CN108619536A

CN108619536A - Bactericidal unit and method are injected in fluid sterilization agent

Info

Publication number: CN108619536A
Application number: CN201810323371.1A
Authority: CN
Inventors: 丹尼尔·皮
Original assignee: Individual
Current assignee: Individual
Priority date: 2011-06-21
Filing date: 2012-06-21
Publication date: 2018-10-09
Also published as: EP2723395A1; CN103813811A; EP2723395B1; US20130008137A1; EP2723395A4; WO2012177933A1; HK1198245A1; BR112013033307A2

Abstract

This application involves fluid sterilization agent injection bactericidal unit and methods.The method for sterilizing to container is provided, wherein penetrating barrier using what injection member penetrated the empty device of sealing.Then fluid sterilization agent is injected into the interior chamber of described device by the injection member.Allow fluid sterilization agent stop in the chamber sufficient amount time so that the room it is sterile or sterilization.Then product can be introduced by the barrier in described sterile or sterilization room.Then generated perforation is sealed again, and product is hermetically sealed in the room.

Description

Bactericidal unit and method are injected in fluid sterilization agent

The application be the applying date be on June 21st, 2012, application No. is " 201280040640.4 ", it is entitled " stream Body bactericidal agent injects bactericidal unit and method " Chinese patent application divisional application, original application be International Application Serial No. PCT/ The National Phase in China application of US2012/043623.

Entitled " the NITRIC OXIDE INJECTION that patent application claims were submitted on June 21st, 2011 The U.S. Provisional Application 35U.S.C. § 119 of STERILIZATION DEVICE AND METHOD ", Serial No. 61/499,626 (e) equity under, is expressly incorporated into herein, using the part as present disclosure.

Technical field

This application involves to sealing empty container sterilizing, and more particularly, to by injecting nitric oxide into container Gas or other fluid sterilization agent are to sealing empty container sterilizing.

Background technology

Often, manufacture container accommodates the sensitive product that must keep sterile, to avoiding any bacterium or microorganism from existing Wherein grow.Such case is often for drug, food, nutriment, ophthalmically acceptable product and other types product.Therefore, It must sterilize to these containers before product filled.Prior art systems are had been set up to execute such task, But these systems may not always integral asepsis, but so that the container is briefly exposed to non-sterile substance, such as Air.On the other hand, some prior art systems can generate the environment of integral asepsis, but implement generally too expensive. Other prior art systems are radiated using γ to sterilizing containers.The shortcomings that this method is that γ radiation can be used in generation appearance The material damage of the sealing of device, the closure (closure) of container or closure or decomposition.

It is an object of the invention to overcome one or more disadvantages of the prior art and/or drawback.

Invention content

According to the first aspect, method includes the following steps：

(i) utilize what injection member (injection member) penetrated the empty device (device) of sealing to penetrate barrier (penetrable septum)；

(ii) fluid sterilization agent (fluid sterilant) is introduced by the interior chamber of described device by injection member In (interior chamber)；

(iii) allow the fluid sterilization agent stop in the chamber sufficient amount time so that the room at least substantially without Bacterium or basic sterilization；

(iv) using inject or filling element penetrate it is described can penetrate barrier, will be produced by the injection or filling element Product are introduced into described sterile or sterilization room；And

(v) generated perforation (penetration aperture) is sealed again, and the product is hermetically sealed within In the room.

In some embodiments, step (i) and (ii) are carried out at fluid sterilization agent station (station), and step (iii) exists Bactericidal agent docking station carries out, and step (iv) is carried out in loading station or product injection station, and step (v) is carried out in resealing station, and In some embodiments, it is also carried out in curing station.

In one embodiment, the method further includes being removed from room before introducing product into room (withdraw) fluid sterilization agent.In some such embodiments, removing step includes by across can penetrate barrier The device of insertion vacuumizes.In some embodiments, the removal of fluid sterilization agent is evacuating station or vacuum station progress.Another In some embodiments, carried out in loading station.

In some embodiments, it is needle across the device of barrier insertion can be penetrated.In some embodiment party of the present invention In case, fluid sterilization agent is nitric oxide or other hydroxyl radical gas (free radicalgas).

Some embodiments further include carrying out sterilizing or decontamination to the penetrable surface of barrier before step (iv) (decontaminating).Some such embodiments further include penetrable surface before the step (i) to barrier into Row sterilizing or decontamination.In some embodiments, include applying to flow to penetrable surface to the sterilizing of penetrable surface or decontamination Body bactericidal agent or radiation.In some embodiments, fluid sterilization agent is hydrogen peroxide (the vaporized hydrogen of vaporization Peroxide, " VHP "), radiation is ultraviolet light (ultraviolet, " UV "), gamma-rays, β rays or electron beam (e-beam).

Some embodiments further include in step (iv) and (v) during introduce the filtrated air of superpressure (overpressure) Or other gases.Some such embodiments further include introduced during step (i) and (ii) superpressure filtrated air or its His gas.

In some embodiments, then sealing step includes applying fluid sealant to generated perforation.At some this In the embodiment of sample, then sealing step further includes applying radiation or energy to fluid sealant so that fluid sealant is from liquid phase It is solidified into solid phase.In some such embodiments, radiation is UV radiation, such as high energy pulse UV radiation.In the present invention Other embodiments in, barrier can be by sealing again to its application radiation or energy, then sealing step is included in institute Apply radiation or energy to barrier at the perforation of generation and perforation heat is made to seal again (thermally resealing).Another In some embodiments, barrier hot can again seal, and radiation or energy are laser or heat radiation or energy.

According to other side, equipment (apparatus) includes：

(i) device penetrates barrier it includes the empty room of sealing and with what the room was connected to；With

(ii) the fluid sterilization agent source being connected to injection member, the injection member are used to flow by the injection member Body bactericidal agent is introduced into the room of described device, and allow the fluid sterilization agent stop in the chamber the time of sufficient amount with Keep the room sterile or sterilizes.

In some embodiments of the present invention, the equipment includes also product source, in the product room to be loaded into, and And the product source is communicatively connect with injection or filling element fluid, the injection or filling element are used to utilize injection or dress Barrier can be penetrated and be introduced product into the room by injection member by filling out element and penetrating.Some such embodiments are also Including resealing station, is used to seal generated perforation again so that product to be hermetically sealed in room.It is such real at some It applies in scheme, resealing station includes fluid sealant source, is used in generated perforation metering liquid sealant and close again Seal the barrier.In some such embodiments, resealing station includes radiation or energy source, is used for hydraulic seal (transmit) radiation or energy are transmitted in agent so that sealant is solidified into solid phase from liquid phase.In other embodiment party of the present invention In case, resealing station includes radiation or energy source, is used at generated perforation apply radiation or energy simultaneously to barrier Make again seal by the perforation that radiation or energy (such as laser emission) seal again.

According on the other hand, the present invention relates to a kind of equipment, it includes：

(ii) first component (means), barrier can be penetrated and fluid is gone out by that can penetrate barrier by being used to penetrate Microbial inoculum is introduced into the room of described device, and allow fluid sterilization agent stopped in room sufficient amount time so that the room at least Substantially sterile or basic sterilization.

Some embodiments further include that can penetrate barrier for penetrating and introduced product by that can penetrate barrier Second component in room.Some embodiments further include for sealing the generated third member perforated again.Some embodiment party Case further includes for going out to the penetrable surface of barrier before penetrating barrier using the first component or second component 4th component of bacterium or decontamination.In some embodiments, the first component is injection member and is in fluid communication with injection member The fluid sterilization agent source of ground connection；Second component be injection or filling element and with it is described injection or filling element fluid communicatively The product source of connection；Third member is fluid sealant or radiation；And the 4th component is fluid sterilization agent or radiation.

In some embodiments, for the injection member of fluid sterilization agent, the device for vacuumizing and/or for producing The injection of product or filling element can be same, and as an alternative, the element or device can be with bactericidal agent source, vacuum Source is connected with product source.In some embodiments, fluid sterilization agent station or module, bactericidal agent docking station or module, evacuation It stands or vacuum station or module, loading station or module, resealing station or module, and/or curing station or mould one or more in the block Kind is combined so that one process can be performed for more than at single station or module.

An advantage of the invention that the fluid sterilization agent of injection makes the inside sterilizing or decontamination of device, so as to avoid Use γ radiation or necessity of the sterilizing of other prior arts and/or decontamination plant and method.And be can be for another advantage It sterilizes in same facility or uniform machinery before facing filling and with described device.

It is of the invention and/or its is currently preferred by the described in detail below of currently preferred embodiment and attached drawing The other objects and advantages of some embodiments will be apparent.

Description of the drawings

Fig. 1 is for carrying out sterilizing to sealing empty container and being carried out then to sterile chamber product filled and to container close again The sterilizing of envelope and the schematic diagram of loading system；With

Fig. 2 is the schematic diagram for showing another sterilizing and loading system.

Specific implementation mode

In fig. 1 it is shown that the schematic diagram of the disinfection system for sterilizing to sealing empty container.The disinfection system Including multiple stations, the station includes fluid sterilization agent injection station 14, bactericidal agent docking station 16, product injection station 18, resealing station 20 and curing station 22.Multiple fan/filter components (assembly) 24 are installed with the station fluid flow communication, optionally every The filtrated air or other gases of superpressure are provided in one station.Device building station can be provided before disinfection system to manufacture dress Set 10.

Manufacturing device 10 in station 12 or device building station is completely molded shown in fig. 2, therefore, in some embodiments In, the snap ring (snap- for including check valve is formed by co-molded (co-molding) or secondary molding (over-molding) ring).In comprising some of snap ring embodiments, the secondary molding valve deck (valve cover) on valve body, and it is parallel Ground, injection molding (in.jection molded) preform (pre-form) are simultaneously blow molded in turn to form pouch (pouch). It can be according to device disclosed in following application and manufacturing method construction device 10：It is entitled in what is submitted May 18 in 2007 “Delivery Device with Separate Medicament and Beverage Chambers Connectable The U.S. of the co-pending of in Fluid Communication When Ready for Use, and Related Method " Apply for No.11/804,431, the application requires the U.S. Provisional Application of similar title submitted on May 18th, 2006 The priority of No.60/801,978；Entitled " the Co-Extrusion Blow Molding submitted on October 9th, 2009 The U. S. application No.12/577 of the co-pending of Apparatus and Method, and Sealed Empty Devices ", 104, the application requires the U.S. Provisional Application No.61/104 for the similar title submitted on October 10th, 2008,649 it is excellent First weigh；Entitled " the Device with Co-Extruded Body and Flexible submitted on October 9th, 2009 The U. S. application No.12/ for the co-pending that Inner Bladder and Related Apparatus and Method are 577,126, the application requires the U.S. Provisional Application No.61/104 for the similar title submitted on October 10th, 2008, and 613 Priority；And entitled " Device with the Co-Molded Closure, One- submitted on October 8th, 2010 The co-pending of Way Valve and Variable-Volume Storage Chamber and Related Method " U. S. application No.12/901,420, entitled " the Device with Co- that the application requirement was submitted on October 9th, 2010 Molded One-Way Valve and Variable-Volume Storage Chamber and Related Method” U.S. Provisional Application No.61/250,363 priority；Herein by each of these applications all by quoting clearly It is incorporated to, using the part as present disclosure, as fully provided herein.Apparatus main body 26 also with apparatus main body 26 Closure 28 (such as above-mentioned snap ring/valve deck) and other assemblies parallelly mold.When all components are completed, automaton (robotic machine), which attaches together snap ring and valve group, is assigned to pouch to form sealing sky device 10.Then can sterilizing and/ Or assembly sealing sky device 10 before filling.When fully assembled, each device 10 is the empty container of sealing, and it includes main bodys 26, the sealing room 30 in the closure 28 and main body 26 of the opening of sealed body.

After complete assembly, device 10 is transferred to fluid sterilization agent injection station 14.At the station, can for example, by It applies ultraviolet radiation or is radiated by the sterilizing such as radiation of electron beam, γ or the β of any other form as known in the art It sterilizes come the penetrable surface (such as surface of closure 28) to device.In some embodiments, to outer surface and Penetrable surface is further sterilized.Then, needle 32 or other injection members are inserted into and penetrate closure 28.When with needle 32 When penetrating closure 28 to make needle 32 or pin hole and the sealing room 30 of main body 26 be in fluid communication, by needle 32 by fluid sterilization agent (such as nitric oxide gas (NO)) is injected into the inside of sealing room 30.After bactericidal agent (such as NO) is introduced into room 30, Needle 32 can be removed.Used fluid sterilization agent is not limited to NO, and can be any suitable bactericidal agent as known in the art, Including vaporized hydrogen peroxide (" VHP ").

Device 10, fluid sterilization agent injection station 14, closure 28, needle 32 can be provided according to the introduction of following application Deng：Entitled " Device with Penetrable Septum, the Filling Needle submitted on June 13rd, 2012 The U. S. application No.61/659 of and Pe netrable Closure, and Related Method ", 382；In 2012 4 The U. S. application No.13/450 for entitled " the Needle With Closure and Method " that the moon is submitted on the 18th, 306, institute Application is stated to require to submit the U.S. Provisional Application of entitled " Filling Needle and Method " on April 18th, 2011 The equity of No.61/476,523；The U.S. of entitled " the Self Closing Connector " that is submitted on April 18th, 2011 Apply for No.61/635,258；And/or entitled " the Self Closing Connector " submitted on April 17th, 2012 U. S. application No.61/625,663；These applications are expressly incorporated into herein, using as one of present disclosure Point, as fully provided herein.It should also be understood that application listed above is not limited to those of previous enumeration element, But any needle or injection member, injection station can be provided according to these applications or are related to injecting a fluid into device 10 It stands.

Alternatively, device 10 can be provided according to the introduction of following patent and co-pending patent application：In April, 2006 Entitled " Medicament Vial Having a Heat-sealable Cap, the and Apparatus and authorized for 25th The United States Patent (USP) No.7 of Method for Filling the Vial ", 032,631, the patent is on October 19th, 2004 The United States Patent (USP) No.6 for the similar title authorized, 805,170 part continuation application, the latter authorized on 2 3rd, 2004 United States Patent (USP) No.6,684,916 continuation application, United States Patent (USP) No.6,684,916 be in the class authorized on the 12nd of August in 2003 Like the United States Patent (USP) No.6 of title, 604,561 division, No.6,604,561 United States Patent (USP)s require again on 2 11st, 2000 The Serial No. No.60/182 for the similar title submitted, the priority of 139 U.S. Provisional Application, and also require in 2003 It the U.S. Provisional Patent Application No.60/442,526 of the similar title submitted on January 28, and is submitted on June 30th, 2003 The priority of the U.S. Provisional Patent Application No.60/484,204 of similar title；

In entitled " the Sealed Containers and Methods of Making that September in 2006 is authorized on the 5th The United States Patent (USP) No.7 of and Filling Same ", 100,646, the patent be authorized on 2 3rd, 2004 it is entitled " Medicament Vial Having a Heat-sealable Cap, and Apparatus and Method for The United States Patent (USP) No.6 of Filling the Vial ", 684,916 part continuation application, the latter are awarded within 12nd in August in 2003 The United States Patent (USP) No.6 of the similar title given, 604,561 division, United States Patent (USP) No.6,604,561 are required in 2000 years 2 again The Serial No. No.60/182 for the similar title that the moon is submitted on the 11st, the priority of 139 U.S. Provisional Application, and also require In entitled " the Sealed Containers And Methods Of Making And that September in 2002 is submitted on the 3rd The priority of the U.S. Provisional Patent Application No.60/408,068 of Filling Same "；And it is submitted on April 18th, 2011 Entitled " Filling Needle and Method " co-pending U.S. Provisional Application No.61/476,523；Herein Each of these applications is all expressly incorporated into, using the part as present disclosure, as herein In fully provide.

For example, may include or limit can be by its application radiation or penetrating of sealing again of energy and can be again for closure 28 Hermetic unit or element.In some such embodiments, it can penetrate and resealable part can be reclosable by heat Thermoplastic material is formed, can be by airtightly sealing pin hole to its application heat, heating or laser emission or energy.At some In embodiment, can penetrate and resealable part be can be again by applying the laser of predetermined wavelength and/or predetermined power to it Sealing.It can penetrate and resealable part limits：(i) predetermined wall thickness in its axial direction, (ii) predetermined color and opaque It spends (opacity), substantially absorb the laser emission of predetermined wavelength and prevents radiation by its predetermined wall thickness substantially, and/or (iii) predetermined color and opacity cause the laser emission of predetermined wavelength and/or power gas in such as predetermined amount of time Thickly seal the pin hole wherein formed and described can penetrate and resealable part is (that is, in the molecule of material of not burning substantially Irreversible variation is not generated in terms of structure or chemical property).In some embodiments, predetermined amount of time is about 2 seconds, is less than Or equal to 1.5 seconds or less than or equal to about 1 second.In some embodiments, the predetermined wavelength of laser emission is about 980nm, And the predetermined power of each laser is less than about 30 watts or less than or equal to about 10 watts or is about 8 to about 10 watts It is special.In addition, in these embodiments some, the predetermined color of material is grey or green, predetermined opacity by with The grey or green colourant (or pigment) that the amount of by weight about 0.3% to about 0.6% is added in material limit.

In some embodiments, it can penetrate and resealable part includes base portion (base portion) or basal part (underlying portion) and it is covered in sealing again on base portion or resealable part.In some such embodiments In, base portion is in response to can penetrate and resealable part applies radiation or when energy can be substantially non-fusible.In some realities It applies in scheme, can penetrate and the thickness of resealable part and/or resealable part substantially prevents enough radiation or energy Amount or its power reach base portion.In some embodiments, base portion is formed by the material not radiated or energy seals again.One In a little embodiments, base portion is vulcanized rubber (vulcanized rubber) or silicone (silicone) material.In some implementations In scheme, the material with to be placed to indoor substance (for example, certain drug) it is compatible (for example, inertia).In some implementations In scheme, resealable part is thermoplastic material.In some embodiments, then hermetic unit be in response in for example radiation or The curable materials of energy form base with sealed penetration and in room (a) 30 and at least one of base portion between (b) ambient air This airtight sealing.In addition, basal part and the one or more of covering part have one or more layers.

It is understood, however, that can penetrate and resealable element can be by being currently known or then becoming known a variety of Any one of different materials (such as a variety of different any one of thermoplasticity and/or elastic material, including such as low-density Polyethylene) it is made to implement the function of resealable element described herein.

In addition, if desired, can penetrate and in resealable part addition or comprising related field ordinary skill people The lubricant of member's known type can be penetrated and resealable with preventing or otherwise reducing being penetrated with needle or filling element Partly and/or by needle or load formation of the element from particle when can penetrate and resealable part removes.In an embodiment In, lubricant is mineral oil, when being penetrated with needle or other filling elements by be enough to prevent or prevent particle from being formed substantially Amount be added in styrene block copolymer or other thermoplastic compounds.In another embodiment, lubricant is silicon Ketone, such as the liquid silicones or silicone sold with title " 360Medical Fluid, 350 CST " by Dow Corning companies Oil is added to styrene when being penetrated with needle or other filling elements with the amount for being enough to prevent or prevent particle from being formed substantially In block copolymer or other thermoplastic compounds.In such embodiment, including silicone oil amount be by weight Gauge about 0.4% to about 1%, such as by weight about 0.4% to 0.6%, or even by weight about 0.51% to about 0.5%.

In addition, according to some embodiments, closure 28 includes：(i) by weight about 80% to about 97% (such as by weight Gauge 95%) styrene block copolymer；(ii) alkene of by weight about 3% to about 20% (for example, about 5%), such as Ethylene ' alpha '-olefin, polyolefin or alkene；(iii) pigment or colorant, additive amount are enough such as (but not limited to) are less than Laser energy is absorbed in about 2 seconds or the period less than about 1.5 seconds or less than about 1 second, radiation is transformed into heat and depth of fusion Equal to the stopper material of at least about 1/3 to about 1/2 of such as pin hole depth.In some such embodiments, it can add It is enough to reduce the frictional force at needle interface during needle is penetrated and/or removed and then prevents the lubricant for the amount that particle formed substantially, Such as above-mentioned mineral oil, liquid silicones or silicone oil.

In addition, penetrating the needle of closure 28, vacuum plant, injection or loading the construction of element 32,46,48 as that can also control Frictional force that needle processed/material interface generates and/or across the needle stroke (stroke) of closure 28 to further decrease or substantially Prevent the formation of the particle when penetrating plug with needle.In other embodiments, needle etc. can also be at least in needle and closure 28 Material interface include needle on lubricant or reduce friction coating.

In addition to controlling one or more above-mentioned parameters to reduce and/or eliminate the formation of particle (for example, in thermoplasticity Close in object includes silicone oil or other lubricants, and the frictional force degree, and/or needle of the construction of control needle, needle/plug interface Across the stroke of plug) except, or alternatively, its each can be used alone or being applied in combination with any desired, Selection can penetrate and the different elongations of the component of resealable part (elongation) are to reduce or eliminate the formation of particle.

According to some such embodiments, can penetrate and resealable part may include with the first elongation first Material, and the second material with the second elongation different from (for example, being less than) described first elongation.As one In embodiment, the first material includes the first thermoplasticity material of by weight about 80% to about 97% and the first elongation of restriction Material, the second material include by weight about 3% to about 20% and limit the of the second elongation less than the first material percentage elongation Two thermoplastic materials.In some such embodiments, addition is enough such as (but not limited to) less than about 2 seconds or is less than about Laser energy is absorbed in 1.5 seconds or the period less than about 1 second, radiation is transformed into heat and seals such as depth is again equal to pin hole The pigment or colorant of the amount of the stopper material of at least about 1/3 to about 1/2 of depth.It can penetrate and resealable part can be optional Ground includes lubricant, such as above-mentioned mineral oil, liquid silicones or silicone oil, and additive amount is enough big during penetrating plug with needle Width reduces the frictional force at needle/plug interface and then prevents the formation of particle substantially.

In some embodiments, it can penetrate and resealable part has enough lubricities or otherwise by itself It reduces the frictional force between material and needle etc. or the material of included lubricant is made, then need not just add additional profit It lubrication prescription and/or need not be formed using above-mentioned needle etc. with reducing or preventing particle.For example, in the application being incorporated above and also residing in The U.S. Provisional Application of entitled " the Modular Filling Apparatus and Method " that submits on April 13rd, 2012 There are these characteristics, the document to be incorporated herein by reference in their entirety for No.61/686, the silicone material described in 867.

In some embodiments, closure 28 by can at least substantially redeformation return its original shape elastic force it is suitable Elastic material is formed, therefore at least any hole at pin hole position caused by base closed or notch after removal of the needle (breach), thus basically prevent injection fluid sterilization agent escape from room.Then automaton (not shown) (such as is chosen Select and place machine) device 10 for having loaded fluid sterilization agent is transferred to bactericidal agent docking station 16.The device of bactericidal agent is loaded 10 stop the inner sterilization for the device 10 for making to be exposed to fluid sterilization agent or required make a reservation for that sterilize in bactericidal agent docking station 16 Residence time.

In another embodiment, bactericidal agent docking station 16 can be gaseous sterilization unit 34 as an alternative.Such as Fig. 2 Shown, gaseous sterilization unit 34 includes the conveyer belt 36 for transporting the device 10 for having loaded bactericidal agent.Bactericidal agent is loaded Device 10 is placed on conveyer belt 36 and is transported along roundabout by automaton 38, allows when device 10 advances along path It is sterilized to the inside of device 10 with bactericidal agent fluid.The path length by gaseous sterilization unit 34 and transport by device 10 Velocity correlation joins, so that inner sterilization of the haulage time at least equal to the device 10 for making to be exposed to fluid sterilization agent or sterilizing institute The predetermined parking time needed.

Nitric oxide gas is naturally-produced little module hydrophobic free base gas.NO shows wide reactivity and passes through life The characteristic that object entity is spread rapidly.For this purpose, NO is natively generated as a part for body immune defence in human body.Table Bright NO is especially antimicrobial in nature, directly inhibits the growth of bacterium, killing is also served as in the immunocyte of activation Molecule.It has been proved that when the time of NO gases sufficient amount present in an amount sufficient, inhibit and prevent multiple-microorganism cause of disease The growth of body.Therefore, as device 10 is transported through bactericidal agent docking station 16 or gaseous sterilization unit 34, as the NO injected When stop is enough to realize a period of time of sterilizing in room, the NO injected makes the inner surface of container sterilize.Related field is common Technical staff will recognize based on introduction herein, can also use appointing in the fluid sterilization agent of various other types Any one of one kind, including be currently known or then become known a variety of different types of hydroxyl radical gas.

When device 10 leaves bactericidal agent docking station 16, the inside of device is sterile, therefore device is to be injected in product Stand 18 or load module sterilizing filling get ready.The automaton 40 of automaton such as Fig. 2 can be by device 10 by going out Microbial inoculum docking station 16 or gaseous sterilization unit 34 are transferred to the conveyer belt 42 or complete loading station 44 of product injection station 18.It is producing Product injection station 18, if it is desired to or need, can for example this field be radiated or pass through by applying high-intensity ultraviolet (" UV ") The sterilizing (such as electron beam irradiation, γ radiation or β radiation) of known arbitrary other forms to the available needle of device penetrates table Face (such as surface of closure 28) sterilizes.Then, identical position or different position needles are being injected from bactericidal agent 46 or vacuum plant penetrate closure 28 or barrier, and vacuumized with from the sterilization of device 10 or sterile inner removal with needle Fluid sterilization agent (such as NO).The evacuation can also be generated by the vacuum pipeline formed in needle or on the outer perimeter of needle.

Then needle 46 or filling will be loaded in the same area or different parts being inserted into needle before or injection member is inserted Enter and pass through closure 28 or barrier, and desired product is loaded into cleanly or with sterile manner by desinfection chamber by needle 46 In 30.

In some embodiments, from the step of inner pumping fluid sterilization agent of device 10 may be it is unnecessary and It can not use.This may depend on the product in used fluid sterilization agent and device to be loaded into.For example, if fluid goes out Microbial inoculum does not influence product, or relative to the product in device 10 to be loaded into be it is inert, then it may not be necessary to Product sterilely removing fluids bactericidal agent before filling device 10.In such a case, it is possible to skip evacuation of fluids bactericidal agent Step, and fluid sterilization agent can be made still to retain in apparatus 10 while with desired product filling device 10.

In other embodiments, needle 48 can be it is known and described above in the United States Patent (USP) No.6 that is incorporated to, " two-chamber " needle in 604,561 or multi-cavity needle, the needle set be useful for by product be injected into first fluid channel in room 30 or Conduit and for the suction during filling or for example by replacing bactericidal agent or by vacuum (such as by second with institute product filled Fluid channel is connected with vacuum source) come the second fluid channel for making fluid sterilization agent be come out from room 30 or conduit.

In addition, in some embodiments, in the filtrated air of superpressure or other gases (such as nitrogen or inert gas) The lower operation for carrying out evacuation of fluids bactericidal agent and filling device 10, to help to maintain sterilizing.

After product is loaded into room 30, device 10 is transferred in resealing station 20 to seal generated wear again Hole.In embodiment shown in Fig. 1, when in resealing station 20, into closure 28, generated needle perforation, which applies, measures The fluid sealant 50 (such as silicone sealant) of amount airtightly seals closure to be combined with closure 28 or barrier 28.Then device 10 is transferred in curing station 22, pulsed ultraviolet light source 52 emits arteries and veins on fluid sealant 50 here Ultraviolet radiation is rushed so that sealant cures, cause it from liquid phase at solid phase, then airtightly seals following needle perforation. The process has in previously cited patent application to be further described in detail.

It, can be as described above and according to the patent of following patent and co-pending in as some of replacement embodiments The introduction of application carrys out perforation caused by laser resealable：In the entitled " Medicament that on April 25th, 2006 authorizes Vial Having a Heat-sealable Cap, and Apparatus and Method for Filling the The United States Patent (USP) No.7 of Vial ", 032,631, the patent is that the U.S. for the similar title authorized on October 19th, 2004 is special Sharp No.6,805,170 part continuation application, the latter are the United States Patent (USP) No.6 authorized on 2 3rd, 2004,684,916 Continuation application, United States Patent (USP) No.6,684,916 be the United States Patent (USP) No.6 for the similar title authorized for 12nd in August in 2003, 604,561 division, United States Patent (USP) No.6,604,561 require in the sequence number of the 11 days 2 months similar titles submitted in 2000 again For No.60/182, the priority of 139 U.S. Provisional Application, and also require the similar title submitted on January 28th, 2003 U.S. Provisional Patent Application No.60/442,526 and the similar title submitted on June 30th, 2003 US provisional patent Apply for the priority of No.60/484,204；In entitled " the Sealed Containers and that September in 2006 is authorized on the 5th The United States Patent (USP) No.7 of Methods of Making and Filling Same ", 100,646, the patent is in 2004 2 Entitled " Medicament Vial Having a Heat-sealable Cap, the and Apparatus that the moon is authorized on the 3rd The United States Patent (USP) No.6 of and Method for Filling the Vial ", 684,916 part continuation application, the latter be in The United States Patent (USP) No.6 for the similar title that August in 2003 is authorized on the 12nd, 604,561 division, United States Patent (USP) No.6,604,561 Again require in the 11 days 2 months similar titles submitted in 2000 Serial No. No.60/182,139 U.S. Provisional Application it is excellent It first weighs, and also requires entitled " the Sealed Containers And Methods Of submitted for 3rd in September in 2002 The priority of the U.S. Provisional Patent Application No.60/408,068 of Making And Filling Same "；And in 2011 4 The U.S. Provisional Application No.61/ of the co-pending for entitled " the Filling Needle and Method " that the moon is submitted on the 18th 476,523；Each of these applications is all expressly incorporated into herein, using as one of present disclosure Point, as fully provided herein.

In other embodiments, such as example the U. S. application No.61/659 being above incorporated to, 382 and beautiful State patent No.7, described in 100,646, can by placing covering or covering part on hole come sealed penetration again, from And substantially gas-tight sealing is formed between (b) ambient air in room (a) 30 and at least one of closure 28.The covering Or covering part can be used as the moisture for alternately or in addition contributing to provide therebetween and penetrate (moisture vapor Transmission, MVT) barrier.In some embodiments, covering or covering part are transparent, thus in order to After sealing again from room 30 removing substances, can by needle or other remove devices be inserted into room 30 across covering, without Covering or closure 28 are removed, exposure of the substance to ambient air in room 30 is reduced.

At this point it is possible to which device 10 is transferred to vanning (boxing) by automaton (such as automaton 54 of Fig. 2) Vanning with labeling station 58 and labelling conveyer belt 56, device 10 is that packing is prepared here.

In some embodiments, used conveyer belt can be manufactured by Switzerland Co., Ltd Montech AG " Montrac " conveyer belt.For example, for the embodiment of Fig. 2, pass through the gaseous sterilization conveyer belt of the operation of gaseous sterilization unit 34 36, Montrac conveyer belts can respectively be used by loading conveyer belt 42 and vanning and label transport band 56.Each conveyer belt It is configured so as to along respective conveyer belt conveyer 10 in a manner of known to the person of ordinary skill in the relevant.

In another embodiment, each module of each disinfection system may include multiple stations.For example, disinfection system is each Module may include 3 stations.In this exemplary embodiment, each module has 3 ultraviolet disinfection stations (it may include ultraviolet light Sterilizing, fluid sterilization agent injection and bactericidal agent stop), 3 NO evacuations/vacuum stations, 3 product loading station, 3 fluid sealants It stands and 3 ultraviolet curing stations.The quantity at the station of each module can be increased or decreased to match desired system throughput.

In another embodiment of the present invention, each module of each disinfection system may include only one station.At one In such exemplary implementation scheme, module may include that a ultraviolet disinfection station, (it can be wrapped a fluid sterilization agent injection station Stopped containing bactericidal agent) and laser resealing station.In this exemplary embodiment, evacuation of fluids bactericidal agent is not needed, because its No adverse reaction is loaded to product.

In other embodiments, according to by quoting the United States Patent (USP) No.7 that is integrally incorporated, 096,896 introduction, One or more above-mentioned stations or module and/or its function can be merged, to which at one, station or position are performed for more than one Function.In some such embodiments, not needing conveyer belt or automatic device makes device 10 be moved between " combination " stands It is dynamic.

In other embodiments, needle 32,46 and 48 can be combined, so that being carried out using a needle It is more than a kind of function in bactericidal agent injection, vacuum and filling function.For example, closure 28 can be penetrated using needle 32 and injected Then bactericidal agent makes bactericidal agent source be disconnected with needle for example, by valve or other methods, and may then pass through such as valve Or other methods make needle be connect with vacuum source.In other embodiments, closure 28 and applying vacuum are penetrated using needle 46, So that vacuum source is disconnected with needle for example, by valve or other methods, and so that needle is connected with product source for example, by valve or other methods It connects to load room 30.In other embodiments, a needle can be used only, alternately connect bactericidal agent, vacuum and product. In some such embodiments, multi-cavity element (there are two or more fluid channels) can be used, different chambers connects Connect or can connect different sources.In some such embodiments, reduces and need to penetrate closure 28 (and therefrom removing) Number, reduce total processing time, reduce the number penetrated in closure 28, and may decrease and seal number again (the less hole of sealing), improves the sealing integrity of closure, has reduced or eliminated and gone out again to the exposed surface of closure 28 The needs of bacterium, and reduce the potential pollution to room 30 and/or product therein.

Based on introduction herein, related field those skilled in the art, which will appreciate that, is outlined above the present invention Embodiment and other embodiments make various changes and modifications, without departing from this hair limited in the following claims Bright range.Further, it is possible to use any of the above-described feature and being combined with each other in any way.Therefore, the present invention is not limited to have The embodiment of body description and combination, but may include or exclude the combination of arbitrary characteristics or feature.It therefore, should be by embodiment party These detailed descriptions of case are interpreted as illustrative rather than restrictive meaning.

The invention further relates to following embodiments：

1. a kind of method comprising following steps：

(i) barrier is penetrated using what injection member penetrated the empty device of sealing；

(ii) fluid sterilization agent is introduced into the interior chamber of described device by the injection member；

(iii) the fluid sterilization agent is allowed to stop the time of sufficient amount in the chamber so that the room is sterile or kill Bacterium；

(iv) it is introduced product into described sterile or sterilization room by the barrier；And

(v) generated perforation is sealed again, and the product is hermetically sealed in the room.

2. the method as defined by embodiment 1 further includes before the product is introduced into the room from institute State removing fluids bactericidal agent in room.

3. the method as defined by embodiment 2, wherein the removing step includes that described can penetrate barrier by passing through The device that object is inserted into vacuumizes.

4. the method as defined by embodiment 3, wherein described device are limited by the injection member.

5. the method as defined by embodiment 3, wherein being needle across the described device that can penetrate barrier insertion.

6. the method as defined by any one of embodiment 1 to 5, wherein the step of introducing product includes passing through institute It states injection member and introduces the product.

7. the method as defined by any one of embodiment 1 to 5, wherein the step of introducing product includes with filling Element penetrates and described can penetrate barrier and the product is introduced into described sterile or sterilization room by the filling element In.

8. the method as defined by any one of foregoing embodiments, wherein the fluid sterilization agent is nitric oxide.

9. the method as defined by any one of foregoing embodiments further includes at least one in step (i) and (iv) Sterilizing or decontamination are carried out to the penetrable surface of the barrier before a.

10. the method as defined by embodiment 9, wherein the sterilizing or decontamination of the penetrable surface include to it is described can It penetrates surface and applies fluid sterilization agent or radiation.

11. the method as defined by embodiment 10, wherein the fluid sterilization agent is VHP, the radiation is UV.

12. the method as defined by any one of foregoing embodiments, further include step (i), (ii), (iv) and (v) filtrated air or other gases of superpressure are introduced during at least one step.

13. the method as defined by any one of embodiment 1 to 12, wherein the sealing step again includes to produced Perforation apply fluid sealant.

14. the method as defined by embodiment 13, wherein the sealing step again further includes to the fluid sealant Apply radiation or energy, so that the fluid sealant is solidified into solid phase from liquid phase.

15. the method as defined by embodiment 14, wherein the radiation or energy are UV.

16. the method as defined by any one of embodiment 1 to 12, wherein produced by the sealing step again is included in Perforation at apply radiation or energy to the barrier and make the perforation is hot to seal again.

17. a kind of equipment, it includes：

Device penetrates barrier it includes the empty room of sealing and with what the room was connected to；With

The fluid sterilization agent source being connected to injection member, the injection member is for penetrating the barrier and by described Fluid sterilization agent is introduced into the room of described device by injection member, and the fluid sterilization agent is allowed to stop foot in the chamber Time for enough measuring is so that the room is sterile or sterilization.

18. the equipment as defined by embodiment 17, also includes：

Product source, the product wait being loaded into the room, and the product source is with (a) described injection member and (b) Load the fluid flow communication connection of one of element, the filling element be used for using the filling element penetrate described in can penetrate resistance Parting, the product to be introduced into described sterile or sterilization room by the injection member and the filling element.

19. the equipment as defined by embodiment 18 also includes resealing station, the resealing station for sealing institute again The perforation of generation, the product is hermetically sealed in the room.

20. the device as defined by embodiment 18 or 19 also includes fluid sealant source, the fluid sealant source For distributing fluid sealant in generated perforation and sealing the barrier again.

21. the device as defined by embodiment 20, also includes radiation or energy source, the radiation or energy source are used for Transmission radiation or energy are so that the sealant is solidified into solid phase by liquid phase on the fluid sealant.

22. the device as defined by embodiment 19, wherein the resealing station includes radiation or energy source, the radiation Or energy source is used at generated perforation apply radiation or energy to the barrier and the perforation heat is made to seal again.

23. a kind of equipment, it includes：

The first component, being used to penetrate described can penetrate barrier and can penetrate barrier by fluid sterilization agent by described It is introduced into the room of described device, and the fluid sterilization agent is allowed to stop the time of sufficient amount in the chamber so that the room Sterile or sterilization.

24. the equipment as defined by embodiment 23, also includes second component, the second component is used for by described Barrier can be penetrated to introduce product into described sterile or sterilization room.

25. the equipment as defined by embodiment 24 also includes third member, the third member for sealing institute again The perforation of generation.

26. the equipment as defined by embodiment 24 or 25, also includes the 4th component, the 4th component is used in profit It goes out to the penetrable surface of the barrier before penetrating the barrier with the first component or the second component Bacterium or decontamination.

27. the equipment as defined by any one of embodiment 23 to 26, wherein the first component be injection member and The fluid sterilization agent source being connect with the injection member fluid flow communication；The second component is in injection member and filling element One kind, and with the injection member or the product source that communicatively connect of filling element fluid；The third member is liquid Sealant or radiation；And the 4th component is fluid sterilization agent or radiation.

Claims

1. a kind of method comprising following steps：

(i) barrier that penetrates of the empty device of sealing with interior chamber is penetrated using injection member, it is opposite in the interior chamber It is to seal in ambient air；

(iii) the fluid sterilization agent is allowed to stop the time of sufficient amount in the chamber so that the room is sterile or sterilization；

(iv) fluid sterilization agent is removed from the room；

(v) it after removing fluid sterilization agent in the room, introduces product into described sterile by the barrier or kills In the room of bacterium；And

(vi) generated perforation is sealed again, and the product is hermetically sealed in the room；

After can penetrating barrier described in wherein being penetrated in the injection member, the room is sealing so that the injection member Part is in fluid communication with the sealing room, and the fluid sterilization agent is injected into the sealing room by the injection member It is internal.

2. method as defined in claim 1, wherein the removing step includes by passing through the barrier that can penetrate to insert The device that enters vacuumizes.

3. method as defined in claim 2, wherein described device are limited by the injection member.

4. method as defined in claim 2, wherein being needle across the described device that can penetrate barrier insertion.

5. method as defined in claim 1, wherein the step of introducing product includes being introduced by the injection member The product.

6. method as defined in claim 1, wherein the step of introducing product include with filling element penetrate it is described can It penetrates barrier and the product is introduced into described sterile or sterilization room by the filling element.

7. method as defined in claim 1, wherein the fluid sterilization agent is nitric oxide.

8. method as defined in claim 1, further include step (i) and (v) it is at least one before to the barrier The penetrable surface of object carries out sterilizing or decontamination.

9. method as defined in claim 8, wherein the sterilizing or decontamination of the penetrable surface include being penetrated to described Surface applies fluid sterilization agent or radiation.

10. method as defined in claim 9, wherein the fluid sterilization agent is VHP, the radiation is UV.

11. method as defined in claim 1 further includes at least one step in step (i), (ii), (v) and (vi) Period introduces the filtrated air or other gases of superpressure.

12. the method as defined by any one of claim 1 to 11, wherein the sealing step again includes being worn to generated Hole applies fluid sealant.

13. method as defined in claim 12, wherein the sealing step again further includes applying to the fluid sealant Radiation or energy, so that the fluid sealant is solidified into solid phase from liquid phase.

14. method as defined in claim 13, wherein the radiation or energy are UV.

15. the method as defined by any one of claim 1 to 11, wherein the sealing step again is included in generated wear Apply radiation or energy to the barrier at hole and the perforation heat is made to seal again.

16. a kind of equipment, it includes：

Device, what is be connected to it includes empty room and with the room penetrates barrier, and it is close that ambient air is equivalent in the empty room Envelope；With

The fluid sterilization agent source being connected to injection member, the injection member is for penetrating the barrier and by the injection Fluid sterilization agent is introduced into the room of described device by element, and the fluid sterilization agent is allowed to stop sufficient amount in the chamber Time so that the room it is sterile or sterilization, and from the room remove fluid sterilization agent,

17. equipment as defined in claim 16 also includes：

Product source, the product wait being loaded into the room, and the product source is loaded with (a) described injection member and (b) One of element fluid flow communication connect, the filling element be used for using the filling element penetrate described in can penetrate barrier Object, the product to be introduced into described sterile or sterilization room by the injection member and the filling element.

18. equipment as defined by claim 17 also includes resealing station, the resealing station for produced by sealing again Perforation, the product is hermetically sealed in the room.

19. equipment as defined by claim 17, also includes fluid sealant source, the fluid sealant source is used for institute Fluid sealant is distributed in the perforation of generation and seals the barrier again.

20. the equipment as defined by claim 19, also includes radiation or energy source, the radiation or energy source are used for institute It states and transmits radiation or energy on fluid sealant so that the sealant is solidified into solid phase by liquid phase.

21. equipment as defined in claim 18, wherein the resealing station includes radiation or energy source, the radiation or energy Amount source is used at generated perforation apply radiation or energy to the barrier and the perforation heat is made to seal again.

22. a kind of equipment, it includes：

The first component, being used to penetrate described can penetrate barrier and can penetrate barrier by described and introduce fluid sterilization agent Into the room of described device, and the fluid sterilization agent is allowed to stop the time of sufficient amount in the chamber so that the room is sterile Or sterilization,

After can penetrating barrier described in wherein being penetrated in the first component, the room is sealing so that described first Part is in fluid communication with the sealing room, and the fluid sterilization agent is injected into the sealing room by the first component It is internal.

23. the equipment as defined by claim 22, also includes second component, the second component is used to wear by described Saturating barrier introduces product into described sterile or sterilization room.

24. equipment as defined in claim 23 also includes third member, the third member for produced by sealing again Perforation.

Also include the 4th component 25. equipment as defined in claim 23, the 4th component is used to utilize described the One component or the second component carry out sterilizing or decontamination before penetrating the barrier to the penetrable surface of the barrier.

26. the equipment as defined by any one of claim 22 to 25, wherein the first component be injection member and with institute State the fluid sterilization agent source of injection member fluid flow communication connection；The second component is one in injection member and filling element It plants, and the product source communicatively being connect with the injection member or filling element fluid；The third member is hydraulic seal Agent or radiation；And the 4th component is fluid sterilization agent or radiation.

27. method as defined in claim 1, wherein remove fluid sterilization agent by injection member, the injection member with By fluid sterilization agent be introduced into the interior chamber by injection member be same injection member.

28. the method as defined by claim 27, wherein the injection member alternately connects bactericidal agent and product, Huo Zhesuo It is multi-cavity element to state injection member, connects or can connect bactericidal agent and product.

29. method as defined in claim 2 is gone out wherein alternately being connected by the device that can penetrate barrier insertion Microbial inoculum and vacuum source or the connection of multi-cavity element can connect bactericidal agent and vacuum source.

Also include vacuum source 30. equipment as defined in claim 16, the vacuum source is suitable for by for from the room The injection member for removing fluid sterilization agent vacuumizes, wherein the injection member is suitable for alternately connecting fluid bactericidal agent source and very Empty source or the injection member are multi-cavity elements, connect or can connect bactericidal agent source and vacuum source.

31. equipment as defined by claim 17, wherein the injection member or the filling element are suitable for alternately connecting Fluid sterilization agent source and product source or the injection member or the filling element are multi-cavity elements, are adapted to fluid Bactericidal agent source and product source.

32. the equipment as defined by claim 22 is also comprised mean for for removing fluid sterilization agent from the room The vacuum component that injection member vacuumizes, wherein the injection member is suitable for alternately connecting fluid bactericidal agent source and vacuum Part or the injection member are multi-cavity elements, connection or can connecting fluid bactericidal agent source and vacuum component.

33. equipment as defined in claim 23, wherein second component are suitable for alternately connecting fluid bactericidal agent source and product Source or the second component are multi-cavity elements, are adapted to fluid sterilization agent source and product source.