Empowering the Next Revolution

Over the past 20 years, the bioprocessing landscape has undergone multiple transformations. Some of those were driven by biological innovations as new therapeutic platforms and modalities were introduced; others were driven by advancements in engineering and applied technologies such as single-use solutions, automation, and artificial intelligence. But the industry’s mission of making life-saving medicines that are effective, safe, and affordable remains the same. It’s rewarding to work in a field that aims to improve people’s health and life expectancies and provide a realistic hope of survival for those with terminal illnesses. Perhaps the most astonishing development and the best example of the industry’s capability is the development of COVID-19 vaccines. The speed at which the industry proposed innovative platforms to prevent or mitigate viral infection, moved projects swiftly through the development stages, tackled immense difficulties associated with regulations and governing agencies, scaled up processes, established analytical workflows, and completed large-scale production is remarkable. Undoubtedly, that experience has confirmed the crucial impact of the industry on humanity.

Regulatory Impact: The effects of stricter regulations on the industry also are important to mention. With tight FDA regulations, especially in early development phases of therapeutic platforms, the cost of R&D continues to rise for biopharmaceutical companies. Some experts estimate the average cost of oncology and immunology drugs to be US$3–4 billion in investment. Considering that only one in every few thousand drug candidates advances from discovery phase to commercial manufacturing, managing risks, costs, and timelines associated with R&D projects has never been more important. That fact is what led our industry to the single-use “revolution” in the mid-2000s. The advent of single-use bioreactor bags demonstrated the efficiency and productivity gains by eliminating the cleaning, sterilization, and validation steps required for stainless-steel bioreactors. And the rest is history.

Single-Use Technology (SUT) has proven to reduce manufacturing footprints, shorten the time needed for plant start-up, significantly lessen cross-contamination risks, and increase much-needed flexibility in manufacturing environments. The capital expenditure required to set up a SUT-based manufacturing site is about half of that of a facility equipped and designed with fixed stainless-steel unit operations. Unsurprisingly, SUTs are a prevalent part of bioprocessing, specifically in preclinical and clinical manufacturing phases. The COVID-era supply-chain crunch taught us that the industry is short of SUT manufacturers and products and that more work must be done to secure supply for critical SUT components.

Although SUTs have had widespread application in upstream bioprocessing (e.g., bags for media and bioreactors, depth filters, single-use clarification units, and disposable connectors and cartridges and biosensors), SUTs for downstream purification have lagged behind in development. The high cost of chromatography resins and prepacked chromatography columns is a main reason behind the slow adoption of SUTs in downstream processes. Typical chromatography resins can go through numerous clean-in-place (CIP) cycles in a stainless-steel column. They then can be stored and reused for many manufacturing campaigns (of the same drug). Thus, process chromatography using stainless steel is viable in commercial biomanufacturing because purification costs can be depreciated over a resin’s life cycle. However, in preclinical and clinical manufacturing, only a limited number of batches are manufactured, so resins and reusable columns become a significant expense in an overall manufacturing budget.

Downstream Solutions: Tosoh Bioscience continues to create value for customers and the biomanufacturing industry. In my eight years at Tosoh, I have witnessed one product launch after another while the company focused on pushing the boundaries of resin productivity and maintaining the highest standards for quality and safety. One of the most recent innovations is a series of salt-tolerant ion-exchange resins. Toyopearl NH2-750F and Toyopearl Sulfate-650F resins purify biomolecules at physiological salt concentrations and provide excellent binding capacity and chromatographic performance. The most exciting feature of using such resin technology is that thanks to their unique chemistries, the resins can reduce the number of polishing steps. The result is capital expenditure (CapEx) and operating expenditure (OpEx) savings for manufacturing processes. The value proposition immediately resonated with biomanufacturers that sought improved process economics. Within a few months, the resins were placed in clinical production, a journey that would typically take two to five years.

I’m also excited to be part of Tosoh Bioscience’s recent strategic investments in SkillPak prepacked chromatography columns and multicolumn chromatography (MCC) technology. We just launched an extended range of prepacked columns and plan to add further single-use solutions/options and capacity to remove existing hurdles and bottlenecks for our customers. Perhaps even more exciting for our team is the advent of MCC technology in bioprocessing for continuous downstream manufacturing. Although the technology itself has been used in the chemical industry for over 60 years, the application in bioprocessing has just started to gain momentum, with the FDA and other regulatory agencies encouraging the adoption by introducing a draft guidance for quality considerations.

The MCC technique holds promise for tremendous savings in chromatography resin consumption, required buffer volumes, and processing times. Those are the justifications behind Tosoh Bioscience’s October 2021 decision to acquire Semba Biosciences, a global leader in simulated moving-bed (SMB) technology. We already have begun to optimize the applications of our best-in-class chromatography resins and SkillPak prepacked columns under MCC operating conditions and are excited to launch those products later this year. One of our collaborators, Catalent Biologics, put our first prototype MCC instrument ProGMP to the test at kilogram scale at its facility in Madison, WI. Catalent purified 250 L of monoclonal antibody feedstock at an expression level of 6.2 g/L titer in under four hours using only 4.7 L of Tosoh’s Toyopearl AF-rProtein A HC-650F resin packed in 6× SkillPak columns. In a collaborative presentation at an ACS conference in 2021, Catalent reported achieving 83 g/L/h of steady-state productivity, with a 70% decrease in chromatography resin cost, and a 45% reduction in buffer consumption while maintaining the same level of purity and quality compared with results from using the company’s traditional batch process. Our goal for the near future is to extend our platform solution to applications in gene therapy and other drug products with the help of our collaborators and suppliers.

Emerging Therapies: Over the past 20 years, new drug products have emerged, including small molecules, antibodies, and oligonucleotides. The latter class gained attention with the introduction of Pfizer–BioNTech’s and Moderna’s COVID-19 mRNA vaccines. Oligonucleotides — particularly platforms based on RNA interference (RNAi) — have been part of the biopharmaceutical industry for over 20 years and used to treat different illnesses. In 2018, The Medicine Company (now part of Novartis), a small biotechnology firm from Boston, MA, reached a major milestone with a later-stage FDA approval of a highly effective small interfering RNA (siRNA) inclisiran cholesterol drug. Another success story is a patisiran drug developed by Alnylam to treat Corino de Andrade’s disease using a similar siRNA platform.

Historically, reversed-phase chromatography (RPC) resins have been used with organic solvents to purify RNAi molecules and antisense oligonucleotides. The method produces low yield because of a lack of resolution, and it cannot accommodate higher loading applications effectively. Through collaborations and partnerships with leading innovators and manufacturers of oligonucleotides, Tosoh Bioscience is a pioneer in developing high-resolution resins with high productivity for such modalities. The company has established a high standard of purification using its anion-exchange TSKgel SuperQ-5PW(20) resin, as noted in a publication by Alnylam in Nature Biotechnology (1). Tosoh Bioscience customers can achieve loading capacities that are up to 33% higher than with their current platforms while improving the purity of a final drug product.

The Bio Revolution: I’m very excited about the future of bioprocessing and believe the transformation has just begun. I consider myself fortunate to live in and be part of the “bio” revolution of this era. It is an amazing feeling to know that our team’s efforts are making a small difference in the lives of many people. I’m thankful to Tosoh Bioscience for giving me the opportunity to pursue my true passion, and I am indebted to all my colleagues and team members who continue to educate me every day. I hope that I can pass on this knowledge and passion to my son, a middle school student interested in STEM education, and to all young enthusiasts exploring career opportunities in biotechnology and biomanufacturing.

Reference
1 Brown KM, et al. Expanding RNAi Therapeutics to Extrahepatic Tissues with Lipophilic Conjugates. Nat. Biotechnol. 2 June 2022; https://doi.org/10.1038/s41587-022-01334-x.

Ali Soleymannezhad is executive vice president and a member of the board of directors, separations and purification business, at Tosoh Bioscience; [email protected].