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F2V: A sterile, customisable liquid fill-finish platform for the total lifecycle

Published in the October issue ('Pre-filled Syringes and Injection Devices') of the OnDrug Delivery magazine.

In this article, Simon Strothers, Director of Business Development, 3P innovation, presents an integrated fill-finish platform, F2V, designed to represent a commercial filling system as a bench-top solution. The article also includes a recent case study where the F2V was used by Consort Medical to help develop and industrialise a flagship delivery device. Finally, a summary is provided of the key factors that should be considered to help ensure success in new drug and device development and industrialisation.

Current market trends indicate that next-generation biopharmaceuticals will have a major impact on the way drugs are formulated and the devices that deliver them. The pharmaceutical industry is also increasingly seeing a  rise in the development of personalised medicines, which are tailor-made solutions designed specifically to meet the needs of a particular patient. These drug products require low-volume manufacture and a high degree of flexibility. Regulatory pressures to improve the patient experience are also driving new combination products and associated device developments. Many companies involved in this area are small start-ups, university spin-offs and venture-capital-backed businesses usually with some novel intellectual property.

Production of parenteral products, especially primary drug filling and finishing, demands sterile production environments with aseptic manufacturing systems and know-how. Regulators are demanding that parenteral manufacturers “automate more” during preclinical and early clinical phases to reduce human operator influences on the process to improve product quality and safety.

The combined effect of the above is having a significant impact on existing supply chains and manufacturing models. Equipment innovation and sterile facilities are required that can fill a much wider variety of container formats in smaller volumes. There are new challenges for liquid filling; higher accuracies, highly viscous products and multi-product devices demanding more advanced pump technologies and inspection methods.

PLANNING FOR SUCCESS

Built on previous project experience we propose a simple framework to consider when planning and resourcing for a new drug or device development project (see Figure 1). The four headings represent the key activities that should be considered when developing a new combination product. Drug, Device and Manufacturing Process are the three main work-streams that typically demand different resources and skills sets and which should be considered in parallel to ensure the interdependencies are explored, defined and considered from the start.

F2V – LIQUID FILL-FINISH PLATFORM

With the objective of helping customers to address all of the key activities and workstreams highlighted in Figure 1, 3P has developed F2V, an isolator-ready, flexible, customisable platform for both filling and finishing of a wide variety of containers and devices including syringes, cartridges, vials, bottles and customised drug containers.

Whereas most lab-scale systems offer individual process stations only, F2V (shown in Figure 2) provides a GMP-compliant, all-in-one integrated system for nitrogen purging, liquid filling, vacuum stoppering and other processes on the same machine. This increased level of automation improves productivity, product quality and patient safety, whilst still providing the flexibility you would expect from a bench-top, low-volume system. Operators are not required to transfer containers between the critical fill and stoppering processes, thereby simplifying the process and reducing risk.

With ongoing support from the 3P team, the F2V platform is fully customisable and comprises a series of fully programmable, servo-controlled modules for bottom-up filling, nitrogen purging, vacuum stoppering and stopper pick-and-place. A separate bench-top Rotary Crimper is also available and enables customers to complete the finishing process for cartridges and vials. An easy-to-use, touch-screen display enables easy adjustment of speeds and strokes to suit individual container types and dimensions.

Recipes can be created and recorded to suit different container types and sizes. Once recorded, the associated parameters will be stored against the named recipe. Operators can then reselect a recipe at a later date to retrieve the exact same settings and conditions for production. This option speeds up changeovers between batches and supports development activities such as design of experiment (DoE) and sensitivity analysis.

Containers are loaded manually into a transfer puck. Pucks are custom-designed, specific to a particular container type. The puck is connected by to a servo motor-controlled arm which gently moves the container between the filling and finishing stations. A gentle motion profile prevents spillage or unwanted movement of liquid up the sides of the container, which may affect stoppering and the sterile barrier.

The transfer puck forms part of the F2V change tooling set (Figure 3) and can be rapidly changed over to take different container sizes and types. For example, following filling of a batch of cartridges, F2V can be quickly changed over to fill a batch of vials. As required, this could be with a different pump technology, a different liquid and a different dose weight.

Complete Lifecycle Service

3P provides a complete lifecycle service to support its machines in operation. During the container development phase, new change parts can be 3D-printed by our engineers to enable initial test fills and supply of samples. As a design becomes firm, 3P will support with manufacture and supply of GMP-compliant change parts, suitable for clinical and production manufacturing.

A major benefit of F2V is therefore its ability to accommodate late-stage changes in device and container design. F2V is intentionally designed as a flexible and versatile production platform rather than a single, fixed machine. An F2V system can be configured to suit specific processes which may be applicable to individual containers or a range of container types. Figure 4 shows how a new system is configured by choosing the required processes combined with a choice of pump type.

It is also possible to supply multiple pump types for a given process. For example, we can supply rotary piston pumps, more suitable for higher-accuracy or higher-viscosity drug products as well as peristaltic pumps, ideal for single-use, biopharmaceutical filling.

F2V STATIONS AND THEIR APPLICATIONS

Different F2V stations perform specific functions supporting the development and manufacture of various container types

Liquid Filling and Nitrogen Purge

The liquid filling module integrates with any pump format as required to suit the application, including peristaltic, and rotary piston pumps. A wide choice of nozzle types and sizes is available to suit the dose volume, liquid and container type. Programmable bottom-up filling enables fine adjustment of needle position, speed of lift and fill rate, avoiding splashing, frothing or contamination of the stoppering zone. A nitrogen purge option is available which uses the same programmable controls as for liquid filling.

Pump Innovation

The novel rotary pump module from 3P’s pump partner, Bio Solutions Gate (BSG, Francheville, France), compliments the F2V system, providing the same degree of flexibility and reconfiguration in one integrated system. Isolator-ready, the compact, bench-top system uses high-quality ceramic pumps from Neoceram (Strépy-Bracquegnies, Belgium), providing very high accuracy and repeatability, ultra-low particle release, no interaction with the drug product and long life-time capability. Connected to the F2V system, the BSG pump can fill liquids from 0.03-175 mL (depending on selected ceramic pump) with an accuracy up to ±0.1%. Toolless assembly is enabled by BSG’s fast-locking concept. An alternative dosing unit is also available, dedicated to micro-dosing and capable of fill volumes from 0.01-8.5 mL, also with an accuracy up to ±0.1%.

Vacuum Stoppering

Suitable for closing cartridges, syringes and other special containers, the vacuum stoppering station integrates with a standard vacuum pump. Vacuum levels can easily be adjusted and a sensor ensures target vacuum has been achieved prior to motorised insertion of the stopper. The stopper insertion depth is finely adjustable via the touch-screen human-machine interface (HMI).

Stoppers are loaded manually into a device-specific housing. This housing forms part of the F2V change tooling set. All change tooling can be removed quickly and easily, without the need for tools or equipment and can be disassembled, cleaned and sterilised using conventional sterilisation equipment.

Stopper Pick and Place

The stopper pick-and-place station uses a vacuum to pick and transfer stoppers and caps to close vials, bottles and other special containers. Stoppers and caps are loaded manually, followed by automated picking and placement onto the container.

Scale Up and Scale Out

The F2V platform is designed to enable fast, easy scale-up through simple change parts and, if necessary, adding additional pumps to the system. Figure 7 shows how the container puck can be designed to hold one, two or three containers at a time. Filling needles and change tooling for the vacuum stoppering station are similarly configured to process one, two or three products at a time.

When higher volumes are required, 3P supports with the design and supply of faster machines or, as indicated previously, through scale-out by implementing multiple F2V machines, which may be sufficient to generate significant volumes for late-stage clinical and even commercial volumes depending on the product and the market demand.

F2V – Rotary Crimper

The spin crimper is supplied as a separate module to enable segregation from the filling and finishing processes. This is typical best practice to minimise risk due to generation of particulates. The module is designed for aseptic processing, suitable for use in sterile isolators and for fully automated and manual sterilisation processes such as hydrogen peroxide vapour (HPV) sterilisation.

CONCLUSION

In addition to the equipment it supplies to its partners, 3P’s reputation is built on providing first-class service and support. The combination of these elements – equipment with service and support – is one of the key factors for project success. The below section provides a summary of other key factors to include, together with pitfalls to avoid, to ensure successful project outcomes. Developing and refining device design has been made easier by F2V. This invention allows for the end-product to be tested sooner to measure feasibility quicker. In addition, the individual unit operations are representative of production, meaning that validation does not need to be repeated when a scaled-up solution is required. The F2V is flexible, scalable, easy to use and clean, and can be integrated with other modules for higher-volume semi-automated and fully automated production. The result is a faster product launch and faster return on investment.

If you are interested then please give us a call on 01926 408933 or email us at  [email protected]

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