Although introduced just about 30 years ago, single-use technologies have become widely adopted across all aspects of biologics development and manufacturing activities. Efforts continue to be directed at developing innovative plastic compositions and SUT designs to further expand their reliability and applicability. The industry is also focused on addressing potential future supply-chain security concerns and enhancing the sustainability of disposable biomanufacturing.
Why Single-Use Technologies?
Single-use technologies (SUTs) for biopharmaceutical manufacturing find applications today across all aspects of upstream and downstream processing. Shake flasks, 2D- and 3D-bioreactors, tubing, connectors, biocontainers and bags, mixers, filters, chromatography columns, filling systems, and sensors are all available and used not only during R&D phases but for clinical and commercial production of all types of biologics, from conventional recombinant proteins and monoclonal antibodies (mAbs) to novel modalities, including viral vectors and cell therapies.
SUTs are generally intended for one-time use and composed of various plastics (e.g., polyamide, polycarbonate, polyethylene, polyethersulfone, polypropylene, polytetrafluorethylene, polyvinyl chloride, cellulose acetate, or ethylene vinyl acetate), often multiple layers to leverage their different properties for specific applications.1 Most today are offered as presterilized (typically via gamma irradiation) assemblies. They are available in sizes that support a wide range of production scales.
There are numerous benefits to shifting from stainless-steel to SUTs. The original driver for their use was to avoid cleaning processes and potential contamination issues associated with permanent production equipment.2 There is no potential for cross-contamination due to the one-time use of SUTs. Manufacturers have come to realize many other advantages to SUTs since that time, and now disposable systems are viewed as offering safety, time, and cost advantages.3–9
Setup and changeover of manufacturing processes using SUTs is much quicker (hours rather than weeks), enabling greater efficiency and productivity. Avoiding steam-in-place and clean-in-place processes reduces energy and water consumption and waste generation, leading to lower carbon footprints. For new facilities, capital expenditures are construction timelines are significantly lower compared with those for installation of stainless-steel equipment. Operating expenses can be reduced by as much as a quarter, and SUTs also support closed processing, increasing both product and operator safety. Finally, SUTs offer real flexibility to respond to changing market demand and facilitate multiproduct manufacturing. Overall, therefore, they reduce the cost and time required for drug development and manufacturing.
From Filters to Biocontainers
The first single-use products — small filter capsules — were introduced to the biopharma market in the late 1970s and garnered notable interest by the early 1980s.1,2,10 In the late 1980s, the company Hyclone (since acquired by Thermo Fisher Scientific) introduced SU biocontainers for serum, buffer, and media storage and transport based on technology adopted from the food industry. Larger filter capsules were introduced to the market in the late 1980s/early 1990s, and larger biocontainers followed in the early 2000s. By the 2010s, SU filters and both 2D and 3D biocontainers were widely used in R&D and clinical production.
Disposable Bioreactors Make a Big Splash
The success of larger SU biocontainers for storage, transport, and mixing drove development of biocontainers specifically for use as bioreactors. The first — the rocking WAVE Bioreactor from GE (now Cytiva) — was introduced in the late 1990s.11 SU stirred-tank bioreactors came to the market in the mid-2000s, with the first introduced by Hyclone.12 Single-use mixing technology also entered the market in the 2000s, increasing the productivity of buffer preparation.
Bioreactor innovation continued through the next couple of decades, leading to a range of shapes and sizes, stirring technologies, and in-built monitoring capabilities.5 Today, while 2000-L SU bioreactors are most common for large-scale commercial manufacturing, some vendors offer larger options up to 6,000 L. For upstream processing today, SUTs are available for all activities from cell banking to cell culture. Solutions have also been developed for microbial fermentation applications, with SU fermenters up to 1,000 L available.
Specialty bioreactors and supporting equipment have also been developed to support different types of cell culture, including continuous processing via perfusion.5 Single-use alternating tangential flow (ATF) and tangential‐flow filtration (TFF) systems represent disposable solutions for cell retention, while fixed-bed bioreactors support scalable adherent cell culture in a single-use format. Packed-bed and hollow-fiber reactors are also available. Process intensification has also been achieved by several companies through integration of SU bioreactors with other SUTs in fully enclosed systems. The NevoLineTM Upstream platform (Universals Technologies) for vaccine production and CliniMACS Prodigy (Miltenyi Biotec) and Cocoon (Lonza) systems for cell therapy production are leading examples.
Moving on to Assemblies
Initially, biopharma manufacturers had to purchase individual SU components and assemble them themselves. When biopharma customers began to request that suppliers offer preconnected systems, biocontainers with attached tubing and filter capsules began to appear on the market in the mid-1990s.10 Soon thereafter, these systems were provided pre-sterilized via gamma irradiation. The introduction of large-scale tube welders and sterile/aseptic connectors in the early 2000s then made it possible to connect different sterilized systems together. The first SU systems were launched in the early 2010s, and validated, sterile complex assemblies eventually became available.12
Unlike permanent stainless-steel equipment, SUTs have a supply-chain component. When SUT suppliers could not keep up with increasing demand for customized assemblies, "first-level integrators” began to appear.13 These companies took the responsibility of assembly production off the shoulders of SUT manufacturers to produce sterilized assemblies in cleanrooms from individual components. In many cases, biopharma customers view these SUT assembly producers as outsourced partners rather than simple suppliers.
Downstream and Fill/Finish Solutions Complete the Picture
Through the late 2010s, upstream processing applications dominated the SUT market, although innovation in SU solutions for downstream processing were expanding. Many new filtration offerings are now available in SU format, such as membrane systems for clarification and depth filtration, virus removal, and ultrafiltration/diafilitraiton.14 Single-pass TFF (SPTFF) systems enable continuous processing with reduced shear.5 SU centrifugation systems are also available for harvest and clarification, while growing numbers of SU chromatography offerings have appeared on the market. Current disposable chromatography systems support not only traditional resin-based systems (e.g., pre-packed columns) but also membrane and monolithic approaches.15 Many options are also available for continuous chromatography operations and are finding use at both the clinic and commercial scale, particularly in multi-product facilities.
Despite concerns over extractable and leachable (E&L) issues, the desire to achieve end-to-end SU manufacturing has also driven the development of effective SUTs for fill/finish operations.5 Complete systems include previously existing components such as bulk drug substance containers, formulation mixers, and filters, as well as filling needles and pumps that form complete assemblies capable of operating in automated mode. SU pumps include disposable pump chambers specially designed to minimize E&L while providing consistent performance.
Don’t Forget the Sensors
One of the bigger challenges that SUT suppliers have had to address is the need for sensors suitable for use with their products. Initially traditional reusable sensors were used with disposable systems, but they introduced cross-contamination risks. Vendors responded with a variety of options, including SU sheaths for housing permanent sensors to fit-for-purpose, pre-sterilized disposable sensors.5 Many have been developed to allow integration into SUS systems for real-time monitoring. Others are designed to function within a specialized sampling port. Over the last several years, not only has the variety, but also the robustness, accuracy, and overall performance of SU sensors increased.
Enabling Key Industry Shifts
A few important trends in the biopharma industry have been facilitated by the increasing availability and acceptance of SUTs. The growing focus on orphan/rare disease drugs is supported by access to flexible, smaller-volume, SUT production systems that are ideal for use in facilities producing multiple smaller-volume products but can be scaled to larger volumes if market demand changes.1 Similarly, SUTs have helped contract manufacturers respond to the growing demand for their services as biopharma manufacturers have increased reliance on outsourcing partners with specialized expertise and capabilities.
Dramatic improvements in titer for conventional mAbs, the advent of highly potent products with lower dosage requirements (e.g., antibody–drug conjugates) and the emergence of personalized medicines, notably gene and adoptive cell therapies, have all fit well with the greater adoption of SUTs for not only clinical, but commercial manufacturing.5,9 SUTs are also ideally suited for modular manufacturing facilities designed to meet the requirement of many governments for in-country drug manufacturing.11 Furthermore, combination of SUTs with automation systems further increases the time and cost savings that can be achieved.4
SUTs have also facilitated the move to closed processing, which allows reduction of the need for expensive cleanroom technologies while ensuring product safety and quality. The ability to integrate multiple SUT systems has also facilitated the implementation of continuous processing for both upstream and downstream unit operations.5 In some cases, specific SUTs, such as SPTFF and simulated moving bed chromatography systems, have been crucial enablers
Some Limitations and Concerns
As with any technology, SU bioprocessing does have some limitations, and disposable equipment, while offering many advantages, does carry some risks. For those that can be addressed, solutions have been developed or are anticipated.
The first limitation is a practical one. The biopharma industry has a large installed base of stainless-steel equipment. Removal and replacement of this base with SUTs often does not make financial sense, particularly for large-volume, established products. Typically, replacement with disposable systems only occurs when existing systems have reached their end of life.3 SUTs are, however, typically leveraged for at least some unit operations in all new production suites/facilities. The rare exceptions involved products that must be produced in very large volumes, that involve raw materials/reagents not compatible with SUTs, and products produced via large-scale fermentation.11
Other concerns the industry has worked to address include the potential for contamination by extractables and leachables, the risk of leakage, the high cost of consumables, supply chain security issues, the lack of standardization, and the potential environmental impact of plastic waste generation.5
E&L contaminants can impact not only product quality and safety, but process performance. As such, SUT suppliers have invested significantly in the development of plastic compositions with minimal E&L profiles.7 Furthermore, industry groups, such as the BioProcess Systems Alliance (BPSA), BioPhorum, ASTM, ISPE, the Parenteral Drug Association (PDA), and U.S. Pharmacopeial Convention (USP), to develop best practices for evaluating the risk posed by E&Ls for biologic drug substances/products and for ensuring the integrity of SUTs.
Other studies have shown that the plastic waste generated through the use of disposable processing equipment contributes only a minor fraction to the environmental impact of drug manufacturing, while the use of SUTs can significantly decrease energy, water, and cleaning chemicals consumption, wastewater generation, and the overall carbon footprint of biologics production operations.7 Even so, given the growing use of disposable technologies, suppliers are currently investigating the use of recycled and biodegradable plastics for SUT manufacture.
Security of supply for SUT consumables became a real issue during the COVID-19 pandemic, when a dramatic increase in demand occurred in a short period of time.16 Concerns about gamma irradiation capacity have also arisen in recent years.17 The industry overall is taking steps to prevent these issues from disrupting future SUT supply. Suppliers have dramatically increased production capacity for SUTs and put in place processes for ensuring more rapid response to changing market conditions. Both individual SUT manufacturers and industry groups have also pursued alternative sterilization technologies, most notably X-ray irradiation, which has been used for other applications in the past.
Wide Acceptance and Recognition
Overt the last 30 years, SUTs have become widely used across all aspects of biologic drug development and manufacturing. No longer are they larger used for upstream processing or in the R&D laboratory. Effective, high-performing SUTs are now available for all upstream and downstream unit operations, whether run in batch or continuous mode, leveraging cell culture or fermentation, at lab to commercial scale, or in mobile/modular or stick-built facilities, and for all modalities. They are, in fact, recognized by the U.S. Food and Drug Administration to facilitate compliance with GMP requirements and simplify product development.5 Most drug makers have worked to establish strong, strategic relationships with suppliers of SUT components and assemblies.18
Nearly all biopharma production facilities employ SUTs for at least some of their bioprocessing operations, and disposable processing has enabled many important shifts within the biopharma industry. Indeed, during the COVID-19 pandemic, access to SUTs was a key factor contributing to the speed at which new vaccine and therapeutic production processes were developed and implemented.7 Advances continue to be made in disposable sensor, automation, and data management technologies, allowing capture of more types of important process data and integration with existing systems.12 Innovative plastic compositions and SUT designs are further expanding the reliability and applicability of SUTs. Looking forward, continued emphasis will be placed on ensuring security of supply and increasing the sustainability of disposable technologies while meeting the growing needs of the expanding biopharma industry.
Our parent company, That’s Nice, is committed to supporting the companies and innovators driving the next wave of pharma and biotech innovation. To celebrate That’s Nice’s 30th anniversary, Pharma’s Almanac is diving into 30 groundbreaking advancements, trends, and breakthroughs that have shaped the life sciences, highlighting the industry-defining milestones our agency has had the pleasure of growing alongside. Here’s to 30 years of innovation and the future ahead!
References
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