Zero-Loss Aseptic Liquid Filling Isolator

Case Study

Project Scope

Our customer required the precise filling of small batches of ready-to-use (RTU) vials with expensive liquid drug substances in compliance with EU GMP Annex 1 regulations. It was crucial to offer the flexibility to accommodate various vial sizes and ensure high dosing accuracy while minimizing product loss.

Our Solution

We have designed our DecFill® - SB (Small Batch) aseptic filling line to be housed within a state-of-the-art high containment isolator. This isolator meets the rigorous standards required by the pharmaceutical industry, ensuring the highest level of quality and safety for our customers.

DecFill® - SB

Contamination Control

We offer essential contamination control strategies that are implemented throughout the entire filling process. Our equipment is specifically designed for cleanroom application (Grade C) to minimize human interaction and ensure compliance with cGMP regulations. Prior to commencing sterile production, the entire equipment undergoes decontamination using Vaporized Hydrogen Peroxide (VHP). The installation is equipped to conduct two types of VHP decontamination procedures: full isolator decontamination and decontamination for packaging materials in the Fast Gassing Airlock (FGA).

Utmost sterility is maintained throughout the entire filling process by implementing VHP decontamination in all chambers, including the filling and stoppering, tray off-loading, and capping chambers. Additionally, viable/non-viable monitoring systems are integrated to further enhance the aseptic environment. The filling line is strategically designed with a pressure cascade from the filling and stoppering chambers into both directions. The entire filling process is operated under positive pressure and unidirectional airflow at a certain air velocity to minimize air fluctuation and reduce particulate generation within the isolator.

4.30 The speed of air supplied by unidirectional airflow systems should be clearly justified in the qualification protocol including the location for air speed measurement. Air speed should be designed, measured and maintained to ensure that appropriate unidirectional air movement provides protection of the product and open components at the working position (e.g. where high-risk operations occur and where product and/or components are exposed). Unidirectional airflow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position, unless otherwise scientifically justified in the CCS. Airflow visualization studies should correlate with the air speed measurement.

Source: The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use

Key Objectives

Four key missions were crucial in successfully completing the project and achieving our objectives.

Objective # 1 – Zero product loss

With costly pharmaceuticals at stake, the main objective for this project was to maximize product yield and cost efficiency. Therefore, the accuracy and precision of the filling operation were vital components in achieving our goal.

To ensure high precision, we have provided a peristaltic pump liquid filling technique that offers an efficient and accurate solution for industries such as biopharmaceutical, diagnostics, and cGMP pharmaceuticals. This technique not only guarantees cleanliness and hygiene but also prevents product dripping from the needle, thus enhancing filling precision. The closed fluid path eliminates the risk of cross-contamination, further enhancing the quality of the filling process.

With a remarkable accuracy of ± 0.5 %, this filling technology does not cause foaming, splashing, and dripping between fills. Additionally, the peristaltic pump is highly versatile when it comes to the need of adjusting dosing volumes, making it a perfect solution for filling liquids into single-use and ready-to-use containers.

DecFill® - SB Filling Process

Objective # 2 – Flexibility to handle different vial sizes

Our production line is equipped to accommodate standard vial dimensions ranging from 2R to 100H. The tray unloading mechanism is versatile, allowing for seamless adjustment to different vial sizes without the need for part changes. Changeover procedures are designed for minimal tool usage. Operators have the option to manually change vial sizes. Changeover will necessitate a complete cleaning and sterilization of the equipment.

Objective # 3 – Minimal operator intervention

Before starting the filling process, the incoming bags containing the ready-to-use vial trays undergo decontamination. The bags are stacked on a rack inside the FGA chamber and the VHP (Vaporized Hydrogen Peroxide) cycle is initiated.

After debagging by the operator, the vial trays are manually pushed through a mouse hole from the FGA to the tray unloading section where they are picked up by the operator for Tyvek seal delidding. The tray is then placed on a rotating device, in which the tray is inverted to position the vials upright on a stainless-steel platform, from where they are pushed onto the Infeed Turn Table, which feeds the vials to the filling and capping process.

DecFill® - SB tray unloading chamber

This is a crucial section linking two important chambers – the FGA and the filling chamber – enabling operators to unpack RTU vials in a completely sterile manner. The rotating device and the infeed turntable allow operators to easily place vials upright on the platform and move them into filling position without any manual contact, reducing the risk of human errors and product damage.

Objective # 4 - Designing the Isolator with Side-mounted Filtration Units to Optimize Room Height Compatibility

In this challenge, we need to develop an isolator that incorporates filtration units positioned on the sides. This design approach is essential to ensure that the overall height of the unit remains within the constraints of the room's vertical space. Key considerations will include the dimensions and arrangement of the filtration systems, as well as ensuring efficient airflow and ease of access for maintenance, all while adhering to safety and operational standards.

Peristaltic Pump	Peristaltic pump suitable for single-use silicone tubing The stepper motor-controlled dispenser head creates the required accurate dosing of the liquid To prevent drops of product from falling off the needle and to maintain accuracy, the pump has a back system using a back step of the dispenser head
IPC Weight System	The weight of the empty vial is measured; Tare weight The weight of the filled vial is measured; Gross weight Nett weight will be calculated; Gross weight–Tare weight If the weight is below the target, the vial will be flagged as reject and the machine will stop to enable the operator to initiate a re-fill via HMI.
Infeed Turntable	Tray inverter designed for different vial sizes Infeed turntable, controlled by a Variable Frequency Drive
Containment System	UDF with air velocity optimized to 0,45 m/s at product container level To reduce the amount of air needed for the process, around 80% of the air is recirculated inside of the chambers, and only around 20% of fresh air is added to be able to control temperature and humidity  Operating under positive pressure from the outside environment (particle control) ·      Filling and stoppering chamber: 35 Pa ·      Tray off-loading chamber: 30 Pa ·      Tray gassing chamber: 25 Pa ·      Capping chamber: 25 Pa FGA for RTU vials packaging decontamination Integrated Viable/Non-Viable Monitoring System

Technical Details

Formats & Output

• Semi-/Automatic container placement

• Vials 2 – 100 ml

• Syringes 0.5 – 20 ml

• Cartridges 0.5 – 20 ml

• Max 60 vials per minute

• Indexing-intermittent container transport

• IPC/ Check weighing

• Stoppering and/or (screw)capping

• Audit trail/batch reporting

• GDP documented design verification

Line Configuration

DecFill® - SB Top-Down View

Fast Gassing Airlock

• VHP Decontamination of RTU vials package

Tray Unloading Section

• Off-loading RTU vials on the tray

Filling Section

• Infeed Unit: Turntable

• Main Transport Unit: Main Transport

• Liquid Filling Unit (Liquid Filling) + Weighing Unit (Tare/Gross weighing)

• Rubber Stoppering Unit: Rubber Stoppering

Capping Section

• Capping Unit: Alu Capping Placement & Sealing

• Reject Unit: Reject

Outfeed section

• Outfeed Unit: Tray loading

Conclusion

The Filling line is meticulously designed to handle various sizes of vials, ensuring sterile conditions throughout the processing and filling processes. Operated within an isolator, the system maintains stringent control over airspeed, pressure, and airflow direction to guarantee the highest level of product safety and quality.

Dec offers expert guidance on Contamination Control Strategies to minimize and eliminate particle contamination guaranteeing a sterile and aseptic filling process that prioritizes the safety of the product, operators, and patients. Our team of experts works closely with our clients to assess their specific needs and develop a comprehensive strategy that includes facility design, process validation and maintenance to provide a fully customized turnkey solutions from a single source.