阅读说明：本技术 一种气雾剂的无菌生产方法 (Aseptic production method of aerosol ) 是由 张祖兵 张青松 李盎 肖彬 刘勇 于 2020-04-27 设计创作，主要内容包括：本发明公开了一种气雾剂的无菌生产方法,原料包括抛射剂,将抛射剂冷冻成液体后无菌罐装。本申请抛射剂冷冻成液体进行除菌过滤,实现了药液的无菌、以及生产设备的无菌；采用了加长加宽的隧道烘箱,使气雾罐达到在170℃-180℃干热灭菌1小时的要求,实现气雾罐的在线灭菌生产。(The invention discloses an aseptic production method of aerosol, which comprises the steps of preparing a propellant, freezing the propellant into liquid, and aseptically canning. The propellant is frozen into liquid for sterilization and filtration, so that the sterility of liquid medicine and the sterility of production equipment are realized; the lengthened and widened tunnel oven is adopted, so that the aerosol can meets the requirement of dry heat sterilization for 1 hour at 170-180 ℃, and the online sterilization production of the aerosol can is realized.)

1. An aseptic production method of aerosol is characterized in that: freezing the propellant into liquid, filtering for sterilization, and aseptic canning.

2. A method of sterile production of an aerosol formulation as claimed in claim 1 wherein the propellant comprises at least one of ethane, propane, butane and hydrofluorocarbons having a carbon chain length greater than 4.

3. A method of sterile production of an aerosol formulation as claimed in claim 1 wherein the propellant is at least one of tetrafluoroethane, propane, n-butane, isobutane, ethyl chloride, pentafluoropropane.

4. The aseptic production method of an aerosol according to claim 3, wherein the tetrafluoroethane, propane, n-butane, isobutane and chloroethane are stored at-5 to 5 ℃ for more than 4h before being filled, and the pentafluoropropane is stored at 18 to 28 ℃ for more than 8h before being filled.

5. The aseptic production method of aerosol according to claim 4, wherein the liquid preparation is carried out before filling, the liquid preparation is carried out by cooling pentafluoropropane to below 18 ℃, and then uniformly mixing with quantitative tetrafluoroethane, propane, n-butane, isobutane or chloroethane to obtain a mixed liquid, and the temperature of the mixed liquid is-10 ℃.

6. The aseptic production method of aerosol according to claim 5, wherein the liquid preparation is carried out in a liquid preparation room, the temperature of the liquid preparation room is 10-28 ℃, the relative humidity is 35-75%, and the relative negative pressure is not less than 5 Pa.

7. The method of claim 3, wherein the mixture is filtered through one or more 0.22 μm cartridges and filled into the aerosol canister.

8. The aseptic production method of aerosol according to claim 1, further comprising raw materials and auxiliary materials, wherein the raw materials and auxiliary materials are added into the injection water solution, and then are subjected to aseptic filtration and filling.

9. The sterile production method of aerosol according to claim 1, wherein before filling, the aerosol canister is cleaned and dried, and then is subjected to dry heat sterilization for 1 hour by using a tunnel oven with a length of 3.8-5.2 m and a width of 0.8-1.2 m at 170-180 ℃ under 100-grade or A-grade laminar flow protection.

10. The method of claim 5, wherein the aerosol valve, valve actuator and cap associated with the aerosol canister are sterilized by cobalt 60 irradiation prior to assembly.

Technical Field

The invention relates to the technical field of aerosol production, in particular to an aseptic production method of an aerosol.

Background

In the specific aseptic production process of the aerosol, the propellant in the aerosol is compressed and then filled, but raw materials and production equipment for compressing the propellant cannot be sterilized and cleaned effectively, and the production of the aseptic aerosol is not facilitated. In addition, the temperature and time of the conventional washing and drying aerosol can cannot reach the level of dry heat sterilization at 170-180 ℃ for 1 hour, and other sterilization modes are not beneficial to the sterility guarantee of online production, so that the aseptic production of the aerosol is difficult to realize. The new food is checked by a new food checking center in southwest information center of the scientific technology department in 2019, the sterilization method adopted at present avoids the problem that equipment cannot be aseptically produced and filled, and the new food checking shows that relevant domestic literature research reports are not found.

Disclosure of Invention

The invention aims to provide an aseptic production method of aerosol, which solves the problem that equipment for compressing a propellant in the prior art cannot be sterilized effectively, so that the production of the aseptic aerosol is not facilitated.

In order to solve the technical problems, the invention adopts the following technical scheme:

an aseptic aerosol is prepared through freezing propellant to become liquid, filtering for sterilization, and aseptic canning.

Preferably, the propellant comprises at least one of an ethane, a propane and a hydrofluorocarbon having a carbon chain length greater than 4.

Preferably, the propellant is at least one of tetrafluoroethane, propane, n-butane, isobutane, ethyl chloride and pentafluoropropane.

Preferably, the tetrafluoroethane, the propane, the n-butane, the isobutane and the chloroethane are stored for more than 4 hours at the temperature of-5 ℃ before being filled, and the pentafluoropropane is stored for more than 8 hours at the temperature of 18-28 ℃ before being filled.

Preferably, liquid preparation is carried out before filling, wherein the liquid preparation is to cool pentafluoropropane to below 18 ℃, and then uniformly mix with quantitative tetrafluoroethane, propane, n-butane, chloroethane or isobutane to obtain a mixed liquid, and the temperature of the mixed liquid is-10 ℃.

Preferably, the liquid preparation is carried out in a liquid preparation room, the temperature of the liquid preparation room is 10-28 ℃, the relative humidity is 35-75%, and the relative negative pressure is not less than 5 Pa.

Preferably, the mixed solution is filtered by a one-stage or multi-stage 0.22 μm filter element and then filled into an aerosol can.

Preferably, the injection also comprises raw and auxiliary materials, and after the raw and auxiliary materials are added into the injection water for liquid preparation, the sterilization, filtration and filling are carried out.

Preferably, before filling, the aerosol cans are cleaned and dried, and then a tunnel oven with the length of 3.8-5.2 meters and the width of 0.8-1.2 meters is adopted for dry heat sterilization for 1 hour at 170-180 ℃ under the protection of 100-grade or A-grade laminar flow. The aerosol can, the filling liquid medicine, the propellant, the installation of an aerosol valve, a valve actuator and the like can be subjected to dry heat sterilization for 1h under the laminar flow protection of 100 grade or A grade, thereby ensuring that the product achieves the purpose of sterility

Preferably, the aerosol valve, valve actuator and cap associated with the aerosol canister are sterilised by irradiation with cobalt 60 prior to assembly.

Compared with the prior art, the invention has the beneficial effects of at least one of the following:

the propellant is frozen into liquid for sterilization and filtration, and the sterility of liquid medicine and the sterility of production equipment are realized.

The tunnel oven which is 3.8-5.2 meters long and 0.8-1.2 meters wide and is lengthened and widened is adopted, so that the aerosol can meets the requirement of dry heat sterilization for 1 hour at 170-180 ℃, and online sterilization production of the aerosol can is realized.

The conventional propellant filling equipment for aerosol filling is removed, and the problem that the equipment cannot realize aseptic filling is avoided.

The aerosol drying tank, the liquid medicine filling tank, the propellant, the installation of an aerosol valve, a valve actuator and the like are all produced under 100-grade or A-grade laminar flow protection, and the aim of asepsis of products is fulfilled.

The sterile aerosol can be produced by only using the propellant without adding raw and auxiliary materials.

Drawings

FIG. 1 is a process flow diagram of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Example 1:

a method for the sterile production of an aerosol formulation comprising the steps of, in order:

preparing: cleaning external packages of used raw materials, aerosol cans, aerosol valves, valve actuators, caps and the like, wiping the packages with 75% ethanol for disinfection, and entering a clean area for later use through an internal package airlock; the pressure difference between the inner packing material airlock and the inner packing material unpacking is more than 10 Pa;

raw material treatment: storing propellants such as tetrafluoroethane, propane, n-butane and isobutane for 4 hours at-5 ℃ before filling, and storing propellants such as pentafluoropropane for 8 hours at 18 ℃ before filling;

preparing liquid: cooling pentafluoropropane to 18 ℃, and then uniformly mixing with quantitative tetrafluoroethane, propane, normal butane and isobutane to obtain a mixed solution, wherein the temperature of the mixed solution is-10 ℃; the temperature of the preparation room is 10-28 ℃, the relative humidity is 35-75%, and the relative negative pressure is more than or equal to 5 Pa;

raw materials and auxiliary materials: adding the raw and auxiliary materials into injection water for liquid preparation, and then performing sterilization filtration;

and (3) sterilization: cleaning and drying the aerosol can, and then performing dry heat sterilization by adopting a lengthened and widened tunnel oven at the temperature of 180 ℃ at 170-; an aerosol valve, a valve actuator and a cap which are matched with the aerosol can are sterilized by cobalt 60 irradiation before assembly;

filling: filtering the mixed solution and the raw and auxiliary materials by two-stage 0.22 mu m filter elements respectively, and filling into an aerosol can; opening a 100-level laminar flow cover for self-cleaning for more than 15 minutes; the mixed liquid and the raw and auxiliary materials are respectively connected in series with two cylinder filters with 0.22um filter cores and connected with a liquid medicine pipeline. The sterilized aerosol can is conveyed to a filling production line through a tunnel oven, an aerosol valve, a valve actuator and a cap enter a filling and sealing chamber through a material cleaning procedure, a sterilized breathing bag is removed, the aerosol valve is placed in a hopper for automatically feeding the valve, the valve actuator is placed in a plugging hopper, the liquid medicine and the propellant which are subjected to sterilization and filtration are respectively filled, the aerosol valve is automatically fed and locked, the valve actuator and the cap are automatically fed, and the liquid medicine and the propellant are conveyed out of the filling and sealing chamber;

and (4) leakage detection: and (4) after canning, the aerosol can is subjected to leakage detection. The leakage detection is that the aerosol cans are placed in an environment with the temperature of 48-50 ℃ and stored for more than 8 hours, and the aerosol cans with large weight errors are removed;

warehousing: and (5) after leakage is detected, labeling, packaging and warehousing are carried out.

Example 2:

a method for the sterile production of an aerosol formulation comprising the steps of, in order:

raw material treatment: storing propellants of tetrafluoroethane and propane at 5 ℃ for 6h before filling, and storing the propellants of pentafluoropropane at 28 ℃ for 12h before filling;

preparing liquid: cooling pentafluoropropane to 14 ℃, and then uniformly mixing with quantitative tetrafluoroethane and propane to obtain a mixed solution, wherein the temperature of the mixed solution is 8 ℃; the temperature of the preparation room is 10-28 ℃, the relative humidity is 35-75%, and the relative negative pressure is more than or equal to 5 Pa;

raw materials and auxiliary materials: adding the raw and auxiliary materials into injection water for liquid preparation, and then performing sterilization filtration;

and (3) sterilization: cleaning and drying the aerosol can, and then carrying out dry heat sterilization by adopting a lengthened and widened tunnel oven at the temperature of 170-180 ℃; an aerosol valve, a valve actuator and a cap which are matched with the aerosol can are sterilized by cobalt 60 irradiation before assembly;

filling: filtering the mixed solution and the raw and auxiliary materials by two-stage 0.22 mu m filter elements respectively, and filling into an aerosol can;

and (4) leakage detection: and (4) after canning, the aerosol can is subjected to leakage detection. And the leakage detection is to place the aerosol cans in an environment of 48-50 ℃ for more than 8h, and reject the aerosol cans with large weight errors.

Example 3:

a method for the sterile production of an aerosol formulation comprising the steps of, in order:

raw material treatment: storing propellants of tetrafluoroethane and n-butane at 0 ℃ for more than 5h before filling, and storing pentafluoropropane at 23 ℃ for 9h before filling;

preparing liquid: cooling pentafluoropropane to 15 ℃, and then uniformly mixing with quantitative tetrafluoroethane or propane to obtain a mixed solution, wherein the temperature of the mixed solution is 0-2 ℃; the temperature of the preparation room is 10-28 ℃, the relative humidity is 35-75%, and the relative negative pressure is more than or equal to 5 Pa;

and (3) sterilization: cleaning and drying the aerosol can, and then carrying out dry heat sterilization by adopting a lengthened and widened tunnel oven at the temperature of 170-180 ℃; an aerosol valve, a valve actuator and a cap which are matched with the aerosol can are sterilized by cobalt 60 irradiation before assembly;

filling: filtering the mixed solution by two-stage 0.22 μm filter elements, and filling into an aerosol can;

and (4) leakage detection: and (4) after canning, the aerosol can is subjected to leakage detection. And the step of leakage detection is to place the aerosol cans in an environment of 18-50 ℃ for 10h and remove the aerosol cans with large weight errors.

The product is subjected to sterility test according to the sterility test rule of 1101 of the four-part general rule of 2015 th pharmacopoeia, 10ml of content is taken and directly inoculated into a culture medium, and the results are shown in the table.

Item	Production batch	Detecting the amount	Detection method	The result of the detection
					EXAMPLE 1 sterile Aerosol	20191201	120 bottle	Direct inoculation method	Detection of no bacteria
EXAMPLE 2 sterile Aerosol	20191202	120 bottle	Direct inoculation method	Detection of no bacteria
					Practice ofEXAMPLE 3 sterile Aerosol	20191203	120 bottle	Direct inoculation method	Detection of no bacteria

Although the invention has been described herein with reference to a number of illustrative embodiments thereof, it should be understood that numerous other modifications and embodiments can be devised by those skilled in the art that will fall within the spirit and scope of the principles of this disclosure. More specifically, various variations and modifications are possible in the component parts and/or arrangements of the subject combination arrangement within the scope of the disclosure, the drawings and the appended claims. In addition to variations and modifications in the component parts and/or arrangements, other uses will also be apparent to those skilled in the art.