Usually, the requirements for raw materials and excipients of small-volume injections are consistent with those of large-volume injections. Injection raw materials are generally required to use injection-grade specifications. If the requirements are not met, they can be refined by themselves to meet the injection-grade requirements; injection raw materials and excipients have control requirements for microbial limits, pyrogens, etc. For liquid preparations that cannot be sterile filtered and sterile powder injections that are directly packaged, sterile-grade raw materials and excipients must be used, and liquid preparation and sterile filling production must be carried out according to aseptic processes; for products that cannot be terminally sterilized after filling, aseptic filling (or packaging) production must also be carried out according to aseptic processes. If the product can withstand terminal sterilization conditions, the terminal sterilization process should be used first, and the aseptic process should not be used to replace the terminal sterilization process. At the same time, the raw materials and excipients for injection must be weighed in the clean area to avoid environmental contamination; according to the physical properties and biological activity of the raw materials and excipients, their weighing should be completed in a completely independent area (independent airflow protection and dust capture). According to the requirements of the feeding environment level or the results of the process risk assessment, select a Class D, Class C or Class A weighing environment. Sterile materials are weighed in sterilized containers under Class A conditions, and then transferred to liquid containers under Class A cleanliness level. The background environment must meet the requirements of Class B cleanliness level. Since the air may contain dust (from solid materials) or particles, which may affect personnel, personnel must be protected during the material handling process; when weighing sterile materials, personnel clothing must meet the requirements of Class B cleanliness level, which not only reduces the risk of personnel to the sterility of materials, but also plays a role in protecting personnel.
There are two methods for weighing raw and auxiliary materials: one method is to set up a raw and auxiliary material processing, weighing and zeroing room with the same clean level as the production environment near the raw and auxiliary material warehouse, take out the raw and auxiliary materials required for production from the warehouse, weigh and pack the raw and auxiliary materials according to the product prescription and production batch, and seal the packed raw and auxiliary materials in double-layer plastic bags and place them in covered plastic barrels, and send them to the weighing room in the production area for review and confirmation, feeding and liquid preparation according to the feeding amount of each batch. The other method is to take out a certain amount of raw and auxiliary materials from the warehouse according to the packaging size of the raw and auxiliary materials, place them in the raw and auxiliary material temporary storage room in the production area, take out the raw and auxiliary materials required for the batch production from the raw and auxiliary material temporary storage room according to the batch production instructions, select the metering device with appropriate accuracy under the unidirectional flow in the weighing room of the production area to weigh and check the raw and auxiliary materials respectively, and store them in double-layer plastic bags and seal them for standby use.
For terminally sterilized small-volume injections, general filling and sealing can be carried out in a Class C environment. For terminally sterilized products with high contamination risks, filling and sealing are generally required to be carried out at a local Class A under a Class C background. For non-terminally sterilized liquid filling (such as freeze-dried powder injection products), since it is impossible to sterilize the filled product, this type of filling operation must be carried out at Class A under a Class B area background. Considering the particularity of the aseptic production process, material transfer generally requires closed transfer under a Class B background, or transfer under a B+A environment. Non-terminally sterilized liquid filling must be carried out in a sterile environment, and an automated filling system should be used as much as possible. If the automated equipment is installed in an isolator, the risk of contamination will be minimized and the environmental level of the background area can be reduced. ①Process introduction: For aseptic filling process, vials/ampoules under the protection of Class A area (or RABS) are conveyed into the filler; various instruments (such as filling needles, filling hoses, and filling pump components) have been sterilized in the temporary storage room of instruments. The inner packaging is opened in the unidirectional flow Class A area or RABS, the inlet pump of the filler is connected, and the filler is started. The rubber stopper is transferred to the stopper, and the rubber stopper is poured onto the stopper under unidirectional flow or RABS; the semi-stoppered vials are sent to the freeze dryer under the protection of unidirectional flow; after the feeding is completed, the plate probe is inserted, the freeze dryer door is closed, and the freeze drying process is carried out according to the specified freeze drying curve; after the freeze drying is completed, the door of the drying box is opened, and the fully plugged dry semi-finished products are taken out from the freeze dryer drying box from bottom to top under the protection of unidirectional flow, and sent to the capping buffer table. The processes of vial liquid filling, half-stoppering, freeze drying, and capping can realize a fully automated linkage line, and the freeze dryer can adopt a fully automatic material transfer and inlet and outlet system. The liquid filling, liquid preparation process, and filling process of vials and ampoules are the same, but the sealing process is different: vials of liquid preparations require full stoppering and capping; vials of freeze-dried powder injection preparations require half stoppering, freeze drying, pressure stoppering, and capping; ampoule liquid preparations do not require stoppering and capping, and can be directly melt-sealed. For the filling of terminally sterilized products of ampoules/vials, strict aseptic processes are not required. For vial products that do not require freeze drying, the full stoppering process is adopted, and the capping is directly removed, and then the product is sterilized. For ampoule filling, stoppering and capping are not required. After filling, they are directly heated and melt-sealed, and then terminally sterilized.
