On the BFS aseptic filling production line

At present, BFS technology is recognized as an energy-saving, environmentally friendly, and aseptic process with high product added value. The BFS aseptic filling production line has been well applied in the production of aseptic medicines, aseptic functional foods and aseptic cosmetics. This article briefly introduces the concept, process layout and aseptic preparation system of the blow-fill-seal (BFS) aseptic filling production line, and analyzes the particularity of the BFS aseptic production line from the aspects of risk prevention and practical application.

Blow/Fill/Seal (hereinafter referred to as BFS technology) aseptic filling production line consists of a set of aseptic preparation systems and a BFS aseptic filling machine. It is currently a relatively complete aseptic filling production line. The production line has full-line CIP/SIP functions and runs under the protection of positive pressure, airtight, and laminar flow. Container production, product filling, and container sealing (Blow / Fill / Seal) are all completed under the aseptic protection of Class A air shower, which can effectively prevent various contamination and cross-contamination that may occur during the process. The process parameters such as temperature, pressure, pH, weight, time/rotation speed in the process can be monitored online and recorded in real time, which fully meets the requirements of aseptic process. Because the BFS aseptic filling production line has a strong sterility guarantee ability, no preservatives are added to the product, "non-terminal sterilization" can be realized, and the internal quality of the product is high, and the safety is good.

At present, BFS technology is recognized as an energy-saving, environmentally friendly, aseptic process with high product added value. The BFS aseptic filling production line has been well applied in the production of aseptic medicines, aseptic functional foods and aseptic cosmetics.

The current "Pharmaceutical Manufacturing Quality Management Regulations" (hereinafter referred to as "Specifications") Appendix 1 (Sterile Drugs) China has introduced two new aseptic technologies, one of which is Blow Fill Seal (BFS) technology.

Process layout of BFS aseptic filling production line

The process layout of the BFS aseptic filling production line must not only meet the requirements of the aseptic process, but also fully consider the particularity of the BFS aseptic production line.

According to the requirements of aseptic technology, a shower room should be provided at the back of the general change. Because the filling area is a Class C clean environment, it is managed according to Class A/B clean environment (personnel dressing should conform to the style of Class A/B clean area), the filling area and the preparation area should have their own independent flow channels. In the production of antibiotics/hormone products, the preparation room should be designed with an independent exit channel to prevent material dust from causing cross-contamination of the clean dressing room; the preparation area should have an independent filter cleaning and testing room, so that after the sterilization filtration is completed, it can be Check the integrity of the filter immediately.

Sterilization UV lamps should be added to the buffer room of the logistics channel to reduce the contamination of the preparation area caused by microorganisms carried by the package. Material weighing should be carried out in a negative pressure weighing room with A-level laminar flow protection, so that the exposed materials are always under the protection of A-level laminar flow, and at the same time protect the operator and the environment from material pollution and cross-contamination. The laminar flow in the weighing room should be designed as a self-circulating and filtered air flow method to avoid affecting the pressure difference between adjacent rooms.

Airflow organization between negative pressure weighing

BFS aseptic filling production line process layout

Interlocking devices and observation windows should be reasonably set up between each function to prevent the phenomenon of "channels" during the production process, and at the same time, it is also convenient for observation and communication during the production process, and minimizes the cleanliness caused by factors such as operation and management. Pollution from the production area. In the BFS process, it is very important to prevent plastic particles from being polluted by dust during the supply process, and an independent plastic particle supply room should be set up. When conveying materials in a vacuum mode, an air filter device should be installed above the plastic particle supply box to prevent the inhaled dust and particles from affecting the quality of the container; in seasons and environments with large temperature differences, plastic particles should enter the temporary space 24 hours in advance. Store room to avoid the influence of temperature and humidity on the container.

Implement CIP/SIP, airtight, positive pressure operation aseptic preparation system, mixing tank and aseptic storage tank can be located in the same room, but the aseptic demarcation point must be strictly defined, it must be divided by sterilizing grade filter instead of reducing Bacteria filter. A process room can be added to the adjacent room of the preparation room according to the process requirements, which can not only meet the needs of process treatment before mixing (such as ultrafiltration equipment, homogenizer, etc.), but also prevent pollution to the preparation room. Because the filling area of the BFS aseptic filling production line is managed according to the A/B level clean area, there must be no tools and equipment washing and sanitary clean rooms, and no drainage floor drains. Tools and utensils that need to be cleaned should be passed to the washing room in the preparation area through an independent one-way transfer window (room) for cleaning. The cleaned tools and utensils must be sterilized by a double-door sterilizer before being passed to the filling area. Save under A-level laminar flow. The transfer window (room) must have ventilation function, the two ends must have pressure difference protection, and the logistics routes before and after sterilization must not overlap.

Laminar flow protection of BFS filling machine and water collection tank between auxiliary machines

The BFS machines of the BFS aseptic filling production line must be installed in "black and white partitions". The blowing, filling, and sealing parts are installed in a Class C clean area according to the requirements of the "Specifications", and the auxiliary machine parts are installed in the ordinary production area. When implementing aseptic process (production of non-terminally sterilized products), according to the requirements of aseptic process, A-level laminar flow protection should be installed above the filling area of the BFS machine (some equipment comes with laminar flow protection); airborne air The shower room should be designed to take air under Class A laminar flow. When designing the air volume and pressure difference in the filling room, it is necessary to fully consider the pressure difference and air volume loss caused by the product channel and the exhaust fan. The CIP/SIP water discharge port of the BFS machine should be located in the auxiliary machine room of the ordinary production area, and an air blocking device should be installed to eliminate back pressure.

Aseptic preparation system of BFS aseptic filling production line

The aseptic preparation system of the BFS aseptic filling production line is an important part of the BFS aseptic filling process. In order to meet the needs of process diversity, it should be designed as a system that can work with the BFS machine, but also can perform CIP/SIP independently, and can be designed for automatic and manual operation according to process needs. It is necessary to scientifically and reasonably set the collection points and collection methods of various monitoring data in the production process, and verify the authenticity and completeness of the various data through verification.

During the entire aseptic preparation process, the basic principles of aseptic protection of laminar flow protection, airtight, and positive pressure operation must be strictly followed. The design of the process pipeline between the mixing tank and the aseptic storage tank must have a strict aseptic demarcation point; process water, compressed gas, and aseptic clean steam must be sterilized and filtered by a sterile-grade filter before entering the preparation system; all The sterilization-grade filter must be "integrity inspection" before and after use; the filter setting should be installed in the order of pre-filtration, sterilization-grade filtration, and sterilization-grade filtration; some sterilization-grade filters can be cleaned and tested offline , Online sterilization, complete integrity test immediately after use.

Due to the particularity of the BFS machine (the filling volume control adopts the time/pressure method), in order to ensure the CIP/SIP effect and filling accuracy of the BFS aseptic filling production line, it is best not to use infusion pumps that are not easy to clean and sterilize. Clean compressed gas should be used as the material transportation power. The stirrer in the tank should be a suspension magnetic stirrer that can guarantee the CIP/SIP effect; the cleaning ball in the tank should be a 360-degree powerful cleaning ball with better cleaning effect; the turbulent flow rate that can be generated by the process pipeline in the system should not be lower than 1.5～2 m/s, the Reynolds coefficient should be controlled between 3 000～9 000 in actual operation; the process pipelines installed in parallel in the system should have a certain slope and minimize the length; no installation on the tank body that is difficult to clean Sterilized level gauges should be measured with a precise weighing system; explosion-proof membranes that can perform CIP/SIP are used to replace safety valves that are not easy to clean.

The sterilization grade filter should be installed at the highest point of the system

In order to ensure the reliability of the aseptic preparation process, prevent potential safety hazards, and ensure the authenticity and integrity of various parameters in the process, an online monitoring system should be set up in the preparation room (data can be transmitted to the BFS machine computer system for storage ), online dynamic monitoring of process parameters such as temperature, pressure, metering and pH value of the entire production process.

In order to prevent the “back pressure” generated during the discharge of SIP steam, CIP water and compressed gas from causing system pollution, the aseptic preparation system and the BFS machine must have their own independent discharge systems. The installation slope of the flat discharge pipeline shall not be less than 3‰, and an emptying device with air barrier function shall be installed at the total discharge port to eliminate the risk of system back pressure.

When using the BFS aseptic production line to produce concentrated foods and cosmetics, because of the large molecular weight of the effective ingredients in many products, it is not easy to use the sterilization filtration process. "Ultra-high temperature instantaneous sterilization" can be added between the mixing tank and the aseptic storage tank. The device sterilizes the materials and enters the aseptic storage tank after cooling down. The production line does not install or select a suitable filter before CIP/SIP. This combination of processes can not only complete the sterilization of the material in a short time, maximize the retention of the effective ingredients and original flavor in the material, but also prevent the "terminal sterilization" of the product after potting, causing plastic Deformation of the container.

Application of BFS aseptic production line

The BFS machine can automatically complete the CIP/SIP of all material pipelines under the control of the computer program. The screw extruder and the parison extrusion head form the plastic particles into a tube blank at a high temperature of 170-230°C and a pressure greater than 350 bar. The three processes of container production, product filling, and container sealing (Blow / Fill / Seal) are all completed in the same aseptic station under the protection of the airborne Class A air shower. Under normal circumstances, the equipment runs automatically under the program control of the on-board computer, and no human operation is required in the filling room, so as to prevent possible pollution and human errors to the greatest extent. The process parameters of the entire production process are completely stored in the on-board computer system, which can be consulted at any time but cannot be changed. It can be said that the BFS aseptic filling production line is currently the aseptic filling production line with the strongest aseptic guarantee capability and the highest degree of intelligence.

Application of BFS Technology in the Production of Sterile Drugs

Compared with the traditional aseptic production process, the biggest advantage of the BFS aseptic filling process in the production of aseptic drugs is that the entire production process of the product is under the control of the on-board computer program and is automatically completed according to the verified process. Few human intervention, strong sterility protection ability. Each key station of the production line has a strong function of sterility protection, which is rarely affected by the fluctuation of the external environment, and can effectively control and prevent various risks that may occur. In the production of sterile drugs, due to sound regulations and mature technology, the products can achieve "sterile production and sterile use".

Application of BFS technology in food and cosmetics production

BFS aseptic filling technology was initially applied in aseptic food production. Currently in the domestic market, limited by production technology, many functional foods and cosmetics are not produced using aseptic processes. To prevent product deterioration, they all contain preservatives. The antiseptic principle of preservatives is to prevent or eliminate microbial pollution, inhibit the growth and metabolism of microbes, and kill microbes. In terms of the antiseptic principle of preservatives, preservatives are harmful to human tissues. The use of BFS aseptic process to produce food and cosmetics does not need to add preservatives. It is especially suitable for the production of plant essence products such as medicinal and food homology, such as ginseng essence. The small single-use sterile cosmetics are not only accurate in measurement, but also convenient to use and carry. , Can also prevent pollution and cross-contamination caused during use. Such as various essences in cosmetics, sterile facial masks, etc.

Public works of BFS aseptic filling production line

The public works of the BFS aseptic filling production line must not only meet the requirements of aseptic technology, but also meet the special needs of BFS technology.

The HVAC system (air conditioning purification system) is one of the important conditions for the BFS aseptic filling production line to achieve aseptic protection. According to the requirements of the "Specifications", according to the function and particularity of the BFS machine, the BFS aseptic filling machine that produces non-terminally sterilized products should be installed at least in a clean environment of class C managed according to class A/B; the auxiliary machine part should be installed in Ordinary production area, and install A-level laminar flow protection above the filling part. In order to maintain a stable gradient pressure difference between the C-level background area, the A-level laminar flow area and the A-level airborne air shower, the A-level laminar flow should be designed to take air in the C-level background area; the airborne A-level air shower The room should be designed to take air under Class A laminar flow; the pressure difference in different areas will form a linked gradient pressure difference and cleanliness under the action of the fan and the filter. In order to increase the coverage area of the air flow in the clean area and improve the self-purification capacity of the clean environment, the spiral baffle recommended by the WHO should be installed under the air outlet.

Local process pipeline setting

The water production and pure steam system are important auxiliary equipment to ensure the CIP/SIP effect and product quality of the BFS aseptic filling production line. In order to prevent possible risks, it is recommended to adopt a double-plate tube structure. In order to ensure the CIP effect, there must be a pressure regulating device in the process water system. It is not recommended to use U-shaped elbows at each point of use, and a T-shaped valve with small residual volume and no blind cavity should be used. The BFS production line SIP should ensure the stability of temperature and pressure. It is recommended to use a pure steam generator with a power that is 20% larger than the theoretical design. The discharge of condensate is one of the main reasons leading to the failure of SIP. In addition to the insulation of the steam pipeline according to the specifications, a condensate discharge point should be added within a distance of no more than 15 m from the main steam line to reduce the harm caused by condensate. .

BFS aseptic filling production line

Because the BFS machine filling system adopts the "time/pressure method", the power of material transportation and the cooling and drying after SIP are all clean compressed gas. In the BFS process, the clean compressed gas is in direct contact with the material, so the clean compressed gas is also one of the key conditions for the BFS production line to achieve sterility assurance. The compressed gas system should be managed aseptically, and the process pipeline should have CIP/SIP functions. Before entering the compressed gas point of use, in addition to filtering and separating oil, water, particles, and microorganisms, an activated carbon filter must be installed to absorb the peculiar smell formed in the gas such as atomized oil.

In short, the BFS aseptic filling process is currently recognized as an aseptic filling process with strong aseptic protection capabilities, high technical content, high production efficiency, high product added value, energy saving and environmental protection. The BFS aseptic filling process and the special functions of the product determine that it will gradually replace the traditional "washing, filling and sealing process" and become the inevitable development trend of aseptic product production.