Aseptic filling equipment can be complicated to operate but is the safest option for manufacturing parenterals that cannot undergo terminal sterilization.
The goal of any aseptic filling process is to completely eliminate microorganism and particulate contamination. While an aseptic filling process can be expensive and complicated to set up, it is necessary for products which cannot be terminally sterilized. Parenteral products bypass many of the body’s natural defenses, and so must be processed with great care in order to ensure patient safety. Below are three main concerns when setting up an aseptic filling process.
An aseptic filling line begins with sterile materials and containers.
Heat, radiation, filtering, and ethylene oxide are all ways to sterilize materials before processing. Each method has advantages and disadvantages, and which method is right will depend on the materials to be processed.
- Heat and radiation are simple and effective against microorganisms as well as endotoxins, but can have a destabilizing effect on many materials.
- Filtering is effective against microorganisms, but the materials must first be dissolved in water for injection, and filtering cannot protect against endotoxins. Further, filtering is not useful for solutions with particles larger than .2 microns.
- Ethylene oxide gas can provide sterilization for materials which cannot be dissolved, heated, or irradiated, but requires a process to keep levels within regulations in the final product.
Sterile containers are also a necessary aspect of aseptic filling. The most common types are glass and plastic. Those working with glass containers should pre-sterilize them through washing, then expose them to dry heat for sterilization. Because heating can deform plastic containers, they should be sterilized with either radiation or ethylene oxide. Again, the process must ensure that residual ethylene oxide is within acceptable limits.
Train aseptic filling line operators to minimize direct intervention.
Personnel present the greatest risk of contamination. It is up to pharmaceutical manufacturers, therefore, to design lines with minimal human intervention, and train operators in proper cleanroom behavior. Each operator should have a clear understanding of hygiene and gowning, as well as training in microbiology and the risks posed to patients by nonsterile products.
Finally, it is essential that training include highly specific written procedures covering operations within the aseptic manufacturing area, including the use of either isolators or restricted access barrier systems.
Operate sterile equipment and machinery using techniques that avoid contamination.
The most complicated part of any aseptic filling process is ensuring an aseptic environment. Either an isolator or a Restricted Access Barrier System (RABS) can achieve an ISO 5 cleanroom environment which will meet regulatory requirements.
Isolators are completely enclosed, stainless steel systems with unidirectional, HEPA-filtered airflow provided. Glove ports and half suits allow access for operators, and mouse-holes, airlocks, and rapid transfer ports provide access for sterile containers, stopper components, and monitoring instruments.
The major advantage isolators have over RABS is that decontamination of the system is an automated process using hydrogen peroxide vapor. The major disadvantage, however, is that changeover in an isolator is difficult, so they are best-suited for lines creating one product continuously.
RABS offer reduced start-up and changeover times, and allow for easier renovations. According to the FDA, a RABS must have barriers to prevent human intervention, especially in the critical zone; airflow for an ISO 5, at least in the critical zone; glove and transfer ports for interventions; high-level disinfection; and well-defined and highly automated procedures for the rare cases of open-door intervention.
Because RABS are not as separate from their surroundings as isolators, these best practices ensure a contaminant free production line:
- No open-door interventions – if the barriers become compromised during production, the whole batch must be eliminated and the entire line cleaned.
- Thorough disinfection – after each batch, the operators must open the barriers for cleaning and disinfection with sporicidal solutions.
- Check glove integrity – A pressure-decay test can indicate the level of wear and tear on the gloves. Even the smallest damage can compromise the entire system. The gloves should then be decontaminated and replaced in the glove ports.
- Aseptic transfer systems – Materials and packaging only move in the ISO 5 area using aseptic transfer systems. They must be sterilized in one of the above-mentioned ways and double-packaged. The outer package is sterilized with alcohol, moved through a lock, where an operator removes the package through glove ports, and moves the materials through to the ISO 5 area.
Though aseptic filling requires great care and forethought to set up, it is absolutely necessary for products which for one reason or another cannot be terminally sterilized. Because parenterals bypass the body’s natural barriers, they present a great risk for potential patient infection. A well-designed aseptic fill line with well-trained personnel is therefore essential for patient safety.