Frequently Asked Questions
The term “ready to use” or “ready to fill” describes containers that have undergone washing, depyrogenation, packaging and a final sterilization process using gamma irradiation, EtO or autoclave sterilization. The packaging typically consists of a plastic nest that holds each individual and is located within a plastic tub. A loose sheet of Tyvek, referred to as a “liner”, is placed over the tops of the containers within the nest and the tub is sealed with another Tyvek sheet, often times called a “lid”, to seal the sterile containers until it is removed prior to aseptic filling. The advantages of getting containers in this pre-sterilized state include eliminating expensive equipment that has to be purchased with the filling machine to wash and depyrogenate the containers before filling. One must also consider the facilities, utilities and personnel activities that are required to support the process of preparing containers to receive the sterile drug product. The Water for Injection (WFI) system, cleanroom space, maintenance and validation for these systems all go away. This enables a simple and more nimble manufacturing environment with less infrastructure and support requirements. There are many commercially available RTU options available for syringes vials and cartridges from several reputable suppliers including; Ompi, SiO2, Schott, Becton-Dickenson, and West to name a few.
Many different factors need to be considered when selecting the optimal dispensing system. Both the ASEPTiCell® and GENiSYS® systems can be integrated with several different dispensing systems such as peristaltic and rotary piston pumps. Below are a couple of key considerations; Product viscosity can greatly influence dispense accuracy and limit dispense options. Generally viscous products are best suited for rotary piston pumps. Many of the biologic products such as mono-clonal antibodies (MABs), proteins and other biologic proteins can be shear sensitive. Therefore choosing a dispensing technology that induces the least amount of shear is preferred. Peristaltic pumps and time-pressure dispense are the best options, however peristaltic has the advantage of providing a completely disposable option that is pre-sterilized and doesn’t have to be cleaned post filling. Product potency can be challenging because of the cleaning and product carry-over risk from one batch to another. Also keeping protection of personnel is essential to minimize product exposure to potent material. Single-use disposable fluid pathways are generally the best means of isolating and disposing of potent materials while minimizing cleaning and exposure risks. Given this, peristaltic pumps would be the recommended option. Peristaltic and rotary piston pumps provide repeatable and accurate dosing typically within 1%-2% of the desired dispense volume. Peristaltic pumps are extremely versatile with accuracy being highly dependent upon the diameter of the fluid path tubing and filling needle. Rotary piston pumps are equally accurate but require specific cylinder and piston combinations to dispense the correct volume.
Product, container – piston combination, and whether the syringe or cartridge will be used with a medical device like an injection pen, are the most common factors to consider when deciding which method is best for placing the piston within a syringe. Vacuum piston insertion has the advantage of reducing the air bubbling that is common to the mechanical vent-tube method. This reduction of air bubbles within the syringe eliminates potential oxidation problems with the product and can increase product shelf life. Vacuum can be provided with a mechanical assist, uses a pin to accurately position the piston after vacuum has been pulled. This is commonly done for syringes and cartridges that will be used with medical devices so that they can dispense accurately. Finally, certain silicon free syringes like West Pharmaceuticals CZ syringe require vacuum to be used because of the material mechanical properties of the piston exterior coating. Syringe piston insertion using a mechanical vent-tube approach is good for application using a glass syringe with a bromobutyl stopper, for products with low vacuum pressure and where product oxidation is not a risk.
Non-viable and viable monitoring is required to provide qualitative (viable active and passive air sampling) and quantitative (non-viable particle sample) data to confirm that the environment the drug product was filled within met the regulatory requirement for an aseptic process. Therefore, it is important that each application determine the risk areas of the aseptic process and place monitoring instrumentation in these locations such that ample supportive data can be provided to assure the quality of the aseptic environment and process. AST works with each one of our customer’s to properly assess the risk of the particular line design to determine the amounts of station required for the given application.
Robots are uniquely suited for aseptic applications and environments. Aseptic processed require absolute repeatability and exactness, and to do so without compromising the aseptic environment. Robots are able to provide extremely repeatable, are factory certified to be ISO Class 100 or better, and can be bio-decontaminated either manually or automatically. Not all robots designs are well suited for aseptic applications because of the design, particle generation, compatibility with typical industry disinfectants, and materials of construction. AST is an Elite Partner Integrator for Staübli Robotics and integrates the Staübli TX series Stericlean robots within the ASEPTiCell® and GENiSYS® aseptic filling systems. The Staübli Stericlean robot is the most widely used robotic system for aseptic applications worldwide. Their industry leading reliability, aseptic design and compatibility with bio-decontamination is second to none for critical aseptic applications.
There are various robotic systems available that are compatible with isolator integration and bio-decontamination using hydrogen peroxide. AST’s ASEPTiCell® and GENiSYS® i20 aseptic filling systems integrates Staubli’s TX series Stericlean robot for isolator applications that require in-situ bio-decontamination using hydrogen peroxide. The Stericlean was the very first robot designed specifically isolator environments and is the most widely used robot in the pharmaceutical industry in critical aseptic applications.
The FDA has openly endorsed robotic technologies as an acceptable solution to reduce risk to an aseptic process. In the FDA cGMP Guidance it states that “automation of other process steps, including the use of technologies such as robotics, can further reduce risk to the product” (Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, Pg. 10).
Robotic filling systems such as AST’s ASEPTiCell® offer several significant advantages when compared to traditional vial or syringe processing lines and include the following:
- Enhanced Sterility Assurance. Robotic systems can completely automate the aseptic fill-finish manufacturing process to the degree that the operator is removed from the most critical aseptic operations. By removing the operator from the aseptic process contamination risks are reduced along with process variability that the operator could introduce.
- Improved Cleanability. Traditional filling lines have many machine elements that are required to fill and close the container it is processing. Couple this with the number mechanized parts that penetrate through the machine base plate you have a maze of difficult and time consuming spaces to clean. With robotics systems the robotic arms integrated with the machine eliminate the complexity of parts and base plate penetration to process the very same container. This provides fewer parts and easy to access open surfaces that can be easily cleaned.
- Fewer Change Parts. Change parts can be expensive, time consuming to place and remove from the machine and can be subject to improper setup or adjustment by the operator. Robotic systems reduce the number of formats parts required, and what change parts are required are very simple and easy for the operator to install. A trained operator can typical change over a robotic system in 30 minutes when compared to upwards of twice or more for a traditional filling machine.
- Flexibility. Traditional aseptic filling equipment typically is dedicated to a single container such as a vial or syringe. Robotic systems can provide the capability of processing multiple container options such as vials, syringes and cartridges on the same aseptic fill-finish machine. In addition with the ability to process multiple container types robotic systems like the ASEPTiCell® are not constrained like other systems to use specific components, such as press-fit caps, but can process a wide range of traditional components.
- Minimal Particle Generation. AST integrates Staubli TX series articulating arms. These robotic arms come standard with an ISO 5 certification and can be provided with an improved rating if required. The Staubli TX series robots are widely used in semi-conductor applications that cannot tolerate particle contaminations and thus required a robot that can achieve Sub Class 1. To compliment this capability AST’s ASEPTiCell® format parts are static and do not have motion outside of the robotic arm itself to eliminate and particles that can be created from sliding or rotating motion.
- No Trolleys.Robotic machines have flexibility “baked into” the system and can process multiple container formats with few and simple change parts. AST’s ASEPTiCell® does not require specific and dedicated machine trolleys to dock with an isolator to provide process and container flexibility. This minimizes cost, maintenance on several machines, change parts and storage space for multiple trolleys.
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