Yingtai: Enhancing Lyophilization Efficiency - Choosing The Right Freeze-Dryer

Yingtai: Enhancing Lyophilization Efficiency - Choosing the Right Freeze-Dryer

Introduction: Enhancing lyophilization efficiency can reduce the cost of products, which can enhance the competitiveness of pharmaceutical companies to a certain extent. Especially for national centralized procurement items, the cost of a single product may determine the survival of a company.

Main Text: The first step in enhancing lyophilization efficiency is to select the right lyophilization parameters. Taking conventional chemical drugs as an example, the product temperature should approach the collapse temperature as closely as possible to ensure that the product sublimates more efficiently while meeting quality requirements. It is important to note that a higher product temperature does not necessarily mean a faster sublimation rate.

In the early stages of process design, various detection methods should be used to confirm the glass transition temperature and collapse temperature of the product, and then increase the shelf temperature to raise the product temperature to the desired level. However, parameters obtained may become ineffective during the scale-up process, commonly seen in product melting. If this problem is not encountered, my personal view is that the lyophilization parameters are not aggressive enough, and there is still a lot of room for optimization in the lyophilization curve.

Taking a laboratory-scale freeze-dryer with an area of 0.5 square meters as an example, when only dozens of vials or hundreds of milliliters of drug solution are placed, the water vapor flow rate at the maximum allowable product temperature is much lower than that under full load conditions, and the given shelf temperature will also be higher. If only the product temperature is used as a reference, when the product temperature under full load reaches the maximum allowable temperature, the sublimation rate may be lower than that when only dozens of vials or hundreds of milliliters of drug solution are placed, and the given shelf temperature under full load is also too low. The apparent factor causing this situation is that the water vapor concentration in the front chamber reaches its limit, and the sublimation of water vapor from the product is hindered. The energy transferred from the shelf to the ice crystals does not cause more ice crystals to sublimate, and the energy accumulates in the product, causing the product temperature to rise.

When it comes to commercial freeze-dryers, increasing the shelf temperature to speed up the sublimation rate of ice crystals, when the water vapor concentration in the front chamber reaches its limit, further increasing the shelf temperature will cause the product to melt. The front chamber water vapor concentration reaching its limit is inevitably due to the inability to further improve the transfer of water vapor from the front chamber to the condenser. The lyophilization process is a process of heat and mass transfer, dividing lyophilization into four processes:

1. The shelf transfers energy to the ice crystals: In this process, as long as the energy provided by the shelf is high enough, the energy absorbed by the product is also high enough.

2. Ice crystals absorbing energy sublimate and overflow from the product to the front chamber: In this process, the more energy the ice crystals absorb per unit of time, the greater the amount of sublimation per unit of time, and the faster the sublimation rate, until the front chamber reaches the saturated vapor pressure, and the rate of water vapor overflowing from the product equals the rate of water vapor returning to the product, at which point the energy absorbed by the ice crystals in the product cannot be released, and the product temperature rises rapidly.

3. Water vapor in the front chamber flows to the condenser: Water vapor always moves in the direction of lower energy, and the driving force comes from the low temperature of the condenser. The greater the temperature difference between the front chamber and the cold trap, the faster the speed of water vapor flow, until it reaches the limit, such as the speed of sound or close to the speed of sound. At this point, the amount of water vapor passing through the front chamber and cold trap channel per unit cross-sectional area is consistent. To further increase the water vapor flow rate, it is only possible to increase the cross-sectional area of the box trap channel.

4. Water vapor concentrates on the surface of the condenser: Water vapor attached to the surface of the condenser does not stop moving because the temperature on the surface of the condenser is definitely different. For traditional condensers, the refrigerant in the coil is Freon, and the temperature at the bend of the coil is always lower than at the straight pipe. The water vapor attached to the straight pipe also moves towards the bend, and the macroscopic phenomenon is that the bend has thicker ice.

In the above four stages, the ice capture rate limited by equipment performance is stages three and four. First, the box trap channel of conventional freeze-dryers is often at its limit due to the mechanical strength of the freeze-dryer, and it is almost impossible to further increase the cross-sectional area of the box trap channel. At this time, as a user, I hope that the pharmaceutical machinery factory can introduce a freeze-dryer that surpasses the conventional structure and can effectively increase the cross-sectional area of the box trap channel. Second, the ice capture efficiency and total ice capture of the condenser are other factors in improving efficiency. A large amount of water vapor continuously concentrates on the surface of the condenser, and ensuring that water vapor is continuously and rapidly captured requires a larger windward area in contact with the water vapor and a low temperature that can still be stably maintained. When multiple batches of lyophilization are not defrosted and sterilized between batches, I would like to see that the ice on the surface of the condenser does not cause too much or basically no effect on the lyophilization rate of subsequent batches. Therefore, I hope that the freeze-dryer uses a more reasonable design, a condenser structure that can greatly increase the windward area, and can maintain a stable low temperature. When the performance and layout of the lyophilization system are exactly the same, how to dig out the last bit of potential to continue to reduce costs, consider the loading quantity of the same freeze-drying area, and use a reasonable loading method to produce more products in the same unit production cycle. Due to the influence of processing technology and the limitations of mechanical strength, it is difficult to continue to increase the length and width of the shelf after reaching the upper limit. The appropriate length and width matched with the product loading are all within the maximum allowable length and width of the shelf. For small bottle lyophilization, this method basically cannot improve efficiency, but for lyophilization of tablets, the number of blisters on the large blister board is different according to different designs, and the unit area of blisters is different. A reasonable blister layout increases the product loading quantity per unit freeze-drying area, and obtaining more products in the same freeze-drying cycle is also a way to improve efficiency. Finally: The above expectations for the freeze-dryer only represent personal opinions. Improving lyophilization efficiency through the above methods is only limited to conventional chemical drug small bottle lyophilization with large drug liquid thickness, bulk drug lyophilization, lyophilization of tablets, and spray lyophilization. It is not suitable for products such as biopharmaceuticals, blood products, and vesicle-encapsulated products, which have a great impact on product efficacy due to stress. For these products, maximizing the elimination of stress on efficacy has determined the slower sublimation rate control in the lyophilization process, and the water vapor flow rate is far below the limit of the freeze-dryer's performance.