By Russell Darley, Director of Global Medical R&D, Sealed Air Corporation
Over the last decade, single-use technology (SUT) has revolutionized the biomanufacturing industry through key advantages related to flexibility, lower capital costs, and reduced cross-contamination. The growing adoption of SUT has led to a shift from traditional stainless steel to disposable equipment in clinical and commercial manufacturing environments. However, with all of the benefits that come with SUT, there also come new challenges with its implementation. First-generation films used to create today’s disposable equipment were not originally designed for bioprocessing but rather were developed with food-grade materials and then repurposed for use in drug development. Looking into this issue further, a group of industry experts examined the effects of this plastic on the biomanufacturing process, specifically as it relates to cell growth. 1 They found that a compound leaching from the breakdown of a commonly used antioxidant (AO) was damaging to cell culture growth. Other industry concerns related to single-use film are its performance and fitness for use.
Cytiva was aware of this need and wanted to build a platform film for bioprocessing while also enhancing performance across its applications. Sealed Air (SEE) sought out customers that had a strong understanding of the critical pain points of the existing bioprocessing films and a willingness to explore solutions through partnership. Cytiva recognized SEE as the best in the business and believed the company could help find a solution to this problem. Thus, in 2016, the two companies committed to a strategic alliance aimed at creating a clean, worry-free material compatible with bioprocessing materials. The project began by gathering core team members from both companies to discuss Cytiva's vision, the shortcomings of existing films on the market, and how the companies would work together to achieve their common goal.
The overarching goal was to combine Cytiva's industry knowledge and vast product portfolio with SEE’s material experience and expertise in polymers to develop a high-quality film engineered and manufactured specifically for bioprocessing. As the impact of extractables and leachables (E&L) on product stability gained greater visibility in relation to single-use technology (SUT), the partnership between Cytiva and SEE was intended to address the issues with the current film structures in today’s biopharma market. These included, but were not limited to, continuity of supply and film failures, which could result in the loss of a production batch, often worth over $1 million. Ultimately, the partnership resulted in the development of FortemTM - a technology designed specifically for bioprocessing that is now used for Cytiva’s entire portfolio of single-use film systems.
Fig 1. Quality By Design gives Fortem film its built-in strength
With over 30 years of experience in providing polyolefin films to the parenteral solution markets, Sealed Air (SEE) knows that strategic sourcing of raw materials is vitally important to the security of supply and the continuous quality of a product. That is why a significant amount of time and energy goes into selecting SEE’s raw material suppliers, as SEE must ensure its suppliers have a clear understanding of the medical space and its requirements. Asking questions about where and how resins are made and what additives are used provides insight into the chemical composition of the raw materials and ensures the materials are a good fit for pharmaceutical customers. Establishing a good understanding of change control and using a change notification process additionally allows SEE to maintain the continuity of its products, so it can continually meet the industry’s stringent regulatory expectations.
A Collaboration Built On Communication
The challenge of designing a universal film requires a number of competing properties, and the functional requirements of every application must be balanced against one another. A number of considerations must be measured while doing so. These include: choice of polymers, film thickness, flexural properties, degree of crystallinity, resistance to gas transmission, and many more. SEE leveraged its long-standing relationships with major resin vendors to optimize an AO a material formulation that would not impact the film’s performance and stability over time. Polymers were hand-selected from specific raw material suppliers and quality checks were put into place to manage tight tolerances around the film’s performance. An open loop of feedback from Cytiva was imperative when it came to making modifications to continually improve product performance, especially since SEE had to consider barrier, flex fatigue, and sealing requirements throughout the design and qualification process.
SEE worked with Cytiva to develop testing protocols and procedures that accurately represented real-world film performance. Test plans were often a combination of standardized industry test methods, such as ASTM and ISO, as well as internally developed evaluations. As integrity is a critical requirement for film performance, much focus was dedicated to the area of “fitness for use”. In the early phases of film development, gelbo flex testing (ASTM F-392) was used to screen prototype materials for flex fatigue that can result in pinholes. The knowledge gained from the relatively quick execution and minimal test material needed from the gelbo flex test was applied to creating film formulations that were then tested on a Cytiva WAVE Bioreactor™ for 45 days. Seal strength is another critical component to maintaining integrity. The project team had a minimum peel force target; however, the failure mode of the seal was also characterized. Extensive peel testing of bags, as well as drop testing of filled bags, was conducted to deeply understand sealing windows and the behavior of the multilayer film under various distribution and use conditions. Finally, a critical success factor to ensure alignment among companies was that SEE and Cytiva spent time together in each other’s facilities observing testing equipment and test method execution. This collaboration allowed the team to remain aligned on testing procedures and avoid test method variation that can often lead to confusion, lost development time, and unnecessary reformulation.
Fig 2. ISO7 Cleanroom production for both extrusion and slitting
Most innovation projects come with a fair share of challenges, and the project shared between SEE and Cytiva was no different. Yet, what made this collaboration unique was the way in which SEE and Cytiva addressed these project challenges. Both companies possess strong fundamental science and problem-solving skills, which were evident and beneficial as the teams discussed, collaborated, and resolved each hurdle faced along the journey. A testament to this came from an SEE employee who was not team member but attended a joint SEE/Cytiva project meeting as a guest. At the conclusion of the meeting, he stated that the teams interacted so well together over the course of the discussions that he could not differentiate between the SEE team members and Cytiva team members. It is this cohesiveness that allowed SEE and Cytiva to quickly diagnose problems, address any issues, and proceed forward, making collaboration a key to success during Fortem film’s development.
- Hammond, Matthew, et. al. (2013). Identification of a Leachable Compound Detrimental to Cell Growth in Single-Use Bioprocess Containers. PDA journal of pharmaceutical science and technology / PDA. 67. 123-34. 10.5731/pdajpst.2013.00905.