Phenomenon 1: Excessive water content
The water content specified in the quality standard for freeze-dried powder injection is relatively low. The main reasons for its water content exceeding the standard are: too much liquid medicine is loaded into the container, and the liquid medicine layer is too thick; Insufficient heating during the drying process reduces its evaporation capacity; Insufficient vacuum prevents the smooth discharge of water vapor; The temperature of the condensation chamber is too high to effectively capture water vapor; The freeze-drying time is relatively short; The air humidity of the vacuum drying oven is high; When leaving the box, the temperature of the product is lower than room temperature, resulting in moisture absorption of the product.
Measures: Production personnel must take corresponding solutions for different reasons. If the specifications of penicillin bottles are adjusted according to the volume of the drug solution to reduce the filling thickness, it should generally be controlled within 10-15mm; Strengthen heat supply and promote water evaporation; Check the cause of low vacuum and eliminate any leaks or abnormalities in the vacuum system; Reduce the temperature of the condenser below -60 ℃; Re develop the freeze-drying curve to ensure that the moisture content of the freeze-drying product is qualified; The gas placed in the box should be sterilized, dehydrated, and dried, especially for products that are prone to moisture absorption; The temperature when the product is shipped out should be slightly higher than the production environment temperature.
Phenomenon 2: Spray bottle
Spray bottle is due to the temperature not reaching the co melting point of the product during pre freezing, resulting in incomplete freezing of the product; During sublimation drying, if the temperature rises too fast, local overheating occurs, and some products dissolve into liquid. Under high vacuum conditions, a small amount of liquid is sprayed from the surface of the dried solid through the pores to form.
Measures: In order to prevent bottle spraying, the pre freezing temperature should be strictly controlled between 10 ℃ and 20 ℃ at the co melting point, and maintained for more than 2 hours to allow the drug to freeze and solidify before heating up. At the same time, the heat supply during sublimation drying should be well controlled, the heating rate should be appropriately slowed down, and the temperature should not exceed the co melting point. This can overcome the phenomenon of bottle spraying.
Phenomenon 3: Unqualified appearance
The normal appearance of freeze-dried powder needles should be uniform in color, with dense pores, maintaining the volume and shape before freeze-drying, and forming a block or sponge like block structure. However, if the weight concentration of the solution is greater than 30%, the product is prone to shrinkage, collapse, and fullness. In addition, during drying, the frozen surface first dehydrates to form a structurally dense dry shell, and the sublimated water vapor below escapes from the gaps between the molecules on the dried surface. At this point, if the concentration of the solution is too high, the gap between molecules is small, the ventilation is poor, the resistance of water vapor passing through is large, and a large number of water molecules cannot escape in time. The stagnation time in the drying layer is long, causing some dried drugs to gradually deliquescence, which will cause the volume of the product to shrink, and the appearance may not be full or collapse. If the weight concentration of the drug solution is less than 4%, the drug will fly away with the water vapor during vacuum pumping; Or, after drying, it becomes a fluffy and loose structure. After releasing the vacuum, the substance of this structure will dissipate, causing the product to become hollow. Another situation is that the concentration of the drug solution is too low, making the product loose and prone to moisture. At the same time, due to the large specific surface area, the product is prone to shrinkage. The mechanical strength of the dried product is too low, and once vibrated, it disperses into powder and adheres to the bottle wall.
In terms of freeze-drying technology, if the thickness of the drug solution is greater than 20mm and the drying time is extended, it will also cause the appearance of the product to be unqualified. In addition, at the beginning of freezing, the cooling rate is fast, causing the product to form fine crystals with high density and resistance to sublimation. Water is not easy to evaporate, and the product will gradually deliquescence, causing volume shrinkage and resulting in an incomplete or clumpy appearance. If the freezing speed is too slow and the ice crystal grows for a long time, it is prone to concentration, resulting in separation of drugs and solvents, and uneven structure of the finished product.
Measure: Reasonably design the formula of freeze-drying solution. It is generally recommended to have a weight concentration between 4% and 25%, with an optimal concentration of 10% to 15%. If the concentration is lower than 4%, excipients (such as Mannitol, Dextran, lactose, etc.) can be added appropriately. If the concentration is high, the thickness of the freeze-dried product must be controlled, or the concentration must be reduced, and a large container must be used to fill the liquid medicine. During the freeze-drying process, the cooling rate should be controlled to decrease by 5 ℃ to 6 ℃ per hour. In the first stage of sublimation drying, the temperature of the product should be lower than the co melting point, and the heating should not be fast, controlled at around 5 ℃ per hour. If the heating is too fast, when there is a large amount of water in the product, the temperature exceeds its melting point, which will cause the product to melt and cause appearance defects. In the second stage of sublimation, although the water content in the product is already low and the heating rate can be appropriately increased, the temperature should be controlled below a safe temperature, otherwise there may be agglomeration. In addition, the airtightness of product packaging is not good, and there may be appearance or even internal quality defects within the validity period.
Phenomenon 4: Cold explosion and bottoming of products
The main reason is that the pre freezing stage did not freeze the product firmly. If the product is not yet fully frozen, the system begins to vacuum the box. When the pressure reaches a certain value, the unfrozen part begins to evaporate and boil, causing heat release. The temperature of the product drops sharply, and when it reaches the eutectic point temperature, the product freezes, leading to bottle explosion and bottoming. As the pressure continues to decrease, the temperature also decreases accordingly. The vacuum pump of a general freeze-drying machine can reach below 0.1 Pa, which means that the temperature of the medicine inside the box can reach around -60 ℃. Due to the lack of evaporation and freezing characteristics between the bottom and lower layers of the penicillin bottle, it cannot withstand such a large temperature difference in a short period of time, resulting in the cold explosion and bottom detachment of the penicillin bottle.
Measures: To solve the problem of cold explosion and bottom detachment, production personnel need to strictly implement the pre freezing parameters, confirm that the products are frozen solid, and then vacuum them.
