With the rapid development of biopharmaceutical technologies such as vaccines, antibodies, weight loss drugs, and injectable medical beauty products, and the increasing demand of consumers for self-administration, the market for ready-to-use packaging materials (RTU, Ready to Use Container) is growing rapidly, among which RTU prefilled syringes are the most widely used. RTU packaging materials do not require upstream cleaning and sterilization steps, with small initial fixed asset investment, flexible production, and simple use. They can reduce registration and approval and production time, allowing products to be put on the market faster. In the actual application of RTU packaging materials, the sterility assurance requirements in the process far exceed those of traditional bulk glass containers. Against this background, the risk link in the filling process of RTU packaging materials - sterility control during the bag opening process is becoming a challenging issue.
Article 4.10 of EU Annex 1 states that "equipment and materials entering and leaving clean rooms and critical areas are one of the major potential sources of contamination. Any activity that may compromise the cleanliness of clean rooms or critical areas should be evaluated and, if it cannot be eliminated, appropriate control measures should be implemented." Under this regulation and regulatory requirement, the No-Touch-Transfer (NTT) system is reshaping the quality and safety standards of biopharmaceutical production lines with its unique advantages.
RTU packaging materials are usually packed in honeycomb trays or trays to avoid collisions between glass and glass. Depending on the packaging format (such as syringes, vials and cartridges), the containers are pre-assembled and processed (such as cleaning and siliconization). RTU packaging materials for aseptic processing are pre-sterilized in their outer packaging by irradiation (gamma irradiation or other irradiation) or ethylene oxide gas treatment.
The currently generally accepted RTU packaging material delivery methods are:
Step 1
In the C-level area, wipe and disinfect the packaging material with the plastic outer bag with alcohol and place it on the C-level feeding conveyor;
Step 2
Under the protection of the A-level air supply in the C-level environment, cut the plastic outer bag of the package manually or automatically;
Step 3
Push it into the A-level environment without touching the outer bag near the transfer port (rat hole) of the A-level area and then fill it.
This method is acceptable in China at this stage, but as the supervision is aligned with the international standards, there are more and more challenges to the potential contamination risks of the nest box.
At present, the industry has successfully established two different methods to deal with the challenge of possible contamination of nest boxes.
▅ Non-contact transfer (NTT): The packaging is opened and removed gradually in an automatic or semi-automatic manner in a clean room with unidirectional airflow. Currently, single-layer or double-layer bag packaging is already available on the market.
▅ The nest boxes sealed with Tyvek breathing paper after unpacking are re-sterilized using different technologies. The currently recognized effective methods are:
- Electron beam irradiation (E-beam)
Achieve 6-log sterilization effect
- Vaporized Hydrogen Peroxide Sterilization (VHP)
Achieve 6-log sterilization effect
- Pulsed UV
Achieve 4-log sterilization effect
A basic requirement for NTT is reliable and durable bag opening technology and transfer system. Double-layer bags are becoming the mainstream packaging form because they have double safety and damage prevention functions to ensure the sterility of the nest box to a higher degree. In the past, the opening process of double-layer bags was usually manual. Because the inner bag is usually folded around the nest box, it must be unfolded before the inner bag opening process begins, otherwise it is not easy for the cutter to completely open the bag. Various automation solutions have also appeared on the market to avoid manual handling of bags, such as vacuum chambers, roller gripping, pressurized needle puncture, brush gripping, etc. In the design of the transfer system, the transfer systems for opening the outer/inner bags are independent of each other to avoid crossing. Before the inner bag is opened, the container is not exposed to the environment. Therefore, the external environment of the transfer part can be defined as Class C, with internal Class A air supply. The inner bag is opened at the rat hole as close to the Class A area as possible, and the exposed surface of the nest box is protected by Class A air from the isolator and quickly transferred to the Class A area.
There are currently many ways to deliver RTU packaging materials to the Class A filling area, and pharmaceutical companies need to carefully evaluate and decide based on their own production processes and SOPs. However, due to the advantages of NTT method, which can achieve high-speed production, no harmful substances remain, and is accepted by regulators, it will become the trend of aseptic process in the future.
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