February 1, 2017 POP-M02-17-NI-001
In 2014, the global revenue for single-use technology was $1.7 billion, but the market is expected to continue its current growth to $3 billion, at a compound annual growth rate (CAGR) of 11.7%, by 2019.2 This increase is likely due to general improvements in manufacturing as well as to growth of biopharmaceuticals. For example, titres have increased significantly, improving productivity as much as ten-fold and allowing the size of bioreactors to shrink. As a result, many manufacturers have moved to smaller batch sizes to help mitigate the effects of production issues and allow for greater flexibility.1 None of this is to say, however, that transitioning to single-use manufacturing for any upstream or downstream process is easy or should be taken lightly.
This transition requires a significant amount of planning, design and expertise in addition to staff training and procedural updates. Advancements in automation alleviates some of the challenges following implementation, but the successful continued use of a single-use manufacturing line begins before system design and installation. Vendor quality and, more importantly, a thorough understanding of the polymers, or plastics, used in every single-use component - including bags; tubing; connectors, valves, retainers, and chromatography - as well as the way processing conditions and additives affect performance, must be understood at the onset.
The production of the actual single-use system components and the system as a whole must be completed in a manner that minimizes contamination and the risk of damage. One of the primary benefits of single-use technology is that it eliminates the cost and time associated with the cleaning and sterilization of traditional equipment. Though it should be recognized that this convenience puts considerable pressure on the component manufacturers, designers, and builders of these systems. Visual inspection and pressure decay - the industry standard for verifying single-use systems - should be implemented with all components and can be effective, but there are limitations.1 Just as biopharmaceutical manufacturing must remain sterile, so too must the manufacturing of single-use components.
To help ensure the highest quality possible, cleanrooms are often used in the manufacturing and assembly of the components themselves; additional considerations must be made to prevent contamination and damage. The atmosphere provided by a cleanroom helps reduce particulates - foreign and those native to the manufacturing of polymers - by allowing for the control of airflow and humidity; additional measures to remove particulates (i.e. laminar airflow across components) that may inevitably occur with production helps to further combat the issue.3 Finally, simple facility considerations such as rounded edges and corners on all work surfaces help reduce the likelihood of puncture and other physical damage more likely to result from manual handling and physical assembly than inherent material flaws.1 However, it must be said that a supply chain is only as strong as its weakest link - or disposable filter cartridge, bag, tube etc. In other words, the process of ensuring product integrity is meaningless unless companies focus not only on the quality of the components, but also on the quality and properties of the polymer materials that make them possible.
Since single-use options first entered the market in the late 1970s via capsules and filters, much has changed in the way of product options.4 Part of that change is improved polymer materials crucial to greater reliability and the industry’s better understanding of how these material perform, but risks remain due primarily to the inherent vulnerabilities of plastics and the lingering unknowns surrounding many of the materials currently in use.4 Though the polymers used to make single-use equipment can impact various pharmaceutical drug products, biopharmaceuticals are particularly susceptible to harm due to sterilization requirements and the use of cells and proteins. These risks warrant additional focus from the broader pharmaceutical community.
In 2015, the Engineering Conference International (ECI) organization offered a platform for representatives from the pharmaceutical industry, academia and polymer suppliers to come together at the “Single- Use Technologies: Bridging Polymer Science to Biotechnology Applications” conference.5 Concurrently, the Bio-Process Systems Alliance (BPSA) updated its prior guidelines and released the BPSA 2015 Quality Test Matrices Guide to help the industry understand best practices for component quality testing as single-use technology continues to evolve. Additionally, ongoing studies from suppliers and end-users continues to help facilitate the implementation of improved single-use technologies by way of improved polymer technologies and a better understanding of the factors that contribute to the complex interactions which can occur in the manufacturing environment.
Before being designed into a system, typical polymers for the pharmaceuticals industry - polyethylene (PE), polypropylene (PP), polycarbonate (PC), polyamide, polyethersulfone (PES), polytetrafluorethylene (PTFE), polyvinyl chloride (PVC), cellulose acetate, ethylene vinyl acetate (EVA) and fluoropolymers, one of the most inert, nontoxic polymers currently available - should be carefully validated. 4 Factors including barrier properties, resilience to extreme temperatures (for example, many current materials must be used between -2°C and 4°C), performance in sterilization conditions and, arguably the most significant concern, risk of leachables and extractables (L/E) should be well understood, specifically in regards to the needs and chemistries of the biopharmaceutical production environment.3,6 In general, current material compatibility issues arise as a result of legacy plastics that remain on the market and/or a general lack of understanding/testing.
First, legacy materials - those grandfathered in from medical device and pharmaceutical packaging use - were often approved with testing criteria that is widely regarded as outdated and thus no long sufficient to determine acceptable use with biopharmaceuticals. Secondly, in many cases there is not enough documentation on the behaviors of these polymers with today’s additives and processing conditions.6 For example, full chemistry and toxicology data from multiyear studies are often unavailable and, due to the materials’ limited time in the market, modern safety assessments accounting for long-term exposure have not been completed.6
These unknowns do not mean polymers are unsafe, but they do pose questions regarding the efficacy of some materials, especially given the cost of testing to prove that they do not impact product purity (approximately $100,000 for each contact plastic).6 Overcoming these challenges remains a group effort and hinges largely on regulations, which currently complicate the market by remaining regionally specific and focused on risk rather than quality.5 With clarified expectations in the regulatory arena, the focus can turn to understanding what constitutes a quality polymer, based on the unique needs of drug development - a process that requires close collaboration between suppliers, sub-suppliers and the biopharmaceutical industry. For example, catalysts and additives (both byproducts and intentionally added chemicals such as antioxidants and processing agents) are potential L/E, but the formulation, converting, and post-treatment processes for the plastics themselves can also make a difference.3,5 Further, many plastics manufacturers and sub suppliers focus on multiple industries, meaning the pharmaceutical industry is poised to learn from the successes of these industries while also enhancing supplier awareness and shaping manufacturing processes by fostering a transparent relationship at all levels of the supply chain.5
Regardless of lingering L/E concerns, especially regarding plastic interactions with proteins, and additional material compatibility testing still required in many areas, successful single-use technology implementation continues across the industry.5 For example, GE Healthcare’s 2013 acquisition of Xcellerex expanded the company’s SUS capabilities, as did Patheon's 2014 acquisition of Gallus BioPharmaceuticals. Also in 2014, Advanced Scientifics (ASI) and Chemic Laboratories announced a partnership to collaborate on product development projects focused on L/E analytical data supporting single-use systems.4 Today, single-use technology can even be delivered quickly, with companies such as Parker Domnick Hunter boasting conception to delivery of a custom system in 8-plus weeks, nearly half the typical lead time.1
To make the most of these promising developments, however, the pharmaceutical industry, as a whole needs to remain closely tied to polymer manufacturers. Ensuring that plastics technologies keep pace with biopharmaceutical drug production will only become more important as these already unique and mounting production demands continue to evolve.
Mr. Walker is the founder and managing director of That’s Nice LLC, a research-driven marketing agency with 20 years dedicated to life sciences. Nigel harnesses the strategic capabilities of Nice Insight, the research arm of That’s Nice, to help companies communicate science-based visions to grow their businesses. Mr. Walker earned a bachelor’s degree in graphic design with honors from London College of Communication, University of the Arts London, England.
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