Impact of the new version of GMP on air volume and pharmacological control of pharmaceutical companies
1 The new requirements of the new version of GMP for purification air conditioning systems are mainly reflected in the following aspects :
1) Regarding purification air-conditioning, no matter the level, system, air flow and detection, it has higher requirements than in the past.
2) Dynamic monitoring of suspended particles.
3) For the background environment of the high-risk operation area, a 100 times higher cleanliness requirement than in the past is proposed.
4) The cross-section wind speed of the table in the laminar flow area is not required by the 1998 GMP, and it is higher than that of the conventional clean room.
5) A new requirement for the number of air exchanges in the turbulent clean room was proposed.
6) The system operation requirements are put forward for the purification and air-conditioning system of sterile medicines.
7) Super professional requirements for the role of airflow.
8) The first request for isolation operation.
9) An indicator of the amount of bacteria on the surface was proposed.
10) Only appropriate requirements for lighting, temperature and humidity are proposed, and inappropriate numbers are not given.
11) High pressure requirements of not less than 10 Pa are required for adjacent rooms of different levels, and adjacent rooms of the same level should also have appropriate pressure differences.
2 Clean room air volume and static pressure difference control
GMP has specific control requirements for the parameters that affect the quality of the drug, such as the cross-section wind speed, the number of ventilations, the static pressure difference, temperature and humidity, illuminance, noise and fresh air volume.
2.1 Air volume control
For clean room air conditioning systems, the air supply volume of the clean room is a very important parameter, which determines the number of air changes and self-clean air changes in the clean room. From a certain perspective, it ensures that the indoor air volume is constant, that is, Ensure the stability of indoor cleanliness parameters. Therefore, how to keep the air volume in the clean room constant during the design and operation of the clean room air-conditioning system is a question worth studying. First of all, when selecting a filter, the designer chose that the actual air volume of the filter is less than its rated air volume. The imbalance of resistance is achieved by installing a regulating valve, so the resistance of the high-efficiency air filter in the same clean area is not very close. Air volume adjustment is troublesome. Secondly, during the actual operation of the purification air-conditioning system, due to the constant change of the resistance of the high-efficiency, medium-efficiency, and initial-efficiency filters, the resistance change of the surface cooler in dry and wet conditions will cause the total resistance of the air pipe network to change. As a result, the working condition of the fan changes, which is very unfavorable for clean rooms that require constant air volume.
2.2 Static pressure difference control
Theoretically, the static pressure difference should have two functions: when the door and window are closed, prevent the pollution from the clean outdoor from seeping into the room through the gap; when the door is opened, ensure that there is sufficient airflow to flow outward, and try to reduce the action of opening the door as much as possible The flow of air brought in by people at the moment of entry, and when the door is opened later, ensure that the direction of the air flow is outward, so as to reduce the introduced pollution to a minimum . The important link to ensure the quality of medicines is the production method. Its pros and cons are determined by the production technology and production environment. The main purpose of the production environment control of the pharmaceutical factory is to prevent situations that endanger the product quality due to pollution or cross-contamination. Therefore, for some key production process operation rooms, while reducing the pollution in the room, ensuring the pressure difference with respect to adjacent rooms has become an important factor to ensure cleanliness and thus the quality of medicines.
The new version of GMP has new requirements for the control of differential pressure: it puts forward a high requirement of not less than 10 Pa for the pressure difference between adjacent rooms of different levels, and adjacent rooms of the same level should also have an appropriate differential pressure. China's GMP and related regulations on the differential pressure are shown in Table 1 [1, 3]:
2.3 Static pressure difference control method 
At present, the static pressure difference control methods of the production environment of pharmaceutical factories mainly include: constant air volume control. There are two main methods of constant air volume control: manual control and constant air volume valve control.
Endless loop control. Direct pressure control is often used, that is, maintaining the indoor pressure difference to control fresh air or return air or exhaust air as a variable. There are mainly four methods of using indoor positive pressure to maintain and control fresh air as a variable, maintaining indoor pressure difference to control return air as a variable, using indoor pressure difference to maintain and control exhaust air as a variable, and independent positive pressure supply air pressure differential control.
Residual pressure valve control. When the air pressure in the purification room exceeds the standard air pressure, the pressure reducing valve opens automatically. When the air pressure is lower than the standard air pressure, the valve returns to a closed state, thereby balancing the air pressure.
Residual air volume control. Maintaining a certain air volume difference (called residual air volume) between the supply air volume and exhaust air volume of the clean room will inevitably lead to a certain pressure difference in the clean room. Residual air volume (airflow tracking) control means that the control system measures the air volume (supply and exhaust air volume) changes in real time. By adjusting the supply or exhaust air volume, the corresponding air volume balance can be dynamically achieved, so that Maintain a constant air volume difference between them, thus maintaining a constant pressure difference.
Mixed control. It is the control in which the differential pressure control and the residual air volume control are connected in series. Use the residual air volume as the basic control method, and add a differential pressure sensor to reset the residual air volume.
3 Smart Venturi valve
Because manual control is currently widely used in biopharmaceutical clean rooms, there are many problems with this method: when the system is running, the blocking degree or resistance of each high-efficiency filter varies unevenly. The use of variable frequency fans can solve the problem of air supply, but The valve must be adjusted frequently to achieve air volume balance. When the system is dynamic and static, the pressure difference in the room changes greatly, which causes many problems. The system's anti-interference ability is relatively weak. When the outdoor wind pressure changes or the pipe resistance changes, each The air supply volume of the room is redistributed, and the pressure changes accordingly. In order to keep the supply air, return air, and exhaust air constant when there is local exhaust, the exhaust air and the blower must be opened and stopped at the same time, wasting energy. Therefore, it is proposed to use the intelligent Venturi valve to gradually replace the manual control valve. The control method is shown in Figure 1.
3.1 Features and principles of intelligent Venturi valve
Intelligent Venturi valve is based on the traditional Venturi air flow control valve, which provides a precise air flow measurement circuit. As a result, the traditional Venturi valve relies on the feedback circuit to provide "unreal" flow, and it also provides the safety and accuracy of the Venturi air flow control valve. Intelligent Venturi control valve is a pressure-independent air volume control device with high precision and high speed response. It has a self-adjusting mechanical structure that is not affected by the static pressure change in the pipe and accurately maintains the set air volume. It can provide accurate true air volume feedback, and is widely used in chemical laboratories, biosafety laboratories, clean rooms, animal feeding facilities, pressure rooms, a member of the operating room and other places where precise control of air flow is required. The intelligent venturi valve maintains a constant air flow by changing the position of the spool. Each Venturi valve has a spool assembly with a built-in stainless steel spring. When the static pressure of the duct is low, the pressure on the spool becomes smaller, and the spring in the spool opens. The combination of large flow area provides ideal flow; when high static pressure occurs, the pressure on the valve core increases, the spring compresses and the valve core moves forward, reducing the flow area, maintaining high pressure and small opening Combination to maintain a stable flow.
3.2 Advantages of Intelligent Venturi Valve Control Method
The air volume is always constant. The Venturi valve with constant air volume is adopted to adjust the self-adjustment of the high-efficiency filter to keep the air supply pressure constant and the pressure of the duct changes without causing the air volume controlled by the Venturi valve to change.
Room pressure is guaranteed. The return air is also a constant air volume Venturi valve. The residual air volume method is used to ensure that the indoor pressure is stable. A further solution is to use a variable air volume Venturi valve to facilitate quick and easy commissioning.
Save energy. The air supply volume is controlled quantitatively, and the appropriate air supply volume is determined according to the cleanliness standard.
4 Application of Intelligent Venturi Valve in a Pharmaceutical Factory
Aiming at the environmental control problem of an established pharmaceutical factory in Shanghai, the improvement measures of the intelligent venturi valve are adopted, as shown in Figure 1. Mainly, the intelligent venturi valve is installed in the original air supply system and the return air system, and corresponding control elements are configured, and the entire system is comprehensively debugged and tested. Figure 2 shows the installation axis of the Venturi valve.
Table 2 shows the air supply volume and static pressure difference of the laboratory before and after the intelligent venturi valve is used in some rooms. Figure 3 is the experimental results of the laboratory air supply volume before and after the Venturi valve is used.
From Table 2 and Figure 3, it can be seen that before installing the intelligent venturi valve, the air supply volume of each room is very different from the designed air supply. The static pressure difference is unevenly distributed. Some rooms are relatively close to the low-level clean room, while others are very small, and even negative pressure appears. After the intelligent venturi valve is installed, the air supply volume of each room is compared. The supply air volume is close to the design. After commissioning, the arithmetic average of the ratio of the air volume to the design air volume is 1.02. The static pressure difference of the room relative to the low-level clean room tends to be stable.
The implementation of the new version of GMP has brought China's pharmaceutical production environment in line with international standards, bringing opportunities and challenges. The requirements for plant buildings and purification equipment are higher, the classification of clean rooms is more reasonable, and the requirements for clean room control are more stringent. The corresponding equipment update or improvement of pharmaceutical factories is necessary. And clean room control, including air volume and static pressure difference control, is a very important aspect to achieve cleanliness, meet production, and adapt to the new version of GMP. The use of intelligent venturi valves to stabilize the air volume in clean rooms is an effective method for environmental control of clean rooms. It is worthy of further discussion, improvement and application.
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