A detailed introduction to the cleaning process of dispensing system in pharmaceutical industry

[technical article of China Pharmaceutical network] pharmaceutical solution preparation system is mainly used for the preparation, sterilization and filtration of sterile drugs, biological products, important preparations and other pharmaceutical solutions in pharmaceutical plants In order to ensure the quality of drugs, it is very important to use safe and reliable cleaning technology to remove the residues in the pharmaceutical dispensing system (picture source: Baidu picture) this paper comprehensively introduces the design principle of online cleaning workstation, and systematically analyzes the advantages and realizability of online cleaning from the perspective of cleaning verification, which provides a good choice for cleaning process of liquid distribution system in pharmaceutical industry Pharmaceutical dispensing system is widely used in the field of pharmaceutical production and biotechnology It is very important to use safe and reliable cleaning technology to remove residues in pharmaceutical dispensing system CIP (clean in place, on-line cleaning) refers to the method of cleaning the solution preparation system under closed conditions without dismantling the pharmaceutical solution preparation production equipment, which is compared with the traditional cop (clean out of Compared with the CIP cleaning method, CIP cleaning method has the advantages of repeatedly verified cleaning effect, saving operation time, improving production efficiency, saving labor, safety and reliability, saving cleaning water, adjustable cleaning procedures, environmental protection and energy saving, easy installation and operation, modular production and factory acceptance test Cleaning principle the main principle of cleaning is to apply heating energy, mechanical energy and chemical energy to the residues on the surface of the equipment, and realize the cleaning of the equipment under the joint action of these energy Temperature, mechanical action, chemical action and time are the four basic elements in the cleaning process In order to achieve the purpose of cleaning, the above four elements are indispensable, interactive and complementary The temperature research shows that the chemical reaction speed will be increased by 1.5 ~ 2 times and the cleaning speed will be increased accordingly with the increase of temperature by 10 ℃ The relationship between cleaning temperature and cleaning time Properly increasing the temperature will help to save cleaning time When the temperature exceeds 80 ℃, the cleaning time will not change Therefore, considering the comprehensive energy consumption and cleaning effect, CIP program often chooses 60 ~ 70 ℃ as the standard cleaning temperature The mechanical function of mechanical cleaning is mainly realized by flow rate and pressure The cleaning process in turbulent state can effectively remove system residues The cleaning effect is closely related to the cleaning balls selected At present, in the conventional liquid distribution system, the rotary cleaning balls and tangent water cleaning balls have been widely promoted in the pharmaceutical engineering industry due to their advantages of economy, energy saving and water saving The cleaning effect is closely related to the dead angle of the system The cleaning verification of the dead angle shows that the proper increase of the system flow rate has a significant impact on the cleaning effect; at the same time, the smaller the dead angle control of the system, the lower the cleaning flow rate required In order to ensure a good cleaning effect of pharmaceutical dispensing system, enterprises need to strictly follow the "3D dead angle principle" For example, the biopharmaceutical industry often adopts the design concept of multi-channel valve without dead angle to effectively eliminate cross contamination of the system In engineering, the cleaning flow rate is generally controlled at 1.5-2m/s, and the empirical value of cleaning flow is generally 4-12l / min / m2 (internal surface area of tank) Chemical action can shorten the cleaning time or make up for the lack of cleaning temperature At present, the cleaning agents used in pharmaceutical preparation system are mainly divided into acid cleaning agents and alkaline cleaning agents Alkali detergent (such as 1% ~ 3% NaOH) has a good removal effect on the dirt with high protein content; acid detergent (such as 1% ~ 2% HNO3) has a good effect on the stubborn dirt that can not be removed by alkaline detergent, and acid detergent has a certain corrosiveness to metal, which needs to be neutralized in time and washed with clear water after use Time in the case of ensuring cleaning effect, shortening cleaning time is very important to improve production efficiency Cleaning time depends on the nature of dirt, chemical action, mechanical action, temperature, dead angle, surface polishing degree and other factors For example, electropolishing can effectively save cleaning time The cleaning time required for each liquid distribution system will be different, and the actual cleaning time can be confirmed in PQ (performance confirmation) stage The application of CIP workstation CIP system was applied in American dairy industry as early as 1950s In 1955, CIP system combined with automatic control system effectively solved the stability and reproducibility of cleaning effect, which made it widely used in pharmaceutical industry CIP workstation is a set of fixed online cleaning device, which adopts touch operation mode, can automatically adjust cleaning time, cleaning agent concentration, cleaning temperature, cleaning flow rate and other parameters All operations can be recorded for certification According to the number of tanks in the work station, CIP work station can be divided into single tank CIP system, double tank CIP system and multi tank CIP system Pharmaceutical enterprises can reasonably choose according to the actual needs According to the usage of cleaning agent, CIP workstation can be divided into single batch CIP system and reuse CIP system The cleaning agent of CIP workstation used in a single batch is ready to use, which can completely eliminate the cross pollution caused by cleaning agent, and is favored by most pharmaceutical enterprises For example, in fermentation biological products, freeze-dried preparations and blood products, the dual tank CIP workstation is widely used (Figure 5) In aseptic APIs, chemicals and traditional Chinese medicine aseptic preparations, the risk of cross contamination of products brought by cleaning is relatively small Some enterprises will also choose three or more tanks of CIP system for online cleaning of liquid distribution system, so as to save operating investment of cleaning agent and cleaning water CIP workstation is recommended to use professional 3D design software for framework modular design and assembly guidance Modular design is conducive to the realization of factory performance test, saving floor space, beautiful and easy to operate, fully in line with the design concept of ASME BPE The distribution frame system of CIP workstation is mainly composed of the following components: cleaning solution storage tank, final drenching water storage tank, CIP supply pump with frequency conversion control and heat exchanger The CIP workstation shall record the following important indicators: Cleaning agent concentration, CIP flow, CIP pressure, final shower conductivity, cleaning agent temperature and cleaning time According to the actual demand, CIP reflux pump can also be integrated into the distribution framework Figure 6 is a typical CIP workstation distribution framework system The cleaning process of standard CIP workstation mainly includes pre washing, cleaning agent circulation cleaning and final washing The practice shows that adding sterile compressed air purging procedure can effectively save cleaning time and water In Appendix 1: sterile drugs, the 2010 version of GMP clearly stipulates that the final pouring water of sterile drug preparation system shall meet the quality standard of water for injection CIP workstation can automatically determine the end point of system cleaning through circuit conductivity sensor It is concluded that CIP workstation combined with process analysis technology (PAT) has become a very mature online cleaning method in the pharmaceutical industry With the official promulgation of the new GMP and the new pharmacopoeia, the requirements for the design, installation and product quality of the dispensing system in the pharmaceutical industry in China are more stringent, and CIP workstation will be more widely used in the cleaning of the dispensing system in China.