Industry Information

Discussion on the freeze-drying broken vials and Solutions

Date:2018-10-16 views:360

1. Introduction


In recent years, vacuum freeze-drying technology has developed rapidly in China. After more than ten years of market competition and optimized combination, more than 10 professional manufacturers of freeze-drying machines have been formed. The technical performance of freeze-drying machine for pharmaceutical has been basically mature, and the corresponding industry standards have been formulated in China.


The two freeze-drying machines currently used by North China Pharmaceutical are the products of bocedwards in the UK (started in 1998) and Shanghai dongfulong Technology Co, Ltd. (started in 2002). Through the comparison in recent years, there is no obvious difference in the overall performance and stability of the machines, and the quality indexes of the final products are basically the same. It can be seen that the products of famous brands in China at present It can completely replace the imported equipment. From the actual production problems, since the use of domestic penicillin bottles, it is found that the problem of bottle breakage in the freeze-drying process is relatively prominent. Therefore, the relevant departments have done a lot of work, starting from the process, equipment and quality of the vials, and finally solved the long-standing problem.


2. Reasons for equipment manufacturing


At present, there are still many deficiencies in the domestic freeze-drying machine. Some enterprises are still imitating the structure of foreign freeze-drying machine, and do not have a thorough understanding of the design and manufacturing principles. There is no unified standard due to different comprehensive technical quality, design structure and manufacturing process. The shelf flatness of some manufacturers' products is not good, especially for the shelf with large area, the pressure distribution is not uniform when pressing after the freeze-drying, resulting in individual bottles being crushed.


3. The quality of the vial itself


This is an important factor affecting the broken rate of freeze-drying bottles. We know that before filling, the vials need to undergo ultrasonic cleaning and high-temperature sterilization to remove heat sources. No matter which process, it is a test for the vials. The intensity of ultrasonic wave and the impact of water vapor will have a certain impact on the glass, and the uneven distribution of tunnel oven temperature is easy to produce sudden heat and cold, which is a major damage to the quality of the vials. Although the appearance of the bottle may not be visible to the naked eye, it may produce tiny cracks that are insufficient to withstand the temperature changes during the subsequent freeze-drying process. We have been using imported helvoet vials all the time, and occasionally broken bottles have happened, but almost negligible. Later, considering the cost problem, we began to investigate the samples of vials provided by many domestic manufacturers. We found that under the premise of the same process, various domestic vials had different degrees of broken bottles, some of which even reached more than 10%. However, the broken rate of the best domestic bottles was far from that of imported ones.


4. Influence of freeze-drying process


In general, the glass bottle has a large temperature tolerance range when it is evenly heated, such as baking in an oven or freezing in an environment of minus dozens of degrees Celsius. However, if the temperature of different parts of the same bottle (especially the bottom of the bottle) changes suddenly, resulting in relatively large temperature difference, all parts of the bottle will be subject to different expansion forces. When the force exceeds the bearing capacity of the glass, the glass will be damaged. This is very easy to happen in the process of freeze-drying.


When we freeze-drying a certain antibiotic, we start by placing the preparation bottle on the shelf in the drying box of the freeze-drying machine. The shelf is filled with heat-conducting medium, and the temperature is controlled by external equipment. In the pre freezing period of the product, since the temperature is reduced at atmospheric pressure, the heat transfer is conducted in three ways: conduction, convection and radiation. The temperature difference between each part of the glass bottle is not large, so the glass bottle will not be broken. Due to the low vacuum state, the heat transfer is mainly in the form of radiation and conduction, and the convection effect is very weak and can be ignored. The heating of the shelf will directly act on the upper part of the glass bottle, and the heat radiation of the upper shelf to the products only acts on the upper part of the glass bottle. However, when the conduction heat conduction is blocked, the radiation heat conduction is weak, and the convection heat conduction is almost nonexistent, the original low-temperature state is basically maintained at the bottom of the glass bottle and the bottle body. The temperature of the bottle is the lowest because of the heat absorbed by the sublimation of water. At this time, the lower the pressure, the faster the temperature rise, the higher the thickness of the grain, the greater the temperature difference, and the stronger the stress on the bottle wall. Furthermore, those glass bottles with poor quality or defects will first come off the bottom and break. The number and degree of fragmentation are related to the rate of temperature difference.


The key to solve the problem of fragmentation and debinding is to reduce the temperature difference of each part of the glass bottle. In the freeze-drying process curve, the temperature line interval between the shelf temperature curve and the sample temperature curve is reduced. This can be achieved by vacuum control and temperature control in practice.


The samples were pre cooled to 20 ℃ below the eutectic point and kept at a temperature of 1 hour. When the condenser temperature reached below - 60 ℃, the whole system was vacuumed. After reaching the preset value, the heating and drying began. At this time, the shelf temperature is set to be 15 ℃ higher than that of the sample. Meanwhile, the main butterfly valve is adjusted to increase the steam pressure in the drying chamber, so as to strengthen the convective heat transfer, accelerate the heat transfer process, and make the sample temperature rise with the shelf temperature. When