(12) INTERNATIONAL APPLICATIO:\T PUBLISHED UNDER THE PATEl\T COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`20 January 2011 (20.01.2011)
`
`PCT
`
`I IIIII IIIIIIII II IIIIII IIIII IIIII IIIII IIII I II Ill lllll lllll lllll lllll lllll llll 1111111111111111111
`(10) International Publication Number
`WO 2011/006877 Al
`
`CA, CH, CL, CN, CO, Cl<, CU, CZ, Dh, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`IIN, IIR, IIU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`Mh, MU, MK, MN, MW, MX, MY, MZ, NA, NU, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TII, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless orherwise indicated, fi1r every
`kind of regional protection available): ARIPO (BW, GR
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KO, KZ, MD, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GD, GR, IIR, IIU, ill, IS, ff, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK,
`SM, Tl{), OAPI (HF, HJ, CF, CU, Cl, CM, Cit\, UN, UQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Declarations nnder Rnle 4.17:
`as ro applicant's e11titleme111 to apply _for and be gra111ed
`a patent (Rule 4.17(ii)J
`
`Published:
`with internarional search reporr (Arr. 21 (3))
`
`be.fore the expiration o.f the time limit .for amending the
`claims and to be republished in the event o( receipr of
`amendments (Rule 48.2(h))
`
`(51) International Patent Classification:
`A61L 2/00 (2006.01)
`A61L 2/08 (2006.01)
`A61L 2120 (2006.01)
`B65B 55/08 (2006.01)
`R65R 55//0 (2006.01)
`
`(21) International Application Number:
`PCT/IJP2010/06001 l
`
`(22) lnternational Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`13 July2010 (13.07.2010)
`
`(S4)
`
`English
`
`English
`
`(30) Priority Data:
`09165456.6
`
`14 July 2009 (14.07.2009)
`
`EP
`
`(71) Applicant (for all designated States except US): NO(cid:173)
`VARTIS AG [CH/CH]; Lichtstrasse 35, CH-4056 Basel
`(CH).
`
`(72)
`(75)
`
`Inventor; and
`(for US on(y): SIGG. Jiirgen
`Inventor/Applicant
`[Dh/CHJ; c/o Novartis Pharma AU, Pmllach, CH-Kasel
`(CH).
`
`(74) Agent: SPINNER, David, Richard; Novartis Pharma
`AG, Patent Department, CH-4002 Ba,el (CH).
`
`(81) Designated States (unless orherwise indi.cared. _for every
`kind of national protection available): AD, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`
`--
`
`-----= -
`
`= =
`-=
`
`(54) Title: SURFACE DECONTAMINATION OF PREFILLED CONTAINERS IN SECONDARY PACKAGING
`
`(57) Abstract: Methods and systems for the tenninal sterilization and surface decontamination of prefilled containers containing
`sensitive drug products, such as biotech drug products that are otherwise temperature or radiation sensitive, and thus not suitable
`for terminal sterilization by cfassical methods involving steam or gamma rays. The methods and systems are especially suited for
`prefilled containers in secondaiy packaging. Methods include tem1inal sterilization by exposing prefilled containers in seconda1y
`packaging to humble-beta radiation and further include tenninal sterilization by exposing prefilled containers to controllable va(cid:173)
`porized-hydrogen peroxide, including application of measure, to reduce or prevent diffusion of vaporized-hydrogen peroxide into
`prefilled containers.
`
`Regeneron Exhibit 1007 .001
`
`

`

`WO 2011/006877
`
`PCT/EP2010/060011
`
`Surface Decontamination of Prefilled Containers
`in Secondary Packaging
`
`FIELD OF THE INVENTION
`
`5
`
`This invention relates to a method and system for terminal sterilization of the
`outer surface and/or surface decontamination of prefilled containers in secondary
`
`packaging, wherein the prefilled container contains a pharmaceutical or biological drug
`
`product.
`
`BACKGROUND
`
`1 O
`
`Prefilled containers are a type of medical device that are filled by
`
`the
`
`manufacturer at the time of assembly and provided to the end user, generally a health(cid:173)
`
`care provider or a patient requiring treatment, in a sterile condition.
`
`Prefilled containers offer several advantages over traditional packaging of
`
`therapeutics, including ease of use, reduced risk of contamination, elimination of dosing
`
`15
`
`errors, increased drug supply and reduced waste. Of the various types of prefilled
`containers, prefilled syringes are the most common and best suited for parenteral
`
`administration of therapeutic products.
`
`Various methods of sterilization of medical devices are known, but not all
`methods work with syringes, especially syringes prefilled with a drug or protein solution.
`
`20
`
`Steam sterilization is commonly employed for sterilizing medical devices, which
`
`typically involves heating the device in a steam autoclave. The heat and pressure
`
`generated in the autoclave, however, can have an adverse effect on the device and,
`more importantly, on the integrity of the drug product filled into the device. Steam
`
`sterilization may compromise
`
`the aesthetics of the product due
`
`to packaging
`
`25
`
`degradation from high temperature steam treatment. Moreover, the high temperatures
`
`of the process (e.g. 120° C -
`
`132° C) preclude its use with heat sensitive materials,
`
`such as biotech drug products, specifically protein or other biological solutions.
`
`Radiation exposure is also commonly employed for sterilizing medical devices,
`in which the product is subjected to ionizing radiation, such as gamma irradiation.
`
`30 Radiation exposure results
`
`in harmful damage to sensitive solutions, specifically
`
`causing destruction to sensitive biologicals such as proteins, as well as generation of
`
`massive amounts of peroxides in aqueous solutions that in a secondary reaction further
`
`Regeneron Exhibit 1007 .002
`
`

`

`WO 2011/006877
`
`PCT/EP2010/060011
`
`may damage the active ingredient. Further, sterilizing doses of gamma rays cause a
`
`brown discoloration of glass parts of the device, and is prone to damage elastomeric
`materials like plunger stoppers. This destruction of the elastomers leads to increased
`
`stickiness of the components thus impairing the functionality of the system. Thus
`
`5
`
`radiation is not an appropriate means for sterilizing prefilled containers, such as
`
`syringes, containing a biotech drug product.
`Cold sterilization is a term collectively used for sterilization methods carried out at
`
`temperatures substantially below those of the steam process; attempts have been made
`to use ethylene oxide and hydrogen peroxide vapors as sterilants for this treatment.
`
`1 O Treatment with sterilizing gasses, however, bears the risk of insufficient removal of the
`
`oxidizing gas. Diffusion of gas into the product container affects the stability of the drug
`
`product through chemical modification by gas vapors, such as alkylation and oxidation.
`
`Prefilled syringes, although filled under aseptic conditions, are not packed into
`their secondary packaging in an aseptic environment and are therefore likely to be
`
`15 microbiologically contaminated at
`
`their outside. Terminal sterilization of prefilled
`
`containers in secondary packaging is one way to provide the device to an end user with
`
`a low bio-burden and low risk of contaminants, for safe application of the product by the
`end user. Moreover there is a strong market need for terminally antimicrobially-treated
`
`medical devices, such as prefilled syringes used for intravitreal injections.
`
`20
`
`Due to the sensitive nature of certain drug products, such as proteins, it is not
`
`possible to perform terminal sterilization and surface decontamination of containers
`
`filled with such products using current methods, like steam,
`
`irradiation or cold
`
`sterilization. Specifically, high temperatures are known to denature proteins and
`
`gamma radiation has been shown to chemically modify biological solutions. Radiation
`
`25
`
`techniques, such as sterilization using gamma or beta radiation causes discoloring of
`packaging material and affects the long term stability of therapeutic agents such as
`
`protein or peptide solutions. As discussed above, oxidizing gases, while efficient for
`
`killing bacterial contamination, also harm biological molecules in sensitive therapeutic
`solutions.
`
`30
`
`As protein and biological molecules will be more and more developed for
`
`therapeutic use,
`
`the need
`
`for a
`
`terminal surface sterilization and surface
`
`2
`
`Regeneron Exhibit 1007 .003
`
`

`

`WO 2011/006877
`
`PCT/EP2010/060011
`
`decontamination method that is not harmful to the drug product will continually increase
`
`in the near future. Moreover, as regulatory agencies may require higher levels of sterility
`assurance, pharmaceutical and biotech companies will seek alternative procedures to
`
`approach or meet mandated-microbiological purity levels, without compromising the
`
`5
`
`safety and efficacy of pharmaceutical preparations.
`
`SUMMARY
`
`is a terminal sterilization and surface decontamination
`Described herein
`treatment of prefilled containers, specifically for sterilization of prefilled containers
`
`1 O containing sensitive solutions, such as a drug product or biological therapeutic, within
`
`secondary packaging. In one embodiment, terminal sterilization is achieved by treating
`
`prefilled containers within secondary packaging with controllable vaporized-hydrogen
`
`peroxide (VHP). The principle is the formation a vapor of hydrogen peroxide in
`containment and a subsequent removal or inactivation of vapors in a controlled manner.
`
`15
`
`Prior to removal or inactivation, VHP condenses on all surfaces, creating a microbicidal
`film that decontaminates the container surface.
`
`It has been discovered that by varying the parameters of the antimicrobial
`
`temperature, humidity, treatment duration, pressure, etc.,
`treatment, for example -
`conditions are generated that prevent the leaching of VHP into the syringes. As an
`
`20
`
`example, the application of a vacuum at the end of the treatment will inverse the
`
`diffusion direction and reduce, if not stop, leaching of hydrogen peroxide through the
`
`rubbers. Further, inclusion of a gas plasma treatment after completion of the vaporized
`hydrogen peroxide cycle will further degrade all potentially remaining hydrogen peroxide
`
`residues. Prevention or reduction of leaching of detrimental concentrations of hydrogen
`
`25
`
`peroxide into the protein solution in the syringe, either by removal of vapors or
`inactivation of vapors, ensures that the long-term stability of the protein is not
`
`compromised. It further has been found that among the commercially available primary
`
`packaging components, there are only very few packaging material combinations that
`
`provide the required tightness of the system such as to avoid ingress of sterilizing
`
`30
`
`gasses into the pharmaceutical liquid enclosed by the prefilled container.
`
`3
`
`Regeneron Exhibit 1007 .004
`
`

`

`WO 2011/006877
`
`PCT/EP2010/060011
`
`Further described herein is terminal sanitization or sterilization and surface
`
`decontamination of prefilled containers within secondary packaging by tunable electron
`
`beam (low-energy beta-ray)
`
`irradiation technologies as an alternative to aseptic
`
`inspection and aseptic secondary packaging operations.
`
`5
`
`In one embodiment, the use of low penetration depth radiation from a low-energy
`
`electron beam generator for a new application to sterilize the surface of secondary
`
`packaged drug product containers avoids aseptic packaging. In another embodiment,
`
`the penetration depth of electron beam radiation is tunable by adjustment of the
`
`accelerator voltage of the irradiation generator.
`
`1 O
`
`Generally, the concepts presented herein are applicable to all drug products
`
`having requirements or desirability for absence of viable organisms of the drug product
`
`container surface. The method and system described herein decontaminate or, more
`
`preferably render sterile an outside surface of primary packaged drug products within a
`
`secondary pack, thereby improving safety of products for critical administration (e.g. use
`
`15
`
`in a surgical suite or for intravitreal injections).
`
`The foregoing summary provides an exemplary overview of some aspects of the
`
`invention. It is not intended to be extensive, or absolutely require any key/critical
`
`elements of the invention.
`
`20
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The detailed description is explained with reference to the accompanying figures.
`
`In the figures, the left-most digit(s) of a reference number identifies the figure in which
`
`the reference number first appears.
`
`Fig. 1 shows an exemplary prefilled container in secondary packaging that is
`
`25
`
`decontaminated on surfaces according to the methods detailed herein.
`
`Fig. 2
`
`illustrates a block diagram of an exemplary system
`
`for surface
`
`decontamination of prefilled containers using vaporized-hydrogen peroxide.
`
`Fig. 3
`
`illustrates a block diagram of an exemplary system
`
`for surface
`
`decontamination of prefilled containers using tunable-beta radiation.
`
`30
`
`DETAILED DESCRIPTION
`
`4
`
`Regeneron Exhibit 1007 .005
`
`

`

`WO 2011/006877
`
`PCT/EP2010/060011
`
`The method and system described herein are for the sterilization and surface
`
`decontamination of prefilled containers containing sensitive solutions, such as drug
`products that are otherwise temperature or radiation sensitive or are sensitive to traces
`
`of oxidizing substances, and thus not suitable for terminal sterilization by classical
`
`5 methods involving steam, gamma or beta rays or sterilization with oxidizing gases or
`liquids. The method and system described herein are especially suited for prefilled
`
`containers that have been filled under aseptic conditions and been subject to additional
`
`processing, such as product labeling and subsequent secondary packaging. Methods
`include
`terminal sterilization and surface decontamination by exposing prefilled
`
`1 O containers in secondary packaging to tunable-beta radiation and further include terminal
`
`sterilization and surface decontamination by exposing prefilled containers to controllable
`
`vaporized-hydrogen peroxide, including measures to reduce or prevent the diffusion of
`
`vaporized-hydrogen peroxide into prefilled containers. The methods also include an
`optional step of actively destroying any residual peroxide molecules, for example, by
`
`15 means of gas plasma.
`
`Definitions
`
`In describing and claiming the terminal sterilization and surface decontamination
`method, the following terminology will be used in accordance with the definitions set
`
`20
`
`forth below.
`
`"Aseptic" conditions
`
`refer
`
`to conditions
`
`free of bacterial or microbial
`
`contamination.
`
`"Administration" refers to the method of administering treatment to a subject or
`
`patient in need thereof, such as parenteral administration, intravenous administration
`
`25
`
`and intravitreal administration.
`"Beta irradiation" refers to sterilization methods using beta rays.
`
`"Cold sterilization" refers to sterilization techniques employing chemical agents,
`
`gases, or irradiation. A requirement of cold sterilization is that the technique is carried
`out at temperatures below those used for steam sterilization, such as autoclavation.
`
`30
`
`"Container", as used herein, is meant to include vials, syringes, bags, bottles, or
`
`other means useful for storage of medical treatments, such as drug products, whether in
`
`5
`
`Regeneron Exhibit 1007 .006
`
`

`

`WO 2011/006877
`
`PCT/EP2010/060011
`
`solid or liquid form, and other biological agents, such as peptides, proteins or
`
`recombinant biologicals, whether in solid or liquid form. Containers may be reusable or
`disposable, and may have a medical, veterinary or non-medical purpose.
`
`"Prefilled container", refers to a container, such as a syringe, that is filled with a
`
`5
`
`solution at the time of assembly and packaging and is deliverable for use to an end
`user, such as a health care professional or a patient needing treatment. This term also
`
`refers to prefilled containers integrated into an administration device.
`
`An "instruction" or "instructional material" includes a publication, a recording, a
`diagram, or any other medium of expression which can be used to communicate the
`
`1 O usefulness of the method or system of the invention for its designated use. The
`
`instruction or instruction material may be presented together as part of the system or
`
`provided separately, or independently of the process, to an end user.
`"Isolation", as used herein refers to practices in pharmaceutical production, filling
`
`and packaging, wherein a clean, or sterile environment, is separated from a non-sterile
`
`15
`
`environment to limit or prevent the introduction or spread or contamination of infectious
`agents, such as microorganisms.
`
`"Medical device", as used herein, refers to a device used for administering
`medical
`treatment and whose production or sale must,
`in part, comply with
`
`requirements, such as safety requirements, set forth by a government agency, such as
`
`20
`
`the Food and Drug Administration.
`
`"Solution" as used herein refers to the contents of a container like a vial or a
`
`prefilled syringe and includes solutions of biological therapeutics and drug products,
`
`protein products, peptide products, biological products, imaging solutions and aqueous
`
`solutions.
`
`Ideally, solutions are those that are temperature, oxidation or radiation
`
`25
`
`sensitive due to the molecular make-up of the solution.
`"Secondary packaging" refers to packaging enclosing the prefilled container,
`
`such as plastic wrapping, foil wrapping, paper wrapping or other suitable wrapping, such
`
`as blister packs.
`
`"Terminal-antimicrobial-surface treatment" refers to sanitization or sterilization of
`
`30
`
`an assembled container, such as a syringe filled with a solution that is in turn encased
`
`in secondary packaging. Terminal-antimicrobial treatment, or sterilization, allows a
`
`6
`
`Regeneron Exhibit 1007 .007
`
`

`

`WO 2011/006877
`
`PCT/EP2010/060011
`
`secondarily packaged prefilled container to be provided in sterile outside condition at its
`
`point of use.
`"Vaporized-hydrogen peroxide" refers to hydrogen peroxide in vapor form
`
`5
`
`"antimicrobial
`
`capable of creating a microbicidal film on a surface, such as the surface of a container
`or packaging material.
`The
`terms
`"sterilization",
`
`"decontamination",
`
`"sanitization",
`
`treatment" are used interchangeably herein.
`
`"Sterility" as used herein is meant to refer to complete absence of microbial life
`as defined by a probability of nonsterility or a sterility assurance level (SAL). The
`
`1 O
`
`required SAL for a given product is based on regulatory requirements. For example,
`required SALs for health care products are defined to be at least 1 o-6
`less than 1 :1 million of a non-sterile product for aseptically manufactured and terminally
`
`, i.e. a chance of
`
`sterilized products, respectively.
`Reference herein to "one embodiment" or "an embodiment" means that a
`
`15
`
`particular feature, structure, operation or characteristic described in connection with the
`embodiment is included in at least one embodiment of the invention. Thus, the
`
`appearances of such phrases or formulations herein are not necessarily referring to the
`same embodiment. Furthermore, various particular features, structures, operations or
`
`characteristics may be combined in any suitable manner in one or more embodiments.
`
`20
`
`Terminal sterilization and surface decontamination of prefilled containers
`
`Terminal sterilization is the process of sterilizing and/or decontaminating a final
`packaged product. In contrast, an aseptic packaging process requires individual product
`
`components to be sterilized separately and the final package assembled in a sterile
`
`25
`
`environment. Terminal sterilization of a product provides greater assurance of sterility
`than an aseptic process. Terminal sterilization is also desired and provides a market
`
`advantage in some instances for the use of certain medical devices, such as the use of
`
`secondarily packaged prefilled syringes for intravitreal administration.
`
`Described herein are
`
`terminal-sterilization methods suitable
`
`for prefilled
`
`30
`
`containers containing sensitive products, such as biotech (biological) drug solutions,
`
`which can otherwise be compromised when using classical terminal sterilization
`
`7
`
`Regeneron Exhibit 1007 .008
`
`

`

`WO 2011/006877
`
`PCT/EP2010/060011
`
`processes, such as steam, gamma irradiation or cold sterilization processes currently
`
`used in pharmaceutical production and assembly lines. While reference is given to drug
`products, such as heat or radiation-sensitive drug solutions containing biologicals such
`
`as peptides or proteins, it will be understood by those skilled in the art that any suitable
`
`5
`
`drug product that is considered a therapeutic agent, whether in solution or solid form,
`can be housed - or contained -
`in a prefilled container. Thus, the prefilled container
`
`itself is not drug specific.
`
`It has now been discovered that treatment of prefilled containers in secondary
`packaging by an application of vaporized-hydrogen peroxide, in which vapors are
`
`1 O controllable by certain post-treatment measures, and exposure
`
`to tunable-beta
`
`radiation, in which the depth of penetration of beta rays into secondary packaging are
`
`controllable, are ideal for surface decontamination of prefilled containers, yet not
`
`harmful to the stability or integrity of the contents of the prefilled container.
`The methods and embodiments described herein are suitable for use
`
`in
`
`15
`
`isolation.
`isolation or outside of
`in
`pharmaceutical production and packaging
`Furthermore, the methods described herein are adaptable to different container formats
`
`or types, with minimal incremental costs to production plant design. A system is also
`
`provided which allows for surface decontamination of prefilled containers in secondary
`packaging, as well as a kit comprising instructional material for practicing the method
`
`20
`
`and system described herein.
`
`Referring to Fig. 1, a prefilled container 100 previously filled under aseptic
`conditions is decontaminated on surfaces 102 following encasement or packaging in a
`secondary package 104 by vaporized-hydrogen peroxide or tunable-beta radiation as
`described herein. Fig. 1 shows one exemplary prefilled container, however, it will be
`
`25
`
`understood by those skilled in the art that various containers, other than a syringe, are
`also suitable. Moreover, while the exemplary container shown at Fig. 1 is a syringe in a
`
`closed and assembled position,
`
`it should be understood that other variants are
`
`envisioned. For example, a prefilled container not sealed by a stopper, plunger or other
`sealing mechanism can be surface decontaminated on interior portions of the container.
`
`8
`
`Regeneron Exhibit 1007 .009
`
`

`

`WO 2011/006877
`
`PCT/EP2010/060011
`
`In one embodiment, the prefilled container is a syringe. Other suitable prefilled
`
`containers include vials, bottles, bags and other medical devices capable of containing
`a sterile solution or a solution requiring sterilization.
`
`In one embodiment, the syringe is filled with a drug product, such as in the form
`
`5
`
`of liquid, solution, powder or solid. In another embodiment the drug product is a solution
`such as a drug solution or protein solution that is otherwise sensitive to exposure to high
`
`temperatures, such as those used in steam sterilization, and ionizing energy, such as
`
`gamma or beta rays and oxidizing gasses. In yet another embodiment the drug product
`is one that has been lyophilized, in other words a solid, and requires reconstitution in
`
`10
`
`liquid or solution prior to use.
`
`In another embodiment, a solution is any drug product having requirements or
`
`In one particular
`desirability for sterility of the drug product container surface.
`embodiment, the drug product is a protein solution, such as ranibizumab (e.g. 6mg/ml or
`
`10 mg/ml) solution for intravitreal injection.
`
`15
`
`In one embodiment, the container is filled with solution under aseptic conditions,
`whether by an automated or manual process. Thus, the contents of the container are
`
`sterile and unaffected by surface decontamination methods as described herein. The
`
`term "filled" is meant to refer to the placement of contents, such as solution, into the
`container in an appropriate amount, such as an appropriate volume or appropriate
`
`20
`
`concentration. The appropriate amount, volume or concentration will vary depending on
`
`the nature of the contents and their intended use.
`
`In one embodiment, the container is considered a primary packaging for the
`
`solution contained within. In another embodiment, the prefilled container is packaged
`
`within a secondary package or packaging encasing the prefilled container. Suitable
`
`25
`
`secondary packaging includes wrappings, such as paper, plastic or foil, and blister
`packs impermeable for microbes.
`
`In one embodiment the prefilled container in secondary packaging undergoes
`
`decontamination, such that the contents of the secondary packaging, specifically the
`surfaces of the prefilled container, are decontaminated and terminally sterilized. Thus,
`
`30
`
`prefilled container surfaces enclosed in a secondary packaging decontaminated by the
`
`9
`
`Regeneron Exhibit 1007.010
`
`

`

`WO 2011/006877
`
`PCT/EP2010/060011
`
`methods described herein can be presented to, and opened within, a critical or sterile
`
`environment, such as a surgical suite.
`
`In one embodiment, terminal sterilization and surface decontamination of prefilled
`
`containers within secondary packaging is carried out by treating surfaces of the prefilled
`
`5
`
`container within secondary packaging with vaporized-hydrogen peroxide and applying
`
`post-treatment measures, within a decontamination chamber.
`
`A suitable
`
`decontamination chamber is any chamber, such as an autoclave, that has the means
`
`for reversibly sealing a closed environment and equipped with means of manipulating
`
`pressure, temperature, inflow and outflow of air within the chamber. Additional elements
`
`1 O of a suitable chamber include the means for accommodating treatment by vaporized(cid:173)
`
`hydrogen peroxide and post-treatment measures to reduce or prevent vaporized(cid:173)
`
`hydrogen peroxide from entering into prefilled containers.
`
`In another embodiment, the chamber is configured to accommodate the quantity
`
`of containers requiring terminal sterilization. Thus,
`
`in
`
`large-scale production and
`
`15
`
`assembly lines, the chamber can be configured to accommodate a large quantity of
`
`containers, accordingly.
`
`Treatment with vaporized-hydrogen peroxide is brought about by the application
`
`or release of hydrogen-peroxide-vapors within the decontamination chamber. In one
`
`embodiment, vapors of hydrogen peroxide are controllable, in other words, certain post-
`
`20
`
`treatment measures are applied to manipulate or control the action of vaporized(cid:173)
`
`hydrogen peroxide. In one embodiment, post-treatment measures are applied that direct
`
`-
`
`or reverse -
`
`the direction of vapor diffusion, such that vapors are prevented from
`
`entering into the prefilled container. In another embodiment, additionally post-treatment
`
`measures are applied that destroy any residual peroxide traces.
`
`25
`
`In one embodiment, post-treatment measures include reducing or eliminating gas
`
`radicals formed by action of vaporized-hydrogen peroxide. In yet another embodiment,
`
`post-treatment measures include inactivating vaporized-hydrogen peroxide action, such
`
`as oxidative action.
`
`In another embodiment, terminal sterilization and surface decontamination of
`
`30
`
`prefilled containers within secondary packaging is achieved by application of tunable
`
`beta ray irradiation. In one embodiment, the surface of a prefilled container in secondary
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`10
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`Regeneron Exhibit 1007.011
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`WO 2011/006877
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`PCT/EP2010/060011
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`packaging is decontaminated by an adjustment of accelerator voltage of an irradiation
`
`generator to provide beta radiation of a sufficient dose to penetrate secondary
`
`packaging without penetrating primary packaging.
`
`In another embodiment,
`
`the accelerator voltage required
`
`to deliver
`
`the
`
`5
`
`appropriate amount of beta radiation
`
`to decontaminate the surface of prefilled
`
`containers depends on the thickness of secondary packaging materials. For example, in
`
`one embodiment, suitable packaging materials are less than or equal to 0.05 mm in
`
`thickness. Such materials of less than or equal to 0.05 mm in thickness may be made of
`foils.
`
`10
`
`In another embodiment a combination of secondary and primary packaging
`
`components, accelerator voltage, irradiation plant design and throughput speed allow
`
`surface decontamination of a prefilled container in secondary packaging, while almost
`
`completely shielding contents of the prefilled container by primary packaging materials.
`
`In one embodiment, a suitable primary packaging is a syringe capable of
`
`15
`
`shielding irradiation sensitive solution contained within. Shielding can be provided by
`
`the thickness of the container walls or the material components of the container.
`
`Shielding effectiveness can be determined by adjustment of the accelerator voltage and
`
`thus the depth of penetration of the beta rays emitted onto the prefilled container.
`
`Furthermore, shielding is determined by measuring the absorbed dosage, such as with
`
`20
`
`a dosimeter.
`
`It is understood by those in the art that a prefilled container is assembled under
`
`aseptic conditions, such that the contents of the container are sterile. While contents of
`
`the container are sterile, the surface of the container is susceptible to contamination
`
`during further packaging and product labeling using standard pharmaceutical packaging
`
`25
`
`protocols. For surface decontamination of prefilled containers, the sterilization methods
`
`herein are adaptable to standard production and packaging of pharmaceutical products
`
`in isolation or outside of isolation.
`
`In one embodiment, a prefilled container previously filled under aseptic
`
`conditions and labeled and packaged into secondary packaging by a manual or
`
`30
`
`automated process is presented to an electron beam tunnel for terminal sterilization and
`
`surface decontamination of the final packaged product. In one embodiment, the prefilled
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`11
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`Regeneron Exhibit 1007.012
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`WO 2011/006877
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`PCT/EP2010/060011
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`container in secondary packaging is
`
`introduced, either by a manual process or
`
`automated process, or a combination of the two, into the electron beam tunnel via an
`inlet and transported for all or a portion of time through the e-beam tunnel to an outlet
`
`as the surfaces of prefilled containers in secondary packaging are exposed to low-
`s energy beta radiation.
`In another embodiment, prefilled containers
`in secondary
`packaging remain stationary for all or a portion of time as the surfaces of prefilled
`
`containers in secondary packaging are exposed to low-energy beta radiation.
`
`In
`
`another embodiment, the electron beams are oscillated, e.g. by application of magnetic
`
`fields, such that the whole surface of the object is scanned by the electron beam. In
`1 O another embodiment, the object is passed below the scanning electron beams by
`
`means of a transport mechanism like a moving conveyor. In another embodiment, the
`chamber for electron beam treatment is open, but shielded to the environment by a
`
`tortuous path of the objects into and out of the chamber.
`
`15
`
`Terminal Sterilization of Prefilled Container by Vaporized-hydrogen peroxide (VHP)
`In one embodiment, terminal sterilization of prefilled containers in secondary
`
`packaging is carried out by antimicrobial treatment in a chamber with vaporized(cid:173)
`hydrogen peroxide, also referred to as "cold sterilization".
`
`The various steps, or operations, involved in the sterilization and surface
`
`20
`
`decontamination process can be performed automatically under the administration of a
`
`system manager, such as a microprocessor. Alternatively, operations can be performed
`
`separately in manual operations. Furthermore, operations can be performed in a
`
`combination of automated and manual processes.
`
`In one embodiment prefilled containers are enclosed in secondary packaging
`following filling of containers under aseptic conditions. In another embodiment, prefilled
`
`25
`
`containers are labeled with any product information, such as product name, indications;
`
`use
`
`instructions