WO2023131130A1

WO2023131130A1 - Ultra-clean production process for disposable multi-layer co-extrusion bag

Info

Publication number: WO2023131130A1
Application number: PCT/CN2023/070220
Authority: WO
Inventors: 王逢; 刘志; 戚欧迪; 李观生; 王浩浩
Original assignee: 上海乐纯生物技术股份有限公司; 上海乐纯乐新材料有限公司
Priority date: 2022-01-10
Filing date: 2023-01-03
Publication date: 2023-07-13
Also published as: CN114392986B; CN114392986A

Abstract

An ultra-clean production process for a disposable multi-layer co-extrusion bag. The process comprises: classifying materials used by the multi-layer co-extrusion bag into a filling needle type material, a pipeline type material, a connector type material, and a membrane type material, and performing cleaning and drying by means of different processes. The number of visible foreign matters in a produced disposable sterile filling bag is reduced by 70% or more compared with the number of visible foreign matters in a disposable sterile filling bag produced by means of a general production process, and the number of insoluble microparticles can be reduced by 50% or more.

Description

Ultra-clean production process for single-use multi-layer co-extruded bags

technical field

The invention relates to the field of medicine, in particular to an ultra-clean production process for disposable multi-layer co-extruded bags.

Background technique

Disposable multi-layer co-extrusion bags are a kind of medical packaging consumables often used in the field of biomedicine and disposable consumables. As packaging consumables that directly contact medicines, they play an extremely important role in the temporary storage and filling process of pharmaceutical production. . The rate of foreign matter is one of the main reasons for the scrapping of downstream products of biopharmaceuticals. If it is not strictly controlled, it will cause irreversible damage to the health of users. YBB00342002-2015 requires that the number of particles of 5 μm and above per 1 ml should not exceed 100, and the number of particles of 10 μm and above per 1 ml should not exceed 20 according to the determination method of insoluble particles in packaging materials (YBB00272004--2015). ; Each 1ml contains no more than 2 particles of 25μm and above.

Disposable multi-layer co-extruded bags need to be produced in a clean area, which is mainly summarized as two production steps: bag making and pipeline assembly. According to the specific types of products, the types of materials involved mainly include filling needle materials, pipeline materials, and joint materials. The main feature of the filling needle material is that it contains a section of pipeline structure of about 5-25cm. In addition to the pipeline structure, it is an additional structure for adapting the machine. It may also contain a protective sleeve made of PP and other materials; pipeline materials It is mainly a certain length of pipeline with an inner diameter of 0.8cm-12.7cm. The material of the pipeline can be silica gel, PE, PVC, PET; the joint material contains the most categories, such as joints, plugs, quick joints, chuck ports, etc. , This type of material is characterized by relatively complex structures such as bends, chamfers, grooves, and channels. There are many kinds of materials, and higher requirements are put forward for the quality control of final products.

Conventional production processes include film cutting, bag opening welding, film lamination, edge sealing welding, integrity testing, pipeline assembly, bag body assembly, light inspection and packaging, etc. Although various production methods currently have certain control over the production environment and production process, such as using C-level production workshops, wearing dust-free clothing, using double-layer packaging, and using dust-free cloth to wipe materials, etc. However, these environmental control methods are basically difficult to meet the standard of A-level environment, resulting in the high rate of foreign matter and the number of insoluble particles in various products on the market.

Maintaining A-level environmental standards throughout the process can certainly improve the overall cleanliness of single-use multi-layer co-extrusion bags, but the maintenance cost of A-level environmental standards is extremely high, which will greatly increase the production cost of single-use multi-layer co-extrusion bags. However, even in a Class A environment, because a small amount of particles are still produced during the production process, it is still difficult to effectively guarantee the cleanliness of the product. How to effectively control the cleanliness of single-use multi-layer co-extruded bags has become the key to restricting the quality of single-use multi-layer co-extruded bags.

Contents of the invention

The purpose of the present invention is to overcome at least one deficiency of the prior art, and provide an ultra-clean production process for one-time use of multi-layer co-extrusion bags, so as to effectively control the foreign matter rate and the number of insoluble particles.

The technical scheme that the present invention takes is:

The ultra-clean production process for one-time use of multi-layer co-extruded bags includes the following steps:

Material cleaning: According to the characteristics of the material, different cleaning processes are used, including:

The cleaning process for filling needle materials is as follows: use purified water to wash the inner surface of the filling needle pipeline for at least 20s, then perform surface washing for at least 30s, then perform ultrasonic cleaning, replace the purified water, perform surface washing for at least 30s, and then carry out Second ultrasonic cleaning, followed by at least 30s of surface rinsing, and at least 30s of internal and external surface rinsing with purified water;

The cleaning process for pipeline materials is as follows: use purified water to clean the inner diameter of the pipeline for at least 10 minutes, and at the same time use purified water with a pressure above 0.05MPa to spray the surface of the pipeline, and use purified water to clean the inner and outer surfaces for at least 30 seconds. rinse;

The cleaning process for joint materials is as follows: use purified water to wash the surface of all joint materials for at least 30 seconds, use purified water to ultrasonically clean the materials for 10 minutes, use purified water with a pressure above 0.10 MPa to wash the surface for at least 30 seconds, and use purified water again Use water to ultrasonically clean the material, and then use purified water with a pressure above 0.10MPa to wash the surface for at least 30s, and use purified water to wash the inner and outer surfaces for at least 30s;

Membrane materials: surface cleaning;

Material drying: After the material is cleaned, the material is dried, among which: joints and filling needles are dried in a clean environment of grade A; pipeline materials are dried in a clean compressed air environment of grade A;

Pipeline assembly: connect and fix the pipeline and joint materials, and the environments of the connection and fixing operations are isolated from each other.

In some instances, the interval between material washing and material drying does not exceed 180 minutes.

In some instances, the interval between material washing and material drying does not exceed 90 minutes.

In some examples, in the cleaning of the joint-like material, the ratio of the amount of purified water used to the surface area of the material is greater than 3ml/cm ² during the first ultrasonic cleaning.

In some examples, in the cleaning of the connector-like material, the ratio of the amount of purified water used to the surface area of the material in the first ultrasonic cleaning is 3ml/cm ² -6ml/cm ² .

In some examples, during the second ultrasonic cleaning, the ratio of the amount of purified water used to the surface area of the material is greater than 2ml/cm ² .

In some examples, during the second ultrasonic cleaning, the ratio of the amount of purified water used to the surface area of the material is 2ml/cm ² -3ml/cm ² .

In some examples, the time for the first ultrasonic cleaning is 10-20 minutes.

In some examples, the time for the second ultrasonic cleaning is 10-20 minutes.

In some instances, pipeline materials are dried with clean compressed air with a pressure of ≥0.35MPa.

In some instances, the piping materials are dried for at least 3 minutes after being visibly free of moisture.

In some examples, the operator's hands and arms are protected by using the same film material as the multi-layer co-extrusion bag.

In some instances, the pressure of the purified water for cleaning the filling needles and connectors is not lower than 0.10Mpa.

In some instances, the pressure of the purified water used to clean pipeline materials is not lower than 0.05 MPa.

In some instances, after the material is washed, it is dried at 55-60° C. for at least 20 minutes in a clean oven conforming to a Class A environment.

In some instances, the production process of materials after cleaning is under the A-level environment; the production process of membrane materials after film cutting is under the A-level environment.

In some instances, the power of ultrasonic cleaning is not lower than 500W.

In some examples, the power of ultrasonic cleaning is 500-700W.

The beneficial effects of the present invention are:

Experimental data shows that the amount of visible foreign matter in the disposable aseptic filling bags produced by the ultra-clean production process of some examples of the present invention is reduced by more than 70% compared with the number of visible foreign matter in the disposable aseptic filling bags produced by the general production process , can reduce the number of insoluble particles by more than 50%, greatly improving the quality of the product.

The ultra-clean production process of some examples of the present invention avoids the pollution of insoluble particles and fine visible foreign matters to the greatest extent. At the same time, it can also increase the cleanliness of disposable multi-layer co-extruded bags and their accessories in terms of TOC and electrical conductivity. It can minimize the scrapping of medical products and possible health risks caused by insufficient cleanliness of consumables.

Detailed ways

The environmental standards at all levels of the present invention are environmental standards under the current GMP standard.

The inventor found that in order to realize the ultra-clean production of disposable multi-layer co-extruded bags, the key lies in the following points:

Partial A-level environment: In a C-level clean environment, an A-level environment covering all links that need to be controlled in the product production process is established, and a balance point is obtained between product quality and environmental construction costs.

A process that is difficult to control through the environment, using a unique process. If the cleanliness of the raw materials does not meet the production requirements of the A-level environment, a special process: the cleaning combination of purified water cleaning + injection water rinsing, ultrasonic cleaning + purified water cleaning + compressed air blowing is used to clean the raw materials. The degree is improved to meet the use requirements of Class A environment.

Personnel pollution control: In the production process, personnel operation is also one of the important sources of pollution, and most of the pollution caused by personnel operation is introduced from the outside by the hands and arms of the operator. In view of the above situation, it is creatively proposed to use membrane materials (excess raw materials in production) to make protective devices for personnel to operate, and use the characteristics of smooth outer membrane and adhesive inner membrane of membrane materials to control the pollution introduced by personnel from the C-level environment and reduce Pollution generated during operation.

Avoid cross-contamination: one-way flow, distributed production mode, avoid cross-contamination from the production mode.

Based on the results of long-term research, the inventor has developed an ultra-clean production process for one-time use of multi-layer co-extruded bags, including the following steps:

Membrane materials: surface cleaning;

Purified water includes but not limited to distilled water, double distilled water, and water for injection. The pressure of compressed air is the pressure measured when the line is closed.

By shortening the interval between washing and drying, the time the material is exposed to moisture is reduced, reducing the risk of microbial contamination.

In this case, the effect of ultrasonic cleaning can be guaranteed, and the consumption of purified water can be reduced.

In some examples, the time for the first ultrasonic cleaning is 10-20 minutes.

In some examples, the time for the second ultrasonic cleaning is 10-20 minutes.

In some instances, after the material is washed, it is dried at 55-60° C. for at least 20 minutes in a clean oven conforming to a Class A environment. This can further reduce the possibility of microbial growth.

In some instances, the power of ultrasonic cleaning is not lower than 500W.

In some examples, the power of ultrasonic cleaning is 500-700W.

Example 1

Taking SB010-2R as an example to illustrate the all-round improvement of the ultra-clean production process in terms of visible foreign matter, insoluble particles, TOC, and electrical conductivity of the product. The specific SB010-2R ultra-clean production process is:

S1) All ultra-clean equipment starts to clean for 30 minutes, including ultra-clean workbench, FFU, laminar flow transfer vehicle, and clean oven. Cut the film on the continuous automatic film cutting machine (the film is in the pre-composite state at this time), cut the remaining scraps of the film to a suitable size, then carry out trial welding and make protective sleeves for personnel, and start production after confirming that the equipment is normal;

S2) The specific operation of ultra-clean bag production includes light inspection after cutting the film, bag opening (the bag mouth has been cleaned and dried), bag mouth welding, film lamination, edge sealing welding, integrity inspection, and cleaning after the integrity inspection. The laminar flow transfer vehicle transfers the bags to the ultra-clean assembly workshop. The production process of ultra-clean bags is progressive production;

S3) The ultra-clean cleaning workshop simultaneously cleans all joint materials. The specific operation includes cutting all the pipelines to the required length in the C-level environment, and after counting the joints, plugs, bag openings, quick joints, and chuck openings, place them in stainless steel mesh baskets. Put it in a grade A environment, wash the surface with purified water for 30s, and ensure that the pressure is ≥0.10MPa when the pipeline status remains unchanged (when the switch status is constant, ensure that the internal pressure of the pipeline is ≥0.10MPa). After cleaning, transfer the stainless steel mesh basket to the compressed air purging ultra-clean workbench for surface purging and drying of the material (compressed air pressure ≥ 0.35Mpa), and then transfer to a clean oven for 30 minutes at 55-60°C for circulation drying;

S4) After drying, use a clean laminar flow transfer vehicle to transfer the materials to the ultra-clean bag-making workshop and the ultra-clean assembly workshop;

S5) Assemble all pipelines, joints and other accessories with reference to the drawings, and assemble the pipelines with the bag after the pipelines are assembled. After the assembly is completed, check and double-layer vacuum packaging is carried out after the inspection is correct, and then the third vacuum packaging is carried out in a C-level environment, with a total of 3 layers of vacuum packaging.

Comparative example 1:

As a comparison, the general production process of SB010-2R is as follows:

S1) In a Class C clean workshop that meets GMP requirements, the production operation is carried out in accordance with GMP requirements. In the C-level environment, place the film roll on the film frame of the film cutting machine, and use the film cutting machine to cut the film. Fold the inner film of the cut film facing the upward curved surface, place it on the light inspection table for light inspection, combine the welding surface of the bag mouth with the inner surface of the film, place it on the mold of the bag mouth welding machine, and weld according to the corresponding process;

S2) The operator refers to the product drawing to align and match the inner film of the semi-finished film, transfers the semi-finished film that has been laminated to the edge-sealing welding machine, performs edge-sealing welding according to the corresponding process, and lays the welded semi-finished product on the transfer vehicle According to the size of the bag mouth, use the corresponding accessories to seal the bag body, and select the corresponding pressure according to the size of the bag body for integrity testing. After the test is passed, the bag body is pumped and placed on the transfer vehicle;

S3) The operator cuts the pipeline to a suitable length according to the product drawing, assembles and fixes the cut pipeline with other accessories (such as joints, filling needles, chuck ports, plugs, etc.), and the pipeline assembly is completed Finally, assemble and fix the assembled pipeline and bag body according to the product drawings. After the product is assembled, it is packaged and inspected on a light inspection table. After passing the inspection, double-layer vacuum packaging is carried out.

The same product produced by different production processes was tested to determine its visible foreign matter, insoluble particles, TOC and electrical conductivity. The results are shown in Table 1 and Table 2.

Table 1. Test results of ultra-clean production process products

Table 2. Test results of clean products in general production process

It can be seen from the above steps that the products produced by the ultra-clean production process of the present invention can reduce the number of visible foreign matter by about 70%, and the number of insoluble particles by about 50%, and at the same time, there are some improvements in TOC and electrical conductivity.

Example 2:

Taking the LE177579SU filling needle as an example to illustrate the all-round improvement of the ultra-clean cleaning process to improve the visible foreign matter, insoluble particles, TOC, and conductivity of the filling needle material. The specific cleaning process is:

S1) Take 40 filling needles as a cleaning batch, place the filling needles evenly and dispersedly in the stainless steel cleaning basket, transfer to the A-level environment for at least 30s of overall surface washing, and then perform at least 20s of filling Flush the inner cavity of the needle, and ensure that the internal pressure of the pipeline is ≥0.10MPa when the valve switch is opened;

S2) Place the stainless steel mesh basket in an ultrasonic cleaning machine, add 8L of purified water, and perform 15min ultrasonic cleaning with 600W ultrasonic power;

S3) Take out the stainless steel mesh basket from the ultrasonic cleaner, rinse it with purified water for at least 30 seconds, replace the purified water in the ultrasonic cleaner, place the stainless steel mesh basket in the ultrasonic cleaner, and perform 15min ultrasonic cleaning with 600W power;

S4) Take the stainless steel mesh basket out of the ultrasonic cleaning machine, rinse it with purified water for at least 30 seconds, transfer it to the ultra-clean workbench, use clean compressed air with a pipeline pressure ≥ 0.35MPa for at least 5 minutes, and use a clean oven for 30 minutes Drying cycle of 55-60°C.

Test each group of 10 filling needles before and after cleaning to determine the visible foreign matter, insoluble particles, TOC and conductivity. The results are shown in Table 3 and Table 4.

Table 3. Test results before cleaning the filling needle

Table 4. Test results after filling needle cleaning

From the above results, it can be seen that the ultra-clean cleaning process of the present invention can greatly reduce the number of visible foreign matter and insoluble particles in the filling needle material, and also improve the TOC and electrical conductivity of the filling needle material.

The above is a further detailed description of the present invention, and should not be regarded as a limitation to the specific implementation of the present invention. For those of ordinary skill in the technical field to which the present invention belongs, simple deduction or replacement without departing from the concept of the present invention is within the protection scope of the present invention.

Claims

The ultra-clean production process for one-time use of multi-layer co-extruded bags includes the following steps:

Material cleaning: According to the characteristics of the material, different cleaning processes are used, including:

The cleaning process for filling needle materials is as follows: use purified water to wash the inner surface of the filling needle pipeline for at least 20s, then perform surface washing for at least 30s, then perform ultrasonic cleaning, replace the purified water, perform surface washing for at least 30s, and then carry out Second ultrasonic cleaning, followed by at least 30s of surface rinsing, and at least 30s of internal and external surface rinsing with purified water;

The cleaning process for pipeline materials is as follows: use purified water to clean the inner diameter of the pipeline for at least 10 minutes, and at the same time use purified water with a pressure above 0.05MPa to spray the surface of the pipeline, and use purified water to clean the inner and outer surfaces for at least 30 seconds. rinse;

The cleaning process of joint materials is as follows: use purified water to wash the surface of all joint materials for at least 30 seconds, use purified water to ultrasonically clean the materials for 10 minutes, use purified water with a pressure above 0.10 MPa to wash the surface for at least 30 seconds, and use purified water again Use water to ultrasonically clean the material, and then use purified water with a pressure above 0.10MPa to wash the surface for at least 30s, and use purified water to wash the inner and outer surfaces for at least 30s;

Membrane materials: surface cleaning;

Material drying: After the material is cleaned, the material is dried, among which: joints and filling needles are dried in a clean environment of grade A; pipeline materials are dried in a clean compressed air environment of grade A;

Pipeline assembly: connect and fix the pipeline and joint materials, and the environments of the connection and fixing operations are isolated from each other.
The ultra-clean production process according to claim 1, characterized in that: the interval between material cleaning and material drying is no more than 180min.
The ultra-clean production process according to claim 1, characterized in that: in the cleaning of the joint material, during the first ultrasonic cleaning, the ratio of the amount of purified water used to the surface area of the material is greater than 3ml/cm 2 ; and /or

During the second ultrasonic cleaning, the ratio of the amount of purified water used to the surface area of the material is greater than 2ml/cm 2 .
The ultra-clean production process according to claim 3, characterized in that: the time for the first ultrasonic cleaning is 10-20 minutes; and/or

The time for the second ultrasonic cleaning is 10-20 minutes.
The ultra-clean production process according to claim 1, characterized in that: after the material is cleaned, it is dried at 55-60°C for at least 20 minutes in a clean oven conforming to Class A environment.
The ultra-clean production process according to any one of claims 1 to 5, characterized in that the pipeline materials are dried with clean compressed air with a pressure of ≥0.35 MPa.
According to the ultra-clean production process described in any one of claims 1-5, it is characterized in that: after the pipeline material is dried until it is visually free of moisture, it continues to be purged for at least 3 minutes.
The ultra-clean production process according to any one of claims 1-5, characterized in that: using the same film material as the multi-layer co-extruded bag to protect the hands and arms of the operator.
The ultra-clean production process according to any one of claims 1-5, characterized in that: the pressure of the purified water for cleaning and filling needle materials and joint materials is not lower than 0.10 MPa; and/or

The pressure of the purified water for cleaning pipeline materials is not lower than 0.05MPa.
According to the ultra-clean production process described in any one of claims 1 to 5, it is characterized in that: the production process of the material after cleaning is under the A-level environment; the production process of the membrane material after film cutting is under the A-level environment Down.