Methods of sterilisation

Abstract

This application relates, inter alia, to a method of sterilizing the exterior surface of at least one sealed container and to a plurality of sealed containers sterilized by the method. In the method the at least one sealed container each comprise at least one pharmaceutical in fluid form, and the method comprises the step of treating the exterior surface of the at least one sealed container with an alkylene oxide at a concentration of at least 450 mg / L for longer than 350 minutes.

Description

METHOD OF STERILISATIONTECHNICAL FIELD

[0001] The present invention relates to a method of sterilizing the exterior surface of at least one sealed container, in which the at least one sealed container comprises a pharmaceutical in fluid form. The present invention also relates to at least one sealed container sterilized by the method.BACKGROUND ART

[0002] It will be clearly understood that, if a prior art publication is referred to herein, this reference does not constitute an admission that the publication forms part of the common general knowledge in the art in Australia or in any other country.

[0003] Many commonly used pharmaceuticals are sensitive to oxygen and / or heat based degradation, and many of these are often used as emergency injectable pharmaceuticals in operating theatres. Common examples of such sensitive drugs of importance in emergency departments and in operating theatres include metaraminol, catecholamines (including adrenaline, noradrenaline, isoprenaline, dopamine and dobutamine), opioids (including morphine, fentanyl, sufentanyl), clonidine and combinations including these drugs such as adrenaline and lignocaine and adrenaline and bupivacaine.

[0004] There are at least two major problems associated with preparing pharmaceuticals for use in emergency departments and operating theatres. First, the pharmaceutical must be prepared in a sterile and stable form, so that it does not quickly degrade. Secondly, and especially for operating theatres and / or where a “sterile field " is advantageous, the exterior surface of the container the pharmaceutical is stored in must be sterile so as not to add to any contamination during operating procedures and importantly to allow rapid use of the drug in serious situations.

[0005] To prepare the pharmaceutical in a container in a sterile and stable form, standard manufacturing methods include use of nitrogen or inert gas sparging and overlay and / or terminal or aseptic fill. Another suitable method may include the addition of chemicals to inhibit or react with residual oxygen, and these chemicals may include sodium metabisulphite, ethylenediaminetetraacetic acid (EDTA) or butylated hydroxytoluene (BHT) as examples.

[0006] In relation to sterilising the exterior surface of the pharmaceutical container (such as an ampoule or vial), this can be achieved in two ways: (i) the container is exteriorly sterilised with alcohol or similar sterilant prior to entering the theatre or (ii) the entire container is held in an extraouter container or packaging of which the content is pre- sterilised (commonly known as a “theatre pack”). The latter is the preferred option, as the simple and usually smooth outer pack shell can be sterilised prior to entry and when needed the vial or ampoule can be held in the operating theatre and the drug extracted or decanted directly into or onto a sterile field for rapid use without further sterilization. This facilitates a greater degree of control of contamination and allows a faster use of the contained pharmaceutical for the clinician and patient.

[0007] Traditionally ampoules have been used in these situations and as they have a continuous and smooth surface it is simpler to sterilise the exterior with a high degree of certainty. However, within the theatre, ampoules are a safety concern as the tops must be broken off for access to the drug and this may lead to both glass injuries for the staff and the possibility of glass fragments entering the ampoule prior to drug extraction.

[0008] Given these issues, vials are a preferred option as the plastic or aluminium tops can be safely removed for access to the pharmaceutical via a syringe. In some instances, to facilitate a speed or safety of delivery, a syringe may be used. However, vials or syringes are significantly more difficult to sterilize than an ampoule as the exterior surface of a vial includes undercuts around the plunger, cap and seal.

[0009] For more stable pharmaceuticals, a steam autoclave may be used to sterilize the exterior surface of a vial containing the pharmaceutical. This may be achieved in a single step. However, a drawback is that the vial must be steam sterilized for a longer period than normal to allow penetration through an outer packing or container, as well as to the actual vial containing the pharmaceutical. Vials containing heat sensitive pharmaceuticals are not able to be prepared this way. For heat sensitive pharmaceuticals, the vials containing the pharmaceuticals are generally aseptically prepared, the vial is examined for low bioburden, and then the vial is placed into an outer container or pack which is then sterilized by ethylene oxide. This is a multi-step procedure. For the above reasons, few pharmaceuticals (especially heat sensitive pharmaceuticals) are provided in theatre pack form unless they are in simple ampoules.SUMMARY OF INVENTION

[0010] In various aspects, there is therefore a need to be able to effectively sterilize a container containing a pharmaceutical, especially a sensitive pharmaceutical. In another aspect, there is a need for a method that enables sterilization of vials containing sensitive pharmaceuticals in theatre pack form.

[0011] In one aspect, the present invention is directed to a method of sterilizing the outersurface of a container containing at least one pharmaceutical which may at least partially overcome at least one of the abovementioned disadvantages or provide the consumer with a safe as well as useful or commercial choice.

[0012] With the foregoing in view, the present invention in one form, resides broadly in a method of sterilizing the exterior surface of a container.

[0013] In a first aspect, the present invention relates to a method of sterilizing the exterior surface of at least one sealed container, wherein the at least one sealed container each comprise at least one pharmaceutical in fluid form, wherein said method comprises the step of treating the exterior surface of the at least one of sealed container with an alkylene oxide at a concentration of at least 450 mg / L for longer than 350 minutes.

[0014] For highly sensitive pharmaceuticals, such as adrenaline, the inventors were unable to find any literature or information guiding to an efficient and reproducible method of steam sterilization within a theatre pack, or alternatively, a procedure to allow use of an alkylene oxide to sterilize a theatre pack.

[0015] Initial trials examining sterility and drug stability based on a half cycle of terminal sterilisation by steam of the pharmaceutical pre-packed in a plastic based outer theatre pack (a combination of adrenaline and bupivacaine) demonstrated that to achieve maximum heat penetration and allow effective sterilisation of the vial contents and the outer vial surface in the outer theatre pack required a long and economically impractical sterilisation cycle of some 3.5 hours. As well, the length of this cycle damaged the drug stability of the adrenaline. Significant issues were also shown to exist in drying and removing the vapour that collected in the theatre pack between its outer shell and the vial itself. In this case the adrenaline level dropped to 88.9% of the pre-autoclave value. This method also left a wrinkled and deformed outer surface.

[0016] Features of the first aspect of the invention may be as described below, and in any suitable combination.

[0017] The at least one sealed container may be in any suitable form. In one embodiment, the at least one sealed container is at least one sealed ampoule, or at least one sealed vial, or at least one sealed syringe, or at least one sealed cartridge; especially at least one sealed vial. The at least one sealed vial may have a detachable lid, tag or cap. The lid may be a screw top lid. The at least one sealed vial may comprise a lower component which contains the pharmaceutical, and an upper component (or lid) which is partially or entirely detachable from the lower component. The upper component may comprise a sealing bung with an enclosure (such as a lid or cap). The lid or aportion of the lid may be peelable or flippable from a lower component. The lower component may be made of any suitable material, such as glass, rubber or plastic. The lower component may comprise a screw thread. The upper component (or lid) may be made of any suitable material, for example glass, rubber or plastic (especially plastic). The upper component (or lid) may comprise an engaging portion for engaging with the screw thread of the lower component to thereby seal the vial. The upper component (or lid) may comprise a rubber bung. The upper component (or lid) may comprise a peelable exterior surface covering the bung. The peelable exterior surface may comprise, for example, aluminium. The at least one sealed syringe may comprise a body, a plunger, and a peelable exterior surface covering the nozzle. The peelable exterior surface may comprise, for example, aluminium, rubber and / or plastic. The sealed container may be suitable for use in hospital emergency rooms and / or operating theatres. Consequently, the exterior surface of the sealed container may be made of any suitable material, such as glass or plastic.

[0018] The sealed containers may have any suitable volume. In one embodiment, the sealed containers (especially sealed vials) have a volume of from 0.1 mL to 100 mL, or from 0.25 mL to 100 mL, or from 0.5 mL to 100 mL, or from 0.5 mL to 50 mL, especially from 0.5 mL to 30 mL, or from 5 mL to 25 mL, or from 0.1 mL to 20 mL, or from 0.5 mL to 20 mL, or from 1 mL to 20 mL, or from 2 mL to 20 mL, or from 0.1 mL to 5 mL, or from 0.25 mL to 5 mL, or from 0.25 mL to 2 mL, or from 0.25 mL to 1 mL, or from 0.1 mL to 2 mL, or from 0.1 mL to 1 mL. The sealed containers (especially vials) may have a volume of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 50 mL.

[0019] The sealed containers each comprise at least one pharmaceutical in fluid form. The fluid may be a liquid or a gel, especially a liquid. The at least one pharmaceutical may be dissolved in the liquid. The at least one pharmaceutical may be suspended in the liquid. The liquid may be transparent, or it may be opaque. The liquid may be syringeable. The liquid may be in the form of a solution, suspension, emulsion or colloid. The liquid may be a lotion. As used herein, the term “liquid” comprises free-flowing solutions, for example, aqueous solutions (for example a solution which does not comprise a gelation agent).

[0020] The fluid may have any suitable pH suitable for injection. In one embodiment, the fluid has a pH of about 2 to about 9, or about 3 to about 8, or from about 3 to about 5.5, or from about 6.5 to about 8.

[0021] In one embodiment, the fluid is an aqueous liquid. The fluid may be a deoxygenated liquid, especially a deoxygenated aqueous liquid. The fluid may comprise one or more additives. Such additives may include one or more of an oxygen scavenger (or antioxidant), preservative, ordye (such as an eye dye, including trypan blue and indigocarmine). The presence of an oxygen scavenger may be advantageous, for example to assist in minimizing the concentration or amount of oxygen present in the at least one sealed container.

[0022] The oxygen scavenger (or antioxidant) may be selected from the group consisting of (but not limited to): ascorbic acid, acetyl cysteine, ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), thiourea, a sulfite or a combination thereof. The sulfite may be a metabisulfite (especially sodium metabisulfite).

[0023] Any suitable amount of the oxygen scavenger (or antioxidant) may be present in the at least one sealed container. In one embodiment, the amount of the oxygen scavenger (or antioxidant) in the composition prepared by the method of the first aspect is from about 0.001 wt% to about 0.50 wt % of the composition, especially from about 0.005 wt% to about 0.35 wt %, or from about 0.01 wt % to about 0.25 wt %, or from about 0.05 wt % to about 0.20 wt %, or about 0.1 wt % of the composition.

[0024] The at least one pharmaceutical may be at least two pharmaceuticals or at least three pharmaceuticals. In one embodiment, the pharmaceutical is one, two, three, four or five pharmaceuticals. The at least one pharmaceutical may be a combination of an analgesic, an anaesthetic, a vasodilator and a vasoconstrictor. However, where the at least one pharmaceutical is two or more pharmaceuticals it may include multiple analgesics, multiple anaesthetics, multiple vasodilators, multiple vasoconstrictors, or combinations thereof. For example, the at least one pharmaceutical may be two or more pharmaceuticals of one type, such as lignocaine and tetracaine; or lignocaine and mepivacaine. The at least one pharmaceutical may be adrenaline, lignocaine and tetracaine; it may be adrenaline and lignocaine; it may be adrenaline and bupivacaine; it may be adrenaline and chirocaine; or it may be adrenaline and mepivacaine.

[0025] At least one of said pharmaceutical may be a sensitive pharmaceutical. At least one of said pharmaceutical may be sensitive to oxygen and / or temperature. For example, at least one said pharmaceutical may degrade in the presence of oxygen. At least one said pharmaceutical may be sensitive to temperature (or significantly degrade at elevated temperatures), such as to a temperature exceeding 10 °C, exceeding 15 °C, exceeding 20 °C, exceeding 25 °C, exceeding 30 °C, exceeding 35 °C, exceeding 40 °C, exceeding 45 °C, exceeding 50 °C, exceeding 55 °C, exceeding 60 °C, exceeding 65 °C, exceeding 70 °C, exceeding 75 °C, exceeding 80 °C, exceeding 85 °C, exceeding 90 °C, exceeding 95 °C or exceeding 100 °C.

[0026] The at least one pharmaceutical may be at least one selected from the group consistingof: an analgesic, an anaesthetic, a vasodilator and a vasoconstrictor, and combinations thereof. The vasoconstrictor may be selected from the group consisting of: adrenaline, metaraminol, noradrenaline, and clonidine, or combinations thereof. The analgesic may be an opioid analgesic, especially selected from the group consisting of: morphine, fentanyl, alfentanil, remifentanil and sufentanil, or combinations thereof.

[0027] The anaesthetic may be a local anaesthetic, especially selected from the group consisting of lignocaine (lidocaine), bupivacaine, chirocaine, ropivacaine, procaine, chloroprocaine, tetracaine, oxybupivicaine and mepivacaine, or combinations thereof. The anaesthetic may be selected from the group consisting of: an ester-type anaesthetic, an amide-type anaesthetic, or a combination thereof. Exemplary amide-type anaesthetics include: Articaine, Bupivacaine, Cinchocaine, Etidocaine, Levo-bupivacaine, Lidocaine (lignocaine), Mepivacaine, Oxetacaine, Prilocaine, Ropivacaine, Tolycaine and Trimecaine or a combination thereof. Exemplary ester-type anaesthetics include: Amylocaine, Cocaine, Propanocaine, esters of paraaminobenzoic acid and esters of meta-benzoic acid or a combination thereof. Exemplary esters of para aminobenzoic acid include: Benzocaine, Butacaine, Butoxycaine, Butyl aminobenzoate, Chloroprocaine, Oxybuprocaine, Parethoxycaine, Procaine, Propoxycaine, Tetracaine and Tricaine, or a combination thereof. Exemplary esters of meta-benzoic acid include proxymetacaine. The anaesthetic may also be one of the group consisting of: diperodon, dyclonine, ethyl chloride, ketocaine, myrtecaine, octacaine, pramocaine, propipocaine and quinisocaine or a combination thereof. The anaesthetic may also be a combination of the aforementioned anaesthetics, and may include D and L forms of the aforementioned anaesthetics (if they exist).

[0028] The at least one pharmaceutical may comprise at least one sensitive pharmaceutical and at least one non-sensitive or further pharmaceutical. However, in some embodiments, the at least one pharmaceutical may comprise non-sensitive pharmaceuticals. Examples of sensitive pharmaceuticals include metaraminol, catecholamines (including adrenaline, noradrenaline, isoprenaline, dopamine and dobutamine), opioids (including morphine, fentanyl, sufentanyl), and clonidine.

[0029] The at least one pharmaceutical may be at least one selected from the group consisting of: metaraminol, a catecholamine, an opioid, and clonidine, or a combination thereof. The catecholamine may be selected from the group consisting of: adrenaline, noradrenaline, isoprenaline, dopamine and dobutamine, or a combination thereof. Chemically, the catechol substructure of such catecholamines appear to be primarily responsible for the propensity to oxidize of these pharmaceuticals. The opioid may be selected from the group consisting of (butnot limited to): morphine, codeine, pethidine, fentanyl, alfentanil, remifentanil and sufentanil, or a combination thereof.

[0030] For example, while combinations including adrenaline may have some stability if stored at lower temperatures, dramatic decreases in the concentration of adrenaline may be observed if compositions are stored at higher temperatures. For example, it was found that adrenaline can be stable for at least 28 days under both acidic and basic conditions when stored in a freezer, but at higher temperatures (4 °C and above) concentration loss of 100% was observed after 2 days, or within 90 minutes at 22 °C (Palazzolo et al).

[0031] The at least one pharmaceutical may be present in the fluid at any suitable concentration. In one embodiment, the at least one or each pharmaceutical may be at a concentration of from 0.01% to 10%, or from 0.05% to 5% (w / v). The anesthetic (such as lignocaine or bupivacaine) may be at a concentration of from 0.05% to 5.0%, especially from 0.1 % to 3.0%, or from 0.25% to 2.0%. The vasoconstrictor (such as adrenaline) may be at a concentration of from 1:100,000 to 1:500,000, or from 1:200,000 to 1:400,000.

[0032] The at least one sealed container may comprise a gaseous headspace. The gas in the headspace may comprise less than 10% oxygen (by volume), especially less than 7.5% oxygen, or less than 5% oxygen, or less than 4.5%, less than 4%, less than 3.5%, less than 3%, less than 2.5%, less than 2%, less than 1.5%, less than 1%, less than 0.75%, less than 0.50%, or less than 0.25% oxygen.

[0033] The gas in the headspace may comprise an inert gas. Exemplary inert gases may include nitrogen, or a noble gas. The noble gas may be selected from the group consisting of helium, neon, argon, krypton, xenon and radon; especially helium, neon or argon; more especially argon. In one embodiment, the inert gas is nitrogen or argon; especially nitrogen. The gas in the headspace may comprise at least 50% inert gas (by volume), especially at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% inert gas.

[0034] The at least one sealed container may be any number of sealed containers. In one embodiment the at least one sealed container may be at least two sealed containers, or a plurality of sealed containers. In one embodiment, the at least one sealed container is at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95 or at least 100 sealed containers, especially at least 20 sealed containers, more especially 30 sealedcontainers, or more than 50 sealed containers, or more than 60 sealed containers. In another embodiment, the at least one sealed container is at least 100, at least 200, at least 300, at least 400, at least 500, at least 800, at least 1000, at least 1500, at least 2000, at least 2500, at least 3000, at least 3500 or at least 4000 sealed containers.

[0035] In one embodiment, the method may comprise applying an outer casing to each at least one sealed container. At least one (especially each one) sealed container may comprise an outer casing. The outer casing may be a wrap. The outer casing may be formed of any suitable material. The outer casing may be or comprise a plastic. The outer casing may comprise at least one layer, especially an inner layer and an outer layer.

[0036] The inner layer may be or comprise a polyalkylene. The polyalkylene may be polypropylene (PP) or polyethylene terephthalate glycol (PETG). The inner layer may especially be PETG. PETG has an advantage over PP as it is more transparent and allows the inner vial label to be read.

[0037] The outer layer may comprise or be a polymer. The polymer may comprise fibers. The polymer may be a poly alkylene polymer. The polymer may comprise poly alkylene fibers. The polyalkylene may be polyethylene. The polymer may comprise polyethylene fibers. The polymer may comprise spunbound polyethylene fibers. A polymer comprising a layer of spunbound polyethylene fibers is Tyvek®.

[0038] The wrap may be water-resistant. The wrap may be durable. The wrap may be printable. The wrap may allow for the alkylene oxide to penetrate and exit (or ingress and egress). Advantageously, Tyvek® is durable, water-resistant, printable and allows ethylene oxide penetration and egress following the method.

[0039] In one embodiment, the method of the first aspect comprises:(i) Initially sterilizing the exterior surface of the at least one sealed container;(ii) applying an outer casing to each at least one sealed container (such as wrapping the outer casing onto the at least one sealed container, as discussed above); and(iii) sterilizing the exterior surface of the at least one sealed container (comprising an outer casing), by treating the exterior surface of the at least one of sealed container with an alkylene oxide at a concentration of at least 450 mg / L for longer than 350 minutes (i.e. using the sterilization described above).

[0040] The step of initially sterilizing the exterior surface of the at least one sealed container(step (i)) may comprise heat or aseptic sterilization. A step of heat sterilization may comprise using an autoclave. However, in some embodiments there may be no initial sterilization step.

[0041] In one embodiment, after step (i), but before applying an outer casing, each at least one sealed container is labelled.

[0042] In one embodiment, after step (i), but before applying an outer casing, each at least one sealed container is inspected for defects.

[0043] In one embodiment, the method comprises the step of placing each at least one sealed container into a pack, especially wherein the at least one sealed container comprises an outer casing. Consequently, after step (ii) the method may comprise the step of placing the at least one sealed container into a pack.

[0044] In one embodiment, the method of the first aspect is a method of sterilizing at least one pack, wherein each said pack comprises at least one sealed container (especially wherein each of the at least one sealed container comprises an outer casing). The at least one pack may be at least two packs, or a plurality of packs.

[0045] One factor in the design of the sterilisation parameters is that after sterilisation and a vacuum removal of the alkylene oxide residues, that the seal remains intact and so unusual or extended stress is a factor in the development of a sterilisation procedure. A further factor is the bioburden load on the vial once it is sterilised, wrapped by the wrap, labelled and serialised, and prior to insertion into the pack. Experimentally the inventors found that post terminal sterilisation, the bioburden can be maintained below a level of less than 50CFU per device (especially with a PETG / Tyvek® pack) however as the biological indicators added to any load contain over 106spores per unit provided that the sterilised vials are kept in clean storage the external vial bioburden is a low issue.

[0046] Each pack may comprise at least one container, or at least 2 containers, especially at least 3 or at least 4 or at least 5 containers. Each pack may comprise less than 20 containers, especially less than 15 containers, or less than 10 containers. In one embodiment, each pack comprises 5 containers.

[0047] In one embodiment, the at least one, or a plurality of packs may be present in a box or carton. Consequently, in one embodiment, the method of the first aspect is a method of gaseous sterilizing a box or carton, or a plurality of boxes or cartons (or at least two boxes or cartons), wherein each said box or carton comprises at least one of pack which each comprise at least onesealed container. In another embodiment, the method of the first aspect is a method of sterilizing a box or carton, or a plurality of boxes or cartons, wherein each said box or carton comprises a plurality of the sealed containers. The box or carton may be made of any suitable material, for example a cellulosic material, especially cardboard.

[0048] The box or carton may comprise an upper portion and a lower portion. The box or carton may form a cube or a rectangular prism. The lower portion may have a base and four side walls which extend from the base. The four side walls may comprise two pairs of opposed side walls. The upper portion may be a lid. The upper portion may be removable from the lower portion. The upper portion may be connected to the lower portion, for example via a hinge along one side wall. The box or carton may be a shipper.

[0049] The box or carton may comprise any number of packs. In one embodiment, each box or carton comprises from 5 to 30 packs, especially from 10 to 20 packs, or from 15 to 20 packs, or 16 packs. In one embodiment, each box or carton comprises from 40 to 150 sealed containers, especially from 40 to 120 sealed containers, more especially from 50 to 110 sealed containers, or from 60 to 100 sealed containers, or from 70 to 90 sealed containers, or about 80 sealed containers.

[0050] Each box or carton may have any suitable height, width and length. In one embodiment, each box or carton has a height of from 50 mm to 500 mm, especially from 50 mm to 400 mm, or from 100 mm to 350 mm, or from 150 mm to 300 mm, or from 200 mm to 250 mm or from 210 mm to 230 mm or about 218 mm. In some embodiments, each box or carton has a length of from 200 mm to 700 mm, especially from 250 mm to 500 mm, or from 300 mm to 450 mm or from 350 mm to 400 mm or about 375 mm. In some embodiments, each box or carton has a depth of from 50 mm to 500 mm, especially from 100 mm to 400 mm, or from 150 mm to 350 mm, or from 200 mm to 300 mm, or from 230 mm to 280 mm or from 240 mm to 270 mm or about 256 mm. In one embodiment, each box or carton is 375 mm x 256 mm x 218 mm.

[0051] In one embodiment, the plurality of boxes or cartons may provide a pallet. Consequently, in one embodiment, the method of the first aspect is a method of sterilizing a pallet or a plurality of pallets, wherein each said pallet comprises a plurality of the sealed containers. In another embodiment, the method of the first aspect is a method of sterilizing a pallet or a plurality of pallets, wherein each said pallet comprises a plurality of boxes or cartons, wherein each said box or carton comprises a plurality of the sealed containers. In a further embodiment, the method of the first aspect is a method of sterilizing a pallet or a plurality of pallets, wherein each said pallet comprises a plurality of boxes or cartons, wherein each said box or carton comprises a plurality of packs, wherein each pack comprises a plurality of the sealed containers.

[0052] In one embodiment, in the pallet each box or carton comprises at least a first side and at least a second side; wherein the at least a first side of each box or carton is entirely unobstructed in the pallet, and at least a second side of each box or carton is at least partially unobstructed in the pallet. In one embodiment, at least one face of each box or carton is unobstructed in the pallet. In another embodiment, at least a first face of each box or carton is unobstructed in the pallet, and at least a second face of each box or carton is at least partially unobstructed in the pallet. If the box or carton is a cube or rectangular prism then each said box or carton has six faces.

[0053] In one embodiment, from 12% to 100% of the surface area of each box or carton is unobstructed in the pallet (or exposed surface area), especially from 12% to 80%, or from 12 % to 70% of the surface area of each box or carton is unobstructed in the pallet (or exposed surface area). In one embodiment, at least 10% of the surface area of each box or carton is unobstructed in the pallet (or exposed surface area), especially at least 12% of the surface area of each box or carton is unobstructed in the pallet (or exposed surface area), more especially at least 13%, 14% or 15% of the surface area of each box or carton is unobstructed in the pallet (or exposed surface area). In another embodiment, at least 20% of the surface area of each box or carton is unobstructed in the pallet (or exposed surface area), especially at least 25% of the surface area of each box or carton is unobstructed in the pallet (or exposed surface area), more especially at least 30%, 32% or 34% of the surface area of each box or carton is unobstructed in the pallet (or exposed surface area). It was found that if the exposed surface area of each box or carton on the pallet was too low, then this may decrease the effectiveness of the sterilisation procedure. This packing arrangement is not consistent with standard pallet packing arrangements, where the maximum number of boxes or cartons are typically placed in a given volume.

[0054] As used herein, the term “unobstructed” means that said face or side is not abutting another box or container. An unobstructed face or side is therefore exposed to surrounding gases.

[0055] The pallet may be of any suitable dimensions. In one embodiment, the pallet has dimensions of from 500 mm to 2000 mm in width or length, especially from 800 mm to 1500 mm in width or length, most especially from 1000 mm to 1400 mm in width or length, or about 1165mm in width and / or length. The pallet may be of any suitable height. In one embodiment, the height of the boxes or cartons on the pallet is less than 800 mm, especially less than 650 mm or less than 600 mm. In one embodiment, the height of the boxes or cartons on the pallet is 594 mm. In one embodiment, there are no more than 2 rows of boxes or cartons on the pallet. The inventors have advantageously found that when there are no more than 2 rows of boxes or cartons on the pallet or when the height of the boxes or cartons on the pallet is less than 600 mm, then thealkylene oxide is better able to permeate the boxes and cartons and sterilise the at least one container (or the plurality of containers).

[0056] In one embodiment, the total volume of the pallet is less than 1.2 m3, especially less than 1.1 m3, or less than 1 m3, or less than 0.9 m3. In one embodiment, the total volume of the pallet is about 0.8 m3. The total weight of the pallet may be from 100 to 200 kg, especially from 120 to 160 kg, or 130 to 150 kg or about 141.5 kg (excluding the pallet frame itself, such as a wooden pallet frame). Including the pallet frame, the total weight of the pallet may be from 120 to 220 kg, especially from 140 to 200 kg, or 150 to 190 kg, or 165 to 175 kg or about 171.5 kg. The total density of the pallet (including frame) may be from 100 to 300 kg / m3, especially from 160 to 260 kg / m3, or from 180 to 240 kg / m3, or from 205 to 225 kg / m3, or about 212.8 kg / m3. The total density of the pallet may be less than 300 kg / m3, especially less than 250 kg / m3.

[0057] The pallet may have less than 35 boxes or cartons, especially less than 30 boxes or cartons, or less than 26 boxes or cartons. The pallet may have from 10 to 35 boxes or cartons, or from 20 to 30 boxes or cartons, or from 23 to 28 boxes or cartons, or from 25 to 27 boxes or cartons, or about 26 boxes or cartons.

[0058] More than one pallet may be sterilised at any one time. In one embodiment 1, 2, 3 or 4 pallets may be treated with the alkylene oxide at one time. In one embodiment, during the treating step the pallet(s) (or the at least one sealed container) occupy less than 60%, less than 50%, less than 40% or less than 30% of the sterilization chamber volume.

[0059] In one embodiment, the pallet does not include an outer wrap to hold the boxes or cartons in place. In another embodiment, the pallet does not include a polyvinyl chloride (PVC) outer wrap. Advantageously, the inventors have found that use of a PVC outer wrap may impede alkylene oxide penetration. However, an outer wrap that is permeable to an alkylene oxide may be used.

[0060] The step of treating the exterior surface of the at least one sealed container is a step of sterilizing the exterior surface of the at least one sealed container.

[0061] As used herein, the term “sterilized” or “sterilizing” does not mean that the exterior surface is completely sterile, however the exterior surface must be sufficiently sterile for use in emergency departments and operating rooms. In one embodiment, the exterior surface of the container is sterilized if it has fewer than 100 CFU per container, especially less than 75 CFU per container, or less than 50 CFU per container.

[0062] The alkylene oxide may be a C2-C6 alkylene oxide, especially ethylene oxide, propylene oxide or butylene oxide, most especially ethylene oxide.

[0063] The concentration of the alkylene oxide may be greater than 500 mg / L. The concentration of the alkylene oxide may be no more than 1000 mg / L. In one embodiment, the concentration of the alkylene oxide may be from 500 to 850 mg / L, especially from 550 to 800 mg / L or from 600 to 800 mg / L. This is higher than a typical ethylene oxide sterilisation.

[0064] The treatment (exposure time) with the alkylene oxide may be greater than 400 minutes, especially greater than 430 minutes, or greater than 440 minutes, or greater than 450 minutes, or greater than 460 minutes or greater than 470 minutes, or greater than 480 minutes. In one embodiment, the treatment (exposure time) with the alkylene oxide may be less than 800 minutes, especially less than 700 minutes, or less than 650 minutes, or less than 600 minutes, or less than 550 minutes, or less than 500 minutes. The treatment (exposure time) with the alkylene oxide may be from 400 minutes to 800 minutes, especially from 420 minutes to 650 minutes, or from 430 to 550 minutes, or from 440 to 500 minutes. The treatment (exposure time) with the alkylene oxide may about 480 to 485 minutes. This is significantly longer than a typical ethylene oxide sterilisation which is typically about 180 minutes. Advantageously, the inventors found that the longer sterilisation time was critical to enable the alkylene oxide to pass throughout the load and provide even penetration.

[0065] The mass of alkylene oxide used in the chamber may be from 30 kg to 40 kg, especially from 32 to 38 kg, or from 35 to 36 kg.

[0066] The chamber temperature in the treatment step may be from 40 to 70 °C, especially from 45 to 65 °C, or from 50 to 65 °C, or from 50 to 60 °C, or from 55 to 65 °C, or from 55 to 63 °C.

[0067] The chamber humidity in the treatment step may be from 35 to 100 %, especially from 35 to 90% or from 35 to 85%.

[0068] The chamber pressure (alkylene oxide dwell) may be from 40 kPa to 75 kPa, especially from 42 kPa to 73 kPa, more especially from 45 kPa to 70 kPa.

[0069] The method may include a step of preconditioning the at least one container before the treatment with the alkylene oxide. The preconditioning step may be a step of acclimating the at least one container to the temperature and humidity used for the treatment step.

[0070] The preconditioning step may be performed for more than 5 hours, especially more than 6 hours, or more than 7, 8, 9, 10, 11 or 12 hours.

[0071] The preconditioning step may be performed at a temperature of from 40 to 70 °C, especially from 45 to 65 °C, or from 50 to 60 °C.

[0072] The preconditioning step may be performed at a humidity of from 35 to 100 %, especially from 35 to 90% or from 35 to 85%.

[0073] The preconditioning step may have a transfer time of less than 1.5 hours, especially less than 1.2 hours or less than 1 hour.

[0074] The method may include a step of aeration after the step of treatment with the alkylene oxide.

[0075] The aeration step may be performed for at least 8 hours, especially at least 9 hours, or at least 10 hours.

[0076] The aeration step may be performed at a temperature of from 40 to 70 °C, especially from 45 to 65 °C, or from 45 to 60 °C, or from 50 to 60 °C, or 45 to 55 °C, or about 50 °C.

[0077] In a second aspect, the present invention relates to at least one sealed container sterilized by the method of the first aspect.

[0078] In the present specification and claims, the word ‘comprising’ and its derivatives including ‘comprises’ and ‘comprise’ include each of the stated integers but does not exclude the inclusion of one or more further integers.

[0079] The transitional phrase "consisting of’ excludes any element or step not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.

[0080] The transitional phrase "consisting essentially of" is used to define a composition, process or method that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term "consisting essentially of" occupies a middle ground between "comprising"and "consisting of".

[0081] Where the applicant has defined an invention or a portion thereof with an open-ended term such as "comprising", it should be readily understood that (unless otherwise stated) the description should be interpreted to also describe such an invention using the terms "consisting essentially of' or "consisting of." In other words, with respect to the terms “comprising”, “consisting of’, and “consisting essentially of’, where one of these three terms is used herein, the presently disclosed and claimed subject matter may include the use of either of the other two terms. Thus, in some embodiments not otherwise explicitly recited, any instance of “comprising” may be replaced by “consisting of’ or, alternatively, by “consisting essentially of’.

[0082] Any of the features described herein can be combined in any combination with any one or more of the other features described herein within the scope of the invention.BRIEF DESCRIPTION OF DRAWINGS

[0083] Examples of the invention will now be described by way of example with reference to the accompanying Figures, in which:

[0084] Figure 1 provides a perspective view of a pallet of boxes or cartons for sterilization, wherein each box or carton comprises a plurality of containers, in which the pallet comprises two rows of boxes or cartons;

[0085] Figure 2 provides a perspective view of a pallet of boxes or cartons for sterilization, wherein each box or carton comprises a plurality of containers, in which the pallet comprises one row of boxes or cartons;

[0086] Figure 3 provides a top view of the pallet of Figure 1 or Figure 2; and

[0087] Figure 4 provides a perspective view of a box or carton used in Figure 1 or Figure 2.

[0088] Preferred features, embodiments and variations of the invention may be discerned from the following Examples which provides sufficient information for those skilled in the art to perform the invention. The following Examples are not to be regarded as limiting the scope of the preceding Summary of the Invention in any way.EXAMPEES

[0089] The below Examples relate to containers in which the pharmaceutical is a combination of adrenaline and bupivacaine, or adrenaline and lidocaine (lignocaine). Adrenaline is sensitiveto the presence of oxygen and heat, and consequently the concentration of adrenaline in the container may be affected by these factors. The pharmaceutical is present in an aqueous solution at a pH of from about 3.0 to 5.5.Example 1 : Pallet preparation

[0090] Containers were used, in the form of vials (20 mF) with typical rubber bung seals held in place by flip top aluminium closures. The pharmaceutical composition of the interior of the containers comprised the adrenaline and bupivacaine aqueous solution, or the adrenaline and lidocaine aqueous solution. After sealing the vials, and terminal sterilization, the vials were all inspected for faults, including glass fractures, particulates or other unacceptable cosmetic damage or contamination. Vials were then labelled and serialized (if required) and individual vials were prepared by wrapping each vial in an outer casing. The outer casing comprised two layers, with the inner layer being polyethylene terephthalate glycol (PETG) or polypropylene (PP). It was found that use of PETG was advantageous as it was more transparent and it allowed the vial label to be read. The outer layer was a Tyvek® sheet. Tyvek® is a polymer comprising a layer of spunbound polyethylene fibers.

[0091] 16 packs (each of 5 vials) were then placed in each cardboard box or carton. Each box or carton has a height of 218 mm, a width of 256 mm and a length of 375 mm. The box comprises a lower portion (having a base and four side walls) and an upper portion which is a lid hinged along one sidewall of the lower portion. An exemplary box or carton 10 is illustrated in Figures 1- 4. Each box or carton weighed about 5.45 kg.

[0092] Many of the boxes or cartons were then placed on a pallet 20. The pallet 20 was 1.165m wide and 1.165 m long. 13 boxes or cartons may be placed on each pallet (as shown in Figure 2) or 26 boxes or cartons (as shown in Figure 1). In Figure 2, a comer box or carton has about 50% of the surface area of the box or carton unobstructed (and exposed to the alkylene oxide during sterilization - this does not include exposed area on the underside of the box or carton, where the box or carton abuts the pallet). The centermost box or carton has an exposed surface area of about 55% (not counting the exposed area on the underside of the box or carton, where the box or carton abuts the pallet). However, some of the middle boxes or cartons along the side of the pallet would have an exposed surface area of from about 36% to about 44% (not counting the exposed area on the underside of the box or carton, where the box or carton abuts the pallet).

[0093] In Figure 1, the boxes or cartons in the top level would have an exposed surface area similar to that discussed in the preceding paragraph. However, the boxes or cartons in the lowerlevel would have a smaller exposed surface area. The height of the boxes in Figure 1 was 0.594 m.

[0094] Each total weight of the pallet illustrated in Figure 1 was 141.5 kg for the boxes or cartons, and the wood pallet frame weighed 30 kg, making the total weight of the pallet 171.5kg. The total volume of the pallet illustrated in Figure 1 was 0.806 cubic metres. Therefore, the density of the pallet was 212.8 kg / m3.

[0095] Usually a plastic wrap such as a PVC plastic wrap is used around the outside of a pallet to hold the boxes or cartons in place (this is especially important on a high stacked pallet). Such a plastic wrap was not used on the pallet as it was found that this wrap impeded gas penetration.Example 2: Sterilisation procedure for the Theatre Pack

[0096] A summary of the gaseous sterilization methodology is provided in Table 1. These take into consideration the process characterisation in the first instance as required by ISO 11135:2014, specifically Clause 6.2. In the method below the alkylene oxide used was ethylene oxide. While there are guides for ethylene oxide sterilization (e.g. Steris, Steritech and Booth), the inventors found that these guides did not allow for the development of a sterile theatre pack.Table 1 - Sterilisation procedure

[0097] Of note with reference to the above table is that the preconditioning time above is longer than a standard procedure (which is typically about 10 hours). In the sterilization cycle the mass of ethylene oxide above is significantly higher (in a typical cycle the mass would be about 25 to 26 kg, but the inventors found that this was insufficient for complete sterility). The exposure time was also significantly longer (in a standard cycle the exposure time is typically 180-185minutes. This is an increase of nearly 400% and the inventors found that this was necessary to obtain adequate gas penetration). This in turn means that the concentration of ethylene oxide was higher in the above procedure (a typical ethylene oxide concentration would be about 320 mg / L to 720 mg / L). The pressure was also significantly higher above (a typical pressure would be about 30 kPa to 55 kPa).

[0098] The packing arrangement (as illustrated in the Figures) was also found to be important to enable the ethylene oxide to permeate the boxes and cartons and sterilize a plurality of containers, and further at the end to allow degassing and removal of all residual ethylene oxide. The typical ethylene oxide sterilization chamber pallet load of three pallets needed to have the load more spaced (or reduced) out to fit over 6 pallets (i.e. a doubling of the space requirement). The total load was either 3.22 m3(4 pallets) to 4.8 m3(6 pallets).

[0099] An alternate sterilisation procedure is provided in Table 2.Table 2 - Sterilisation procedure

[0100] Using the adrenaline / bupivacaine containers (vials) or adrenaline / lidocaine containers (vials), the ethylene oxide sterilization process described above effectively sterilized the exterior surface of the containers without compromising the concentration of the sensitive adrenaline in the containers. This is illustrated in the Tables below.Example 3: Results

[0101] Results illustrating the stability and sterilization of vials produced according to the above procedures (Table 1) are shown in Tables 3-12. The formulations shown in Tables 3, 5, 7,10 and 11 are stable for at least 12 months at 25 °C / 60% RH (at least 18 months for Tables 7 and 10; and at least 24 months for Table 11). The formulations shown in Tables 4, 6, 8, 9 and 12 are stable for at least 6 months at 40 °C / 75% RH.Table 3 - Containers in which the pharmaceutical is Lidocaine HC1 1.0% with Adrenaline 1:200,000 Injection 20mL in 20mL Theatre PackAll vials were stored at 25 °C ± 2 °C / 60% ± 5% RHBatch size 200 LTable 4 - Containers in which the pharmaceutical is Lidocaine HC1 1.0% with Adrenaline 1:200,000 Injection 20mL in 20mL Theatre PackAll vials were stored at 40 °C ± 2 °C / 75% ± 5% RHBatch size 200 LTable 5 - Containers in which the pharmaceutical is Lidocaine HC10.5% with Adrenaline 1:200,000 Injection 20mL in 20mL Theatre PackAll vials were stored at 25 °C ± 2 °C / 60% ± 5% RHBatch size 200 LTable 6 - Containers in which the pharmaceutical is Lidocaine HC10.5% with Adrenaline 1:200,000 Injection 20mL in 20mL Theatre PackAll vials were stored at 40 °C ± 2 °C / 75% ± 5% RHBatch size 200 LTable 7 - Containers in which the pharmaceutical is Lidocaine HC12.0% with Adrenaline 1:200,000 Injection 20mL in 20mL Theatre PackAll vials were stored at 25 °C ± 2 °C / 60% ± 5% RHBatch size 200 LTable 8 - Containers in which the pharmaceutical is Lidocaine HC12.0% with Adrenaline 1:200,000 Injection 20mL in 20mL Theatre PackAll vials were stored at 40 °C ± 2 °C / 75% ± 5% RHBatch size 200 LTable 9 - Containers - Pharmaceutical is Bupivacaine hydrochloride 0.25% with Adrenaline 1:400,000 Injection 20mL in 20mL Theatre PackAll vials were stored at 40 °C ± 2 °C / 75% ± 5% RHBatch size 200 LTable 10 - Containers - Pharmaceutical is Bupivacaine hydrochloride 0.25% with Adrenaline 1:400,000 Injection 20mL in 20mL Theatre PackAll vials were stored at 25 °C ± 2 °C / 60% ± 5% RHBatch size 200 LTable 11 - Containers - Pharmaceutical is Bupivacaine hydrochloride 0.5% with Adrenaline 1:200,000 Injection 20mL in 20mL Theatre PackAll vials were stored at 25 °C ± 2 °C / 60% ± 5% RHBatch size 200 LTable 12 - Containers - Pharmaceutical is Bupivacaine hydrochloride 0.5% with Adrenaline 1:200,000 Injection 20mL in 20mL Theatre PackAll vials were stored at 40 °C ± 2 °C / 75% ± 5% RHBatch size 200 L

[0102] Reference throughout this specification to ‘one embodiment’ or ‘an embodiment’ means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearance of the phrases ‘in one embodiment’ or ‘in an embodiment’ in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more combinations.

[0103] In compliance with the statute, the invention has been described in language more or less specific to structural or methodical features. It is to be understood that the invention is not limited to specific features shown or described since the means herein described comprises preferred forms of putting the invention into effect. The invention is, therefore, claimed in any of its forms or modifications within the proper scope of the appended claims (if any) appropriately interpreted by those skilled in the art.ADVANTAGES OF AN EMBODIMENT

[0104] A method of sterilizing at least one sealed container according to one embodiment ofthe method of the first aspect of the invention, may have advantages such as:Maintenance of the concentration of sensitive pharmaceuticals over 24 monthsImproved contamination control;More rapid use;Increased safety and convenience for staff in operating theatres; andA longer product shelf life at room temperature.REFERENCES:A F Booth, 2007: “ Ethylene Oxide Sterilization Validation and Routine Operations HandbooK' Davis Healthcare International PublishingB Cox, “Ethylene Oxide and Radiation Sterilisation. Method Selection and Critical Success Factors” SteritechISO 11135-1 2014: “Sterilisation of Health Care Products - Ethylene Oxide Requirements for the Development, Validation and Routine Control of a Sterilisation Process fo Medical Devices” Arlington VAISO 11135-2 2007 “Sterilisation of Health Care Products - Ethylene Oxide - Part 2: Guidance on the Application of ISO 11135-1 ”” Arlington VAISO 11607-1 2006 “Packaging of Terminally Sterilised Medical Devices - Part 1: Requirements for Materials, Sterile Barrier Systems and Packaging Systems” Third editionISO 11607-2 2006 “Packaging of Sterilsied Medical devices - Part 2: Validation Requiremnts for Forming, Sealing and Assembly Process” Arlington VA First editionISO 10993-7 :2008 “Biological Evaluation of Medical Devices - Part 7: Ethylene Oxide Residuals” Arlington, VA. 2008 RevisionD.L.Palazzolo, S.K. Quadri, 1990 J. Chromat. 518 “Optimal conditions for long term storage of biogenic amines for subsequent analysis by column chromatography with electrochemical detection ”Steris University “Ethylene Oxide Sterilisation”

Claims

CLAIMS1. A method of sterilizing the exterior surface of at least one sealed container, wherein the at least one sealed container each comprise at least one pharmaceutical in fluid form, wherein said method comprises the step of treating the exterior surface of the at least one sealed container with an alkylene oxide at a concentration of at least 450 mg / L for longer than 350 minutes.

2. The method of claim 1, wherein the concentration of the alkylene oxide is greater than 500 mg / L.

3. The method of claim 1 or claim 2, wherein the concentration of the alkylene oxide is from 500 mg / L to 850 mg / L.

4. The method of any one of claims 1 to 3, wherein the at least one sealed container is treated for greater than 450 minutes.

5. The method of any one of claims 1 to 4, wherein the at least one sealed container is at least 20 sealed containers.

6. The method of any one of claims 1 to 5, wherein the at least one sealed container is at least one sealed vial, at least one sealed ampoule, at least one sealed syringe, or at least one sealed cartridge.

7. The method of any one of claims 1 to 6, wherein the at least one sealed container each has a volume of from 0.5 mL to 20 mL.

8. The method of claim 6, wherein the at least one sealed container is at least one sealed vial which is sealed with a screw top lid or a sealing bung and enclosure.

9. The method of any one of claims 1 to 8, wherein the alkylene oxide is ethylene oxide.

10. The method of any one of claims 1 to 9, wherein the at least one pharmaceutical comprises at least one selected from the group consisting of: metaraminol, a catecholamine, an opioid, and clonidine, or a combination thereof.

11. The method of claim 10, wherein the at least one pharmaceutical is a combination of adrenaline and bupivacaine; or the at least one pharmaceutical is a combination of lignocaine and adrenaline.

12. The method of any one of claims 1 to 11, wherein the method is a method of sterilizing at least one of pack, wherein each said pack comprises a plurality of the at least one sealed containers.

13. The method of claim 12, wherein each of the at least one sealed container comprises an outer casing which comprises at least one layer.

14. The method of claim 13, wherein each of the at least one layer comprises an inner layer and an outer layer, and the inner layer is or comprises a polyalkylene.

15. The method of claim 14, wherein the polyalkylene is polypropylene or polyethylene terephthalate glycol.

16. The method of claim 14 or claim 15, wherein the outer layer comprises spunbound polyethylene fibers.

17. The method of any one of claims 13 to 16, wherein the at least one sealed container is present in a box or carton.

18. The method of claim 17, wherein a plurality of the at least one boxes or cartons form a pallet.

19. The method of claim 18, wherein the height of the pallet is less than 650 mm.

20. The method of claim 18 or claim 19, in the pallet each box or carton comprises at least a first side and at least a second side; wherein the at least a first side of each box or carton is entirely unobstructed in the pallet, and at least a second side of each box or carton is at least partially unobstructed in the pallet.

21. The method of claim 18 or claim 19, wherein from 12 to 100% of the surface area of each box or carton is unobstructed in the pallet.

22. The method of any one of claims 18 to 21, wherein the total density of the pallet is less than 300 kg / m3.

23. A plurality of sealed containers sterilized by the method of any one of claims 1 to 22.