Single-Use Systems in Downstream Processes

Ongoing trends in the biopharmaceutical industry, such as faster speed-to-market and more efficient manufacturing, continue to drive development and use of single-use technologies, which are key components of flexible and modular processing systems. Compared to multi-use stainless-steel equipment systems, single-use systems (SUS) help capacity-constrained biopharmaceutical manufacturers use their existing space efficiently (1). SUS are well established in upstream processes and fluid handling; advances are being made in downstream processing operations, such as purification, filtration and separation, as well. 

Pharmaceutical Technology spoke with Stuart Tindal, PhD, product manager Separations, Sartorius, about new technologies and how Sartorius is addressing supply-chain limitations and other challenges.

New technologies

PharmTech: What are the advantages of using SUS vs. reusable systems in downstream processes in particular?

Tindal (Sartorius): There are significant benefits of single-use vs. reusable systems in downstream processes. First, SUS provide a low-risk method for quick turnarounds between batches and products. And, because they eliminate cleaning and sterilization validation efforts and are used where bioburden and cross-contamination risks are highest, they are useful for clinical and low-volume, high-titer production. Secondly, customers are seeking efficient processes, and process intensification (with SUS as a part of that) leads to higher productivities, higher yields/recovery, less effort, less risk of failure, or less cost. It is these business and technical pain points that enhance the applicability and utilization of SUS in this area. Sartorius has seen those outcomes specifically with regards to next-generation treatments like mRNA [messenger RNA], cell/gene therapy for vaccines, and personalized medicine. Third, SUS contribute to the continuing desire for sustainability, which is driving single-use strategies to be accountable through fabrication, use, and disposal. Sartorius has a dedicated function focusing on strong collaboration between drug producers and material suppliers to achieve sustainability success and define suitable metrics.

PharmTech: Have you added any new technologies for single-use downstream equipment for clinical/commercial manufacturing in the past year?

Tindal (Sartorius): Sartorius has launched the third-generation Flexact Modular, a single-use automation platform that addresses an automation need in the current good manufacturing practice (CGMP) clinical/commercial market. This platform improves the efficiencies from manual single-use processing steps and reduces the risk of process deviations that are attributed to human error or failure in system communication protocols and connection to other digital infrastructures. Flexact Modular focuses on the normal flow filtration and fluid management batch process steps. In these downstream processing areas, product concentrations and volumes increase the ergonomic challenges for operator handling. The larger the scale, the stronger the need is for automation to reduce the total time and effort.

We are also addressing a specific downstream processing pain point of packed-bed column usage. Even with pre-packed options, the operation, handling, validation, and storage is a risk-heavy part of purification. The combination of a high-capacity affinity capture membrane and an optimized chromatography system, however, achieves productivity that can exceed packed-bed capture. Currently, the technology is available in smaller-scale multi-use, with clinical- and production-scale SUS coming soon. The combination of SUS and membrane technology promises to revolutionize the chromatography space, particularly for clinical manufacture. It’s a challenge to design a system to optimize the process—with faster valve switching times, low hold-up volumes, and appropriate flowrates. Our philosophy is that as far as possible, our SUS and multi-use systems are equal partners, particularly in terms of chromatography performance and quality of instrumentation.

Challenges

PharmTech: Are supply-chain constraints a challenge for downstream single-use equipment? If so, what are the pinch points and what are some of the best practices for dealing with these?

Tindal (Sartorius): Industry wide, there have been supply-chain challenges because of COVID-19 and the continued ‘warp-speed’ need to support customers with assembling new solutions and equipment. Sartorius has been growing rapidly for decades; we were fortunate to identify many of these supply-chain pinch points pre-pandemic and thus were in the process of further sourcing and establishing supply mitigation strategies.

Supply-chain challenges have taught customers and suppliers that the route to a more robust supply chain is standardization. Standardization, within and between product lines, across different facilities, and eventually industry wide, results in more agility to increase production rates while also better balancing lead times against shelf life when considering inventory policies. Standardization also allows us to better protect supply chains by providing significant leverage to implement effective dual/multi sourcing of components.

PharmTech: What are some other challenges for SUS in downstream processes, and what are the best practices you suggest for handling these challenges?

Tindal (Sartorius): There are several challenges in downstream processes including:

• Process closure: Ensuring no unwanted contaminants enter the process
• Containment and preventing leaks: Ensuring nothing unwanted gets out of the process and poses a threat to the operator or requires decontamination of the cleanroom
• Detecting failures in integrity: Including ‘holes’ in or out of the consumable (in the film, connection point, weld) or through an in-process barrier (filter membrane or packed column) where the ‘holes’ are too big and may impact the integrity performance capability.

Self-contained consumables with diverse aseptic connections and disconnections can help ensure that the process is closed and contained. Integrity testing equipment can be used to test filters and SUS. Other commonly overlooked challenges often encountered in later stages are those around freezing, storage, transport, and thaw of bulk drug substance. These include the sensitivity of biologics to cryo-preservation and thawing, complexities and costs involved in the supply chain, limitations in scalability and safety, and addressing the environmental challenges posed around the refrigerant usage during the storage and shipping process. Sartorius has addressed these challenges with scalable and robust freeze and thaw solutions comprising systems and consumables. Our freeze and thaw portfolio includes plate freezing platforms providing fast freeze and thaw rates for sensitive molecules, preventing cryoconcentration effects while monitoring critical process parameters.

Logistic processes should be qualified and use standard practices for transportation of frozen materials. Our platforms include shipping solutions that are validated with common transportation methods for frozen materials according to International Safe Transit Association and ASTM-recognized standards.

Reference

1. J. Markarian, BioPharm Intl. 34 (11) 29–31 (2021).