1. Introduction

In recent years, the development of vacuum freeze-drying technology in China has been very rapid. After more than a decade of market competition and optimization, there are now more than ten specialized manufacturers of freeze-dryers. The technical performance of freeze-dryers for pharmaceutical use has basically matured, and corresponding industry standards have been established in the country.

Currently, the two freeze-dryers used by North China Pharmaceutical are products from BOCEDWARDS in the UK (put into use in 1998) and Shanghai Dongfulong Technology Co., Ltd. (put into use in 2002). After several years of comparison, there is no significant difference in the overall performance and stability of the machines, and the quality indicators of the final products are also basically comparable. It can be seen that the products of well-known domestic brands can completely replace imported equipment. From the issues observed in actual production, since the adoption of domestically produced vials, the problem of vial breakage during the freeze-drying process has become relatively prominent. As a result, relevant departments have done a lot of work, starting from the process, equipment, and the quality of vials, and have finally solved this long-standing problem.

2. Reasons for Equipment Manufacturing

Currently, domestic freeze-dryers still have many shortcomings. Some enterprises are still imitating the structure of foreign freeze-dryers without fully understanding the principles of design and manufacturing. Due to differences in overall technical quality, design structure, and manufacturing processes, there are no unified standards. Some manufacturers' products have poor shelf flatness, especially for larger shelves. During the stoppering process after freeze-drying, uneven pressure distribution can lead to breakage of individual vials.

3. Quality of the Vials Themselves

This is an important factor affecting the breakage rate of freeze-drying vials. We know that vials must undergo ultrasonic cleaning and high-temperature sterilization to remove heat sources before filling. Each step is a test for the vials. The intensity of the ultrasonic cleaning and the impact of water vapor can have a certain effect on the glass, while uneven temperature distribution in the tunnel oven can easily cause sudden heating and cooling, which can cause significant damage to vials of poor quality. Although the changes in the vials may not be visible to the naked eye, they may produce tiny cracks that are insufficient to withstand the temperature changes during the subsequent freeze-drying process. We previously used imported HELVOET vials, and breakage incidents occurred occasionally, but they were almost negligible. Later, considering cost issues, we began to investigate samples of vials provided by various domestic manufacturers and found that under unchanged processes, vials from different domestic manufacturers exhibited varying degrees of breakage, with severe cases reaching over 10%, while the breakage rate of relatively good domestic vials was still far from that of imported vials.

4. Impact of Freeze-Drying Process

While examining the quality of the vials, we focused on analyzing the reasons for breakage from the perspective of the freeze-drying process. Generally, glass vials have a large temperature tolerance range when heated evenly and do not break, such as when baked in an oven or frozen in an environment of several tens of degrees below zero. However, if different parts of the same vial (especially the bottom) experience sudden cooling or heating, forming a relatively large temperature difference, different expansion forces will act on various parts of the vial. When this force exceeds the glass's tolerance, it will inevitably lead to glass damage. This situation can easily occur during the freeze-drying process.

When freeze-drying a certain antibiotic, the formulation vials are placed on the shelves inside the freeze-dryer. The shelves are filled with a heat transfer medium, and the temperature is controlled by external equipment. During the pre-freezing period, the temperature is lowered under atmospheric pressure, and heat transfer occurs through conduction, convection, and radiation. The temperature difference between different parts of the glass vials is small, and generally, it will not cause the glass vials to break. Since the process is conducted under low vacuum, heat transfer mainly occurs through radiation and conduction, with convection being very weak and negligible. Heating the shelves directly affects the upper part of the glass vials, and the thermal radiation from the upper shelf only acts on the upper part of the glass vials. The formulation column, being obstructed in heat conduction and receiving weak radiation heat, with almost no convection heat transfer, basically maintains its original low temperature, resulting in a temperature difference between the bottom and the body of the glass vial. At this time, the lower the pressure, the faster the temperature rises, and the thicker the formulation column, the greater the temperature difference, leading to stronger stress on the vial walls. Consequently, those vials of poorer quality or with defects will be the first to detach from the bottom and break, with the number and degree of breakage related to the temperature difference and the rate at which the temperature difference is formed.

The key to solving the breakage and detachment problem is to reduce the temperature difference between different parts of the glass vials. This is reflected in the freeze-drying process curve by narrowing the temperature line gap between the shelf temperature curve and the sample temperature curve. In practical operations, this can be achieved through vacuum control and temperature control.

First, cool the sample to 20°C below the eutectic point and maintain the temperature for 1 hour. When the condenser temperature reaches below -60°C, the entire system is evacuated. Once the predetermined value is reached, heating and drying begin. At this time, the shelf temperature is set to be 15°C higher than the sample, while adjusting the main butterfly valve to increase the steam pressure in the drying chamber, which helps enhance convective heat transfer, accelerates the heat transfer process, and promotes the sample temperature to rise along with the shelf temperature. When the pressure increases, closely monitor the changes in gas pressure and temperature to ensure that the temperature difference between the sample and the shelf remains within the range of 10 to 15°C. At this time, the temperature curve of the sample should be accelerated to approach the eutectic point, rapidly sublimating around 5°C below the eutectic point, thus completing the main drying.

After the main drying of the formulation is basically completed, rapid heating can be applied to bring the shelf temperature directly to the set value. Because the moisture inside the glass vials has been mostly sublimated, the factors affecting temperature equalization no longer exist. Even if the temperature difference exceeds 20°C, it will not cause the glass vials to break. Once the shelf temperature curve coincides with the sample temperature curve, insulation drying can be performed, completing the entire freeze-drying process.

Through more than a year of practical work in freeze-drying, using the above methods to adjust the temperature and ensuring that the temperature difference between the sample and the shelf is less than 15°C during the sublimation process, we have shortened the freeze-drying cycle while completely solving the problems of glass vial breakage and detachment during the freeze-drying process. Below is the statistical data on the breakage rates of several types of vials used by North China Pharmaceutical before and after process adjustments (a total of 10 batches, each batch approximately 15,000 vials).