Newsletter Signup - Under Article / In Page
"*" indicates required fields
The biopharmaceutical industry’s pursuit of streamlining complex development and manufacturing workflows is driven by process intensification and integration of automation, continuous processing, and single-use system solutions.
This strategy is especially relevant in the current landscape, where recent global health crises are directing the adoption of more versatile and economical manufacturing solutions, while adhering to stringent regulatory requirements.
Table of contents
Hallmarks of process intensification
Firstly, process intensification affords opportunities for significant cost savings.
“Process intensification strategies may help reduce capital costs by purchasing smaller-scale equipment (and associated consumables), for example. Where continuous processing is implemented, as an example of a process intensification approach, there is a reduction in the requirement for large storage tanks for holding of intermediate process streams.”
Furthermore, implementing process intensification plays a significant role in reducing facility footprints.
As well as improvements in productivity, one of process intensification’s key drivers is to guarantee and eventually improve quality. “With effective monitoring and control tools in place, you should achieve consistent performance, ensuring processes are executed to high standards with the flexibility to refine quality profiles over time,” added Laetitia.
The upside, as a result, is an increased manufacturing success rate, aiding companies in bringing complex therapies to market where they previously failed using traditional methods.
Process intensification strategies that deliver
Laetitia mentioned that one approach for optimization of a fed-batch process could be achieved by working with higher cell densities at the cell bank level. It allows reduction of the expansion phase timelines by reducing the number of passages before a production bioreactor.
This strategy also allows the inoculation of the production bioreactor at higher cell densities, reaching the production phase faster. This helps achieve higher productivity, creates opportunities to reduce timelines during production and improve facility throughput.
Laetitia then explained the benefits of continuous strategies when implemented in upstream processes. “Perfusion, when employed in the expansion phase, can as well reduce timelines,“ she said. “It’s an increasingly adopted process technology, especially for the N-1 stage before the production bioreactor.”
By combining continuous processing with single-use technologies, organizations can enhance productivity and scalability without sacrificing quality. Single-use systems also eliminate the need for stainless steel equipment and associated cleaning between batches.
Additionally, this reduces water and energy consumption and potentially improves the biopharma manufacturing facility’s CO2 footprint.
“Many companies are now opting for single-use systems to offer more flexibility and scalability,” said Laetitia. “It ranges from small to large scale bioreactors that offer similar mass and gas transfer characteristics.”
Moreover, effective process intensification strategies in biopharmaceuticals are evident in the shift towards digitalization and automation to adjust process variables in real-time, reducing variability and minimizing downtime.
Derek Ryan, Senior Director of Analytical Development at KBI Biopharma recently spoke of how the company accelerates analytical studies timelines by up to 25%. “Embedding automation engineers with data scientists and process scientists doing the work, enables key decisions to be made,” said Derek.
Overcoming process intensification challenges in biopharma
Process intensification’s adoption in biopharma also comes with challenges such as scaling up high-cell density seed trains. To achieve optimal cell viabilities and productivities, high-cell density seed trains can benefit from continuous control mechanisms.
“If a perfusion process is implemented there’s the requirement to continuously manage growth conditions and nutrient supply as well as removing waste from the bioreactor and replenishing fresh media,” said Laetitia.
“As cell density increases, gas, and nutrient consumption, along with production rates, evolve, opening up opportunities for innovative process control. This shift offers the potential to enhance both product yield and quality, inviting companies to rethink traditional approaches for better results.”
“Continuous processes such as perfusion enable higher cell densities to be achieved and maintained over longer culture durations. This comes with an increased demand of oxygen compared to classical fed-batch. Successful mitigation strategies have been developed, such as improved aeration systems in single use bioreactors and better bioreactor design to improve gas transfer.”
“Perfusion processes incorporate advanced cell retention devices, often utilizing external filtration systems like alternating tangential flow (ATF) or tangential flow filtration (TFF),” Laetitia explained.
“These systems are designed to support continuous production, but can introduce hydrodynamic shear, which may impact cell viability. To optimize outcomes, we apply targeted strategies to carefully adjust flow rates, protecting cell health while maximizing efficiency.”
These potential technical challenges may not only hinder process scalability but also overall process efficiency and product quality. Establishing reliable control systems and scalability is critical in producing biologics at larger volumes, where balancing efficiency with quality is the key objective.
Intensifying the right process for early success
KBI Biopharma emphasizes that their “right first time” approach starts with high throughput screening to de-risk early process development, selecting suitable process optimizations that align with regulatory and program-specific needs.
Laetitia further illustrates a perfusion culture’s advantages in therapeutic protein production with a recent case study. “This project’s initial goal wasn’t to move to process intensification,” said Laetitia. “It was to ‘rescue’ it. We were working with a molecule that was at risk of being abandoned because it was unstable. The stability issue was solved by moving from a fed-batch to a perfusion process.”
A study was performed to evaluate the performance of two small-scale bioreactor models, with the objective to evaluate the impact on product quality. It was demonstrated that the perfusion approach reduced fragmentation by up to 90%, significantly enhancing product quality attributes.
“We initiated experiments at small-scale, with 10 milliliters production volume, where the end product was 90% more stable compared to the fed-batch approach,” said Laetitia. “Next, we went up to a 20-liter scale perfusion, which is considered high for a lab scale production, and were able to replicate the same improvement in product quality that we observed at the milliliter scale.”
KBI Biopharma: Realizing potential
As biopharma evolves, companies that integrate process intensification solutions will remain competitive and agile to market demands. The future of biopharma will be led by adoption of such advanced methodologies driving growth in an increasingly demanding landscape.
Learn more about Biopharmaceutical Process Development and Manufacturing at KBI Biopharma.
Image Courtesy: KBI Biopharma
