Aseptic filling of sterile drugs is still one of the most critical processes in the production of biologic drugs, as the end user, a patient, is at risk. Given that the performance, quality, and stability of biologic drugs can be negatively affected by methods like autoclaving, dry sterilization, ethylene oxide sterilization, or gamma cobalt 60 radiation, terminal sterilization (sterilizing the drug in its final container) cannot be used. Therefore, biologic and biotechnological drugs are filled aseptically (microbe-free).

To help ensure the stability of the aseptic process, the Parenteral Drug Association (PDA) released its Aseptic Validation Technical Report in 1981. This was further supported by the U.S. Food and Drug Administration (FDA) in 1987 through the development of guidelines for aseptic processes. The International Society of Pharmaceutical Engineering (ISPE) published a list of sterilization equipment as part of their guidelines in 1999, and the FDA later issued final aseptic guidelines in 2003.

Aseptic filling requires close coordination and complex interaction between trained personnel (wearing sterile clothing), the sterile product (through final filtration), filling equipment (which must be thoroughly sterilized before the filling process), clean room facilities (with HEPA filters, Class A under the filling equipment and Class B in the filling room), and supporting equipment (controlling temperature, humidity, and pressure).

Forms of Biologic Drugs

Biologic drugs are primarily filled in two forms: liquid and lyophilized powder.

1- Liquid Form

In the liquid form, biologic drugs are either filled in pre-filled syringes (PFS) or in vials.

1-1- Prefilled syringes(PFS)

While the most conventional form of injectable drug administration involves the classic combination of a vial and a subcutaneous needle, recent innovations have led to advancements in drug injections. Among the most significant developments are prefilled syringes (PFS), which have become an extremely popular method for drug injection over the past few decades.

With a prefilled syringe, the injection process for a pharmaceutical product can be safer, faster, and easier for both nurses and patients. The prefilled nature of these syringes means that nurses or patients do not need to prepare or draw the drug into the needle themselves, as the correct amount is already preloaded into the syringe, ready for a quick injection. This significantly reduces the likelihood of errors in drug preparation and administration.

(Vial) 1-2-

Vials are glass containers used for storing drugs in both liquid and powder forms, and they come in various sizes.

1-3- Lyophilized Powder

Lyophilization (freeze-drying) is a process in which a liquid is transformed into a solid through sublimation and removal of water or other solvents. This process consists of three interrelated stages: freezing, primary drying, and secondary drying. Lyophilization is often used to stabilize active pharmaceutical ingredients (APIs) and formulations that are unstable in liquid or frozen form. Since lyophilization does not require heat, it is an ideal drying method for heat-sensitive APIs and biologics like proteins and peptides. The lyophilization of pharmaceuticals takes place in trays inside a lyophilizer with controlled temperature and pressure. Within a lyophilizer, there are various components that allow for precise control of temperature and pressure, guiding the process steps.

1-3-1. Freezing

During the freezing stage, the water in a product gradually freezes by forming ice crystals, which facilitates the sublimation process. Freezing is the most critical step in the lyophilization process as the crystalline structure created affects all subsequent activities. For example, a slower freezing rate may create smaller ice crystals and protect the pharmaceutical product from damage caused by crystal growth, but it may result in longer primary and secondary drying cycles.

1-3-2. Primary Drying

In the primary drying stage, the pressure is reduced to directly convert water from solid to gas, and the temperature is slightly increased to counteract the cooling effects of sublimation, ensuring that the product temperature remains stable. Continuous contact between the surfaces (vials and shelves) is essential for maintaining consistent heating, which is why many lyophilized products are packaged in vials with flat bottoms to maximize surface contact. In this phase, about 95% of the water is removed, and the product largely becomes a dry powder.

1-3-3. Secondary Drying

Once primary drying is completed, some moisture may still remain in the product, and secondary drying is used to remove it. During this process, the lyophilizer shelf temperature is gradually increased under low pressure, with the rate and extent of temperature increase depending on the product being lyophilized. Ultimately, the goal of secondary drying is to achieve a moisture level of 0.5 to 3 percent, depending on the product. For many products, residual moisture below 1% is ideal, as lower moisture extends shelf life. However, some biologics may exhibit optimal stability with moisture levels between 1% and 3%.