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Frequently Asked Questions
What is 'Ready to Use' or 'Ready to Fill' and what container options are available ready-to-use?
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 SiO2, Schott, Stevanato Group, BD, and West, amongst others.
What are the best options for dispensing drug product into the final product container?
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 monoclonal antibodies (MABs), 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 dispensing 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 due to cleaning and the product carry-over risk from one batch to another. Also, protecting personnel is essential to minimize product exposure to potent materials. 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.
When processing syringes, which method is better for placing the piston into the syringe: vacuum or mechanical vent-tube?
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, which 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’s exterior coating. Syringe piston insertion using a mechanical vent-tube approach is a good approach for applications using a glass syringe with a bromobutyl stopper, for products with low vacuum pressure, and products where oxidation is not a risk.
How do you determine the amount of viable and non-viable monitoring locations within an aseptic filling system?
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 in which the drug product was filled met the regulatory requirements for aseptic processing. The risk areas of the aseptic process for each application must be identified, and monitoring instrumentation must be placed 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 customers to properly assess the risk of the particular line design to determine the amount and ideal placement of all stations required for a given application.
Are robots compatible with aseptic environments?
Robots are uniquely suited for aseptic applications and environments. Aseptic processes require absolute repeatability and exactness, and to do so without compromising the aseptic environment. Robots are extremely repeatable, are factory certified to be ISO Class 100 or better, and can be bio-decontaminated either manually or automatically. Not all robot 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 TX2 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 are second to none for critical aseptic applications.
Can robots be bio-decontaminated using vapor phase hydrogen peroxide inside of an isolator?
There are various robotic systems available that are compatible with isolator integration and bio-decontamination using hydrogen peroxide. AST’s ASEPTiCell® and GENiSYS® aseptic filling systems integrate Staubli’s TX2 series Stericlean robot for isolator applications that require in-situ bio-decontamination using hydrogen peroxide. The Stericlean was the very first robot designed specifically for isolator environments and is the most widely used robot in the pharmaceutical industry in critical aseptic applications.
What does the FDA think about robots used within 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)
What advantages does an aseptic filling machine with robots have compared to traditional or alternative flexible aseptic filling systems?
Robotic filling systems such as AST’s ASEPTiCell® and GENiSYS® R 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 being processed. Couple this with the number of mechanized parts that penetrate through the machine base plate, and 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 format parts required, and the change parts that are needed are simple and easy for the operator to install. A trained operator can typically change over a robotic system in 15 minutes when compared to upwards of three times that duration for a traditional filling machine.
Flexibility – Traditional aseptic filling equipment is typically 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 to 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 TX2 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 TX2 series robots are widely used in semiconductor applications that cannot tolerate particle contamination and thus require a robot that can achieve Sub Class 1. To complement this capability, AST’s ASEPTiCell® format parts are static and do not have motion outside of the robotic arm itself to eliminate particles that can be created from sliding or rotating motion.
No Trolleys – Robotic machines have flexibility designed into the system and can process multiple container formats with few and simple change parts. AST’s ASEPTiCell® and GENiSYS® systems do not require specific and dedicated machine trolleys to dock with an isolator to provide process and container flexibility. This minimizes cost, machine-related maintenance, change parts, and storage space for multiple trolleys.
What is Annex 1, and why is it important?
Annex 1 is an EU standard on the manufacture of sterile medicinal products enforced in the European Union and providing guidance to global regulatory bodies. The revised Annex 1 (published in 2023) is the most comprehensive collaborative regulatory initiative to date, presenting the views of the European Commission, the international PIC/S (Pharmaceutical Inspection Convention & Pharmaceutical Inspection Co-operation Scheme), and the World Health Organization. The PIC/S alone includes over 56 regulatory authorities, including the US Food and Drug Administration.
The 2023 update significantly expanded in length and introduced a new structure and in-depth coverage of areas directly related to manufacturing sterile products. The principle of the document highlights the special requirements needed to minimize contamination and calls for a comprehensive Quality Risk Management approach and a defined Contamination Control Strategy.
Speaking directly to drug product manufacturing considerations, the revised Annex 1 advocates for continual environmental monitoring and use of “appropriate technology,” specifically identifying isolators and robotic systems—a clear indication of the advantage of these solutions for safety, quality, and product integrity. Learn more about how AST solutions align with Annex 1.
What are the different methods of using Hydrogen Peroxide for decontamination in isolators?
Common approaches to isolator decontamination methods have typically utilized high concentrations of hydrogen peroxide with parameters that vary across application: dwell time, strength of concentration, form, and distribution mechanism can all differ, depending on technology.
High-concentration vapor phase hydrogen peroxide (VPHP) can utilize concentrations up to 59 percent, and requires substantial operational consideration for hazmat handling and the safety of personnel. Vapor particles are typically .5 to 1 microns, and application of high-concentration VPHP typically requires a heating mechanism to achieve a gaseous state and an even kill across isolated chambers. However, heating can cause additional issues like microclimates, which can interfere with the oxidation process.
Aerosolized Hydrogen Peroxide (AHP) utilizes larger particles (up to 30 microns) at higher concentrations to wet or saturate the isolated chambers and achieve the necessary 6-log reduction. Due to the size of the particle, AHP requires an atomizer and nozzle, and is applied thoroughly but unevenly. The uneven application often leads to oversaturation and pooling and requires aeration times that can last multiple hours.
While effective, the use of high-concentration hydrogen peroxide leads to extended machine downtime for aeration, limited material compatibility, degradation of sensor instruments, and time-consuming hazmat safety and training protocols.
AST’s Atmos™ isolator utilizes a low-concentration approach in partnership with CURIS System, integrating their 7000ei decontamination system. With complete cycle times in less than 60 minutes (including aeration) and a 7% VPHP application, the Atmos isolator offers fast cycle times with superior material compatibility and virtually no outgassing.
AST isolators achieve greater than a 6-log sporicidal reduction and Grade A / ISO 14644 class 5 operations with CURIS’s patented Pulse™ technology, which maintains an optimal, non-hazardous concentration of VPHP throughout the decontamination process. A validated FDA and Annex 1 compliant solution, efficacy is achieved through small molecule application where micro condensation oxidizes evenly and consistently to inactivate and destroy microbial pathogens.
What can I expect after the purchase of an aseptic processing machine? How can my team be best prepared to receive and set up the equipment ahead of Site Acceptance Testing (SAT)?
In pharmaceutical manufacturing, the decision to acquire aseptic processing equipment is part of the initial steps in the important journey to realizing a drug product. All aseptic processing operations, from initial drug discovery and development to commercial production, require comprehensive resource and schedule planning to meet regulatory standards and save critical time in commissioning and launching the operation.
At AST, once a project is initiated, our project management and Customer Care teams are there from the start to guide customers through operational milestones and help navigate potential hurdles or assist with changes to the scope of the project.
During the initial phase of a project, critical customer requirements are needed to ensure the project milestones are met, including User Requirements Specifications, samples for containers and consumables, and preliminary facility drawings. AST works with the customer, providing resources and expertise to meet these requirements in a timely fashion.
Early equipment integration considerations include facility layout, readiness, equipment installation steps, and the availability of critical consumables and machine spares, which are all crucial for seamless SAT and operational start-up. Additional considerations for facilities include dimensional restrictions, proper utility layout and hookups rated for the equipment, proper panel access, the storage and qualified handling of all necessary tools, safety and rigging equipment for installs, and any compliance-related operational needs related to facility ISO standards or qualified personnel.
After Factory Acceptance Testing (FAT), our team will coordinate with you directly to make sure your equipment is received smoothly, installed, and compliant as soon as possible.
In addition to project ramp-up support, AST offers comprehensive CQV training and services to ensure our customers meet initial cGMP production standards, and end-to-end performance support over the full life of the equipment.