Method and device for steam sterilization of primary packages

Abstract

The invention relates to a method and a device for steam sterilization of primary packages, and to primary packages treated by said method. The primary packages, such as cartridges, vials, syringes, ampoules, or other containers, may be used for pharmaceutical and cosmetic packaging applications. The sterilization method reduces the water marks on the corresponding primary packages.

Description

Technical Field

[0001] The present invention relates to a method and apparatus for steam sterilizing primary packaging, and primary packaging treated by the method. The primary packaging, such as cartridges, vials, syringes, ampoules or other containers, can be used for packaging applications of medicines and cosmetics. The sterilization method reduces water marks on the corresponding primary packaging. Background Art

[0002] Steam sterilization is the state-of-the-art technology for many pharmaceutical and cosmetic products and their respective primary packaging. These primary packaging can be, for example, cartridges, vials, syringes or ampoules made of polymers (usually cyclic olefin polymers (COP) or cyclic olefin copolymers (COC)) or glass. However, there is a specific problem with the sterilization process: water streaks form on the surface of these primary packaging. This problem exists for both materials, but is generally more pronounced with glass.

[0003] The results of the water mark analysis show that the water marks may contain, in particular, silicon-based residues of different molecular weights and / or borates, sodium salts, calcium salts, sulphur salts and nitrates characteristic of glass components. In the case of glass materials, these water marks may be mainly attributed to evaporation products during the hot forming process and are referred to as furnace dust.

[0004] In particular, for sterile pharmaceutical primary packages in the form of so-called RTU (ready-to-use) containers, a typical packaging configuration for transport from the pharmaceutical primary package manufacturer to the pharmaceutical company using the package comprises a tub or tray containing a large number of primary packages sealed with a nonwoven fabric. The nonwoven fabric is usually made of high-density polyethylene (known as DuPont's trademark Of course, it can also be other suitable nonwoven fabrics from other companies. Even after the package is closed, these selectively permeable nonwoven fabrics can allow sterilization by gases or steam such as ethylene oxide, water vapor or hydrogen peroxide. While permeating the sterilizing gas or steam, the selectively permeable nonwoven fabric is essentially impermeable to microorganisms, thereby forming a microbial barrier. "Essentially impermeable to microorganisms" in this article means that the logarithmic reduction value (LRV) of the microbial barrier measured according to ASTM F1608-16 is 2 to 6.

[0005] For the packaging configuration of ready-to-use (RTU) containers used in the market, especially when they are made of glass, without adding a sterile barrier (basin / Standard steam sterilization methods for solid products cannot be used when there is a risk of loss of integrity of the seal seam. The standard method is characterized by the use of large vacuum pulses to remove entrapped air, which may hinder the effective penetration of steam into the product and thus affect effective sterilization. The pressure exchange in the membrane is slower than that in the chamber. Frequent and rapid pressure changes will cause the pressure in the basin and High stresses are generated in the sealing seams between the layers. The slower pressure equalization in the basin promotes The expansion of the seal (when the pressure is reduced) or its adhesion to the package (when the pressure is increased). In addition, the sterilization step is usually carried out at an elevated pressure, wherein after the sterilization process, the pressure is reduced to ambient pressure. The sealing seams between the layers are obtained by means of a glue whose hot melt softening point is close to the steam sterilization conditions, so that the sealing seams cannot withstand the stress of pressure changes at high temperatures.

[0006] Another disadvantage of RTU containers is that saturated steam will penetrate into the basin and condense on surfaces such as the insert, glass or polymer, and on the basin or bag, so the basin may contain a large amount of water that needs to be removed at the end of the sterilization process.

[0007] Patent document WO 2018 / 029590 A2 discloses a method for steam sterilization of glass products, which uses a pulsed steam supply to reduce white spots on the glass and damage to the physical and chemical structure of the glass. The temperature and pressure of the steam flow in the treatment chamber are constantly fluctuating, so its quality is never constant. It should be emphasized that there is no sterilization step in the method where the pressure and / or temperature reaches a static sterilization step, and the system used is an open quality system. The pressure variation range is 0.2 bar to 1.15 bar. These method conditions have different disadvantages. Since the pressure in the chamber is constantly changing, the final basin / The sealing seam is under constant stress. This increases the risk of compromised sterile barriers, requiring resealing and sterilization of the basin or even discarding the glassware in the event of a failure. In addition, pressures predominantly in the subambient range will result in lower steam temperatures, which in turn will require a significant increase in sterilization times to achieve the specified sterilization level. With a recommended pulse duration of 24 min ± 1.5 min, the example graph shows a duration of approximately 450 min for a complete sterilization cycle.

[0008] Therefore, the object of the present invention is to provide a steam sterilization method and a corresponding device to overcome at least one disadvantage of the prior art. In particular, the formation of water marks on the primary packaging, in particular on the inner and / or outer surface of the primary packaging, should be avoided or at least reduced while maintaining the sterility level of the sterile container. Summary of the invention

[0009] According to a first aspect, the present invention relates to a method for steam sterilizing primary packages in a steam sterilization device, comprising the following steps: a) preheating the primary packaging to a temperature T in the steam sterilization device p , wherein the temperature T p At least equal to the predetermined pressure p s and the predetermined temperature T s The dew point temperature T of steam during steam sterilization dp -15°C, preferably at least equal to the predetermined pressure p s and the predetermined temperature T s The dew point temperature T of steam during steam sterilization dp , and / or at least 50°C; b) adjusting the pressure and temperature in the steam sterilization equipment to the predetermined pressure p s and the predetermined temperature T s and by supplying the steam sterilization device with at least a period of time t s The steam is sterilized, the time t s Sufficient to ensure a sterility assurance level of 10 or less as specified in 5.1.1 of the European Pharmacopoeia -6 ;as well as c) During the drying phase, reducing the relative humidity in the steam sterilization apparatus to less than 50%; The drying pressure in the steam sterilization device is maintained at the predetermined pressure p s unchanged, or The drying pressure in the steam sterilization equipment is set to be slightly lower than the predetermined pressure p s ; Thereafter, in a cooling phase, the pressure and temperature in the steam sterilization apparatus are adjusted to ambient pressure and a temperature of less than or equal to 75° C., respectively.

[0010] The drying pressure in the steam sterilization equipment is set to be slightly lower than the predetermined pressure p s It can refer to the pressure from p s A decrease of at most 75 hPa, or at most 50 hPa or at most 25 hPa, and / or at least 5 hPa, or at least 10 hPa or at least 20 hPa.

[0011] According to a second aspect, the present invention relates to a method for steam sterilizing primary packaging in a steam sterilization device, comprising the following steps: a) preheating the primary packaging to a temperature T in the steam sterilization device p , wherein the temperature T p At least equal to the predetermined pressure p s and the predetermined temperature T s The dew point temperature T of steam during steam sterilization dp -15°C, preferably at least equal to the predetermined pressure p s and the predetermined temperature T s The dew point temperature T of steam during steam sterilization dp , and / or at least 50°C; b) sterilizing by supplying steam to the steam sterilization device; and c) During the drying phase, reducing the relative humidity in the steam sterilization apparatus to less than 50%; The drying pressure in the steam sterilization device is maintained at the predetermined pressure p s unchanged, or The drying pressure in the steam sterilization equipment is set to be slightly lower than the predetermined pressure p s ; Then, in a cooling phase, the pressure and temperature in the steam sterilization apparatus are regulated.

[0012] The drying pressure in the steam sterilization equipment is set to be slightly lower than the predetermined pressure p s It can refer to the pressure from p s A decrease of at most 75 hPa, or at most 50 hPa or at most 25 hPa, and / or at least 5 hPa, or at least 10 hPa or at least 20 hPa.

[0013] According to a third aspect, the present invention relates to a method for steam sterilizing primary packaging in a steam sterilization device, comprising the following steps: a) a cleaning step, comprising: washing the inner surface and / or outer surface of the primary packaging with water and / or a polar organic solvent; b) preheating the primary packaging to a temperature T in the steam sterilization device p , wherein the temperature T p At least equal to the predetermined pressure p s and the predetermined temperature T s The dew point temperature T of steam during steam sterilization dp -15°C, preferably at least equal to the predetermined pressure p sand the predetermined temperature T s The dew point temperature T of steam during steam sterilization dp , and / or at least 50°C; c) adjusting the pressure and temperature in the steam sterilization equipment to the predetermined pressure p s and the predetermined temperature T s and sterilize by supplying steam to the s Sterilization is carried out by steam for a time sufficient to ensure a sterility assurance level equal to or less than 10 -6 ;as well as d) During the drying stage, reducing the relative humidity in the steam sterilization apparatus to less than 50%; The drying pressure in the steam sterilization device is maintained at the predetermined pressure p s The drying pressure in the steam sterilization device is set to be slightly lower than the predetermined pressure p s ; Thereafter, in a cooling phase, the pressure and temperature in the steam sterilization apparatus are adjusted to ambient pressure and a temperature of less than or equal to 75° C., respectively.

[0014] The drying pressure in the steam sterilization equipment is set to be slightly lower than the predetermined pressure p s It can refer to the pressure from p s A decrease of at most 75 hPa, or at most 50 hPa or at most 25 hPa, and / or at least 5 hPa, or at least 10 hPa or at least 20 hPa.

[0015] According to a fourth aspect, the present invention relates to an apparatus for steam sterilization of primary packages, comprising: - a chamber for receiving the primary package, wherein the chamber is connected to a steam supply, a compressed air supply and a vacuum pump and is provided with a heating and cooling jacket; and - a controller, for adjusting the temperature and pressure in the chamber through the steam supply device and the compressed air supply device, so as to be configured to perform the steam sterilization method according to one of the above aspects. In particular, the controller can adjust the temperature and pressure in the chamber by providing steam and / or air to the chamber.

[0016] According to a fifth aspect, the present invention relates to a product, wherein the product is a primary package treated by the steam sterilization method according to at least one of the first to third aspects.

[0017] The primary packaging can be a cartridge, a vial, a syringe, an ampoule or other container. For example, it can be used for pharmaceutical and cosmetic packaging applications.

[0018] The sterility assurance level of the primary packaging may be equal to or less than 10 as specified in Article 5.1.1 of the European Pharmacopoeia. -6 .

[0019] According to Article 2.9.20 of the European Pharmacopoeia, the primary packaging may be free from optical defects with respect to water marks, in other words the water marks are not visible.

[0020] The primary packaging may be at least partially coated on the inner surface and / or the outer surface.

[0021] According to a sixth aspect, the present invention relates to use of the primary packaging according to the fifth aspect, wherein the primary packaging is suitable for storing a pharmaceutical composition or a medicine.

[0022] For the purposes of the present invention, water marks can be residues that appear on the surface of sterile containers when sterilization and front-end processes are not properly optimized. They usually appear in the form of more or less prominent irregular white or off-white spots, with a typical size range of 0.005-0.01 square millimeters and can eventually even reach about 7 square millimeters. They can contain silicon-based residues of different molecular weights and / or borates, sodium salts, calcium salts, sulphur salts, nitrates and / or other glass components. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Schematic diagram of steam sterilization equipment.

[0024] Figure 2 A schematic diagram of temperature and pressure in steam sterilization method. DETAILED DESCRIPTION

[0025] The detailed description section relates to various aspects described in the summary section.Any features of the embodiments described below may relate to one or more methods of steam sterilization, steam sterilization equipment, and primary packaging treated by steam sterilization.

[0026] "European Pharmacopoeia 5.1.1" refers to the 11th edition of the European Pharmacopoeia, which specifies the sterilization methods for medicinal products and the sterility assurance level to be achieved. Sterility is defined as the absence of viable microorganisms, expressed as a sterility assurance level equal to or less than 10 -6 Therefore, Article 5.1.1 of the European Pharmacopoeia requires a sterility assurance level of 10 to be demonstrated by correlation of pressure, time and temperature. -6This is accomplished by measuring the temperature in the chamber and in the product during validation, and by performing a biological assessment using appropriate biological indicators.

[0027] “Ph.E. 2.9.20” refers to Ph.E. 2.9.20 of the 11th edition of the Ph.E., which deals with particulate contamination by visible particles.

[0028] The inventors surprisingly found that simply reducing the contamination of the exterior and / or interior of the packaging by silicon-based residues and furnace dust in a cleaning step prior to the sterilization process, which may include cleaning the interior and / or exterior surfaces of the packaging, is not sufficient to effectively inhibit water marks. This only reduces water marks that occur during steam sterilization methods when water condenses and dries.

[0029] After further investigation, the inventors discovered another problem associated with the sterilization stage. At the end of the sterilization stage, the basin can be effectively dried by reducing the pressure to promote water evaporation. However, this may cause the softened basin / The risk of loss of sterile barrier integrity is caused by the formation of sealing seams. Furthermore, lowering the temperature further below the softening point of the glue is not possible, since lower temperatures immediately lead to condensation, which must be avoided for a number of reasons. Condensation collects contaminants located on the surface and concentrates them in a small area during the drying step, which forms visible traces. In addition, organic and silicon-based contaminants constitute hydrophobic surfaces, causing moisture to condense on them as water droplets. In addition, condensation increases the necessary drying time after sterilization. A solution to the condensation problem has been found in separate drying and cooling stages.

[0030] First, during the drying phase, the relative humidity in the chamber is reduced from about 100% to less than 50%, while the drying pressure in the steam sterilization apparatus is kept constant or set to be slightly lower than a predetermined pressure p. s The temperature and pressure are actively reduced only in the subsequent cooling phase. The relative humidity in the chamber can be reduced from about 100% to less than 50%, or from about 100% to less than 40%, or from about 100% to less than 30%. The drying pressure in the steam sterilization device can be kept substantially constant or set to a value slightly below the predetermined pressure p s (sterilization pressure) to release steam and thereby reduce the relative humidity while avoiding the entry of a large amount of compressed air. Therefore, the temperature drop in the steam sterilization device can be minimized, thereby avoiding excessive and too fast cooling of the primary packaging. In particular, by setting the drying pressure slightly below the predetermined pressure p sThe drying pressure in the steam sterilization device is set to be slightly lower than the predetermined pressure p s It can refer to the pressure from p s A decrease of at most 75 hPa, or at most 50 hPa, or at most 25 hPa, and / or at least 5 hPa, or at least 10 hPa or at least 20 hPa.

[0031] Even more surprising to the inventors was that it turned out that even the above-described washing step combined with separate drying and cooling stages was not sufficient to effectively suppress water marks.

[0032] Upon further investigation, they discovered another related problem: when the hotter saturated steam contacts the primary packaging and the final tub, tray or nest, and when the product cools after sterilization, water condenses on the cooler surface of the primary packaging. This condensate, which was already present on the surface of the primary packaging before sterilization, causes evaporative cooling in the tub and reduces the temperature of 100°C by about 25°C, causing the water marks to reappear. The effects of steam condensation only become apparent when the glass or polymer components are viewed directly. Impurities collect in water droplets and leave visible defects (stains) on the glass after drying.

[0033] By measuring the heating rates of RTU containers and basins containing these containers in a furnace preheated to 100°C, it was found that these heating rates are very small (usually less than or equal to 1°C / min). This heating rate is much lower than the heating rate of the medium in the sterilization chamber, where the medium is generally air and steam. The heating rates of RTU containers and basins are slightly different. Compared with basins with lighter weight, that is, basins with lighter glass primary packaging, basins with heavier weight, especially basins with heavier glass primary packaging, will heat up more slowly. The heating time of ordinary standard methods is usually between 10 minutes and 20 minutes. Therefore, the temperature in the basin will be lower than 40°C to 50°C. When saturated steam enters the chamber after the heating phase and the vacuum pulse, the saturated steam will come into contact with the colder surfaces and condense in and on the basin. Because the steam is already saturated, this condensed water cannot be absorbed by the steam. During the sterilization process, this condensed water will remain in the basin.

[0034] In order to avoid water condensation during pretreatment, the RTU container and the basin of the present invention are fully heated in the first stage. The temperature T p At least equal to the dew point temperature T of steam under steam sterilization conditions dp -15°C, preferably at least equal to the predetermined pressure p s and the predetermined temperature T sThe dew point temperature T of steam during steam sterilization dp , and / or at least 50°C. If they have at least the dew point temperature, steam will no longer condense on their surfaces. In general, it has been found that a temperature of at least 50°C can be used. The temperature may be at least 50°C, at least 60°C, at least 70°C, at least 80°C, or at least 85°C. The temperature may be at most the temperature at which steam sterilization is carried out. The temperature may be selected depending on the type of primary packaging. For example, for some primary packagings, a slight preheating to a temperature of at least 50°C or at least 60°C is sufficient, while for other primary packagings, further preheating to a temperature of at least 70°C, at least 80°C, or even at least 85°C is required. In this way, condensation before sterilization can be minimized or eliminated.

[0035] Due to the higher temperatures in the pretreatment phase, the basin / The seal softens, so deep vacuum pulses should be avoided to avoid weakening the sterile barrier. As a result, more air may be present in the basin, which may prevent product sterilization. Depending on the level of pressure applied, a moderate increase in sterilization time can ensure that the desired level of sterility is achieved.

[0036] The combination of separate drying and cooling stages and the avoidance or minimization of water condensation before the sterilization step has proven to be suitable for achieving effective suppression of water marks while maintaining an unchanged sterility level. In addition to these two measures, a cleaning step as described above can also be added; however, it is not sufficient if used in combination with only one of these measures.

[0037] In an embodiment, the primary package may be further placed in a secondary packaging container (e.g., a basin or a tray) sealed with a non-woven fabric, wherein the secondary packaging container may optionally include a nest and / or may optionally contain a plurality of the primary packages. The method disclosed herein may be used with primary packages placed directly in a suitable steam sterilization device, or with a non-woven fabric (particularly ) is used together with the common packaging of RTU containers in the form of sealed basins.

[0038] In an embodiment, the time for preheating in step a) can be 0.5 hours to 3 hours, or 0.75 hours to 2.5 hours, or 1 hour to 2 hours. The time for preheating in step a) can be at least 0.5 hours, or at least 0.75 hours, or at least 1 hour. The time for preheating in step a) can be at most 3 hours, or at most 2.5 hours, or at most 2 hours. It has been found that these preheating times generally provide enough time for common primary packaging materials to be fully heated to the core.

[0039] In an embodiment, the primary package may be preheated in step a) to a temperature T of at least 50°C, or at least 60°C, or at least 70°C, or at least 85°C. p In step a), the primary package may be preheated to a temperature T p , wherein the highest temperature is the temperature T during steam sterilization s , or up to T s -5℃, or the highest is T s -10℃, or the highest is T s -15℃, or the highest is T s -20℃, or the highest is T s -25°C, or up to 100°C. These temperatures have been found to be suitable for preventing or reducing condensation on the surface of the primary packaging sufficiently to prevent the formation of water marks in conjunction with other measures.

[0040] In an embodiment, the steam sterilization in step b) is performed for a time t s The time period may be at least 1.5 hours, or at least 1.0 hours, or at least 0.75 hours, or at least 0.5 hours, or at least 0.3 hours, and / or the temperature T s The temperature is between 120°C and 127°C, or between 120°C and 125°C, or between 121°C and 124°C. The time t for steam sterilization in step b) is s It may be up to 5 hours, or up to 4 hours, or up to 3 hours. It has been found that this can reliably achieve 10 -6 Universal sterilization level.

[0041] In an embodiment, the steam sterilization in step b) can be carried out at a pressure p above the ambient pressure. s Under the condition of s In particular, it is in the range of 1100 hPa to 2500 hPa, or 1400 hPa to 2400 hPa, or 1800 hPa to 2300 hPa. The pressure p at which the steam sterilization is performed in step b) s The pressure p at which steam sterilization is performed in step b) may be at least 1100 hPa, or at least 1400 hPa, or at least 1800 hPa. s It can be up to 2500 hPa, or up to 2400 hPa, or up to 2300 hPa. Sterilization under moderate support pressure conditions can achieve the best efficiency and desired processing time, and reducing the pressure at the end of the sterilization process can also promote final drying. The moderate support pressure can be about 100 hPa higher than the saturated steam absolute pressure. For example, when the saturated steam absolute pressure is about 2100 hPa, the moderate support pressure can be about 2200 hPa.

[0042] In an embodiment, during the cooling phase of step c), the rate of pressure regulation may be at most 500 hPa / min, or at most 250 hPa / min, or at most 100 hPa / min, or at most 75 hPa / min, or at most 50 hPa / min. If the rate is chosen too high, the stress on the nonwoven sealing seam may lead to a loss of integrity.

[0043] In an embodiment, between step a) and step b), the pressure in the steam sterilization apparatus may be reduced to a range of 100 hPa to 1000 hPa, or 250 hPa to 1000 hPa, or 500 hPa to 1000 hPa, or 700 hPa to 1000 hPa, or 800 hPa to 975 hPa, or 900 hPa to 975 hPa, wherein the pressure reduction rate is optionally at most 500 hPa / min, or at most 250 hPa / min, or at most 100 hPa / min, or 75 hPa / min, or at most 50 hPa / min, or at most 25 hPa / min. The pressure in the steam sterilization apparatus may be reduced to not less than 100 hPa, or to not less than 250 hPa, or to not less than 500 hPa, or to not less than 700 hPa, or to not less than 800 hPa, or to not less than 900 hPa. The pressure in the steam sterilization device can be reduced to no more than 975 hPa, or no more than 950 hPa, or no more than 925 hPa or no more than 900 hPa. This helps, especially when adjusting at the above-mentioned rate, to reduce the stress on the nonwoven sealing seam.

[0044] In an embodiment, during the drying phase of step c), the temperature in the steam sterilization device can be increased from T s to a range of 120°C to 90°C, or 115°C to 95°C, or 110°C to 100°C, and / or keeping the pressure in the steam sterilization device constant or just slightly below the predetermined pressure p s (sterilization pressure). The temperature in the steam sterilization equipment can be s The temperature in the steam sterilization device can be reduced from T to a maximum of 120°C, or a maximum of 115°C, or a maximum of 110°C. s The drying pressure in the steam sterilization device can be set to be slightly lower than the predetermined pressure p s(sterilization pressure) to reduce the temperature, thereby releasing steam and thereby reducing the relative humidity, while avoiding the entry of a large amount of compressed air. Therefore, the temperature drop in the steam sterilization device can be minimized, thereby avoiding excessive and too fast cooling of the primary packaging. In particular, by setting the drying pressure slightly lower than the predetermined pressure p s The drying pressure in the steam sterilization device is set to be slightly lower than the predetermined pressure p s It can refer to the pressure from p s A decrease of at most 75 hPa, or at most 50 hPa, or at most 25 hPa, and / or at least 5 hPa, or at least 10 hPa, or at least 20 hPa.

[0045] In an embodiment, between step b) and step c), the pressure in the steam sterilization apparatus can be changed from p to s A reduction of at most 75 hPa, or at most 50 hPa, or at most 25 hPa. A slight reduction in pressure before starting the drying phase may facilitate drying. Only a slight reduction in pressure before starting the drying phase may help avoid a large drop in temperature due to the introduction of too much compressed air.

[0046] In an embodiment, an additional cleaning step may be performed before step a), comprising: washing the outer surface of the primary packaging with water and / or a polar organic solvent. As mentioned above, such a cleaning step alone is not sufficient to avoid the formation of water marks. However, it can be used as an additional step to reduce surface contamination, thereby reducing or eliminating water marks. Since the source of contamination is salts and silicon-based substances in the furnace dust, washing with water or polar organic solvents such as alcohols, esters, ethers, etc. is most effective.

[0047] In an embodiment, for this purpose, the apparatus may further comprise a washing station for washing the outer surface of the primary packaging with water and / or a polar organic solvent.

[0048] Figure 1A schematic diagram of a steam sterilization device 1 is shown. The device 1 comprises a chamber 2 for receiving primary packages to be sterilized. In this figure, the primary packages are shown in a secondary packaging container 10 sealed with a non-woven fabric layer. The chamber 2 is surrounded by a heating and cooling jacket 3, so that a temperature and pressure controller 4 can perform programmed heating and cooling of the chamber 2. The heating and cooling jacket 3 is connected to a cooling water supply 5 for cooling and a steam supply 7 for heating. The chamber 2 is connected to the steam supply 7, a compressed air supply 6 and a vacuum pump 8. The compressed air supply 6 can provide hot or cold air and can also be used to set the temperature and pressure in the chamber 2. Condensed water in the chamber 2 can be discharged through a drain pipe 9. In addition, two ventilation devices of the chamber 2 are shown to help homogenize the air in the chamber 2.

[0049] The controller 4 for the temperature and pressure in the chamber 2 and the steam supply device 7 and the compressed air supply device 6 is configured to perform the steam sterilization method of the present invention.

[0050] Figure 2 Schematic diagram of temperature and pressure in the steam sterilization method according to the present invention. The temperature is shown by a dotted line; the pressure is shown by a solid line. The vertical dotted lines represent the seven program steps i) to vii) of the steam sterilization method. In this example, a pre-vacuum of 900 hPa and a pressurization of 2200 hPa were used in the sterilization phase of a glass cartridge (as a primary packaging) placed in a non-woven sealed basin (as a secondary packaging container 10). All pressure changes were carried out at a rate of 50 hPa / min.

[0051] In the preheating step i), the chamber 2 containing the primary package in the secondary packaging container 10 is preheated to a temperature T 1 within 1.5 hours under constant pressure. p , for example 85° C. At the end of step i), the pressure drops to 900 hPa.

[0052] In the pre-vacuum step ii), the pressure and temperature are kept constant for a time sufficient to balance the pressure inside the secondary packaging container 10, for example, the time is 5 minutes.

[0053] In the pressurization step iii), the chamber 2 is heated; the pressure is first raised to the ambient pressure; then, it is kept constant for a period of time (e.g., 5 minutes); finally, it is raised to the sterilization pressure p s , i.e., 2200 hPa in this example. For example, the set temperature T s It can be 122°C.

[0054] In the sterilization step iv), the sterilization treatment is carried out at a constant pressure and temperature (for example for 1 hour) to achieve 10 -6 Before the sterilization level is reached, the system can be given some time (e.g. 5 minutes) to equilibrate.

[0055] In the drying step v), the relative humidity is reduced to slightly above 30% while the pressure remains constant, while the heating is still continued. Therefore, the temperature only decreases slightly during this step. For example, this step can last for 30 minutes.

[0056] In the drying and cooling step vi), the relative humidity decreases slightly further and stabilizes in this example at a constant value of about 30%. Heating is stopped in this step. For example, this step can last for 60 minutes. The temperature can be reduced to 110° C., while the pressure remains constant.

[0057] In the final cooling and decompression step vii), cooling is initiated and the pressure is released. At the end of this step, the pressure returns to ambient pressure and the temperature is below 75° C. In the example shown, the temperature also returns to ambient temperature of approximately 23° C.

[0058] The cartridges were inspected at the end of the sterilization process and no traces of water were found. Reference numerals 1. Steam sterilization equipment; 2 chambers; 3 Heating and cooling jacket; 4. Temperature and pressure controllers; 5. Cooling water supply device; 6. Compressed air supply device; 7. Steam supply device; 8. Vacuum pump; 9. Drain pipe; 10 Secondary packaging containers.

Claims

1. A method for steam sterilizing primary packaging in a steam sterilization device (1), comprising the following steps: a) preheating the primary packaging to a temperature T in the steam sterilization device (1); p , wherein the temperature T p At least equal to the predetermined pressure p s and the predetermined temperature T s The dew point temperature T of steam during steam sterilization dp -15°C, preferably at least equal to the predetermined pressure p s and the predetermined temperature T s The dew point temperature T of steam during steam sterilization dp , and / or at least 50°C; b) adjusting the pressure and temperature in the steam sterilization device (1) to the predetermined pressure p s and the predetermined temperature T s and by supplying the steam sterilization device (1) with at least a period of time t s The steam is sterilized, the time t s Sufficient to ensure a sterility assurance level of 10 or less as specified in 5.1.1 of the European Pharmacopoeia -6 ;as well as c) During the drying phase, Reducing the relative humidity in the steam sterilization device (1) to less than 50%; The drying pressure in the steam sterilization device is maintained at the predetermined pressure p s remains unchanged, or the drying pressure in the steam sterilization device is reduced from the predetermined pressure p s A decrease of at most 75 hPa, or at most 50 hPa, or at most 25 hPa, and / or at least 5 hPa, or at least 10 hPa or at least 20 hPa; Thereafter, in a cooling phase, the pressure and temperature in the steam sterilization apparatus (1) are adjusted to ambient pressure and a temperature less than or equal to 75°C, respectively.

2. The steam sterilization method according to claim 1, wherein: The primary packaging is further placed in a secondary packaging container (10) sealed with a non-woven fabric, the secondary packaging container (10) being, for example, a basin or a tray, wherein the secondary packaging container (10) optionally includes a nesting piece and / or optionally accommodates a plurality of the primary packagings.

3. The steam sterilization method according to claim 1 or 2, wherein: The preheating time in step a) is 0.5 to 3 hours, or 0.75 to 2.5 hours, or 1 to 2 hours.

4. The steam sterilization method according to any one of the preceding claims, wherein: In step a), the primary packaging is preheated to a temperature T p , the temperature T p At least 60°C, or at least 70°C, or at least 85°C.

5. The steam sterilization method according to any one of the preceding claims, wherein: The steam sterilization in step b) is performed for a period of time t s is at least 1.5 hours, or at least 1.0 hours, or at least 0.75 hours, or at least 0.5 hours, or at least 0.3 hours, and / or the temperature T s Between 120°C and 127°C, or 120°C and 125°C, or 121°C and 124°C.

6. The steam sterilization method according to any one of the preceding claims, wherein: The steam sterilization in step b) is carried out at a pressure p above the ambient pressure. s Under the condition of s In particular, it is between 1100 hPa and 2500 hPa, or between 1400 hPa and 2400 hPa, or between 1800 hPa and 2300 hPa.

7. The steam sterilization method according to any one of the preceding claims, wherein: In the cooling phase of step c), the rate of pressure regulation is at most 500 hPa / min, or at most 250 hPa / min, or at most 100 hPa / min, or at most 75 hPa / min or at most 50 hPa / min.

8. The steam sterilization method according to any one of the preceding claims, wherein: Between step a) and step b), the pressure in the steam sterilization device (1) is reduced to a range of 100 hPa to 1000 hPa, or 250 hPa to 1000 hPa, or 500 hPa to 1000 hPa, or 700 hPa to 1000 hPa, or 800 hPa to 975 hPa or 900 hPa to 975 hPa, wherein the pressure reduction rate is optionally at most 500 hPa / min, or at most 250 hPa / min, or at most 100 hPa / min, or 75 hPa / min, or at most 50 hPa / min or at most 25 hPa / min.

9. The steam sterilization method according to any one of the preceding claims, wherein: In the drying phase of step c), the temperature in the steam sterilization device (1) is reduced from T s The temperature is lowered to a range of 120°C to 90°C, or 115°C to 95°C, or 110°C to 100°C, and / or the pressure in the steam sterilization device (1) is kept constant.

10. The steam sterilization method according to any one of the preceding claims, wherein: Between step b) and step c), the pressure in the steam sterilization apparatus (1) is reduced from p s Reduce by at most 75hPa, or at most 50hPa, or at most 25hPa.

11. The steam sterilization method according to any one of the preceding claims, wherein: Prior to step a), an additional cleaning step is performed, the cleaning step comprising: washing the inner surface and / or outer surface of the primary packaging with water and / or a polar organic solvent.

12. An apparatus (1) for steam sterilizing primary packaging, comprising: - a chamber (2) for receiving the primary package, wherein the chamber is connected to a steam supply (7), a compressed air supply (6) and a vacuum pump (8), and is provided with a heating and cooling jacket (3); and - A controller (4) for adjusting the temperature and pressure in the chamber (2) through the steam supply device (7) and the compressed air supply device (6), so as to be configured to perform the steam sterilization method according to one of the above claims.

13. The steam sterilization device (1) according to claim 12, further comprising: A washing station is used to wash the inner surface and / or outer surface of the primary packaging with water and / or a polar organic solvent.

14. Primary packaging material treated according to the method of any one of claims 1 to 11, wherein: The primary packaging is free from optical defects with respect to water marks according to clause 2.9.20 of the European Pharmacopoeia and / or is at least partially coated on its inner and / or outer surface.

15. Use of a primary package according to claim 14 for storing a pharmaceutical or cosmetic composition or a medicament.

Images