Describe advantages of single-use components compared with conventional stainless-steel components.
DT: The advantages of single use components over the conventional stainless-steel systems are:
- Improvements in process, operational efficiency, and throughput
- Reduced risk of cross-contamination
- Minimal or no sterilization-in-place (SIP) and cleaning-inplace (CIP) process development and its validation
- Potential reduction in capital investment
- Potential faster facility set-up time
- Less man hours for equipment setup
- Batch turnaround times are reduced
- Reduced utility needs
- Reduced equipment footprint
- Reduced down time
- Platform approach – Standardization
- Operational fl exibility
- a. Process portability is greatly increased
- b. Engineering variables upon tech transfer and scale-up can be reduced
AMT: The major motivators for implementing SUS are manufacturing cost reductions, increased production effi ciency, and lowering overall risk factors. These motivators are important for process development and manufacturing engineers and scientists to employ when designing new or upgrading legacy systems. This review the will focus on unit operations having good potential for implementing SUS and its relative impact on costs and production efficiencies.
Major Market Motivators
Time to Market (Process Development and Scale-up):
Reducing the timelines to a marketable drug product can mean billions in potential sales. Knowing solid estimates on the development to production scale-up timelines and costs can provide early cost/ feasibility projections. Utilizing the significantly shorter lead times in qualification and commissioning processes and systems through the use of prefabricated, ready-to-use polymeric devices and systems can provide the flexibility in process and device design not usually possible with SS hardware. Additionally, reduced change control documentation costs and timelines are achievable by using prequalified and acceptable polymeric materials with known risk evaluations.
Cost of Goods:
The direct labor costs for cleaning (CIP) and sterilizing (SIP) SS hardware as well as the utility cost for water (PW/WFI), steam production for autoclaving/SIP and cleaning chemicals can be significantly reduced or completely eliminated when implementing SUS technologies. Overhead costs and other production costs can similarly be reduced or eliminated, for example;
- Capital Investment in SS Hardware tanks and piping are minimized.
- Cleaning validation requirements may be reduced or eliminated.
- Maintenance downtime for SS hardware is reduced or eliminated.
- Chemical waste stream costs will be reduced
Increased Production Efficiencies:
Manufacturing may achieve more turn around cycle times. Reducing the change-out handling operations using SUS offers faster makeup connections of prefabricated assemblies and systems. When drug demand increases, the optimization processes of scale-up, change control documentation, regulatory filings and qualification can be substantially reduced by using the same polymeric materials of construction from the scale-down processes.
Process Control – Risk Assessment:
Batch cross contamination through inadequate CIP procedures or failure to follow proper SIP in SS systems can be reduced or eliminated by implementing SUS. Each system is supplied sterile and assembled prior to use, then discarded after use, thereby reducing risk of cross contamination. Microbial contamination of media/buffer preps, downstream storage/aseptic processes can be reduced thus the lowered risks result in direct cost savings. Extractables & Leachables from polymeric devices/systems meet or exceed regulatory requirements and industry specifications. Through the reduction or elimination of cleaning solutions and chemicals risks of residues or excessive exposure to operators is achieved.
PK: Single-use technology permits more cost-efficient design and swifter implementation compared to conventional stainless-steel components . It allows for the design of bioprocesses with minimized technological and procedural cleaning efforts. Thus, preparation times are shortened, particularly for product changeovers, but also for batch-to-batch preparation during manufacturing. In comparison to different options for the technology set-up, potential cost savings on capital expenditure (Capex) have been estimated:
- 25–45% reduction in process equipment,
- 37–40% reduction for piping and equipment installation
- 36–52% reduction in instrumentation and automation
Savings in Capex are mainly based on absence of the need for complex piping systems required for CIP and SIP, including associated automation components. Similarly, fewer qualification and validation efforts are needed due to vendor-sterilized (gamma-radiated) bags and associated flow paths. In contrast, other cost blocks arise with investment projects (e.g. building, clean room, floor and ceiling construction and associated HVAC) and yield lower or even negligible potential for savings depending on the comfort admitted for operation in the considered studies.
KC: The advantages of single-use most often cited are cost and simplicity. These translate in numerous ways to the practical operation of a process development or biologics manufacturing organization. An aspect of simplicity that may be routinely overlooked is that of distributed operations. In this industry we spend a lot of time talking about scalability. Scalability is only important if one is trying to manufacture a product, a therapeutic. With single-use, simplicity enables biomanufacturing operations in atypical geographic regions with an endogenous workforce supported by an appropriate, but small, group of knowledge workers.
JH: The primary advantage of single-use components is operational flexibility, which as a result contributes to agility and speed. Users are afforded great adaptability because of the single-use systems’ rapid configuration capabilities and ability to fit a wide range of manufacturing processes. Stainless steel components are much more rigid, both literally and figuratively. Once a process has been designed and a facility has been engineered utilizing steel, it requires an extensive overhaul to accommodate change. Alternatively, single-use manufacturing allows users to set up a manufacturing suite according to their current needs, and quickly switch over to meet their future needs when the next molecule emerges in their pipeline. When designing a facility as completely singleuse, it is possible to build manufacturing suites with power, water and gas drops throughout, allowing the equipment to be configured to the needs of the current campaign. Lastly, utility requirements shrink considerably as single-use manufacturing removes the need for CIP and SIP infrastructure. As a result, a smaller initial capital investment can significantly reduce the costs associated with facility construction.
What are the challenges of working with single-use systems?
DT: While their use is growing rapidly, single use systems are in their relative infancy and their true limitations are often not well understood and are continuously evolving. In our opinion, there are at least four major areas of challenge; scale, qualification, training, and documentation. Single-use technologies are currently limited by size. For example, current chromatography systems have flow rate limitations and the current instrumentation and sensors on the manifolds have less sensitivity and accuracy compared to those offered in stainless steel systems. In addition, the largest currently available single-use chromatography columns are only 30 cm in diameter. Likewise, single-use TFF systems are also substantially limited compared to their multi-use counterparts. Current models are limited to 10 m2 surface area. Hence, single-use technologies are increasing in popularity at pilot scale; but their implementation in manufacturing scale remains challenging due to size constraints.
Secondly, implementing traditional qualification methods are often not the best approach to single-use technologies and thinking outside the box is sometimes needed. Currently no clear direction or requirements are available for extractables and leachables for single-use product contact surfaces. For example, most of the studies done for single-use components by various vendors do not include NaOH as one of the standard solution matricies, in spite of it being one of the standard titrants used in the industry.
Thirdly, components such as pinch clamps used on the single manifold are not currently well- labeled therefore writing SOPs and training operators can be challenging. This, coupled with the permanent way in which most connections are made, make revisions of these interconnects, if done improperly, impossible thereby increasing the requirements on training. Educating the internal customers, such as manufacturing operators, as well as external clients on limitations and strengths of single-use technologies needs to be done from start of single-use technology implementation.
Finally, quality release/regulatory compliance documents provided by some vendors are not currently up to the standards of those offered for many re-usable components therefore vendors may need to be engaged early on regarding documentation requirements.
Understanding these limitations and working with a process development group when developing the processes can be very helpful and can enable successful implementation of single-use technologies.
PK: The entire supply chain for components needed throughout the process must be carefully set-up. Shelf-life of gammaradiated components has to be considered for procurement schedule. Vendor qualification is key with respect to securing the supply as well as suitable quality for manufacturing of the components. Warehousing needs to be adapted with respect to storage capacity. Operators must be trained in handling this type of technology, both during set-up of components in preparation of a batch to be manufactured as well as during operation itself.
When using larger scale components, there is a risk in overestimating mechanical strength, particularly of weld seams.
Some process parameters can be measured directly by in-line instrumentation; others still require off-line or indirect measurements, e.g. calculating mass flows based on a change in weight by using load cells data during specific periods of operation.
While disposal of individual single-use components is usually not a challenge, the proper handling of the used bags requires some attention. Upfront autoclaving prior to external disposal or incineration might be required by local legislation when working with cultures containing pathogens.
Applying single-use components by various divisions and departments may generate a variety of component designs within one company. Standardization would simplify the supply chain and lower the cost for sourcing. However, sensible standardization will become an even bigger challenge if such components have been introduced by collaboration partners for specific development projects and their use is registered in CMC dossiers.
KC: Thinking again on biomanufacturing and the appropriate scale for it, interoperability of unit operations comes to mind. The industry’s implementation of single-use is quite limited when compared to conventional technologies. Whereas before, it was possible to scale a piping or tubing run and connect it with the ubiquitous Triclamp ® connections, there are still limits to diameters and connection types have not been harmonized sufficiently (in single-use). JH: Single-use systems do indeed present unique challenges. The scale at which users would like to operate can play a huge role in whether or not single-use is right for them. When you consider risk mitigation, not all companies are comfortable utilizing single-use containers for 2-3K liters of processing fluid. Also, careful economic analysis can be vital when companies determine which steps in their process should be executed using single-use technologies. When factoring in variables such as electricity, water and local labor, the decision between stainless steel and single-use can become more complex. Warehousing is also another consideration. While single-use allows users to downsize the classified space they build and maintain, there must be plans in place to store the necessary supply of single-use materials. The logistics that accompany a single-use operation can certainly be different than a classical operation, and should certainly be considered.
How will single-use systems continue to provide flexible solutions to the end-user?
DT: Single-use systems are flexible solutions especially for many multi-product facilities. They often reduce equipment downtime and can eliminate the need for cleaning thereby enabling increased end-user productivity. In addition, flexibility afforded by single-use systems can provide the end users the ability to customize and leverage “plug-and-play” unit operations to process needs.
KC: Single-use systems, including equipment, tubing sets and connectors, (despite challenges mentioned above), still offer a great deal of flexibility. Changes in process, changes in operating environment and changes in geography may each be accommodated alone or together. Facilities no longer need to be dedicated to a single therapeutic, an organization could have the ability to switch between cell culture and fermentation processes quite easily, and the “laundry list” of local skilled labor (including e.g., sanitary welders, validation support, etc.) all but goes away.
JH: Customers are continuing to demand equipment that will work for their processes from early to late stage clinical development without requiring new capital investment every 12-18 months. Singleuse systems will continue to offer an increased operating range within unit operations, and systems capable of multiple manufacturing steps, (i.e. chromatography and tangential flow filtration), will have a huge impact on the market. The ability to perform two distinct unit operations at multiple scales with a single piece of capital provides the ultimate flexible solution to an end-user. To that end, from a value perspective, there will continue to be a trend toward more ‘all inclusive’ single-use offerings that encompass not only the capital and consumables, but ancillary items like regulatory packages and validation packages that are straightforward for the end-user to execute.
What features of single-use systems help to confront regulatory initiatives head-on?
DT: Single-use technologies have both an advantage and a disadvantage compared to traditional systems when confronting regulatory hurdles. They require minimal or no sterilizationin- place (SIP) and cleaning-in-place (CIP) process development and validation therefore making them attractive option for regulatory expedience but currently there are limited standards and regulatory requirements for single-use systems making benchmarking existing systems challenging. Universal standards will be needed as single-use technologies become more and more accepted in the industry.
KC: Improved quality is first and foremost when considering single-use’s impact on the regulatory front. Just consider how single-use reduces or eliminates risk of cross-contamination, simplifies inter-batch cleaning verification and tames the documentation tiger. The “Agencies” have been adapting. They have been synthesizing new technologies into their guidance and initiatives. Single-use is certainly now part of their lexicon.
JH: The elimination of cleaning validation is certainly a substantial regulatory advantage. In a multi-product facility, users have the ability to leverage single-use technology in order to switch between products. By swapping out the product contact materials via singleuse components, there is no longer a need to run cleaning cycles and the headaches of cleaning validation become a thing of the past. Also, single-use systems can incorporate sterile-to-sterile aseptic connectors that allow much greater operational flexibility in terms of classified space. The evolution of single-use technologies has certainly driven the discussion around gray space manufacturing and enabled greater use of CNC (controlled not classified) space. These concepts are gaining traction within regulatory agencies and would not be remotely possible without single-use technologies.
What are the obstacles in developing reliable and efficient single-use bioreactors?
DT: In our opinion, a vendor’s ability to manufacture product with same consistency, especially with respect to materials, bag film, sensors, etc. is a major obstacle in developing reliable and efficient single-use bioreactors.
PK: Single-use components become more technologically advanced by the development of smart technologies, e.g. for agitation systems or in-line sensors. By definition, single-use components are expected to become low cost components. But hightech development might not be free. The necessary manufacturing efforts versus the targeted unit sales cost might always remain compromises. Maybe higher component production figures could lower the specific unit sales cost.
KC: We need to bear in mind that single-use technology is still young by comparison to what it is replacing. Reliability and efficiency did not happen overnight with conventional technologybased systems either. Buyers and suppliers must recognize their respective roles in the production of a therapeutic. Players will come and go. Buyer processes will change, supplier products will evolve. Market forces and financial incentive will dictate the continuum of outcomes. See also #2 for an example.
JH: Bioreactors were developed using classical biological engineering principles with stainless steel as the backbone. Maintaining a culture and encouraging it to thrive and produce therapeutic proteins was a massive challenge that led to the birth of the biotech industry. Now, vendors are seeking to replace those stainless tanks with single-use bioreactors without sacrificing anything in terms of performance. Given those considerations, accurate and robust sensing technology is one of the biggest pitfalls in the single-use bioreactor space today. Achieving comparable performance between single-use probes and classical electrochemical probes has proven somewhat elusive, but strides are being made every day. End-users are rarely willing to give up accuracy and stability in their sensors for the sake of making them single-use.
What does the future hold for single-use in the next five years?
DT: The future for single-use technologies is very bright as more and more companies embrace the flexibility afforded by single-use technologies – especially in the growing field of potent molecules. We are excited to see that more research and development efforts are being invested to develop and offer single-use technologies for implementation in manufacturing including advancements in size, configurations, mixing capabilities, etc.
PK: A bright future is expected for single-use. The technology gaps or limitations mentioned above will be overcome. Users will gain a better understanding of the potential of such technology and current hesitations may even disappear. Single-use components reflect a very useful amendment of the engineer’s “tool box”. Careful case-bycase verifications will support the broader use.
KC: In the next five years, it is reasonable to believe singleuse will spread further and deeper into all aspects of biopharmaceuticals. Familiarity, industry experience and standardization will play substantial roles in this spread.
JH: I believe the industry will continue to witness the introduction of multi-functional single-use systems that will drive down capital investment costs and level the playing field in single-use manufacturing. As new biopharmaceutical companies emerge, and with the explosion of biosimilar and biobetter companies, any advantage that results in lower cost and faster time to market will drive innovation. More robust regulatory offerings around single-use technologies will define who succeeds in that space. End-users will continue to demand increased levels of support, more detailed traceability and supply-chain transparency from their vendors. Those that can proactively help users to overcome regulatory hurdles are those that will drive the shift of the industry towards single-use manufacturing platforms.
Any additional or closing thoughts?
DT: Single-use technologies can offer flexible solutions to the end user enabling faster set-up of equipment, increasing productivity. However, a keen understanding of the limitations and working constraints can help in smoother implementation. We, at Fujifilm Diosynth Biotechnologies, Inc. have been successfully leveraging disposable systems for many customers including potent molecules and products requiring specialized handling.
PK: The bottom line is that no general statement can be derived on which approach is superior: single-use or stainless-steel systems. The decisive criteria for which technology to select includes the expected volume requirements of the product(s) to be manufactured, the requested flexibility in case of multiproduct activities, and resultant capacity planning with associated volume constraints.
KC: Change is inevitable. Change is constant. We are practicing our professions in a period of significant industry change And, change is harder for some more than others – in the personal sense and for businesses. Single-use has been and will continue to be disruptive to conventional ways of thinking and operating. Single-use may not fit every application today. It will be critically important to be willing and able to apply single-use technologies where it makes the most sense…whether for humans, animals, food supply or the planet.
JH: Single-use technologies and manufacturing platforms are undoubtedly the way of the future. As the science improves around biopharmaceutical manufacturing and as the industry trends towards concepts like personalized medicine, the advantages offered by single-use systems are far too great to ignore. Batch sizes will continue to shrink, governments will continue to insist on local production, multi-product facilities will become the norm and the ‘engineering’ around single-use systems will catch up to (and surpass) stainless steel designs. Coupled with advances in single-use aseptic connection technology, the industry will be able to produce drug products in environments that were unthinkable even 5 years ago. Ultimately, with patient safety as the highest priority, the potential is largely unlimited.
References
- Peter Kraemer et al. GEN Genetic Engineering and Biotechnology News; Sep 1, 2012 (Vol. 15, No. 32)
- Peter Kraemer American Pharmaceutical Review; May /June 2012; Volume 15, Issue 4