Single-Use Technology for Formulation and Filling: A Case Study from Swissfillon AG and Pall Corporation

Swissfillon AG is a contract manufacturing organization (CMO) based in Switzerland. Fully compliant with current good manufacturing practice (CGMP) regulations, it provides state-of-the-art aseptic filling for pharmaceutical and biotechnology companies, from clinical-phase materials to commercial quantities. This CMO specializes in high-value, difficult-to-fill products.

Swissfillon recognized that adoption of single-use systems (SUS) on a commercial scale required major improvements in consistency and reliability compared to manual operations at pilot and clinical-trial scale. The single-use formulation and filling process, which includes an Optima multiuse filling system, was designed to be fully automated and highly flexible. It was finished in 2018, and a further expansion with a second filling line is scheduled to be installed in 2023–2024. The company can fill batch sizes between 1 L and 100 L now, and in the future will handle up to 500 L in vials, syringes, or cartridges.

The multistage system not only incorporates SUS throughout its product-contact flow path from compounding to the filling needle, but also requires hardware and facilities for each unit operation. This includes isolators, transfer ports, cleanroom equipment, mixers, filtration boards, pumps, and integrity test equipment. The filling machine is positioned inside an isolator for filling of potent or toxic drug substances.

Product Life Cycle and
Quality by Design (QbD)
The “Reasons for Choosing Single Use” box lists the main advantages of this design. Swissfillon realized that successful implementation of SUS requires a shared responsibility with the chosen supplier. That supplier must manage the complex structure of the SUS — including components from other suppliers — and provide assurance to end users on elements such as the supply chain, quality (including certification), engineering, manufacturing, quality control, sterilization, packaging, and transportation. In addition, the supplier must provide advice, documentation, and training for the end user’s operational performance of the system.

During discussions on end-user requirements with Pall, the starting point was a well-defined user requirement specification (URS). Throughout the design process, Pall and Swissfillon had to share a great amount of information, and the two organizations formed a close, collaborative partnership. The information exchange ensured that Pall could obtain a thorough understanding of Swissfillon’s product, application, and process to successfully meet the CMO’s objectives. Thus, critical quality attributes (CQA) could be met throughout the entire life cycle of the drug product. Such understanding also facilitated Swissfillon’s risk assessment, minimized validation requirements, and allowed for safe and qualitative drug-product manufacturing within predefined critical process parameters (CPPs).

For example, a failure modes and effects analysis (FMEA) on the initially proposed solution was carried out to identify possible risks of failure that could be addressed by design improvements. FMEA identified high risks in the SUS unpacking and installation procedure and the final filtration stage. Pall proposed improvements in packaging and the manufacture of supporting hardware (using a shadow board) for the filtration stage, both of which ensured consistent installation and ergonomics of the SUS for this critical application. The improvements were trialled in a prototype evaluation, and compliance with objectives was verified.

Design and Operation of the Swissfillon SUS Facility
The filling process starts in the compounding area with a single-use mixer incorporating a closed powder-transfer bag. Drug product is transferred from that mixer to the sterile filtration manifold through a sterile connector.

The sterile filtration system comprises two liquid filters in series. Vent filters and flush biocontainers in the system provide for filter-integrity testing pre- and postuse (PUPSIT) and also leak testing of the SUS before use.

The filtration and filling manifolds, positioned in two different cleanrooms, are connected using a sterile connector in an ISO 7 cleanroom. The single-use filling path is located in an isolator following ISO 5 and consists of a surge bag and tubing connected to a single-use filling needle.

Filtration Manifold Using Shadow Board: The filtration manifold is the most critical system for guaranteeing final sterility of a product. It had to be designed in a simple, safe, and reproducible format to ensure consistent installation regardless of operators and their level of training.

As a perfect solution for Swissfillon, a shadow board was developed with Pall Corporation that clearly shows

This facility allows even inexperienced or new operators to set up the filtration manifold safely in under two minutes. The final preparations including priming and integrity testing then can be performed semiautomatically to prepare the system for filling the drug product. The shadow board was designed to be versatile to manage different filters, filter wetting strategies, and types of integrity tests. It incorporates PUPSIT at point of use.

Single-Use Sterile Connectors for Aseptic Transfer: To facilitate operational control of this complex, single-use, redundant filtration setup with PUPSIT, and to declutter the final filling environment, most of these operations were positioned outside of the filling environment. A sterile connector joins the filtration manifold to the filling manifold.

Barrier Technologies, Isolators, and Rapid Transfer Port Systems: Secure aseptic transfer of the effluent within a closed disposable filtration system to the SU filling manifold inside a closed filling machine is achieved safely with a rapid-transfer port system fitted with alpha and beta locking ports.

Filling Needles: Filling needles traditionally are made from stainless steel, but in recent years, reinforced high-performance plastics have been shown to provide identical, if not more accurate and consistent target dosing. The single-use filling needle met the requirements for needle straightness and accurate, drip-free, uninterrupted dosing of the drug product into the target container. The needle also was sterilizable by irradiation, ready to use, compliant with relevant pharmacopoeias, and cost effective.

Single-Use Technologies in Formulation and Filling
The combination of the Optima multiuse filling system with Pall Corporation as supplier of additional equipment and single-use systems has to date enabled Swissfillon to conduct more than 30 successful media-sterility runs without any failures or lost batches.

This Swissfillon case study demonstrates that SUS can be incorporated successfully into formulation and filling operations, from compounding and formulation of active pharmaceutical ingredients (APIs) down to final filling of the drug product. This result was achieved by clearly defining URSs, performing risk assessments, and establishing a close working relationship with suppliers. In this way, the company achieved a full understanding of the life cycle of the single-use system, operational requirements, and the benefits of a “first-time right” QbD approach.

Delphine Lallement is the global product manager, single-use final filling systems, at Pall Corporation, 3 Rue des Gaudines, 78100 Saint-Germain-en-Laye, Yvelines, France; [email protected].

To find out more about this case study and how Pall and Swissfillon worked together, watch this on-demand webinar: http://www.SUSFandF.com.