Thomas Gervais, head of MSAT Business Unit at Samsung Biologics talks about some of the key issues currently affecting biologics processing.
Q) Bioprocessing at commercial scale is becoming truly industrial in scope. Given your offerings and capabilities, what protein/gene expression or chemistry platforms are offering developers and sponsors better yields, efficiencies, and programme success?
A) There are many contributors to achieving programme success, however, we believe one of the most impactful factor is the use of a CHO platform for the expression of monoclonal antibodies or Fc-fusion proteins. The CHO platform provides predictable performance across scales to facilitate technical transfer and reduce the overall batch failure rate. Although we cannot eliminate the inherent variability in biologics manufacturing, this platform enables the understanding of those components that are controllable.
Moreover, developers can offer better production efficiencies by leveraging best practices across projects. In a recent example, the optimal procedure for the recovery of over-concentrated product into the pool vessel was applied. This approach enabled consistent, high yields at this step with minimal effort, and was built on the understanding that equipment sizing has a greater influence on performance than differences in molecule characteristics or buffer systems.
Q) What aspects of biopharmaceutical technology transfer and scale-up are proving challenging? What sets a bio-technical transfer apart from a small molecule drug?
A) There are many challenges that contract development and manufacturing organisations (CDMOs) are facing surrounding technology transfer and scale-up. These challenges differ depending on whether the company is working with small or large molecule drugs.
One predominant challenge is the ongoing stress on supply chains. This is exacerbated by today’s fast-changing market dynamics. As a result, project timelines are often rescheduled due to changes in the supply of materials, such as virus filters or final containers and other critical single-use components. Within a structured workflow, this can be particularly challenging, as there is limited flexibility. Samsung Biologics has built close relationships with local and global suppliers to alleviate supply chain difficulties.
Another challenge, highlighted by the pandemic, is having gaps in product or process understanding because of limited development data throughout technology transfer. For example, development data for particular processes can be limited when scaling from small batches to larger commercial volumes. One process that is not readily scalable is harvest, specifically depth filtration during recovery of product from cell culture. As a result, the operation is typically fine-tuned at manufacturing-scale during engineering runs. If the performance of the centrifuge during harvest operations is poor, this can negatively impact the performance of downstream filtration steps. In another example, cell culture growth may be impacted by small changes in raw materials or mass transfer limitations upon scale-up of the production bioreactor. This can manifest as undesirable changes to product quality or unexpectedly low titer.
When comparing bio-technical transfer and small molecule drug transfer, it is important to remember that biologics are manufactured using living cells and may consist of genetic material or proteins (e.g., hormones, enzymes, antibodies, etc.). While small molecules are characterised by specific chemical composition and manufactured by chemical synthesis, biologics are larger than small molecules by orders of magnitude and their exact composition is more variable. Therefore, biologics are heavily defined by their complex manufacturing process and raw materials, which leads to an even greater reliance on technical transfer activities to deliver on product quality. For biologics, there is a persistent truth, “the product is the process.”
Overcoming these challenges to ensure successful bio-technical transfer and scale-up heavily relies on strong communication and planning. The volume of information required to describe a complex biologics manufacturing process is immense and requires a balance of time, organisation, and attention to detail to effectively transmit from one party to another. This is ensured by Samsung Biologics’s highly qualified Manufacturing, Science and Technology (MSAT) teams, who have extensive experience of planning and undertaking comprehensive process and facility fit and gap assessments. Evaluations of the manufacturing process, equipment, and facility fit are carried out to improve efficiency and minimise risk.
Q) Continuous manufacturing is being promoted to improve the quality outcomes of drug manufacturing and processing. Are you introducing any of these principles into your cGMP manufacturing environment?
A) At Samsung Biologics, we have integrated several elements of continuous manufacturing into our operations, including N-1 perfusion and single-pass tangential flow filtration (SPTFF). Single use components have also been heavily employed to accommodate the manufacturing of multiple products across each of our plants. Specifically, N-1 perfusion facilitates a significant productivity increase without disruption to our legacy batch processing model, and SPTFF permits relatively simple volume reduction with no capital expenditure.
Continuous manufacturing technologies must be incorporated into the process design prior to technical transfer. At Samsung Biologics, we are seeing an increase in demand from developers for an integrated continuous manufacturing approach at the large 15kL scale that we operate. Although it has been suggested that the purification process can cause a bottleneck in continuous manufacturing when not optimised for highly productive cell culture, Samsung Biologic’s dual purification train setup prevents this. Dual purification allows the processing of batches in an alternating sequence. This approach, coupled with comprehensive process design, allows us to purify cell cultures that achieve up to ~ 8.0 g/L titers without detriment to our production cadence.
With a growing industry momentum for improved quality products, at Samsung Biologics we have introduced digitalised tools into our cGMP manufacturing environment. This has spurred the assessment of various process analytical technologies with in-line monitoring capabilities, such as Raman spectroscopy or Flow VPX, to support our future growth plans. The introduction of automated, real-time testing will reduce the frequency of human errors, reduce the overhead associated with sampling procedures or process holds, and enable progress towards real-time release. It is expected that digital transformation will enable more robust process control and maximise operational efficiency.