Similarly, exit tubes having a rectangular cross section as in FIG.
7C are suitable. The exit tube having a round cross section may be
covered an or filled with a filter 72 as shown in FIG. 7D.
Similarly, entry/exit ports which are windows may have the shapes
shown in FIGS. 7A-7D. It is to be understood that the shapes of the
alternative entry/exit ports or communication ports 30) described
below may also have the shapes shown in FIGS. 7A-7D or other
suitable shapes.
[0164] The criteria for determining whether the various embodiments
of entry/exit port with various shapes cause diffusion restriction
are similar to the criteria for determining whether exit tubes
create diffusion restriction. An exit tube at least 1.0 cm in
length can cause diffusion restriction. Similarly, an entry/exit
port at least 1.0 cm in length can cause diffusion restriction,
regardless of its shape. An exit tube having an internal diameter
of 9 mm or less can cause diffusion restriction in a container 20.
An exit tube having an internal diameter of 9 mm or less has a
cross sectional area of 63.62 mm.sup.2 or less. Entry/exit ports
having alternative shapes such as shown in FIGS. 7A-7D can also
cause diffusion restriction, where the entry/exit ports have cross
sectional areas of 63.62 mm.sup.2 or less, regardless of their
shape. Where the entry/exit port is filled with, for example, a
filter 72, as shown in FIG. 7D, the cross sectional area of the
entry/exit port is reduced by the area filled with the solid
portions of the filter 72. If the solid portion of the filter 72
covers 10% of the cross sectional area of the entry/exit port, for
example, the cross sectional area of the entry/exit port will be
reduced 10% by the filter 72. An entry/exit port which is filled
with the filter 72 which covers 10% of the cross sectional area
will have to have a cross sectional area of 70.69 mm.sup.2 (63.62
mm.sup.2/0.9) or less in order to cause diffusion restriction.
Thus, although the scope of entry/exit ports which can cause
diffusion restriction is broad, there are criteria for determining
whether entry/exit ports of different shapes, for example as shown
in FIGS. 7A-7D, can cause diffusion restriction. A diffusion
restricted environment can be created with a diffusion restricted
port having a length of at least 1.0 cm or a cross-sectional area
of 63.62 mm.sup.2 or less. Alternatively, the diffusion restriction
in the container may result from an entry/exit port with a
length/cross sectional area of at least 10 mm/66.62 mm.sup.2 or
0.157 mm.sup.-1.
[0165] In general, it is a preferred embodiment to have a filter 72
over and/or in the entry/exit port, where the filter 72 is
permeable to gases but impermeable to microorganisms. If the
entry/exit port is covered and/or filled with a filter 72, the
container 20 can be vented without contaminating the interior of
the container 20 or any article contained inside the container
20.
[0166] The term filter 72 is not meant to be limited to a fibrous
material. The term is meant to broadly describe any material which
is permeable to gases but impermeable to microorganisms. For
example, the term filter 72 in this application may describe
something as simple as CSR wrap or TYVEK.TM., which are both
materials which are gas permeable but impermeable to
microorganisms. Alternatively, the filter 72 can be a conventional
fibrous filter which excludes microorganisms.
[0167] FIG. 8 shows an embodiment of a diffusion restricted
container 20 in which the diffusion restriction results from a
communication port 30 comprising a substantially vertical tube 70.
Preferably, there is a filter 72 inside or attached to the vertical
tube 70, where the filter 72 is permeable to gases but does not
allow bacteria to pass. In FIG. 8, the filter 72 is inside the
substantially vertical tube 70. The filter 72 prevents
microorganisms from entering the container when the system is
vented after the article is sterilized. Alternatively, the
gas-permeable and microorganism-impermeable filter 72 may be
present in another part of the system. The diffusion restriction in
the container 20 of FIG. 8 may result from the substantially
vertical tube 70, the filter 72, or a combination of the
substantially vertical tube 70 and the filter 72. When the
diffusion restriction in the container 20 results from the vertical
tube 70, the diffusion restriction in the container 20 may result
from a vertical tube 70 which is at least 1.0 cm in length. The
diffusion restriction in the container 20 may also result from an
entry/exit port which has an internal diameter of 9 mm or less or a
cross sectional area of 63.62 mm.sup.2 or less.
[0168] FIG. 9 shows an alternative embodiment of a
diffusion-restricted container in which the communication port 30
comprises a substantially horizontal tube 74 with a filter 72,
where the filter 72 is permeable to gases but impermeable to
microorganisms. A first end of the substantially horizontal tube 74
is open to the interior of the container 20, and a second end of
the substantially horizontal tube 74 is open to the environment
outside the diffusion-restricted container 20. The diffusion
restriction in the container 20 may result from the substantially
horizontal tube 74, the filter 72, or a combination of the
substantially horizontal tube 74 and the filter 72. The diffusion
restriction in the container 20 may also result from an entry exit
port, where the entry/exit port is at least 1.0 cm in length or
having an internal diameter of 9 mm or less or has a cross
sectional area of 63.62 mm.sup.2 or less. The entry/exit port can
be in any angle relative to the container.
[0169] FIGS. 10 and 11 show embodiments of diffusion restricted
containers in which the diffusion restriction results from a hole
76 as the communication port. The diffusion restriction in the
container 20 may result from a hole 76 which has an internal
diameter of 9 mm or less or a hole 76 with an area of 63.62 mm or
less or from a hole 76 which has a length of 1.0 cm or more. In the
embodiment shown in FIG. 10, a lid 78 on the container 20 is
thicker in the region of the hole 76 than in the remainder of the
lid 78. The hole 76 is therefore like a vertical entry/exit port,
with a longer length than if the lid 78 were of uniform thickness.
A filter 72 preferably covers the hole 76, where the filter 72 is
permeable to gases but impermeable to microorganisms to prevent
bacteria from entering the hole 76 when the system is vented after
sterilization has occurred. The diffusion restriction in the
container 20 may result from the hole 76, the filter 72, or a
combination of the hole 76 and the filter 72. If the diffusion
restriction results from the hole 76, the diffusion restriction in
the container 20 may result from a hole 76 which is at least 1.0 cm
long, has an area of 63.62 min.sup.2 or less, or which has a
diameter of 9 mm or less. The filter 72 may be located above the
hole 76, inside the hole 76, or underneath the hole 76. In FIG. 10,
the filter 72 is below the hole 76.
[0170] In FIG. 11, the diffusion-restricted container 20 comprises
a lid 78 of uniform thickness with a communication port comprising
a hole 76. A gas permeable and microorganism impermeable filter 72
preferably covers the hole 76. The diffusion restriction in the
container 20 of FIG. 11 may result from the hole 76, the filter 72,
or a combination of the hole 76 and the filter 72. If the diffusion
restriction in the container 20 of FIG. 11 results from the hole
76, the lid 78 may have a thickness of 1.0 cm or more, so that the
hole 76 in the lid 78 has a length of at least 1.0 cm.
Alternatively, the hole 76 may have a diameter of 9 mm or less or
an area of 63.62 mm.sup.2 or less. In another embodiment, the
diffusion restriction in the container results from a combination
of the hole 76 and the filter 72. The filter 72 may be located
inside the hole 76, above the hole 76, or below the hole 76. In
FIG. 11, the filter 72 is below the hole 76.
[0171] The embodiment of the diffusion-restricted container 20
shown in FIG. 12 comprises at least one handle 80. The handle 80 of
FIG. 12 comprises a communication port 30 passing from the outside
to the inside of the container 20 through the handle 80. Although
the embodiment shown in FIG. 12 comprises two handles 80 where both
handles 80 have communication ports 30, both the second handle 80
and the second communication port 30 are optional. For example, the
container may have two handles 80 but only one communication port
30. Preferably, there is at least one gas permeable and
microorganism impermeable filter 72 covering the communication port
30 in the handle 80 to prevent bacteria from entering the
diffusion-restricted container 20 after the devices in the
container 20 have been sterilized. In the embodiment shown in FIG.
12, there are two filters 79 on each communication port 30. In
other embodiments, there is only one filter 72 on each
communication port 30. The filter 72 can also be located in the
communication port 30. The diffusion restriction in the embodiment
of the diffusion restricted container 20 shown in FIG. 12 may be
due to the communication port 30, the filter 72, or a combination
of the communication port 30 and the filter 72.
[0172] FIGS. 13 and 14 show two embodiments of
attachable/detachable containers 20 as alternative embodiments of
diffusion-restricted containers suitable for use in various
embodiments of the method of the invention. In the embodiment of
the attachable/detachable container 20 shown in FIG. 13, the
container 20 comprises two ports 55. In other embodiments of the
attachable/detachable container 20, only one port 55 is present. In
the embodiment shown in FIG. 13, a first port 55 comprises a
reducer 81, where the reducer 81 reduces the diameter of the port
55. The reducer 81 may be of any shape. The reducer 81 of FIG. 13
is shaped like a cylinder with a hole along the length of the
cylinder. A gas-permeable and microorganism-impermeable filter 72
is located inside the bore of the reducer 81. Although the
embodiment of the first port 55 shown in FIG. 13 additionally
comprises a valve 82, the valve 82 is optional. The diffusion
restriction in the container 20 of FIG. 13 may result from the port
55, the reducer 81, the filter 72, the valve 82, or any combination
of the port 55, the reducer 81, the filter 72, and the valve 82. In
some embodiments, the port 55 or the reducer 81 is at least 1.0 cm
in length, acting as an entry/exit port and creating diffusion
restriction in the container 20. In other embodiments, the port 55
or reducer 81 has a diameter of 9 mm or less or has an area of
63.62 mm.sup.2 or less, acting as an entry/exit port and creating
diffusion restriction in the container 20. In the embodiment of the
attachable/detachable container 20 shown in FIG. 13, there is a
second port 55 with a valve 82. The second port 55 can be used to
create diffusion restriction instead of the first port 55.
Optionally, the valve 82 may comprise a gas permeable and
microorganism impermeable filter. The filter may be in the bore of
the valve 82 or in the port 55. The filter prevents microorganisms
from entering the container 20 when the system is vented. In an
alternative embodiment, the gas permeable and microorganism
impermeable filter is present elsewhere in the system.
[0173] In the embodiment of the attachable/detachable container 20
shown in FIG. 14, the container 20 comprises two ports 55 and two
valves 82. Optimally, the valve 82 further comprises a gas
permeable and microorganism impermeable filter in the bore of the
valve 82. The diffusion restriction in the attachable/detachable
container 20 shown in FIG. 14 may be due to the valve 82, the
filter, or a combination of the valve 82 and the filter. Although
the embodiment shown in FIG. 14 shows two ports 55 with two valves
82, the second port 55 and valve 82 are optional. Either, or both,
of the two valves 82 can create the diffusion restriction.
[0174] FIGS. 15 and 16 show embodiments of suitable connectors 85
for connecting the attachable/detachable containers 20 shown in
FIGS. 13 and 14 to a source of vacuum, fluid and/or other
feedthrough 88. FIG. 15 shows a tube 84 with a plurality of O-rings
86 on the inside of one end of the tube 84. The O-rings are
preferably made of a material which is resistant to degradation by
hydrogen peroxide. Suitable materials for fabricating the O-rings
include, but are not limited to VITON.TM., TEFLON.TM., or silicone.
In some embodiments, there is only one O-ring 86 inside of the tube
84. The second end of the tube 84 is connected to a source of
vacuum, fluid, and/or other feedthrough 88. The fluid can be a
liquid or a gas. In an embodiment, the fluid comprises peroxide,
preferably hydrogen peroxide or peracetic acid.
[0175] FIG. 16 shows an alternative embodiment of a connector 85
for connecting the attachable/detachable containers 20 of FIGS. 13
and 14 to the source of vacuum, fluid, and/or other feedthrough 88.
The embodiment of the connector 85 shown in FIG. 16 comprises two
tubes 84 with two valves 82. The tubes 84 comprise a plurality of
O-rings 86 inside a first end. The embodiment of the connector 85
shown in FIG. 16, further comprises two sources of vacuum, sources
of fluid, and/or other feedthrough 88. The two tubes 84 and two
sources of vacuum, fluid, and/or other feedthrough 88 can operate
independently of one another by closing one or both valves 82. In
other embodiments of the connector, only one valve 82 and one
source of vacuum, fluid, and/or other feedthrough 88 are
present.
[0176] FIGS. 17-20 show various embodiments of
attachable/detachable containers 20 connected to the connector 85
of FIG. 15. In the embodiment shown in FIG. 17, an
attachable/detachable container 20 with a single port 55 comprising
a reducer 81 with a filter 72 in the bore of the reducer 81 is
attached to the connector 85 of FIG. 15 by connecting the port 55
of the attachable/detachable container 20 to the tube 84 of the
connector 85. The O-rings 86 inside the tube 84 create an air-tight
seal between the port 55 and the tube 84. In the embodiment of the
attachable/detachable container 20 shown in FIG. 17, the diffusion
restriction in the container 20 is created by the port 55, the
reducer 81, the filter 72, or any combination of the port 55, the
reducer 81, and the filter 55.
[0177] The embodiment shown in FIG. 18 is similar to that shown in
FIG. 17, except that the attachable/detachable container 20 has a
port 55 with a valve 82 rather than a reducer 81 and a filter 72,
as in the embodiment shown in FIG. 17. The attachable/detachable
container 20 of FIG. 18 is attached to the connector 85 shown in
FIG. 15. The valve 82 may also have a filter in the bore of the
valve. The diffusion restriction in the attachable/detachable
container of FIG. 18 may be due to the port 55, the valve 82, the
filter, or any combination of the port 55, the filter, and the
valve 82.
[0178] In the embodiment shown in FIG. 19, the
attachable/detachable container 20 has a port 55 with a filter 72
and a valve 82. The attachable/detachable container 20 is attached
to the connector 85 of FIG. 15. The diffusion restriction in the
attachable/detachable container 20 may be due to the valve 82, the
filter 72, or the combination of the valve 82 and the filter 72.
The filter 72 is permeable to gases but impermeable to
microorganisms, so that the attachable/detachable container 20 may
be vented after sterilization without recontaminating the interior
of the attachable/detachable container 20 or any article contained
in the attachable/detachable container 20.
[0179] FIG. 20 shows a attachable/detachable container 20
comprising a filter 72. The attachable/detachable container 20 is
attached to a connector 85 similar to the connector 85 of FIG. 15,
except that the connector 85 in FIG. 20 also comprises a valve 82.
The valve 82 of the connector 85 is located between the
attachable/detachable container 20 and the source of vacuum, fluid,
and/or other feedthrough 88. In the embodiment shown in FIG. 20,
the attachable/detachable container 20 may be vented from the
source of vacuum, fluid, and/or other feedthrough 88 by opening the
valve 82 on the connector 84. The diffusion restriction in the
attachable/detachable container 20 may be due to the valve 82, the
filter 72, or the combination of the valve 82 and the filter 72.
The filter 72 is preferably permeable to gas but impermeable to
microorganisms, so that the attachable/detachable container 20 and
any article inside the container 20 are not recontaminated when the
attachable/detachable container 20 is vented.
[0180] The attachable/detachable container 20 shown in FIG. 21 has
two ports 55. A first port 55 is equipped with a filter 72 and a
valve 82. A second port 55 has a septum 87. The septum 87 is made
of flexible plastic or rubber which is impermeable to gases, so
that the attachable/detachable container 20 may be evacuated. It is
preferred that the plastic or rubber making up the septum 87 is
resistant to hydrogen peroxide. Examples of materials suitable for
forming the septum include, but are not limited to, VITON.TM. or
silicone. In FIG. 21, the septum is punctured by a needlelike
device 89 which is connected to the source of vacuum, fluid, and/or
other feedthrough 88. In this embodiment, the diffusion restriction
in the attachable/detachable container 20 may be due to the
needlelike device 89 which is acting as an entry/exit port. The
entire sterilization process may occur through the needlelike
device 89 as the entry/exit port. If the diffusion restriction in
the container 20 is due to the needlelike device 89, the diffusion
restriction may result from a needlelike device 89 which is at
least 1.0 cm in length, has an internal diameter of 9 mm or less,
or has a cross sectional area of 63.62 mm or less.
[0181] The first port 55 of the attachable/container 20 shown in
FIG. 21 may optionally be attached to a connector 85 which is
attached to the source of vacuum, fluid, and/or other feedthrough
88. In this embodiment, the diffusion restriction in the
attachable/detachable container may be due to the port 55, the
filter 72, the valve 82, or any combination of the port 55, the
filter 72, and the valve 82. The sterilization of the
attachable/detachable container 20 may then occur through the first
port 55 having the valve 82 and the filter 72.
[0182] FIG. 22 shows an attachable/detachable container 20 where
the port 55 has a filter 72 and a restrictor 91. The filter 72 is
permeable to gases but impermeable to microorganisms. The
attachable/detachable container 20 is attached to a connector 85
which is connected to the source of vacuum, fluid, and/or other
feedthrough 88. The connector 85 also has a restrictor 91. In some
embodiments, neither the port 55 with the restrictor 91 nor the
connector 85 with the restrictor 91 in the connector 85 alone
causes diffusion restriction in the attachable/detachable container
20. When the attachable/detachable container 20 with the port 55
with the restrictor 91 is attached to the connector 85 with the
restrictor 91, however, the two restrictors 91 fit together closely
enough that the combination of the port 55 with its restrictor 91
and the connector 85 with its restrictor 91 leads to diffusion
restriction in the container 20. In this embodiment, neither the
port 55 and its restrictor 91 nor the connector 85 with its
restrictor 91 alone cause the diffusion restriction.
[0183] In the embodiment shown in FIG. 23, the
attachable/detachable container 20 of FIG. 13 is attached to the
connector 85 of FIG. 16. The O-rings 86 on the connector 85 form a
vacuum-tight seal with the port 55 of the attachable/detachable
container 20. The diffusion restriction in the
attachable/detachable container 20 in FIG. 23 can be caused by the
port 55, the reducer 81, the filter 72, the valve 82 in the top
port 55, the valve 82 in the connector 85, or a combination.
Alternatively, or in addition, the diffusion restriction in the
attachable/detachable container 20 can be caused by the valve 82 in
the bottom port 55 in FIG. 23. The attachable/detachable container
20 can be exposed to the source of vacuum, fluid, or other
feedthrough 88 through the source 88 on the right side of FIG. 23
or the source 88 at the bottom of FIG. 23.
[0184] FIG. 24 shows the attachable/detachable container 20 of FIG.
14 attached to the embodiment of the connector 85 of FIG. 16. The
diffusion restriction in the attachable/detachable container 20 can
be caused by either or both ports 55 and/or any of the valves 82.
The source of vacuum, source of fluid, or other feedthrough 88 can
be either the source 88 at the right of FIG. 24 or the source 88 at
the bottom of FIG. 24. In other embodiments, an
attachable/detachable container 20 having only one port 55 may be
attached to one of the two tubes 84 of the embodiment of the
connector 85 shown in FIG. 16.
[0185] It is to be understood that the embodiments shown in FIGS.
17-24 are meant to be illustrative of various embodiments, and the
invention is not limited to the embodiments shown in these Figures.
Other combinations of attachable/detachable containers 20 and
connectors 85 can be used as alternative embodiments of the
apparatus and the method of the invention. For example, the tube 84
can be smaller than the port 55, and the tube 84 may be inserted
into the port 55 with the O-rings on the outside of the tube
84.
[0186] Articles may be sterilized with the embodiments of the
attachable/detachable container 20 and connectors 85 shown in FIGS.
13-24 in several embodiments of the method of the invention. An
article to be sterilized is placed into one of the embodiments of
the attachable/detachable container 20. A liquid solution
comprising vaporizable germicide, for example, a source of
peroxide, such as hydrogen peroxide or peracetic acid, is placed
inside the attachable/detachable container 20 or is placed in
contact with the article to be sterilized in the
attachable/detachable container 20. Either before or after the
source of peroxide is contacted with the attachable/detachable
container 20, the attachable/detachable container 20 is attached to
the connector 85, where the connector 85 is in fluid communication
with the source of vacuum, fluid, and/or other feedthrough 88.
[0187] The pressure in the attachable/detachable container 20 is
reduced to vaporize at least a portion of the vaporizable
germicide, sterilizing the article to be sterilized. Plasma may
optionally be generated and contacted with the article to be
sterilized. The attachable/detachable container 20 is vented with a
gas. The venting comprises passing the gas through a gas permeable
and microorganism impermeable filter 72, where the filter is
located either on the attachable/detachable container 20 or in
another part of the system. By venting the attachable/detachable
container 20 through a gas permeable and microorganism impermeable
filter, the sterilized article in the attachable/detachable
container 20 is not reexposed to microorganisms during the
venting.
[0188] The attachable/detachable container 20 may be detached from
the connector 85 either before or after venting. If the
attachable/detachable container 20 is separated from the connector
85 before venting, it is generally preferred that the
attachable/detachable container 20 comprise at least one valve 82
and that the valve 82 be closed before the attachable/detachable
container 20 is separated from the connector 85.
[0189] The attachable/detachable container 20 with the enclosed
sterilized article may optionally be transported. If the valve 82
on the attachable/detachable container 20 is closed, the article in
the attachable/detachable container 20 can remain sterile for
extended periods of time, because the valve 82 isolates the article
from the environment.
[0190] In an embodiment of the method of the invention, an article
is sterilized in an attachable/detachable container 20 comprising a
valve 82, and the valve 82 is closed before detaching the
attachable/detachable container 82 from the connector 85 and the
source of vacuum, fluid, and/or other feedthrough 88. In an
embodiment, the pressure inside the attachable/detachable container
20 after closing the valve 82 and after detaching from the
connector 85 is less than atmospheric pressure. The valve 82 may be
controlled manually or electronically.
[0191] If the attachable/detachable container 20 containing the
sterilized article is stored for extended periods of time, it is
possible that a leak could occur, potentially causing contamination
of the sterilized article. If the pressure inside the
attachabl/detachable container 20 was at less than atmospheric
pressure when the valve 82 was closed, a user can test whether the
attachable/detachable container leaked by listening for the sound
of inflowing gas when the attachable/detachable container 20 is
vented by opening the valve 82. If the attachable/detachable
container 20 has leaked, the attachable/detachable container will
likely be at atmospheric pressure, and the user will not hear the
sound of inflowing gas when the valve 82 is opened. If no leak has
occurred, the user will hear a sound when the container 20 is
vented by opening the valve 82. Storing the sterilized article in
an attachable/detachable container 20 at less than atmospheric
pressure thus provides an opportunity to test whether the container
has leaked. By passing the vent gas through a gas permeable and
microbe-impermeable filter 72 during the venting, the article will
not be contaminated during the testing and venting process.
[0192] In an alternative embodiment, the attachable/detachable
container 20 may be pressurized to a pressure greater than one
atmosphere. In this embodiment, the user will hear the sound of
outflowing gas when the container 20 is vented by opening the valve
82. If no outflowing, gas is heard when the valve 82 is opened, the
user will know that a leak has occurred.
[0193] In another embodiment, one or more pressure measuring
devices such as pressure gauges or transducers are placed on the
attachable/detachable container 20. The pressure in the
attachable/detachable container 20 is measured after sterilization
is complete and the container 20 is sealed. If the pressure as
measured by the pressure measuring device changes during storage,
it may be assumed that the attachable/detachable container 20
leaked during storage.
[0194] In another embodiment, the pressure measuring device
comprises a transparent valve with movable balls. The valve is
attached to the attachable/detachable container 20. The transparent
valve comprises two tubes, an upper tube extending upward from the
center of the valve, and a lower tube extending downward from the
center of the valve. Both the ends of the tubes and the portion of
the tubes next to the center of the valve are constricted to an
area smaller than the area of the balls, so that the balls may not
pass out of the tubes or go beyond the center of the valve. If the
attachable/detachable container 20 is at atmospheric pressure, both
balls are at the lower ends of the respective tubes. If the
attachable/detachable container 20 is above atmospheric pressure,
the ball in the upper tube is forced to the top of the upper tube,
next to the constriction. The ball in the lower tube is at the
bottom of the lower tube, next to the constriction. If the
attachable/detachable container 30 is below atmospheric pressure,
both balls are forced next to the restrictions in the center of the
valve.
[0195] In another embodiment, the pressure indicator comprises a
receptacle with a thin film extending across the receptacle. The
receptacle is attached to the attachable/detachable container 20.
If the attachable/detachable container 20 is at atmospheric
pressure, the film is neither dilated toward the inside nor toward
the outside. If the attachable/detachable container 20 is below
atmospheric pressure, the center of the film is sucked inward
toward the attachable,/detachable container 20. If the
attachable/detachable container is above atmospheric pressure, the
center of the film is pushed outward, away from the
attachable/detachable container 20.
[0196] By using any of these means of measuring pressure or any
other means of pressure indication, it is determined whether the
attachable/detachable container 20 is above, below, or at
atmospheric pressure. If the attachable/detachable container 20 was
either above or below atmospheric pressure when the container 20
was stored and is at atmospheric pressure after being stored, the
attachable/detachable container 20 almost undoubtedly leaked.
Storing the attachable/detachable container 20 at pressures above
or below atmosphere pressure with some means of determining
pressure is therefore a useful way to determine whether the
attachable/detachable container 20 leaked while being stored.
[0197] In an embodiment of the method of the invention, an article
to be sterilized is placed in an attachable/detachable container
20, the attachable/detachable container 20 is attached to a
connector 85 which is fluidly connected with the source of vacuum,
fluid, and/or other feedthrough 88, and the vaporizable germicide
is introduced into the attachable/detachable container 20 from the
source of vacuum, fluid, and/or other feedthrough 88 rather than by
contacting the attachable/detachable container 20 or the article to
be sterilized with the vaporizable germicide. The
attachable/detachable container 20 is then exposed to reduced
pressure to vaporize the germicide, thereby sterilizing the
article.
[0198] In another embodiment, an article having a diffusion
restricted area is sterilized by contacting the
diffusion-restricted area of the article with the vaporizable
germicide, placing the article having a diffusion-restricted area
into the attachable/detachable container 20, where the contacting
and placing can occur in either order, and evacuating the
attachable/detachable container 20 to vaporize the germicide,
sterilizing the diffusion restricted area of the article. If the
attachable/detachable container 20 is diffusion restricted, the
exterior of the article having a diffusion restricted area is also
sterilized.
[0199] FIG. 25 shows an alternative embodiment of the
attachable/detachable container 20 in which the
attachable/detachable container 20 comprises two ports 55. The
second port 55 is optional. The top port 55 in FIG. 25 is equipped
with reducer 81 with a filter 72 in the bore of the reducer 81,
where the filter 72 is gas permeable and microorganism impermeable.
The top port 55 is also equipped with a hinged valve 90, where the
hinged valve 90 comprises a flap 92 on a hinge 94, where the flap
92 has a circular shape, an oval shape, a square shape or any other
shape that closes the opening in the port 55. The hinge 94 is
attached to the interior of the port 55, allowing the flap 92 to
open and close by swinging on the hinge 94. The flap 92 forms a gas
and vacuum-tight seal with the port 55 when the flap 92 is closed.
The hinged valve 90 further comprises a spring (not shown) which
returns the flap 92 to a closed position when there is no external
force on the flap 92 to force the flap 92 open. The hinge 94 may be
either on a side of the flap 92 inside the attachable/detachable
container 20 or on a side of the flap 92 outside of the
attachable/detachable container 20. It is generally preferred that
the hinge 94 be on the side of the flap 92 inside the
attachable/detachable container 20. The second port 55 of the
embodiment of the attachable/detachable container 20 shown in FIG.
25 is equipped with a hinged valve 90.
[0200] Pressurizing attachable/detachable containers 20 to
pressures above atmospheric pressure after sterilization can allow
for detection of leaks, because the user can hear the hiss of the
gas escaping the attachable/detachable container 20 when a valve or
other device is opened to vent the container 20. If there is no
hiss of gas, the attachable/detachable container 20 probably
leaked.
[0201] Testing for leaks by pressurizing the container 20 is
advantageous with containers with hinged valves 90, because the
pressurized gas in the container 20 pushes against the flap 92,
sealing the flap 92 firmly in place in the port 55.
[0202] FIG. 26 shows an alternative embodiment of a connector 85.
The connector 85 of FIG. 26 is essentially identical to the
connector 85 of FIG. 16, with two tubes 84, two sources of vacuum,
fluid, and or other feedthrough 88, and two valves 82. In the
connector 85 shown in FIG. 26 the plurality of O-rings 86 are on
the outside of the tube 84 rather than on the inside of the tube
84, as in the connector 85 shown in FIG. 16. In the embodiment
shown in FIG. 26, one side of the tube 84 is longer than the second
side of the tube 84, so that the end of the tube 84 forms a slanted
line when viewed from the side. In other embodiments, the two sides
of the tube 84 are of equal length.
[0203] FIG. 27 shows the attachable/detachable container 20 of FIG.
25 attached to the connector 85 of FIG. 26. The upper and lower
tubes 84 of the connector 85 are inserted into the hinged valves 90
on the attachable/detachable container 20, opening the flaps 92 on
the hinged valves 90. In the embodiment where one side of the tube
84 is longer than the second side of the tube, the longer side of
the tube 84 helps to push the flap 92 aside. The plurality of
O-rings 86 on the outside of the tubes 84 contact the interior of
the ports 55, making a gas and vacuum-tight seal with the interior
of the ports 55.
[0204] In some embodiments, there is a stop (not shown) inside one
or both of the ports 55 on the attachable/detachable container 20.
The stop limits the travel of the tube 84 of the connector 85
inside the port 55, so that the tube 84 does not penetrate so far
into the port 55 that the O-rings 86 do not contact the inner walls
of the port 55 to make the vacuum-tight seal. If the tube 84
extends too far into the port 55, the O-rings 86 would contact the
flaps 92, and it is unlikely that the O-rings 86 would seal on the
flaps 92. The stop can be, for example, a projection on the
interior of the port 55 which contacts an end of the tube 84,
limiting the travel of the tube 84 into the port 55. The optional
valves 82 on the connector 85 can be used to isolate one or both of
the sources of vacuum, fluid, and/or other feedthrough 88 from the
attachable/detachable container 20.
[0205] After the attachable/detachable container 20 has been
sterilized and vented, the connector 85 and attachable/detachable
container 20 shown in FIG. 27 can be separated. When the connector
85 and the attachable/detachable container 20 of FIG. 27 are
separated from one another, the flaps 92 on the hinged valves 90
close due to the force of the springs (not shown), forming an
air-tight seal with the inner wall of the ports 55, isolating the
interior of the attachable/detachable container 20 from the
environment. The hinged valves 90 of the attachable/detachable
container 20 shown in FIGS. 25 and 27 therefore provide a means of
automatically isolating the interior of the attachable/detachable
container 20 from the environment when the connector 85 is
separated from the attachable/detachable container 20.
[0206] FIGS. 28-31 show various embodiments of containers 20
contained inside attachable/detachable containers 20 as "nested
containers". In FIG. 28, an inner container 20A is contained inside
an attachable/detachable container 20B, where the
attachable/detachable container 20B has a valve 82 on the port 55,
allowing the attachable/detachable container 20B to be
isolated.
[0207] The inner container 20A of FIG. 28 has a communication port
30 on the top of the container, allowing gas such as germicide
vapor to pass from the inner container 20A to the inside of the
attachable/detachable container 20B. The communication port 30 call
be a hole, window, tube, or any other communication port 30 which
allows gas or vapor to pass. Preferably the communication port 30
is either a window which is permeable to gases but impermeable to
microorganisms, or the communication port 30 is covered by a filter
72 which allows vapor to pass but does not allow microorganisms to
pass. The window or filter 72 prevent microorganisms from entering
the inner container 20A when the outer attachable,/detachable
container 20B is vented. The inner container 20A may or may not be
diffusion restricted. The attachable/detachable container 20B is
preferably diffusion restricted.
[0208] FIG. 29 shows an alternative embodiment of nested containers
in which the inner container 20A has a substantially horizontal
tube 74 as the communication port. Preferably, a filter 72 is
placed in the horizontal tube 74, where the filter 72 is permeable
to gases but impermeable to microorganisms. The horizontal tube 74
allows germicide vapor to flow from the interior of the inner
container 20A to the interior of the attachable/detachable
container 20B.
[0209] The attachable/detachable container 20B of FIG. 29 has a
port 55 equipped with a hinged valve 90 and a filter 72, where the
filter 72 is located between the hinged valve 90 and the interior
of the attachable/detachable container 20B. The filter 72 is
permeable to gases but impermeable to microorganism. The filter 72
allows the attachable/detachable container 20B to be vented without
contaminating, the interior of the attachable/detachable container
20B or the interior and exterior of the inner container 20A.
[0210] FIG. 30 shows an alternative embodiment of nested containers
in which the inner container 20A is a pouch. The pouch in FIG. 30
contains a non-lumen device 40, a pair of scissors. The pouch as
the inner container 20A is placed inside an attachable/detachable
container 20B. The attachable/detachable container 20B of FIG. 30
has a port 55 with a valve 82. The diffusion restriction in the
attachable/detachable container 20B may be due to the port 55, the
valve 82, or a combination of the port 55 and the valve 82. In an
embodiment, at least a portion of the pouch as an inner container
20A is made of a gas permeable banner such as TYVEK.TM.. TYVEK.TM.
and CSR wrap barrier are permeable to gases, including hydrogen
peroxide vapor. The balance of the pouch can be made of a gas
impermeable barrier such as MYLAR.TM..
[0211] A device to be sterilized is placed into the pouch as inner
container 20A. A vaporizable germicide such as liquid comprising
hydrogen peroxide is placed inside the attachable/detachable
container 20B, the pouch as the inner container 20A, or both the
attachable/detachable container 20B and the pouch, and a vacuum is
applied to the attachable/detachable container 20B to vaporize the
vaporizable germicide. The germicide vapor passes through the gas
permeable portion of the pouch, either into or out of the pouch,
depending on where the vaporizable germicide was placed, to
sterilize the device, the interior and exterior of the pouch as an
inner container 20A, and the interior of the attachable/detachable
container 20B. Optionally, a plasma may be generated and flowed
into the attachable/detachable container 20B. The device in the
pouch can be either a non-lumen device or a lumen device. Depending
on the length and internal diameter of the lumen, liquid
pretreatment of the interior of the lumen may be required.
[0212] FIG. 31 shows an inner container 20A having a port 55 with a
hinged valve 90 closed by a flap 92 attached to the inside of the
port 55 with a hinge 94. The hinged valve 90 also has a sprint,
(not shown) which forces the flap 92 closed when there is no
pressure on the flap 92. The inner container 20A also has a
communication port 30 on the top of the container 20A, where the
communication port 30 is covered by a filter 72, where the filter
72 is permeable to gases but impermeable to microorganisms. The
communication port 30 can be a hole, a tube, a window, a
rectangular shaped opening, or any other opening. There is no need
for the inner container 20A to be diffusion restricted.
[0213] The inner container 20A is placed in an
attachable/detachable containers 20B with a hinged valve 90 on a
port 55. The hinged valve 90 on the attachable/detachable container
20B is similar to the hinged valve on the inner container 20A. The
communication port 30 on the inner container 20A allows vacuum or
germicide vapor to be transmitted from the inside of the inner
container 20A to the inside of the attachable/detachable container
20B. In the embodiment shown in FIG. 31, the inner container 20A is
placed between two retaining guides 96 attached to the inside of
the attachable/detachable container 20B. The retaining guides 96
fit snugly against the outside of the inner container 20A, securing
and retaining the inner container 20A in a fixed position inside
the attachable/detachable container 20B. The retaining guides 96
can have various shapes. In one embodiment, the retaining guides 96
are long flaps attached to the inner wall of the outer
attachable/detachable container 20B. In another embodiment, the
retaining guides 96 are narrow strips that fit into slots on the
outside of the inner attachable/detachable container 20B. Other
embodiments of retaining guides 96 will be apparent to those
skilled in the art. Although the retaining guides 96 are optional,
having retaining guides 96 on the inside of the
attachable/container 20B is a preferred embodiment, because the
retaining guides 96 hold the inner container 20A firmly in position
inside the attachable/detachable container 20B.
[0214] FIG. 32A shows an embodiment of a connector 85 which may be
connected to the container 20B of FIGS. 29 and 31. The connector 85
comprises a tube 84 with a plurality of O-rings 86 attached to the
outside of the tube 84. One end of the tube 84 is fluidly connected
to a source of vacuum, fluid, and/or other feedthrough 88. The
connector 85 optionally, but preferably, has a stop 98 on the
outside of the tube 84. When the connector 85 is inserted into the
hinged valve 90 of the attachable/detachable container 20B of FIG.
29, the stop 98 contacts the end of the port 55 and prevents the
tube 84 from extending too far into the interior of the
attachable/detachable container 20B. The stop 98 insures that the
plurality of O-rings 86 are in the proper position to form a good
seal with the inside of the port 55. If the O-rings 86 were to
contact the flap 92 rather the interior of the port 55, it is
probable that the O-rings 86 would not be able to form a
vacuum-tight seal. The stop 98 limits the travel of the connector
85 when the stop 98 contacts the end of the port 55. The connector
85 of FIG. 32A may also be used with the attachable/detachable
container 20B shown in FIG. 31 or any other container 20 having a
hinged valve 90. The connector 85 of FIG. 32A may also be used with
attachable/detachable containers having a valve 82 in the port 55,
by inserting the tube 84 into the port 55. The O-rings 86 on the
outside of the tube 84 would form a seal with the inside surface of
the port 55.
[0215] FIG. 32B shows a connector 85 suitable for attaching to the
nested containers 20A and 20B shown in FIG. 31. The connector 85 of
FIG. 32B is similar to the connector 85 of FIG. 32A in comprising a
tube 84 with a plurality of O-rings 86 attached to the outside of
the tube 84. The connector 8$ of FIG. 32B has four O-rings 86
rather than the two O-rings 86 for the connector 85 of FIG. 32A.
The purpose of the four O-rings will become clear when FIGS. 33A
and 33B are described. One end of the tube 84 is fluidly connected
to a source of vacuum, fluid, and/or other feedthrough 88. Although
the connector 85 shown in FIG. 32B does not have a stop as does the
connector 85 shown in FIG. 32A, some embodiments of the connector
85 of FIG. 32A do have a stop.
[0216] The connector of FIG. 32C is identical to the connector of
FIG. 32B, except that there is a hole 76 in the tube 84 on the
connector 85 of FIG. 32C in between the second and the third
O-rings 86. The purpose of the hole 76 will be become clear when
FIG. 33B is described.
[0217] The connectors 85 of FIGS. 32A, 32B, and 32C are shown with
ends of one side of the tube 84 being longer than the second side
of the tube 84, so that the end of the tube 84 forms a slanted line
when viewed from the side. In other embodiments, the two sides of
the tube 84 are of equal length.
[0218] FIGS. 33A and 33B show how the connectors 85 of FIGS. 32B or
32C attach to the nested containers 20A and 20B of FIG. 31. FIG.
33A shows the connector 85 of FIG. 32B inserted into the hinged
valve 90 of the attachable/detachable container 20B of FIG. 31.
When the tube 84 of the connector 85 is pushed against the flaps 92
on the hinged valve 90 of the attachable/detachable container 20B,
the flap 92 is pushed aside against the force of the spring (not
shown), exposing the interior of the attachable/detachable
container 20B to the source of vacuum, source of fluid, and/or
other feedthrough 88. The plurality of O-rings 86 on the outside of
the tube 84 form a vacuum-tight seal with the inside of the port 55
of the attachable/detachable container 20B.
[0219] FIG. 33B shows how the connector 85 of either FIG. 32B or
32C can be inserted into both the hinged valve 90 of the inner
container 20A and the hinged valve 90 of the attachable/detachable
container 20B. When the tube 84 of the connector 85 is pushed
against the flaps 92 on the hinged valve 90 of the
attachable/detachable container 20B and the inner container 20A,
the flaps 92 are pushed aside against the force of the spring (not
shown), exposing the interior of the inner container 20A to the
source of vacuum, source of fluid, and or other feedthrough 88. The
plurality of O-rings 86 on the outside of the tube 84 form
vacuum-tight seals with the inside of the ports 55 of the inner
container 20A and the attachable/detachable container 20B. In an
embodiment, there can be a stop 98 on the connector 85 as in the
connector of FIG. 32A. The stop 98 on the outside of the connector
85 would contact the end of the port 55 on the
attachable/detachable container 20B, limiting the movement of the
tube 84 so that the O-rings 86 are in contact with the inside of
the two ports 55.
[0220] The retaining guides 96 hold the inner container 20A in
place inside the outer attachable/detachable container 20B when the
connector 85 of FIG. 32B or FIG. 32C is pushed through the hinged
valves 90. If the connector 85 of FIG. 32C is used, where there is
a hole 76 between the first two and the last two O-rings 86, the
hole 76 is located between the port 55 of the inner container 20A
and the port 55 of the attachable/detachable container 20B after
the connector 85 is inserted into the two ports 55. Although the
hole 76 can be oriented in any manner, in a preferred embodiment,
the hole 76 in the tube 84 is oriented upwards. If the hole 76 is
oriented upwards, fluid which is introduced into the tube 84 from
the source of vacuum, fluid, and/or other feedthrough 88 can travel
through the tube 84 into the interior of the inner container 20A,
and does not pass through the hole 76. The hole 76 on the connector
85 of FIG. 32C allows the attachable/detachable container 20B to be
evacuated through the connector 85. If the connector 85 of FIG. 32C
is used with the nested containers 20A and 20B shown in FIG. 31, it
is not necessary to have the communication port 30 on the inner
container 20A, because the inner container 20A can be evacuated
through the connector 85, and the attachable/detachable container
20B can be evacuated through the hole 76 in the connector. If
desired, hydrogen peroxide vapor or mist can be introduced into the
inner container 20A through the connector 85 and the
attachable/detachable container 20B through the hole 76 on the
connector 85 of FIG. 32C. In an alternative embodiment, liquid
comprising peroxide may be introduced into the inner container 20A
from the source of vacuum, fluid, and/or other feedthrough 88
through the connector 85.
[0221] A general method of sterilizing articles with the nested
containers 20A and 20B shown in FIGS. 28-31 is given below. The
general method comprises the following: [0222] 1. An article to be
sterilized is placed into the inner container 20A. [0223] 2. A
vaporizable germicide is placed into the inner container 20A and/or
is contacted with the article to be sterilized. [0224] 3. The inner
container 20A is placed into the attachable/detachable container
20B. [0225] 4. The inner container 20A and the
attachable/detachable container 20B are fluidly connected to the
source of vacuum, fluid, and/or other feedthrough 88. In an
embodiment, the containers 20A and 20B are fluidly connected to the
source 88 through the connector 85. The operations 1, 2, 3 and 4
may be in any order. Optionally, the germicide can also be placed
inside the attachable/detachable container 20B. [0226] 5. The
pressure in the inner container 20A and the attachable/detachable
container 20B is reduced to vaporize the germicide, sterilizing the
article in the inner container 20A, the inside and the outside of
the inner container 20A, and the inside of the
attachable/detachable container 20B. The germicide vapor reaches
the inside of the attachable/detachable container 20B through the
communication port 30 in the inner container 20A.
[0227] Optionally, plasma is generated and contacted with the
germicide and/or article to be sterilized and/or the two containers
20. The plasma may be generated inside one or both of the
containers 20.
[0228] In an alternative embodiment, vaporizable germicide is
placed into both the inner container 20A and the
attachable/detachable container 20B. When the pressure in the
attachable/detachable container 20B is reduced by exposing the
connector 85 to a vacuum from the source of vacuum, fluid, and/or
other feedthrough 88, the communication port 30 in the inner
container 20A allows gas to be transferred from the inner container
20A to the attachable/detachable container 20B, reducing the
pressure in the inner container 20A, vaporizing the germicide,
sterilizing the article in the inner container 20A as well as the
interior of the inner container 20A. In another embodiment, there
is no communication port 30 in the inner container 20A, and the
pressure in the attachable/detachable container 20B is reduced
through the hole 76 on the connector 85 of FIG. 32C.
[0229] In another embodiment of the method, germicide such as
peroxide is transferred from the source of vacuum, fluid, and/or
other feedthrough through the connector 85 into the inner container
20A rather than being placed directly into the inner container 20A
or being contacted with the article to be sterilized in the inner
container 20A. This embodiment of the method is applicable to
either embodiment of the method described earlier.
[0230] Plasma may optionally be introduced into either or both of
the containers in any of the embodiments of the method of the
invention.
[0231] In all of the embodiments of the method of the invention, by
properly placing the germicide in the inner container 20A and/or in
the attachable/detachable container 20B, the interior and the
exterior of the inner container 20A, the interior of the outer
attachable/detachable container 20B, and the article in the inner
container 20A are all sterile.
[0232] Having nested containers containing a sterile article, where
the inner container 20A is sterile on exterior and the outer
attachable/detachable container 20B is sterile on the interior, is
useful in a medical setting. For example, the nested containers
containing the sterile article can be transferred to an area close
to an operating room. The outer container 20B can be opened and the
inner container 20A removed. Because the exterior of the inner
container 20A is sterile, the inner container 20A containing the
sterile article can be transferred into a sterile environment such
as an operating room without contaminating the sterile environment.
The sterile article inside the sterile inner container 20A can be
removed from the container and utilized at leisure without concern
about contamination from the container in which it is housed.
[0233] FIGS. 34A, 34B, and and 34C schematically illustrate systems
for sterilizing one, two, and four attachable/detachable
containers, respectively. In FIG. 34A, a single
attachable/detachable container 20 is attached to a system 100 for
sterilizing attachable/detachable containers. The system 100
comprises a source of vacuum, fluid, and/or other feedthrough 88.
The system 100 may further comprise one or more heaters (not shown)
for heating the attachable/detachable container 20 and/or a source
of vaporizable germicide or peroxide (not shown). The system 100
may additionally comprise a source of plasma (not shown) and/or one
or more filters (not shown), where the filters are permeable to gas
and impermeable to microorganisms.
[0234] In the system 100 of FIG. 34A, the attachable/detachable
container 20 is attached to the system 100. The
attachable/detachable container 20 preferably contains an article
to be sterilized. The attachable/detachable container 20 is in
fluid communication with the system 100. Peroxide or other
vaporizable germicide is placed into the interior of the
attachable/detachable container 20 either before or after the
attachable/detachable container 20 is attached to the system 100.
The pressure in the attachable/detachable container 20 is reduced
to vaporize the germicide, sterilizing the article in the
attachable/detachable container 20 as well as the interior of the
attachable/detachable container 20. The germicide and/or the
attachable/detachable container 20 may be optionally heated. Plasma
may optionally be introduced into the attachable/detachable
container 20 before, during, and/or after the germicide is
introduced into the attachable/detachable container 20.
[0235] If the plasma is introduced prior to introducing the
peroxide or germicide, the plasma helps to dry the article to be
sterilized and/or the interior of the attachable/detachable
container 20. If the plasma is introduced during and/or after
introducing the peroxide or germicide, the plasma helps to
sterilize the article inside the attachable/detachable container 20
as well as the interior of the attachable/detachable container 20.
The plasma also helps to remove the residual in the container.
[0236] FIG. 34B shows a schematic diagram of a system 100 for
sterilizing two attachable/detachable containers 20. The system 100
comprises a source of vacuum, fluid, and/or other feedthrough 88.
In the system 100 shown in FIG. 34B, two attachable/detachable
containers 20 may be sterilized simultaneously. Although in some
embodiments, the system 100 for sterilizing two
attachable/detachable containers 20 may compose two separate
sources of vacuum, fluid, and/or other feedthrough 88, it is in
general preferred that the system 100 comprise a single source of
vacuum, fluid, and/or other feedthrough 88, where the source of
vacuum, fluid, and/or other feedthrough further comprises one or
more valves 82 between the source of vacuum, fluid, and/or other
feedthrough 88 and the attachable/detachable containers 20 so that
a first attachable/detachable container 20 can be attached and
detached from the system 100 without interfering with the
operations which are occurring on a second attachable/detachable
container 20. The system 100 may further comprise one or more
heaters for heating the two attachable/detachable containers 20
and/or a source of germicide or peroxide (not shown). The system
100 may additionally comprise one or more sources of plasma (not
shown). The system 100 may additionally comprise one or more
filters (not shown), where the filters are permeable to gas and
impermeable to microorganisms. Although not necessary, it is in
general preferable that the system 100 be able to perform each of
the sterilization steps on the first attachable/detachable
containers 20 independently of the sterilization steps which are
occurring on the second attachable container 20. The two
attachable/detachable containers 20 may therefore be sterilized at
different times or under different conditions.
[0237] With the system 100 of FIG. 34B, the attachable/detachable
containers 20 may be sterilized independently of one another, in a
synchronized manner, in an asynchonized manner, or in a
multitasking manner with at least one vacuum source.
[0238] FIG. 34C shows a schematic diagram of a system 100 for
sterilizing four attachable/detachable containers 20. Preferably,
each of the four attachable/detachable containers 20 in the system
100 can be attached, detached, and sterilized independently. In
other, less preferred embodiments, the attaching, detaching, and
sterilization of each of the attachable/detachable containers 20
occurs simultaneously with the attaching, detaching, and
sterilization of the other attachable/detachable containers 20.
Although performing the operations on each of the
attachable/detachable containers 20 simultaneously with the
operations on the other containers would minimize redundant
equipment, flexibility is lost. For example, if there is only one
vacuum system for the four containers, equipment costs would be
minimized. However, it may take a longer time to multitask and
sterilize all four attachable/detachable containers 20.
[0239] With the system 100 of FIG. 34C, the attachable/detachable
containers 20 may be sterilized independently of one another, in a
synchronized manner, in an asynchonized manner, or in a
multitasking manner with at least one vacuum source.
[0240] In each of the systems 100 illustrated in FIGS. 34A, 34B,
and 34C, articles can be sterilized in attachable/detachable
containers 20 without the need to place the articles in a large
vacuum chamber. There are many advantages to sterilizing articles
in attachable/detachable containers 20 which can be attached,
sterilized, and detached from systems such as shown in FIGS. 34A,
34B, and 34C. First, an individual article to be sterilized can be
placed into an attachable/detachable container 20, attached to a
system 100, and can be sterilized at any time, rather than having
to wait until enough equipment has been accumulated to make it
worthwhile to sterilize a large load in a large sterilization
chamber. Sterilizing an article in an attachable/detachable
container 20 therefore provides flexibility in scheduling
sterilization of individual articles.
[0241] Second, sterilizing an article in an attachable/detachable
container 20 provides flexibility in varying the sterilization
conditions. For example, if an article is to be sterilized with an
unusual set of conditions, it may be sterilized in an
attachable/detachable container 20 without having to sterilize an
entire large load under the same set of conditions in a large
sterilization chamber.
[0242] Third, the sterilized article is contained inside the
attachable/detachable container 20 after being sterilized. The
attachable/detachable container 20 with the sterilized article
inside may be transported large distances inside the
attachable/(detachable container 20 without a need to be concerned
that the article become accidentally contaminated by being exposed
to bacteria. The sterilized article is protected from contamination
by being contained in the attachable/detachable container 20.
[0243] Fourth, the attachable/detachable container 20 which is
sterilized in the system 100 can be a nested container 20, as
shown, for example, in FIGS. 28-31. The sterilized article is
contained in the inner container 20A, which is in turn contained in
the outer attachable/detachable container 20B. Because both the
inside and the outside of the inner container 20A are sterile, the
outer attachable/detachable container 20B can be transported to an
area near to an operating room, the inner container 20A removed,
and the sterile inner container 20A with he sterile article inside
placed in a sterile area such as an operating room without having
concerns about contaminating the sterile area with a nonsterilized
container.
[0244] The various embodiments of attachable/detachable container
20 and the sterilization system shown in FIGS. 34A, 34B, and 34C
therefore provide additional scheduling convenience and flexibility
compared to conventional sterilization systems.
[0245] The sterilization system shown in FIGS. 34A, 34B, and 34C
has been described in terms of introducing a liquid comprising
vaporizable germicide into an attachable/detachable container 20.
In an alternative embodiment, the attachable/detachable containers
20 and the sterilization systems such as shown in FIGS. 34A, 34B,
and 34C can be used with germicide vapor rather than liquid.
[0246] In the embodiments where germicide vapor is used, the
attachable/detachable container 20 can be any kind of container and
is not necessarily diffusion restricted. If germicide vapor is used
to sterilize articles in attachable/detachable containers 20, the
process is as follows. An article to be sterilized is placed into
the attachable/detachable container 20. The container 20 is
attached to a vacuum source. The placing and attaching can be in
either order. The attachable/detachable container 20 is evacuated,
and germicide vapor is introduced into the attachable/detachable
container 20, sterilizing the article and the inside of the
attachable/detachable container 20. The container 20 with the
sterilized article may be detached from the vacuum source. Plasma
may optionally be introduced into the attachable/detachable
container 20 before, during, and/or after the germicide vapor is
introduced into the attachable/detachable container 20. If the
plasma is introduced prior to introducing the germicide vapor, the
plasma helps to dry the article to be sterilized and/or the
interior of the attachable/detachable container 20. If the plasma
is introduced during and/or after introducing the germicide vapor,
the plasma helps to sterilize the article inside the
attachable/detachable container 20 as well as the interior of the
attachable/detachable container 20. The plasma also helps to remove
the residual in the container. The source of germicide vapor can be
liquid or solid.
[0247] Sterilization of articles in attachable/detachable
containers 20 with germicide vapor rather than with liquid
comprising vaporizable germicide has the same advantages as
sterilization of articles in attachable/detachable containers 20
with liquid comprising vaporizable germicide. The advantages of
sterilizing articles in attachable/detachable containers 20 include
flexibility in scheduling, flexibility in varying sterilization
conditions, the ability to transport sterilized articles in the
attachable/detachable container without being concerned that the
article be accidentally contaminated by bacteria, and the ability
to sterilize an article in nested containers, where the outside of
the inner container is sterile.
[0248] While the invention has been described in connection with
preferred liquid sterilant solutions containing hydrogen peroxide,
it will be appreciated by those having ordinary skill in the art
that equivalent sterilization methods can be adapted for other
sources of peroxide sterilants. In an alternative embodiment, a
sterilant having a vapor pressure lower than that of water or other
solvent in which the sterilant may be provided is used. For such
sterilants, it is only important that the vapor pressure be lower
than that of the solvent within the temperature ranges contemplated
herein. In yet other embodiments, a solid source of peroxide
sterilant may be utilized. Such liquid and solid sterilants can be
adapted for the techniques described herein with only minor
adjustments made for the differences in vapor pressure between
hydrogen peroxide and such other sterilant, as can be readily
determined by those having ordinary skill in the art. As long as
the local vapor pressure at the site of the sterilant is below the
vapor pressure of the sterilant, sterilization can be achieved
substantially as described hereinabove.
Conclusion
[0249] Achieving rapid sterilization of lumened devices at low
temperatures using low concentrations of sterilants has, until now,
been exceedingly challenging. A superior method of sterilization
has been discovered which overcomes the problems of the known
methods. By pre-treating articles to be sterilized or a
diffusion-restricted environment containing the articles with a
source of peroxide such as an aqueous solution of hydrogen peroxide
prior to exposure to a vacuum, rapid sterilization can be achieved
at low temperatures, without damage to the articles, without
leaving toxic residues behind, and without the need to attach
special vessels. The method of the present invention is efficient,
nonhazardous, and inexpensive as well.
[0250] Methods are also provided for sterilizing articles in
containers, including attachable/detachable containers and nested
containers. Sterilizing methods in attachable/detachable containers
provides flexibility in scheduling the sterilization as well as
increasing the opportunities for transporting and utilizing the
sterilized article in the attachable/detachable container without
recontaminating the article.
* * * * *