Patent Application
20250041465
This claims priority to European Patent Application EP 23189301.7, filed Aug. 2, 2023 which is hereby incorporated by reference herein.
The present disclosure relates to a process and device for steam sterilization of primary packaging means as well as to a primary packaging means processed by the process. Primary packaging means, such as cartridges, vials, syringes, ampules, or other containers, may be used for pharmaceutical and cosmetic packaging applications. The sterilization process provides reduced water marks on the corresponding primary packaging means.
Steam sterilization is state of the art for many pharmaceutical and cosmetic products and their respective primary packaging means. These primary packaging means may be, for example, cartridges, vials, syringes, or ampules which can be made of a polymer, commonly COP or COC, or of glass. However, there exists a particular problem in the formation of water marks on the surface of these primary packaging means during the sterilization process. This applies to both types of materials but is in general more pronounced with glass.
An analysis of the water marks brought the result that they may comprise in particular silicone residues with different molecular weights and/or borates, sodium, calcium, sulfur salts, and nitrates, that characterize the glass components. In case of glass materials, they may mainly be attributed to evaporates from the hot forming process and are known as smelter dust.
Particularly for sterile pharmaceutical primary packaging means in the form of so called RTU (ready to use) containers, a typical packaging configuration for the transport from a manufacturer of pharmaceutical primary packaging means to a pharmaceutical company using the same comprises a tub or tray holding a multitude of the primary packaging means which is sealed with a non-woven. The non-woven is usually a flash spun plexifilamentary film-fibril structure made of high density polyethylene, which is known under the trademark Tyvek® of the company DuPont, or a spunbonded very fine filaments non-woven. There are of course further applicable non-wovens of other companies. These selectively permeable non-wovens allow for the sterilization by means of gas or vapor, like ethylene oxide, steam, or hydrogen peroxide, even after closing the packaging. While being permeable for the sterilizing gas or vapor, the selectively permeable non-woven is essentially impermeable for microbes and thus forms a microbial barrier. The term “essentially impermeable for microbes” within this context refers to a Microbial Barrier measured according to ASTM F1608-16 of 2 to 6 Log Reduction Value (LRV).
The standard steam sterilization processes for solid products cannot be used without an increased risk of the loss of the integrity of the sterile barrier (tub/Tyvek® seal seam) with the packaging configuration used in the market for RTU containers, particularly when made of glass. The standard process is characterized by a large number of vacuum pulses to remove trapped air, which might hinder effective steam penetration to the product and, consequently, efficient sterilization. A frequent and fast pressure variation results in high stress on the seal seam between the tub and the Tyvek® layer because the pressure exchange through the non-woven Tyvek® membrane is slower than in the chamber. The slower pressure equilibration inside the tub promotes a ballooning of the Tyvek® seal (when pressure is decreased) or its adhesion to the packaged items (when pressure is increased). Additionally, the sterilization step is usually carried out at an increased pressure which is reduced back to ambient pressure after the sterilization process. Since the seal seam between the tub and the Tyvek® layer is obtained by hot melting of a glue with a softening point close to steam sterilization conditions, the seal seam does not withstand the stress of pressure variation at high temperatures.
Another disadvantage for the RTU containers is that the saturated steam penetrates in the tub and condensates on surfaces, such as the nest, the glass or polymer, and the tub or bag, so that the tub may contain a high load of water which needs to be removed at the end of the sterilization procedure.
Document WO 2018/029590 A2 discloses a steam sterilization procedure for glass articles which uses a pulsed feed of steam for a reduction of white patches on the glass and damage to the physical and chemical structure of the glass. The steam flow inside the treatment chamber is oscillating in temperature and pressure and, thus, never has a constant mass. It is underlined that there are no sterilization steps in which pressure and/or temperature reach static sterilization steps and that the system is an open mass system. The pressure is varied in a range of from 0.2 bar to 1.15 bar. These process conditions have different drawbacks. Since there are constant pressure changes in the chamber, an eventual tub/Tyvek® seal seam is under constant stress. This poses an increased risk of damage to the sterile barrier and creates the need to seal and sterilize the tubs anew or even to discard the glass articles in case of failure. Moreover, the pressure predominantly in the sub-ambient range will cause a lower steam temperature which in turn requires considerably increased sterilization times in order to achieve the mandatory sterilization level. With a suggested pulse duration of 24 min 1.5 min, the example graphs show a duration of about 450 min for a complete sterilization cycle.
Hence, it is an object of the present invention to provide a steam sterilization process and a corresponding device which overcome at least one of the drawbacks of the prior art. In particular, the formation of water marks on the primary packaging means, in particular on the inner and/or outer surface of the primary packaging means, should be avoided or at least reduced while maintaining the sterility level of the sterilized containers.
In a first aspect, the disclosure relates to a process for steam sterilization of primary packaging means in a steam sterilization device comprising the steps of
Setting a drying pressure in the steam sterilization device slightly lower than the predetermined pressure ps can mean that the pressure is reduced from ps by at most 75 hPa or at most 50 hPa or at most 25 hPa and/or by at least 5 hPa or at least 10 hPa or at least 20 hPa.
In a second aspect, the disclosure relates to a process for steam sterilization of primary packaging means in a steam sterilization device comprising the steps of
In a third aspect, the disclosure relates to a process for steam sterilization of primary packaging means in a steam sterilization device comprising the steps of
In a fourth aspect, the disclosure relates to a device for steam sterilization of primary packaging means, the device comprising
In a fifth aspect, the disclosure relates to a product, a primary packaging means, processed with a steam sterilization process according to at least one of aspects one to three.
The primary packaging means can be a cartridge, vial, syringe, ampule, or other container. It can for example be used for pharmaceutical and cosmetic packaging applications.
The primary packaging means can have a sterility assurance level of equal to or less than 10−6 according to Ph. Eur. 5.1.1.
The primary packaging means can be optically defect free, in other words not visible, in terms of water marks according to Ph. Eur. 2.9.20.
The primary packaging means can be at least partially coated on either the inner and/or outer surface.
In a sixth aspect, the disclosure relates to usage of a primary packaging means according to the fifth aspect, wherein the primary packaging means is suitable for storing a pharmaceutical composition or drug.
Water marks in the sense of this disclosure can be residuals that appear on the surface of sterilized containers when sterilization and front-end processes are not properly optimized. They can usually appear in the form of more or less prominent irregular white or whitish spots with a typical size range of 0.005-0.01 mm2 and eventually even up to about 7 mm2. They can comprise silicone residues with different molecular weights and/or borates, sodium, calcium, sulfur salts, nitrates, and/or other glass components.
The details of this disclosure relate to the aspects described in the summary of disclosure. Any of the features of the embodiments described hereinafter may relate to one or more of the processes for steam sterilization as well as the device for steam sterilization as well as for the primary packaging means processed with steam sterilization.
When referring to “Ph. Eur. 5.1.1”, this refers to chapter 5.1.1 of the 11th edition of the European Pharmacopoeia defining sterilization methods for medical products and the sterility assurance level to be reached. Sterility is defined there as the absence of viable micro-organisms, as expressed by a sterility assurance level equal to or less than 10−6. Hence, Ph. Eur. 5.1.1 requires demonstrating the sterility assurance level of 10−6 through the correlation of pressure, time, and temperature. This is performed by measuring the temperature in the chamber and in the product, together with the biological assessment using suitable biological indicators during validation.
When referring to “Ph. Eur. 2.9.20”, this refers to chapter 2.9.20 of the 11th edition of the European Pharmacopoeia defining particulate contamination by visible particles.
The inventors have surprisingly found that simply reducing the contamination by silicone residues and smelter dust on the outside and/or inside of the packaging means in a washing step conducted before the sterilization procedure, which washing step can include washing inner and/or outer surfaces of the packaging means, will not be sufficient for an effective suppression of the water marks. Only a mitigation of the occurrence of the water marks upon water condensation and drying in the steam sterilization process was achieved.
After further investigation, another issue has been identified by the inventors which relates to the sterilization phase. At the end of the sterilization phase, the tub might be effectively dried by reducing the pressure that promotes water evaporation. However, this would risk the loss of the sterility barrier integrity due to the softened tub/Tyvek® seal seam. Moreover, a decrease in temperature to further below the softening point of the glue is also not possible because the lower temperature would immediately foster condensation which must be avoided for several reasons. Condensing water collects contamination on the surface and concentrates it in a small area during the drying step, which leads to visual marks. Further, organic and silicone contamination constitute hydrophobic surfaces that lead to condensation of humidity in water droplets. Moreover, condensation leads to an increase of necessary drying time after sterilization. A solution to this problem of condensation has been found in separated drying and cooling phases.
First, in the drying phase the relative humidity in the chamber is reduced from about 100% to <50% while the drying pressure in the steam sterilization device is maintained constant or set slightly lower than the predetermined pressure ps (sterilization pressure). Only subsequently in the cooling phase the temperature and the pressure are actively decreased. The relative humidity in the chamber may be reduced from about 100% to <50% or from about 100% to <40% or from about 100% to <30%. By maintaining the pressure substantially constant or setting the drying pressure in the steam sterilization device slightly lower than the predetermined pressure ps (sterilization pressure), steam can be released, and thereby relative humidity can be reduced, while avoiding ingress of a large amount of compressed air. Thereby, temperature drop in the steam sterilization device can be minimized so as to avoid cooling down the primary packaging means too much and too fast. In particular, by setting the drying pressure slightly lower than the predetermined pressure ps a temperature drop of the primary packaging means below the chamber temperature can be avoided so as to avoid condensation thereon. Setting a drying pressure in the steam sterilization device slightly lower than the predetermined pressure ps can mean that the pressure is reduced from ps by at most 75 hPa or at most 50 hPa or at most 25 hPa and/or by at least 5 hPa or at least 10 hPa or at least 20 hPa.
To the further surprise of the inventors, it turned out that even a combination of the washing step described above with the separated drying and cooling phases will not be sufficient for an effective suppression of the water marks.
After further investigation they have identified another related issue which is the condensation of water on the colder surfaces of the primary packaging means and an eventual tub, tray, or nest when the warmer saturated steam gets in contact with it and when the product is cooled down after sterilization. These condensates that are present on the surfaces of the primary packaging already before sterilization caused an evaporative cooling in the tub and created a temperature drop of about 25° C. below 100° C. which again created water marks. The effect of steam condensation becomes noticeable only when directly looking at the glass or polymer components. The impurities are collected in the water drops that leave visual defects (stains) on the glass upon drying.
By measuring the heating rates of RTU containers and tubs containing them in a heated oven that was pre-heated to 100° C., it was found that these are very small (typically s 1° C./min). Such a heating rate is much smaller than that of the media in a sterilization chamber, i.e., in general air and steam. The heating rates slightly vary with the RTU containers and tubs. Tubs with higher weight, particularly with heavier glass primary packaging means, warm up slower than tubs with a lower weight, namely with lighter glass primary packaging means. The heating time of a common standard process typically is between 10 min and 20 min. Hence, the resulting temperature in a tub will be below 40° C.-50° C. When after the heating phase and the vacuum pulse the saturated steam enters the chamber, it will get in contact with the colder surfaces which consequently causes condensation in and on the tub. This condensed water cannot be taken up by the steam, as this is saturated, and the condensed water will remain inside the tub over the sterilization process.
To avoid water condensation in the pre-treatment, the RTU containers and tubs of this disclosure are sufficiently heated up in a first phase. The temperature Tp to which they are heated is at least equal to the 15° C. below dew point temperature Tdp of the steam at the conditions of the steam sterilization, preferably at least equal to a dew point temperature Tdp of the steam at a predetermined pressure ps and predetermined temperature Ts at which the steam sterilization is to be performed, and/or is at least 50° C. If they have at least the dew point temperature, the steam will no longer condense on their surfaces. As a general rule it has been found that a temperature of at least 50° C. may 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 the steam sterilization is to be performed. The temperature may be chosen depending on the type of the primary packaging means. For example, for certain primary packaging means a minor pre-heating to a temperature of at least 50° C. or at least 60° C. may be sufficient, whereas for other primary packaging means a higher pre-heating to a temperature of at least 70° C., at least 80° C., or even at least 85° C. may be required. With this approach, the condensation before sterilization can be minimized or avoided.
Since these higher temperatures in the pre-treatment phase again result in a softening of the tub/Tyvek® seal seam, a deep vacuum pulse should be avoided in order not to weaken the sterile barrier. Consequently, more air may be present in the tub which might potentially hinder the product sterilization. Depending on the applied pressure level, a corresponding moderate increase in the sterilization time may ensure the desired sterility level.
A combination of the separated drying and cooling phases with this avoiding or minimizing of water condensation before the sterilization step finally proved itself to be suitable for achieving an effective suppression of the water marks while keeping the sterility level intact. A washing step as described above may be installed in addition to these two measures but is insufficient when used in combination with either of them alone.
In embodiments, the primary packaging means may be further packaged in a secondary packaging container, such as a tub or tray, sealed with a non-woven, wherein the secondary packaging container optionally includes a nest and/or optionally holds a multitude of the primary packaging means. The disclosed process may be used with the primary packaging means directly placed in a suitable device for steam sterilization or with the common packaging for RTU containers in the form of a tub sealed with a non-woven, in particular with Tyvek®.
In embodiments, the pre-heating in step a) may executed for 0.5 h to 3 h or for 0.75 h to 2.5 h or for 1 h to 2 h. The pre-heating in step a) may executed for at least 0.5 h or for at least 0.75 h or for at least 1 h. The pre-heating in step a) may executed for at most 3 h or for at most 2.5 h or for at most 2 h. These times for pre-heating have been found to generally provide enough time for the common primary packaging means to sufficiently get heated to the core.
In embodiments, in step a) the primary packaging means can be pre-heated to a temperature Tp of at least 50° C. or at least 60° C. or at least 70° C. or at least 85° C. In step a) the primary packaging means can be pre-heated to a temperature Tp of at most the temperature Ts at which the steam sterilization is to be performed or of at most Ts-5° C. or of at most Ts-10° C. or of at most Ts-15° C. or of at most Ts-20° C. or of at most Ts-25° C. or of at most 100° C. These temperatures have been found to be suitable for preventing or reducing condensation on the surfaces of the primary packaging means sufficient for preventing the formation of water marks in combination with the other measures taken.
In embodiments, the steam sterilization in step b) may be executed for a time ts of at least 1.5 h or at least 1.0 h or at least 0.75 h or at least 0.5 h or at least 0.3 h and/or at a temperature Ts in the range of from 120° C. to 127° C. or from 120° C. to 125° C. or from 121° C. to 124° C. The steam sterilization in step b) may be executed for a time ts of at most 5 h or of at most 4 h of at most 3 h. This has been found to reliably provide the common sterilization level of 10-6.
In embodiments, the steam sterilization in step b) may be executed at a pressure ps which is above ambient pressure, in particular in a range from 1,100 hPa to 2,500 hPa or in a range from 1,400 hPa to 2,400 hPa or in a range from 1,800 hPa to 2,300 hPa. The steam sterilization in step b) may be executed at a pressure ps which at least 1,100 hPa or at least 1,400 hPa or at least 1,800 hPa. The steam sterilization in step b) may be executed at a pressure ps which at most 2,500 hPa or at most 2,400 hPa or at most 2,300 hPa. A sterilization in moderate support pressure conditions provides an optimum of efficiency and required treatment time and facilitates final drying at the end of the sterilization process by reducing the pressure. Moderate support pressure can be approx. 100 hPa above an absolute saturated steam pressure. For example, moderate support pressure can be approx. 2,200 hPa for saturated steam pressure of about 2,100 hPa absolute.
In embodiments, the adjusting of the pressure in the cooling phase in step c) may be executed at a rate of 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 selected too high the stress on the sealing seam of the non-woven might cause a loss of integrity.
In embodiments, between step a) and step b) the pressure in the steam sterilization device may be reduced to a range of 100 hPa to 1,000 hPa or reduced to a range of 250 hPa to 1,000 hPa or reduced to a range of 500 hPa to 1,000 hPa or reduced to a range of 700 hPa to 1,000 hPa or reduced to a range of 800 hPa to 975 hPa or reduced to a range of 900 hPa to 975 hPa, optionally at a rate of 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 device may be reduced to not less than 100 hPa or reduced to not less than 250 hPa or reduced to not less than 500 hPa or reduced to not less than 700 hPa or reduced to not less than 800 hPa or reduced to not less than 900 hPa. The pressure in the steam sterilization device may be reduced to not more than 975 hPa or not more than 950 hPa or not more than 925 hPa or not more than 900 hPa. This helps reducing the stress on the sealing seam of the non-woven, in particular when adjusted at the mentioned rates.
In embodiments, during the drying phase in step c) the temperature in the steam sterilization device may be reduced from Ts to a temperature in the range of from 120° C. to 90° C. or from 115° C. to 95° C. or from 110° C. to 100° C. and/or the pressure in the steam sterilization device is held constant or only slightly lower than the predetermined pressure ps(sterilization pressure). The temperature in the steam sterilization device may be reduced from Ts to a temperature of at most 120° C. or at most 115° C. or at most 110° C. The temperature in the steam sterilization device may be reduced from Ts to a temperature of at least 90° C. or at least 95° C. or at least 100° C. At the beginning of the drying phase, temperature can be at least 100° C. Temperature can be reduced by setting the drying pressure in the steam sterilization device slightly lower than the predetermined pressure ps (sterilization pressure), steam can be released, and thereby relative humidity can be reduced, while avoiding ingress of a large amount of compressed air. Thereby, temperature drop in the steam sterilization device can be minimized so as to avoid cooling down the primary packaging means too much and too fast. In particular, by setting the drying pressure slightly lower than the predetermined pressure ps a temperature drop of the primary packaging means below the chamber temperature can be avoided so as to avoid condensation thereon. Setting a drying pressure in the steam sterilization device slightly lower than the predetermined pressure ps can mean that the pressure is reduced from ps by at most 75 hPa or at most 50 hPa or at most 25 hPa and/or by at least 5 hPa or at least 10 hPa or at least 20 hPa.
In embodiments, between step b) and step c) the pressure in the steam sterilization device may be reduced from ps by at most 75 hPa or at most 50 hPa or at most 25 hPa. A slight reduction of the pressure before initiating the drying phase may be beneficial for drying. An only slight reduction of the pressure before initiating the drying phase may be beneficial for avoiding large temperature drop due to introduction of too much compressed air.
In embodiments, before step a) an additional washing step may be executed comprising a rinsing of the outer surface of the primary packaging means with water and/or a polar organic solvent. As explained above, such a washing step alone will not be sufficient to avoid the formation of water marks. However, it can be used as an additional step to reduce the surface contamination and in doing so improve the reduction or elimination of water marks. Rinsing with water or polar organic solvents, such as alcohols, esters, and ethers, is most effective due to the source of the contamination being salts from the smelter dust and silicones.
In embodiments, the device may for this purpose further comprise a washing station for rinsing of the outer surface of the primary packaging means with water and/or a polar organic solvent.
The controller 4 for temperature and pressure within the chamber 2 and of the supply of steam 7 and the supply of pressurized air 6 is configured to perform a steam sterilization process according to this disclosure.
In pre-heating step i), the chamber 2 with the primary packaging means within the secondary packaging container 10 is pre-heated at constant pressure to a temperature Tp of, for example, 85° C. for 1.5 h. At the end of step i), the pressure is reduced to 900 hPa.
In pre-vacuum step ii), the pressure and temperature are held constant for a time sufficient to equilibrate the pressure inside the secondary packaging container 10, such as 5 min.
In the pressurization step iii), heating of the chamber 2 is started, and the pressure is first increased back to ambient pressure, held constant for a time, such as 5 min, and finally increased to the sterilization pressure ps, i.e., in this example 2,200 hPa. The set temperature Ts may, for example, be 122° C.
In sterilization step iv), the system may again be given some time, such as 5 min, to equilibrate before the sterilization treatment is performed at constant pressure and temperature for, for example, 1 h in order to reach the sterilization level of 10-6.
In the drying step v), while the pressure is constant, the relative humidity is decreased to slightly above 30% while the heating is still turned on. Hence, only a slight decrease in temperature occurs in this step which may be executed, for example, for 30 min.
In the drying and cooling step vi), the relative humidity is further slightly decreased, stabilizing in this example around a constant value of about 30%. The heating is deactivated in this step which may be executed, for example, for 60 min. The temperature may be decreased to 110° C., whereas the pressure is still held constant.
In the final cooling and depressurization step vii), the cooling is activated, and the pressure is released. At the end of the step, the pressure is back to ambient pressure and the temperature below 75° C. In the shown example, the temperature is also brought back to ambient temperature of about 23° C.
The cartridges were examined at the end of the sterilization process and found to be free of water marks.
| Number | Date | Country | Kind |
|---|---|---|---|
| 23189301.7 | Aug 2023 | EP | regional |
