Nitrogen Application

In The Sterile Liquid Bottle Filling and Capping Machine

In the pharmaceutical industry, raw materials such as APIs, inactive ingredients and other chemicals that may be sensitive to oxygen need to be kept in an inert atmosphere to prevent exposure to oxygen and subsequent deterioration due to oxidation. Nitrogen has almost inert gas properties, nitrogen is difficult to easily react with other elements, and "resources" are abundant, after all, the air in the atmosphere is composed of 78% nitrogen and 21% oxygen. Therefore, in the production process, nitrogen is used to replace the air in the packaging material or container void space to increase the stability/shelf life of the drug.

Common nitrogen-filled form
Aside from the method of filling the production environment with nitrogen (in the isolator) and the product storage environment with nitrogen (nitrogen backup pressure in the tank), for the current aseptic filling equipment of Xilin bottles, the common forms of nitrogen filling are needle nitrogen and nitrogen covered tunnel (or wind curtain). According to the design standards of different manufacturers, the nitrogen charging step can be designed as:

1. Before the Sterile Glass vial bottle enters the filling station, the nitrogen filling device fills nitrogen into the bottle and then carries out the aseptic filling, that is, nitrogen is filled before filling.
2. There are also special filling needle designs, filling while filling nitrogen;
3. After filling is completed, the nitrogen purge is carried out on the remaining headspace (headspace) in the bottle that has not been filled, and then the plug is carried out to ensure that nitrogen is sealed in the container. 4. This process is nitrogen filling after filling.
5. Nitrogen filling can be affected by several factors, such as:
6. The volume of the container in which the product is filled, such as a Sterile Glass Vials bottle
7. The volume of liquid (or powder product) filled

Filling production rate
Flow pressure of sterile nitrogen
At a specified flow pressure or velocity, the volume of nitrogen displaces oxygen in the bottle or in the remaining space at the top after filling.
Usually, the requirement for residual oxygen is 2% to 4%, but, without talking about the dissolved oxygen factor of the product here, to achieve the same proportion of residual oxygen, the smaller the headspace volume of the product, the more difficult it is to achieve. To improve the nitrogen-filling effect, we should also pay attention to some easily ignored "dead zones", such as the air carried by the water needle rubber plug, if it is not treated, the air in the rubber plug "groove" will be brought into the bottle during the tamping process, which may affect the final required amount of oxygen residual.

Sterility assurance considerations
Because the nitrogen filling device of the filling machine introduces additional "media" in direct contact with the product in the aseptic core process area, there is a potential pollution risk, so the sterilization and pollution control means of nitrogen itself need to be paid attention to. At the same time, nitrogen-filled parts should also be effectively sterilized as indirect contact parts of the product, and whether nitrogen-filled parts can be VHP "sterilized" in the isolator has also been described before.
In addition, aseptic process simulation (medium filling) is used to simulate the entire aseptic production process to assess the aseptic confidence of the process. Process simulation studies include formulation (preparation), filtration and filling with suitable media. To ensure that commercial batches of conventional processes repeatedly and reliably produce finished products of the required quality
I remember that just a few days ago, from some public accounts, it was also seen that the central flight inspection of a company's deviation "liquid aseptic filling before and after the use of nitrogen filling process (to eliminate the impact of oxygen on the product), the culture medium simulation filling test uses the milk cheese and soybean peptic liquid medium for stereaseptic confirmation, and does not evaluate whether the anaerobic culture medium simulation filling test is used."
For a filling machine with a nitrogen filling device, or even a nitrogen filling design in an isolator environment, attention should be paid to evaluating the effect of the anaerobic environment brought about by nitrogen filling on the aseptic operation and evaluating the need to use an anaerobic medium, such as chocolate liquid medium (FTM) or another suitable medium, when doing a simulated filling of the medium. If anaerobic microorganisms are repeatedly found in the anaerobic aseptic process environment monitoring or the product sterility inspection, the need for additional anaerobic media should be evaluated.