Filling arrangement and decontamination method

Abstract

A filling arrangement (1) for filling a drug substance into a primary packaging (8) comprises: a dosing container (2) housing the drug substance; at least one filling tubing (3) having a first longitudinal end, a second longitudinal end and a channel between the first longitudinal end and the second longitudinal end; and at least one feeding needle (41). The first longitudinal end of each of the at least one filling tubing (3) is connected to the dosing container (2). The second longitudinal end of each of the at least one filling tubing (3) is connected to one of the at least one feeding needle (41). An inner surface of the channel of the filling tubing (3) consists of a low hydrogen peroxide retention material.

Description

DESCRI PTIONTitleFILLING ARRANGEMENT AND DECONTAMINATION METHODTechnical Field

[0001] The present invention relates to a filling arrangement according to the preamble of independent claim 1 and to a decontamination method for a filling arrangement. Such filling arrangements having a dosing container housing the drug substance, at least one feeding needle and at least one filling tubing connected at a first longitudinal end with the dosing container and at a second longitudinal end to the at least one feeding needle are designed to fill a drug substance into a primary packaging.Background Art

[0002] In pharmaceutical industry, drug products are manufactured in highly regulated processes in order to achieve sufficient product quality and to guarantee safety of patients using the manufactured drug products. Typically, the manufacturing processes have to comply with standards accepted by authorities such as the US Food and Drug Administration (FDA) or the European Medicine Agency (EMA). In particular, the European Union (EU) issued rules and regulations for drug product manufacturing as Good Manufacturing Practice (GMP) which allow not only safe and high-quality manufacturing but also reproducibility and validation of the processes involved.

[0003] Often, in drug product manufacturing processes drug substances are aseptically filled in primary packages such as vials, needles, cartridges or syringes. Thereby, certain filling steps are typically performed in isolators or Restricted Area Barrier Systems (RABS) having cleanrooms. The provision of a sterile environment by cleanrooms can be crucial for achieving the required or necessary drug product safety.

[0004] In this context, Annex 1 of the GMP guidelines or other regulations provides rules for minimizing or eliminating the risk of contamination of the drug substance bymicroorganisms, particles or pyrogens in sterile filling processes. Specifically, Annex 1 of the GMP classifies cleanrooms in four categories and defines maximum particle numbers and maximum microbiological contamination for each category. Further, the GMP specifies cycles and events when the cleanrooms shall be decontaminated.

[0005] Cleanrooms are usually decontaminated in the three steps cleaning, disinfection and sterilization. For sterilization of the cleaned and disinfected surfaces of cleanrooms in place, different techniques may be involved to achieve complete non-existence of microbiological live and elimination of spores. Thereby, aside of dry heat and humid heat sterilization by means of hydrogen peroxide is in many processes the sterilization technique of choice due to its efficiency, reliability and cost efficiency.

[0006] However, a disadvantage of using hydrogen peroxide in sterilization of drug substance filling arrangements may be that tubings between drug substance containers and filling structures such as feeding needles retain a certain amount of hydrogen peroxide which may be provided into the drug substance or an API (Active Pharmaceutical Ingredient) in a filling step following the sterilization. Hydrogen peroxide can oxidize the drug substance particularly API which can impair the drug substance and decrease patient safety. Thus, processes involving hydrogen peroxide sterilization usually fail to comply with Annex 1 of the GMP or similar regulations.

[0007] Therefore, there is a need for a sterile drug substance filling system allowing to use hydrogen peroxide for sterilizing cleanrooms or process equipment.Disclosure of the Invention

[0008] According to the invention this need is settled by a filling arrangement as it is defined by the features of independent claim 1 and by a decontamination method as it is defined by the features of claim 16. Preferred embodiments are subject of the dependent claims.

[0009] In one aspect, the invention is a filling arrangement for filling a drug substance into a primary packaging. The filling arrangement comprises a dosing container, at least one filling tubing and at least one feeding needle. The dosing container houses the drug substance. The at least one filling tubing has a first longitudinal end, a second longitudinal end and a channel between the first longitudinal end and the second longitudinal end. The first longitudinal end of each of the at least one filling tubing is connected to thedosing container. The second longitudinal end of each of the at least one filling tubing is connected to one of the at least one feeding needle. An inner surface of the channel of the filling tubing consists of a low hydrogen peroxide (H2O2) retention material.

[0010] The term “drug” as used herein relates to a therapeutically active agent, also commonly called active pharmaceutical ingredient (API), as well as to a combination of plural such therapeutically active substances. The term also encompasses diagnostic or imaging agents, like for example contrast agents (e.g., MRI contrast agents), tracers (e.g., PET tracers) and hormones, that need to be administered in liquid form to the patient.

[0011] The term “drug substance” as used herein relates to a drug as defined above formulated or reconstituted in a form that is suitable for administration to the patient. For example, besides the drug, a drug substance may additionally comprise an excipient and / or other auxiliary ingredients. A particularly preferred drug substance in the context of the invention is a drug solution, in particular a solution for oral administration, injection or infusion.

[0012] The drug substance can particularly be a liquid drug substance. Even though filling of other flowable substances may be possible, the filling arrangement is particularly suitable for filling liquids.

[0013] The term “drug product” as used herein relates to a finished end product comprising a drug substance or a plurality of drug substances. In particular, a drug product may be a ready to use product having the drug substance in an appropriate dosage and / or in an appropriate form for administration. For example, a drug product may include an administration device such as a prefilled syringe or the like.

[0014] The primary packaging can be, e.g., a syringe, a vial or a cartridge. In the final drug product, the primary packaging containing the drug substance can be covered by a secondary or further packaging such as a box, a pouch, a foil or the like.

[0015] The low hydrogen peroxide retention material can be a material which is not or only to a comparably little extent capable of retaining hydrogen peroxide. More specifically, the low hydrogen peroxide retention material can be configured to not retain a sufficient amount of hydrogen peroxide when the filling tubing is sterilized with hydrogen peroxide.

[0016] In industrial processes typically a plurality of filling tubings and feeding needles are provided in the filling arrangement to allow an efficient filling of the primary packagings. For example, between 2 and 30 or between 5 and 30 filling tubings may be connected to one dosing container and to a corresponding number of feeding needles.

[0017] The feeding needle may be a needle in the narrow sense as well as any other filling outlet such as a spout or the like to provide a well-controlled dosage of the drug substance into the primary packaging.

[0018] By means of the low hydrogen peroxide retention material used at least at the surface of the channel of the filling tubing, it can be achieved that the filling arrangement can be sterilized by hydrogen peroxide. This allows a particularly safe and efficient sterilization complying with required standards and regulations such as Annex 1 of the GMP.

[0019] Preferably, the at least one filling tubing consists of the low hydrogen peroxide retention material. Such pure one material design of the filling tubing allows to efficiently provide the filling tubings.

[0020] Preferably, the low hydrogen peroxide retention material is a thermoplastic elastomer (TPE). In studies it has been shown that TPE has on the one hand suitably low tendency to retain hydrogen peroxide, e.g., compared to silicone or other materials. On the other hand, TPE can be comparably flexible and / or elastic which allows a particularly efficient use in the filling arrangement. For example, the flexibility of TPE allows the filling tube to be used for precise dosing and / or for forwarding the drug substance, e.g., peristaltically.

[0021] Thereby, the thermoplastic elastomer preferably comprises or consists of polyvinylidene fluoride, per- and polyfluoroalkyl substances, or non-perfluorinated and polyfluorinated alkyl compounds (PFAS). Polytetrafluoroethylene (PTFE) materials can also be used. Such materials have shown to provide surprisingly low retention capability for H2O2. Furthermore, they are preferably crushable, flexible, robust and elastic such that they are particularly suitable for filling tubings.

[0022] For providing the filling tubings with properties advantageous in application, the thermoplastic elastomer preferably is pressure and heat resistant, flexible, translucent, sterilizable, moldable, heat sealable, weldable, or any combination thereof. Additionallyor alternatively, preferably the thermoplastic elastomer maintains its physical properties following sterilization processes, resists kinking, remains pressure and heat resistant, remains translucent for visible product flow, does not become gummy, or any combination thereof. Such materials can be efficiently used in filling tubings to provide an advantageous and appropriate use of the filling apparatus.

[0023] Further, preferably the thermoplastic elastomer is made from ingredients approved by official authorities such as in particular the United States Food and Drug Administration (FDA), meets Class VI reference standards of the United States Pharmacopeia (USP), meets the 3.2.2.1 standards of the European Pharmacopoeia, is certified free of silicone oils and animal-derived ingredients, is available with validated sterility assurance via gamma irradiation or steam sterilization, is compliant to the European Union (EU) regulation 1907 / 2006 / EC referred to as REACH (Registration, Evaluation, Authorization and Restriction of Chemicals), to the Restrictions of Hazardous Substances (RoHS) of the European Union (EU), e.g., according to the EU directive 2011 / 65 / EU, to the California Proposition 65, or any combination thereof. Such compliant materials allows for providing filling tubings suitable for pharmaceutical applications.

[0024] Preferably, the filling arrangement comprises a cleanroom which houses the dosing container, the at least one filling tubing and the at least one feeding needle. The isolator or the cleanroom may be part of a restricted area barrier system (RABS). Such isolator, cleanroom or RABS comprising filling arrangements allows to apply a filling process complying to the high constraints of regulatories or rules such as the GMP.

[0025] Preferably, the dosing container is pressurized to house the drug substance at a pressure above atmospheric pressure such as, e.g., up to 3 bar or at 5 bar. By such pressurized container, the drug substance can efficiently be provided through the channel of the at least one filling tubing.

[0026] The filling arrangement preferably comprises a squeezing member coupled to the at least one filling tubing, wherein the squeezing member is configured to adapt the at least one filling tubing between a squeezed state and an expanded state. The squeezing member can be embodied as clamp or the like. Particularly when the at least one filling tubing consists of a comparably flexible material such as TPE, the squeezing member allows for a precise dosing of the drug substance.

[0027] Thereby, in the squeezed state the channel of the at least one filling tubing is closed. When the channel of the filling tubing is closed, the filling tubing typically is sealed or tightened. More specifically, in the squeezed state the drug substance may not pass through the channel of the filling tubing. Like this, the squeezing member can stop provision of the drug substance, e.g., while the feeding needle is transferred from one primary packaging to another.

[0028] In the expanded state the channel of the at least one filling tubing preferably is open. When being open, the channel of the filling tubing may be essentially completely open such that liquid may pass more or less unhindered.

[0029] Preferably, the at least one filling tubing has an outer diameter in a range between about 4 Millimeter (mm) and about 12 mm or between about 5 mm and about 12 mm, particularly between about 7.5 mm and about 10 mm, and the channel has a diameter in a range of about 0.8 mm to about 5 mm or in a range of about 3 mm to about 5 mm. Filling tubes of such dimension may be specifically suitable for filling various common primary packagings such as syringes, vials and cartridges.

[0030] In another aspect, the invention is a decontamination method comprising the steps of: (i) obtaining a filling arrangement as described above; (ii) providing saturated steam and / or hydrogen peroxide to the filling arrangement; and (iii) advancing the saturated steam and / or hydrogen peroxide through a filling tubing of the filling arrangement.

[0031] The method according to the invention allows for efficiently achieving the effects and benefits described above in connection with the filling arrangement and its preferred embodiments.

[0032] Preferably, the decontamination method further comprises the steps of: cleaning filling arrangement; disinfecting the filling arrangement; and sterilizing the filling arrangement by the provision of hydrogen peroxide to the filling arrangement and the advancement of the hydrogen peroxide through the filling tubing of the filling arrangement. Like this a complete and sufficient decontamination can be achieved.

[0033] Preferably, sterilizing the filling arrangement comprises sterilizing all surfaces of the filling arrangement. Thereby, the term “all surfaces” may relate to all outer surfaces of the filling arrangement and may also include some or all internal surfaces thereof. Inparticular, the internal of the filling tubing may be included as described, e.g., in connection with the following preferred embodiment.

[0034] Preferably, the filling arrangement is sterilized by the provision of the saturated steam and / or hydrogen peroxide to the filling arrangement and the advancement of the saturated steam and / or hydrogen peroxide through the filling tubing of the filling arrangement. Such embodiment allows to specifically sterilize the internal surface of the filling tubing which can be a crucial step to prevent cross- contamination or the like.

[0035] Preferably, the decontamination method comprises the steps of: positioning the filling arrangement in an isolator or RABS and gassing the isolator or RABS by saturated steam and / or hydrogen peroxide. Such gassing may be performed parallel or subsequent to the provision of the saturated steam and / or hydrogen peroxide. It allows for achieving decontamination of all relevant surfaces including the filling tubing.Brief Description of the Drawings

[0036] The filling arrangement according to the invention and the decontamination method according to the invention are described in more detail hereinbelow by way of exemplary embodiments and with reference to the attached drawings, in which:Fig. 1 shows a schematic view of an embodiment of a filling arrangement according to the invention; andFig. 2 shows a flow scheme of an embodiment of a contamination method according to the invention.Description of Embodiments

[0037] In the following description certain terms are used for reasons of convenience and are not intended to limit the invention. The terms “right”, “left”, “up”, “down”, “under" and “above" refer to directions in the figures. The terminology comprises the explicitly mentioned terms as well as their derivations and terms with a similar meaning. Also, spatially relative terms, such as "beneath", "below", "lower", "above", "upper", "proximal", "distal", and the like, may be used to describe one element's or feature's relationship to another element or feature as illustrated in the figures. These spatially relative terms are intended to encompass different positions and orientations of the devices in use or operation in addition to the position and orientation shown in the figures. For example, ifa device in the figures is turned over, elements described as "below" or "beneath" other elements or features would then be "above" or "over" the other elements or features. Thus, the exemplary term "below" can encompass both positions and orientations of above and below. The devices may be otherwise oriented (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein interpreted accordingly. Likewise, descriptions of movement along and around various axes include various special device positions and orientations.

[0038] To avoid repetition in the figures and the descriptions of the various aspects and illustrative embodiments, it should be understood that many features are common to many aspects and embodiments. Omission of an aspect from a description or figure does not imply that the aspect is missing from embodiments that incorporate that aspect. Instead, the aspect may have been omitted for clarity and to avoid prolix description. In this context, the following applies to the rest of this description: If, in order to clarify the drawings, a figure contains reference signs which are not explained in the directly associated part of the description, then it is referred to previous or following description sections. Further, for reason of lucidity, if in a drawing not all features of a part are provided with reference signs it is referred to other drawings showing the same part. Like numbers in two or more figures represent the same or similar elements.

[0039] Fig. 1 shows an embodiment of a filling arrangement 1 according to the invention for filling a liquid drug substance into vials 8 as primary packagings. The filling arrangement 1 is part of a restricted area barrier system (RABS) and comprises a dosing container 2, six filling tubings 3 consisting of a thermoplastic elastomer (TPE) or of polyvinylidene fluoride (PVDF), a needle assembly 4, a squeezing member 5, a cleanroom 6 and a conveyor belt 7.

[0040] The dosing container 2 is embodied as pressure vessel. It houses the drug substance at a pressure above atmospheric pressure such as at about three or five bar. Like this, the drug substance can efficiently be provided out of the dosing container 2. In particular, the dosing container 2 comprises six ports 21 , wherein to each of the ports 21 one of the filling tubings 3 is connected at a first longitudinal end thereof.

[0041] The squeezing member 5 comprises a platform 52 equipped with six finger clamps 51 . The dosing container 2 is arranged on top of the platform 52 of the squeezingmember 5. Each of the six finger clamps 51 holds one of the six filling tubings 3 approximately at a middle of a longitudinal extension thereof.

[0042] The needle assembly 4 comprises a holder arm 42 and six feeding needles 41 . The holder arm 42 holds the feeding needles 41 in a row and is automatically or robotically movable. Each of the six feeding needles 41 is connected a second longitudinal end of one of the six filling tubings 3. Thus, each filling tubing 3 extends from one of the ports 21 of the dosing container 2 to one of the feeding needles 41 via one of the finger clamps 51. Between the first longitudinal end and the second longitudinal end, each filling tubing 3 has a channel such that each port 21 is in fluid communication with one of the feeding needles 41 .

[0043] Below the needle assembly 4 the conveyor belt 7 is positioned. On top of the conveyor belt 7 the vials 8 are arranged such that they can be forwarded along the conveyor belt 7.

[0044] The cleanroom 6 tightly houses the dosing container 2, the filling tubings 3, the needle assembly 4 and a portion of the conveyor belt 7. It has an airlock port 61 through which the conveyor belt 7 extends.

[0045] Each of the finger clamps 51 of the squeezing member 5 is configured to adapt the associated filling tubing 3 between a squeezed state and an expanded state. In the squeezed state the channel of the respective filling tubing 3 is closed. Thereby, the filling tubing 3 is sealed and tightened such that the drug substance cannot pass through the channel. In the expanded state the channel of the respective filling tubing 3 is open. Thereby, the channel of the filling tubing 3 is essentially completely open such that liquid can efficiently pass through the channel.

[0046] For filling the vials 8, six vials 8 are positioned below the needle assembly 4 such that each feeding needle 41 is associated to one vial 4. Each of the feeding needles 41 then accesses one of the vials 8, e.g., by piercing a septum or a stopper of the respective vial 8. Then the finger clamps 51 are released such that the filling tubings 3 are opened and, due to the pressure in the dosing container 2 the drug substance advances from the dosing container 2 through the channel of the filling tubings 3 into the vials 8. Once a sufficient dosage of drug substance is provided into the vials 8, the finger clamps 51 squeeze the filling tubings 3 such that dosing is stopped.

[0047] The vials 8 are then forwarded by the conveyor belt 7 and further processed such as, e.g., stoppered, capped and / or secondary packaged.

[0048] Between two campaigns or batches of the same or different drug substance(s), the filling arrangement 1 is decontaminated in place by a decontamination method 10 as shown in Fig. 2. In particular, in a step 11 the filling arrangement is conventionally cleaned and in a step 12 it is conventionally disinfected.

[0049] In a step 13, the filling arrangement 1 is sterilized by providing with H2O2 or saturated steam at an elevated pressure. In particular, in a step 131 the H2O2 or saturated steam is advanced through the filling tubings 3 of the filling arrangement 1 . Like this, the inner surfaces of the filling tubings 3 or the channels, respectively, are efficiently sterilized (Sterilization in Place SIP) and / or disinfected. Since the filling tubings 3 consist of TPE or PVDF, which is a very low H2O2 retention material, the filling tubings 3 can safely be reused right after sterilization. No additional treatment is necessary.

[0050] This description and the accompanying drawings that illustrate aspects and embodiments of the present invention should not be taken as limiting the claims defining the protected invention. In other words, while the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. Various mechanical, compositional, structural, electrical, and operational changes may be made without departing from the spirit and scope of this description and the claims. In some instances, well-known circuits, structures and techniques have not been shown in detail in order not to obscure the invention. Thus, it will be understood that changes and modifications may be made by those of ordinary skill within the scope and spirit of the following claims. In particular, the present invention covers further embodiments with any combination of features from different embodiments described above and below.

[0051] The disclosure also covers all further features shown in the Figs, individually although they may not have been described in the afore or following description. Also, single alternatives of the embodiments described in the figures and the description and single alternatives of features thereof can be disclaimed from the subject matter of the invention or from disclosed subject matter. The disclosure comprises subject matter consisting of the features defined in the claims or the exemplary embodiments as well as subject matter comprising said features.

[0052] Furthermore, in the claims the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single unit or step may fulfil the functions of several features recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. The terms “essentially”, “about”, “approximately” and the like in connection with an attribute or a value particularly also define exactly the attribute or exactly the value, respectively. The term “about” in the context of a given numerate value or range refers to a value or range that is, e.g., within 20%, within 10%, within 5%, or within 2% of the given value or range. Components described as coupled or connected may be electrically or mechanically directly coupled, or they may be indirectly coupled via one or more intermediate components. Any reference signs in the claims should not be construed as limiting the scope.

Claims

CLAIMSClaim 1 : A filling arrangement (1 ) for filling a drug substance into a primary packaging (8), comprising a dosing container (2) housing the drug substance; at least one filling tubing (3) having a first longitudinal end, a second longitudinal end and a channel between the first longitudinal end and the second longitudinal end; and at least one feeding needle (41 ), wherein the first longitudinal end of each of the at least one filling tubing(3) is connected to the dosing container (2), and wherein the second longitudinal end of each of the at least one filling tubing (3) is connected to one of the at least one feeding needle (41 ), characterized in that an inner surface of the channel of the filling tubing (3) consists of a low hydrogen peroxide retention material.Claim 2: The filling arrangement (1) of claim 1 , wherein the at least one filling tubing (3) consists of the low hydrogen peroxide retention material.Claim 3: The filling arrangement (1 ) of claim 1 or 2, wherein the low hydrogen peroxide retention material is a thermoplastic elastomer.Claim 4: The filling arrangement (1 ) of claim 3, wherein the thermoplastic elastomer comprises or consists of polyvinylidene fluoride or a per- and polyfluoroalkyl substance.Claim 5: The filling arrangement (1 ) of claim 3, wherein the thermoplastic elastomer comprises or consists of polytetrafluoroethylene.Claim 6: The filling arrangement (1 ) of any one of claims 3 to 5, wherein the thermoplastic elastomer is pressure and heat resistant, flexible, translucent, sterilizable, moldable, heat sealable, weldable, or any combination thereof.Claim 7: The filling arrangement (1 ) of claim 6, wherein the thermoplastic elastomer maintains its physical properties following sterilization processes, resists kinking, remains pressure and heat resistant, remains translucent for visible product flow, does not become gummy, or any combination thereof.Claim 8: The filling arrangement (1 ) of any one of claims 3 to 7, wherein the thermoplastic elastomer is made from FDA-approved ingredients, meets Class VI USP standards, meets European Pharmacopoeia 3.2.2.1 standards, is certified free of silicone oils and animal-derived ingredients, is available with validated sterility assurance via gamma irradiation or steam sterilization, is compliant to REACH, RoHS and / or California Proposition 65, or any combination thereof.Claim 9: The filling arrangement (1 ) of any one of the preceding claims, comprising a cleanroom (6) which houses the dosing container (2), the at least one filling tubing (3) and the at least one feeding needle.Claim 10: The filling arrangement (1 ) of any one of the preceding claims, wherein the dosing container (2) is pressurized to house the drug substance at a pressure above atmospheric pressure.Claim 11 : The filling arrangement (1 ) of any one of the preceding claims, comprising a squeezing member (5) coupled to the at least one filling tubing, wherein the squeezing member (5) is configured to adapt the at least one filling tubing (3) between a squeezed state and an expanded state.Claim 12: The filling arrangement (1 ) of claim 11 , wherein in the squeezed state the channel of the at least one filling tubing (3) is closed.Claim 13: The filling arrangement (1 ) of claim 11 or 12, wherein in the expanded state the channel of the at least one filling tubing (3) is open.Claim 14: The filling arrangement (1 ) of any one of the preceding claims, wherein the at least one filling tubing (3) has an outer diameter in a range between about 4 Millimeter and about 12 Millimeter or in a range between about 5 Millimeter and about 12 Millimeter, particularly between about 7.5 Millimeter and about 10 Millimeter, and the channel has a diameter in a range of about 0.8 Millimeter to about 5 Millimeter or in a range of about 3 Millimeter to about 5 Millimeter.Claim 15: A decontamination method (10) comprising: obtaining a filling arrangement (1 ) according to any one of the preceding claims; providing saturated steam or hydrogen peroxide to the filling arrangement (13); and advancing the saturated steam or hydrogen peroxide through a filling tubing (3) of the filling arrangement (131 ).Claim 16: The decontamination method (10) of claim 15, comprising cleaning the filling arrangement (11 ); disinfecting the filling arrangement (12); and sterilizing the filling arrangement (1 ) by the provision of the saturated steam or hydrogen peroxide to the filling arrangement (1 ).Claim 17: The decontamination method (10) of claim 16, wherein sterilizing the filling arrangement (1 ) comprises sterilizing all surfaces of the filling arrangement (1 ).Claim 18: The decontamination method (10) of claim 16 or 17, wherein the filling arrangement (1 ) is sterilized by the provision of the saturated steam or hydrogen peroxide to the filling arrangement (1 ) and the advancement of the saturated steam or hydrogen peroxide through the filling tubing (3) of the filling arrangement (13).Claim 19: The decontamination method (10) of any one of claims 15 to 18, comprising the steps of positioning the filling arrangement in an isolator or restricted area barrier system and gassing the isolator or restricted area barrier system by saturated steam or hydrogen peroxide.

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