Continuing Innovation with Single -Use Technologies
Amit Chopra
Thermo Fisher Scientific
India and Middle East

Adoption of single-use equipment is increasing at a rapid pace. Users started to embrace the available technologies over 10 years ago to reduce the cost in pre-clinical drug product manufacturing and clinical testing of new therapeutics and vaccines. Today, single-use equipment such as single use bioreactors are being adopted in cGMP suites and entire facilities are being converted to single use. The article will address how successful suppliers are responding to the need to provide higher quality product while continuing to innovate and produce approved molecules to meet the market demand.

Although biopharmaceutical manufacturing has been pursued for just a handful of decades, bioprocess technologies have evolved dramatically. Optimization of cell-culture media and cell clones has led to dramatic increases in productivity. Manufacturing footprints have declined significantly; 20,000-L bioreactors (scale-up approach) have been replaced with 2000-L or multiple 2000-L single use bioreactors(scale-out approach).

These developments have enabled the adoption of single-use (SU) technologies across all scales, from research and development to clinical and commercial manufacturing. SU storage containers and mixers for non-critical applications have been in use for approximately 20 years. Their adoption in critical applications began a decade ago once drug manufacturers realized the myriad benefits afforded by SU technologies and equipment suppliers began to address concerns about waste management, extractables and leachables (E & Ls), and reliability of supply.

The benefits of single-use bioprocessing include both cost and time savings. Because SU systems come presterilized, there is no need for cleaning, sterilization and related validation (or associated consumables for utilities and equipment) between runs, reducing setup and switchover times. Risk of crosscontamination in multi-product facilities is also minimized.

Advances in SU Bioreactor Technology

Development of single-use bioreactors (SUBs) that are well-suited for commercial biopharmaceutical manufacturing was an initial focus of SU suppliers. Vendors collaborated closely with drug manufacturers to establish a range of bioreactors designs. Ease of use, power generation, and effective mixing, along with improvements in film robustness, were achieved.

Today, single-use BioProcess Containers (BPCs) employed with SUBs are manufactured using specialty films engineered for bioprocessing in configurations to fit different frame designs for rocker and stirred tank bioreactors. SUB vessels are functionalized to enable mixing, venting, sparging, monitoring/sensing, sampling, and liquid transfer.

Stirred-tanks SUBs are proven to operate with the same mixing principles found in traditional stainless-steel reactors. With the broad adoption of SUT, users today are looking to optimize performance and reduce the footprint on cell-culture processes. One approach is to improve the performance of stirred-tanks SUBs through implementation of a higher 5:1 turndown ratio. Doing so allows users to eliminate equipment and consumables in their seed trains and thus achieve greater efficiency and cost savings .

In 2017, Thermo Fisher Scientific developed a novel cross flow sparger technology that makes it possible to achieve similar cell-culture performance whether running a bioreactor at 20% or 100% working volume. The bioreactor design is scalable for use in process development, clinical and cGMP manufacturing. Use of this 5:1 turndown ratio bioreactor allows employment of intensified seed trains with fewer vessels, reducing capital and operating expenses and accelerating development and scale up.

The Story of Single-Use Sensors

In addition to advances in bioreactor design, SU vendors have responded to the demand for single-use sensing technologies. Control of important process parameters, such as temperature, pH, dissolved oxygen (DO), and mass transfer, is essential during cell culture to achieve the desired cell density, viability and expression rates.

Approximately five years ago, single use pH and DO sensors were introduced to the market. Since then additional SU sensors for measurement of pressure, cell density and cell (bio) mass, concentrations of cell culture metabolites , and glucose have also been developed. The performance of these devices has improved over time, but further developments are needed to achieve more robust and reliable SU sensing technologies, particularly for determination of pH and metabolites. Single-use equipment manufacturers continue to work diligently to develop.

Expansion across the Process Flow Chain

not restricted to upstream operations, and today a variety of SU solutions are available for downstream processing. In fact, most upstream and downstream unit operations in a biopharmaceutical plant can be performed reliably and costeffectively in SU equipment. The "factory of the future" concept is based on the use of SU technologies across the process flow chain , including media preparation and storage, cell culture, harvesting, buffer preparation and storage, intermediate drug storage, viral inactivation, and final formulation and product storage. Advances continue to be made in the development of cost-effective SU solutions for inline buffer dilution systems, chromatography and ultrafilitration/diafilitration.

Automation Improvements

Another area of focus for SU vendors has been the development of effective control and automation systems for use with their SU technologies. Vendors have worked closely with software developers and device manufacturers to design robust and cost-effective solutions that provide ease of use combined with reliable operation.

Different solutions have been developed for automation and control of non -GMP R & D and process development activities and clinical and commercial manufacturing, which require strict compliance with cGMP guidelines. Different software platforms (Delta V, PLC, and others) have also been adopted by the industry.

Automation and control systems are also elevating the cGMP manufacture of SU -systems to meet the demands of the biopharmaceutical industry. Implementation of semi-automated/automated manufacturing lines using HEPA -filtration has enabled the reduction of particulates during the production of SUTs. Standardization of BPC manufacturing with complete traceability has further ensured compliance with the highest quality levels expected.

Vendors are currently challenged to expand automation and control systems beyond SU bioreactors to all upstream and downstream operations. Many biopharmaceutical manufacturers desire to implement manufacturing execution systems (MESs) such as SmartFactory that integrate all upstream and downstream unit operations and their associated automation systems. At present, however, there are only a limited number of players that can support the MES level of automation in the biopharmaceutical arena.

Making Modular Moves

The needs of biopharmaceutical manufacturers today include reducing time to market, risk, and investment in infrastructure for clinical manufacturing while also producing their products locally. Smaller, flexible, multi -product manufacturing plants that can be replicated in multiple locations around the world are therefore needed.

Modular facilities with single-use technologies are increasingly seen as the answer. It takes as little as 50% of the time to build a modular vs. a traditional stainless-steel plant depending on the size and specifications.4 Modular facilities would not, however, offer the time and cost benefits they do without the deployment of single-use technologies.

Facilitating Continuous Manufacturing

Like modular facilities, continuous bioprocessing is viewed as a way to increase the efficiency and reduce the cost of biopharmaceutical manufacturing. It can also result in quality improvements and reduced environmental impacts, which has led FDA to strongly encourage its implementation.5 There is growing interest in the biopharmaceutical industry , and a number of products are under development that will be produced in the next 3-5 years using continuous processing.

This move is challenging SU suppliers. Continuous bioprocesses can operate for weeks or months, and the product contact time with the SU biocontainer film increases significantly. There is a need for highly reliable and robust SU systems with long-term acceptable E & L profiles. Furthermore, because realtime process control and monitoring are crucial to achieving consistent steadystate conditions, there is greater pressure on SU suppliers to develop robust and reliable SU sensor solutions for the measurement of process parameters.

Addressing Challenges

Initial concerns about E & Ls have been addressed through the development of high-performance, engineered films for the production of biocontainers, tubing, connectors, and other SU components.

Initial guidelines on E & Ls were introduced by the single-use suppliers and biological manufacturers group BPSA (Bio-Process Systems Alliance). A group representing biopharmaceutical manufacturers (BPOG, the BioPhorum Operations Group) and the American Society of Mechanical Engineers (ASME) have since introduced their own guidance materials. Additional guidelines on single-use processing are expected to be released by the US Pharmacopoeia and ASTM International. Due to the lack of a unified approach, SU suppliers are expected to comply with all of these varying regulations and guidelines. The testing required is expensive, and it remains questionable as to who will fund the testing required to comply with these regulations.

Similarly, standardization is needed for both biological manufacturing processes and SU solutions on the supplier side. BPOG and BPSA have initiated efforts in this direction, but much remains to be achieved in the next three to five years. Every bioprocess is unique with unique requirements. One standard set of equipment will therefore be insufficient, and customization will always be necessary. Intellectual property concerns must also be addressed.

BPOG and BPSA are also working to alleviate concerns regarding the need for the dual supply of SU technologies. Due to the widespread use of SU technologies in both upstream and downstream bioprocessing, SU systems have become critical components of biomanufacturing. SU suppliers need to mitigate the risk associated with this aspect of the supply chain.

Dual sourcing requires the identification of two completely independent suppliers or manufacturing facilities of the same supplier with no overlap in their supply chains that offer equivalent materials with respect to both their physicochemical properties and their functional performance. Few SU suppliers at this point have elected to invest in redundant manufacturing facilities to provide the desired level of assurance of supply. Moving forward on this issue requires sharing of all stakeholder perspectives and will be a slow process.

Innovation is No Longer an Option

The numerous benefits realized with the implementation of SU technologies clearly outweigh the challenges associated with their use. SU systems have been adopted in every area of biopharmaceutical manufacturing: r-protein and monoclonal antibodies, vaccines, human/animal blood products, cell- and gene -therapies, and personalized medicines. SU technologies will in fact be essential to the successful commercialization of nextgeneration treatments. As the demand for SU technologies increases with time, suppliers of single -use technologies must continue to innovate to expand the applicability of SU systems across all bioprocessing unit operations - batch and continuous and improve the performance of their products, while also investing to enhance the assurance of supply.