EP3684430A2

EP3684430A2 - Method for reducing microbiological contamination

Info

Publication number: EP3684430A2
Application number: EP18830208.7A
Authority: EP
Inventors: Michael Spallek; Johannes Geser
Original assignee: Kocher Plastik Maschinenbau GmbH
Current assignee: Kocher Plastik Maschinenbau GmbH
Priority date: 2017-12-27
Filing date: 2018-12-17
Publication date: 2020-07-29
Also published as: US11369708B2; WO2019129524A3; RU2020122741A; WO2019129524A2; JP2021508558A; RU2020122741A3; US20210162086A1; DE102017012091A1; CN111491671A

Abstract

The invention relates to a method for reducing the microbiological contamination in a closed space (6), formed from at least two components connected to one another (1,4), by introducing a germicidal medium into the space (6).

Description

Method for reducing microbiological contamination

The invention relates to a method for reducing the microbiological contamination in a closed space, formed from at least two interconnected components. In the context of the present invention, "microbiological contaminants" or "germs" are to be understood as meaning contaminants, as they are also referred to as bioburden in English, which include, among others, bacteria, spores, yeasts, fungi, viruses, etc. In the production of containers, in particular plastic containers, for food, cosmetics or for medical purposes, in particular

Parenteralia or for artificial nutrition, the microbiological quality of the container or spaces of the container system before filling and / or use is essential. For this purpose, it is neces sary to reduce the microbiological contamination. As in

DE 198 12 057 A1 is described, it is state of the art, in the manufac turing empty, sealed container for pharmaceutical purposes, the steril ity of the empty container interior by autoclaving or by Strahlsteri lisation to achieve. In order to avoid the formation of ozone during the radiation sterilization, the container must be filled with an inert gas, such as nitrogen or argon. This method requires radiation stable or sufficiently temperature stable container materials for autoclaving. Even glass needs a chemical stabilization by addition of cerium oxide (EP 0858975 A1). This method is not suitable for container systems in which at least part of the system already contains a sensitive active ingredient and the other part is unfilled. These container systems include, for example, multi-chamber container, such as Dop pelkammer syringes, or infusion bottles with applied cap. Such containers, which are manufactured according to the known BFS process (blow-fill seal), are described in detail in the standard DIN ISO 1 5759.

In these container systems, it is necessary to safely sterilize the sealed, empty, complex shaped space (referred to herein as "space") between the head of a filled infusion bottle and its cap without the temperature-sensitive contents, such as solutions of amino acids, in the In such cases, the usual terminal sterilization, which is usually carried out in standard infusion solutions, such as 0.9% saline, usually by autoclaving at temperatures of more than 100 ° C, is not possible The empty space by electric nenstrahlen or gamma radiation would make very costly and expensive Ab schirmungsmaßnahmen the filled container part necessary not to damage the contents by irradiation .A whatsoever achieved heat treatment, for example by infrared radiation, laser radiation or the like, the empty space , For significant germ reduction heat, is because of the commonly used container materials such as low density polyethylene or polypropylene, which have only a low temperature stability, not possible. Due to the complex geometry of the enclosed space and the resulting shading effects, direct irradiation with light or light pulses is generally unsuitable for reliably reaching all surfaces for key im- mediation. In view of this problem, the invention has the object zugrun de to provide a simple and fast method that makes it possible to significantly reduce the number of microbiological contaminants on the inner surfaces of a microbiologically sealed space complex geometry and low volume, preferably to sterilize ren , In particular a space adjacent to a filled with a liquid or egg nem solid space of the container system.

According to the invention this object is achieved by the angege in claim 1 bene method. Accordingly, the invention provides for a so-called "chemical sterilization" in which a germicidal medium is introduced into the room In the simplest case, the medium introduced prior to closure of the room occurs without any additional external supply of energy the medium for germicidal activity in space.

An enhanced germicidal effect is achievable when the medium within the room is exposed to the action of an energy source.

With particular advantage, a germicidal fluid can be metered into the room as a medium.

Advantageously, in this case the procedure is such that the fluid is at least partially transferred from the liquid phase into the gaseous phase by heating by means of the energy source.

By means of the energy supply, in this case the fluid can be at least partially evaporated ver, so that there is a distribution of fluid and fluid vapors within the space to be sterilized. A particularly rapid evaporation and uniform distribution of fluid and fluid vapors is achievable here, when the energy is introduced to He warming in the form of radiation pulses.

Preferably, the energy supply and the selection of the fluid takes place in such a way that the fluid is at least partially chemically changed or degraded during its residence time in space.

The fluid can be maintained in the room for a residence time that allows at least partial reduction of the concentration of the fluid or degradation products by permeation out of the room. Preferably, the time course of the change in the concentration of the fluid and / or its degradation products in space is followed by spectroscopic methods. For this purpose, preference is given to infrared spectroscopy, particularly preferably laser absorption spectroscopy.

Particularly advantageous is an evaporation of the fluid by its direct, dielectric heating without substantial heating of the walls bounding the space. This can be done by radio waves in the frequency range from 5 MHz to 50 MHz or by dielectric heating by microwaves, whereby a frequency range from 500 MHz to 30 GHz can be provided, preferably frequencies of 950 MHz or 2450 MHz or 5800 MHz. The direct dielectric heating of the fluid allows its direct evaporation and immediate subsequent condensation on the colder walls of the room. The water process (evaporation, distribution and recondensation) can then be repeated in a targeted manner by further radiation pulses.

With particular advantage, the fluid provided is an aqueous and / or alcoholic solution which contains chlorine, ozone and / or a peroxide, preferably hydrogen peroxide. These solutions can be solved with the help of very direct heating and vaporization Ozone or hydrogen peroxide-containing solutions are chemically degraded during the process to the harmless substances water and oxygen.

Likewise, as the fluid, an antiseptic can be used which preferably contains at least one alcoholic active substance, more preferably ethanol and / or isopropanol.

As the space forming components may be provided a cap and the head of a container, preferably a container for medical purposes. In this case, the components can be formed substantially from at least one plastic, preferably from polyolefins, particularly preferably polypropylene or low density polyethylene. These materials do not heat up by radio or microwave radiation or only very slightly so that they provide suitable condensation surfaces for the fluid vapors.

The filled container in question may advantageously be manufactured according to the BFS method, and the filled container may have a head membrane with at least one depression. Such containers, which may be multilayered by coextrusion, may, as in FIG

DE 10 201 3 012 809 A1, be formed.

Below is the invention with reference to the drawing in detail erläu tert. Show it:

Fig. 1 is a drawn in perspective oblique view Teildar position of the prior art Infu sion container, on whose neck collar a cap is attached; Fig. 2 shows a simplified longitudinal section drawn on Behäl ter of Figure 1 attachable cap. and

3 is a simplified longitudinal section of the neck collar of the container of FIG. 1 with attached cap of FIG .. 2

With reference to the attached drawing, the inventive method of chemical sterilization is exemplified by the example of a manufactured according to the known BFS method infusion bottle made of plastic with densely applied plastic cap, wherein as the germicidal medium, an aqueous hydrogen peroxide solution is provided. In an analogous manner, the invention can also apply to other container systems mentioned above ge and with other solvents, germicidal agents, such as with known disinfectants (antiseptics), which are also mentioned above. The container 1 shown in FIG. 1, which is produced and filled by the BFS process, has a neck collar on the container neck 3, as described in DIN ISO 15759

2 and above the same a tight container closure forming head membrane 8, which is perforable for an infusion process.

Fig. 2 shows a cap 4, which made of a rigid plastic material GE and also according to DIN ISO 15759 is formed and, as shown in FIG.

3, at the cap edge along a weld 7 with the Halskra gene 2 of the container 1 is tightly welded, for example by means of Spie gelschweißens. The cap 4 could be tightly connected to the container 1 by syringes too. As shown in Figures 2 and 3, at the opening portions of the top of the cap 4, at locations pierceable by a cannula or mandrel for infusion, there are elastomeric elements 5 which seal the system in use. The elastomer elements 5 are, as shown for example in the one Published prior art application DE 10 201 7 000 048.4 is described, formed from an elastomer which is suitable for cohesive welding with the material of the cap 4. As shown in FIG. 3, when connected to the neck collar 2 cap 4 in this a space 6 is tightly enclosed, which extends along the inside of the kreiszy-cylindrical side wall 10 of the cap 4 and along the top membrane 8 and bil a space of relatively small volume det, which is chemically sterilized by the method according to the invention. In the example of the method to be described here, a small volume (about 0.01 to 0.3 ml) of an aqueous hydrogen peroxide solution, for example by dripping or spraying, is metered onto the head membrane 8 and then the cap 8 is filled with the Collar 2 tightly connected, so that the space 6 is tightly closed. Alternatively, the fluid can also be sprayed onto the inner surfaces of the cap 4. The direct heating of the introduced fluid is effected by microwave radiation. This has the advantage that the fluid is heated directly, while the walls of the space 6, if at all, it is only very low he warms, so the radiation itself contributes only indirectly to the reduction in germ number. At a preferred frequency of the microwave radiation in Fre quenzbereich of 500 MHz to 30 GHz, there is an at least partial evaporation of the fluid and thus to a homogeneous distri ment within the space 6. Due to the increase in volume during evaporation, it comes here in the room 6 an overpressure and thus to a pressure-related overheating of the hydrogen peroxide. This iniitiert on the one hand, the chemical decomposition of hydrogen peroxide to harmless substances water and oxygen, on the other hand are also hard to reach surfaces such as undercuts, cracks, channels and the like safely achieved. Advantageously, microwave pulses are used, which lead to a pulsating continuous, at least partial evaporation and repeated microcondensation of the hydrogen peroxide, a preferred type of condensation, arise in the smallest, not visible to the naked eye droplets. This also begins the thermal decomposition of hydrogen peroxide to water and oxygen. In contrast, care must be taken in the known methods of sterilizing insulators with gaseous hydrogen peroxide that a decomposition does not occur in the evaporator.

An advantage of the method according to the invention is also that no carrier gas is necessary for transporting the gaseous hydrogen peroxide, but gaseous hydrogen peroxide is generated directly in the space 6 to be sterilized and is at least partially degraded there. It was also found that even sensitive products in the container 1 were not measurably impaired. It is believed that the hydrogen peroxide is already largely decomposed before it can come to a noticeable Permea tion into the medium. Due to the low adsorption and permeation of hydrogen peroxide to and in polyolefins, particularly low density polyethylenes, such container materials are preferred. Also, multi-layer containers can be used, such as e.g. in DE 103 47 908 A1 whose barrier layers - for example, from ethylene vinyl alcohol copolymer (EVOH) or cycloolefinic compo nents such as cycloolefin copolymers COC (trade name Topas) or Cyc loolefinpolymere COP (trade name Zeonor) - the permeation of the germinating agents of the fluid, in particular of oxygen or alcohols into the interior of the container 1 but not through the cap 4.

It is also advantageous to use container head pieces with recesses in the head membrane, as shown in detail in DE 10 201 3 012 809 A1, for example. An advantage of the method according to the invention is the very simple about the liquid phase gravimetric or volumetric metering of the fluid and that the sterilization conditions on the volume of the space 6, the geometry of the container system and their germ load on the introduced into the space 6 and concentration of the Hydrogen peroxide solution (typically 3-35%) is easily customizable, and can be controlled by duration, intensity and pulse shape of the microwave. It has been found that a higher microbial reduction can be achieved by several short-term microwave irradiation cycles than by a few, longer lasting ones. Moreover, it has been shown that elevated hydrogen peroxide concentrations in the gas phase advantageously lead to an increased reduction in germ count, and the use of ethanolic-aqueous hydrogen peroxide solutions improves the wetting of the surfaces to be sterilized and thus also increases the reduction in germ number.

Attempts to detect the reduction in germ count were carried out by means of bio-indicators with spores of Geobacillus stearothermophilus. On head membranes 8 different diameters (20-30 mm) of filled 250 ml infusion bottles of LDPE 0.02-0.2 ml 35% aqueous H 2 O 2 solution were abandoned and a HDPE cap 4 welded. The volume of the spaces 6 thus formed was in the range of average Lich about 1 ml to about 3 ml. Sterilisationsversuche were performed with a microwave chamber with a microwave adjustable power of 0.6 KW to 6 KW and a MW transmission frequency of 2450 MHz , A radiation took place parallel to the head membrane 8, that is perpendicular to the longitudinal axis of the container. 1 The filled area of the container 1 was screened additional Lich with a close-meshed wire mesh.

Surprisingly, a significant reduction in germ number was also achieved in narrow gaps only a few millimeters wide, in particular between the head membrane 8 and the cap 4 and between the container head and the head cylindrical part 10 of the cap 4. This was possible the better, the more often it came to microcondensation, so len with increased number of Irradiationzyk and resulting pressure pulses. In addition, the method according to the invention enables simple and direct detection of the leak-free application of the infusion cap 4, for example detection by spectroscopic methods. For this purpose, the content of hydrogen peroxide in the gas phase and / or the oxygen content in Saucer 6 can be determined nondestructively. For example, laser absorption spectrometers with typical wavelengths in the infrared range between 760 nm and 2000 nm are suitable for this purpose. Alternatively, the concentration of the gaseous hydrogen peroxide can be monitored and measured by photon fragmentation laser-induced fluorescence (PF-LIF).

Low power typically suffices to generate the microwave pulses, preferably the frequency of the used microwaves is 896 MHz / 915 MHz / 922 MHz (L band) or 2450 MHz (S band) or 5.8 GHz (C band). When using radio waves (frequency range 5 - 50 MHz) higher power is required due to the weaker coupling, but there is less interference, which significantly reduces so-called hotspots, which are not always avoidable when using microwaves.

Claims

Patent claims

1 . Method for reducing the microbiological contamination in a closed space (6), formed from at least two components (1, 4) connected to one another, by introducing a germicidal medium into the space (6).

2. The method according to claim 1, characterized in that the medium is set within the space (6) of the action of an energy source.

3. The method according to claim 1 or 2, characterized in that as medium in the space (6) a germicidal fluid, preferably in flüssi ger form, is introduced.

4. The method according to any one of the preceding claims, characterized in that the fluid passes at least partially from the liquid phase into the gaseous phase, preferably is converted by heating by means of an energy source in the gaseous phase.

5. The method according to any one of the preceding claims, characterized in that the fluid in the space (6) at least once partially evaporated and condensed, preferably repeatedly evaporated and recondensed.

6. The method according to any one of the preceding claims, characterized in that the energy for heating in the form of ent radiation, preferably in the form of radiation pulses is introduced.

7. The method according to any one of the preceding claims, characterized in that the radiation substantially only directly heats the fluid di.

8. The method according to any one of the preceding claims, characterized in that the fluid during its residence in the space (6) is at least partially chemically modified and / or degraded.

9. The method according to any one of the preceding claims, characterized ge

indicates that the fluid is held in the space (6) for a residence time which allows at least partial reduction of the concentration of the fluid and / or its degradation products by permeation out of the space (6).

10. The method according to any one of the preceding claims, characterized ge

indicates that the course of the change in the concentration of the fluid and / or its degradation products in space (6) is followed by destruction-free, preferably spectroscopic methods.

1 1 .Verfahren according to any one of the preceding claims, characterized ge

indicates that the fluid is vaporized by dielectric heating by radio waves in the frequency range from 5 MHz to 50 MHz.

12. The method according to any one of the preceding claims, characterized ge

indicates that the fluid is vaporized by microwave heating in the frequency range of 500 MHz to 30 GHz, preferably at frequencies of 91 5 MHz or 2450 MHz or 5800 MHz.

1 3. The method according to any one of the preceding claims, characterized ge

indicates that the fluid provided is a solution which contains chlorine, ozone or a peroxide, preferably hydrogen peroxide.

14. The method according to any one of the preceding claims, characterized ge

indicates that a solution is provided as the fluid which and / or at least one alcohol, preferably water and ethanol, as solvent.

1 5. The method according to any one of the preceding claims, characterized in that an antiseptic is provided as the fluid, which preferably contains at least one alcoholic active substance, particularly preferably ethanol and / or isopropanol.

1 6. The method according to any one of the preceding claims, characterized in that as the space (6) forming components, a cap (4) and the head (2) of a container (1) are provided, preferably be a filled container (1) for medical purposes.

1 7. The method according to any one of the preceding claims, characterized in that the components (2,4) are essentially formed of at least one plastic, preferably polyolefin, be particularly preferably polypropylene and / or polyethylene.

18. The method according to any one of the preceding claims, characterized in that the filled container (1) is produced by the BFS process.

1 9. The method according to any one of the preceding claims, characterized in that the filled container (1) has a head membrane (8) with at least one recess.

20. The method according to any one of the preceding claims, characterized in that the filled container (1) is a multilayer Be container, preferably with at least one layer containing ethylene vinyl alcohol copolymer or cycloolefin polymer or Cycloolefinco- polymer.