7 Bioprocess Intensification Strategies
By Matthew Pillar, Editor, Bioprocess Online
Bioprocess intensification concepts have gained traction in biopharmaceutical manufacturing over the past decade, albeit more slowly than analysts had predicted and suppliers had hoped. The promise of streamlined operations that increase productivity, reduce costs, speed time-to-market, and enable adherence to high standards of product quality and safety are certainly intriguing. That said, there’s not been a glut of accessible data on where biopharma manufacturers started their process intensification efforts and where they’ve seen success, much less how they’re quantifying that success.
The reality is that “process intensification” is one of those big umbrella terms that unfairly implies a concept that comes with an instruction manual. It doesn’t. It isn’t prescriptive. It doesn’t have to start in a specific place, and it really never ends.
On June 11 at 11 AM ET, I’ll host AstraZeneca Bioprocess Engineering and Technology group director Irina Ramos, Ph.D., and another special guest on our next Bioprocess Online Live (virtual) discussion on the latest bioprocess intensification plans in practice. These seven concepts, strategies, and focal points are sure to make their way into the conversation.
1. Continuous Bioprocessing
Continuous bioprocessing, or the uninterrupted connection of upstream and downstream unit operations, pares down the line of demarcation between these distinct process sets in an effort to yield higher productivity, a reduced facility footprint, improved product quality, and simplified scale-up procedures.
Traditional batch processing has long been a biopharmaceutical manufacturing hallmark, but leveraging flow chemistry principles in a continuous bioprocessing environment is catching on, again, perhaps more slowly than anticipated. Integrating continuous unit operations such as cell culture, purification, and formulation, according to Grandview Research, creates a potential API savings of more than 60% and a “significant” reduction in time-to-market for the final product.
Despite these advantages, continuous bioprocessing is a long way from standard in all but a few bioprocessing facilities. To learn why that’s the case, check out this recent column from our friend Ioanna Deni at BioPlan Associates.
2. High Cell Density Cultures
Achieving high cell density cultures in upstream processing is key to—and often a first step toward—process intensification. High cell densities provide increased product yields from the same bioreactor volume, improving productivity and reducing costs. It’s not a new concept – for more than a decade, the approach has enabled manufacturers to achieve productivity levels up to four times higher than standard fed-batch processes. Cell densities over 100 g/L dry cell weight or greater than 10^9 cells/mL for bacterial cultures like E. coli using fed-batch mode represented a giant leap in productivity. For mammalian cell cultures producing therapeutic proteins like antibodies, titers in the range of 10 g/L product concentration were considered unattainable just a couple decades ago.
Of course, achieving high cell density cultures requires investment in both equipment and scientific resources. The formula requires experimentation with expression systems, culture medium, growth rates, and oxygen supply, and manipulating those variables is best achieved with an investment in disposable and rocking motion bioreactors, in-line sensing and process analytical technology tools.
Read more on cell growth and cell counting from Bioprocess Online contributor Pankaj Singh here.
3. Multi-Column Chromatography
Multi-column chromatography enables a continuous downstream process by allowing the product stream to flow uninterrupted between columns in different cycle stages. According to major suppliers like Sartorius and Pall, (yes, even those that sell chromatography resins), it can reduce resin costs by up to 80% compared to batch chromatography, because multiple, smaller columns lend to fuller and more efficient use of resin capacity than the larger columns necessary to handle high titers in batch chromatography operations. That’s a particularly admirable goal in applications that require expensive Protein A resins. By simultaneously performing loading, washing, elution, and regeneration steps across multiple columns in parallel cycles, suppliers tell us multi-column chromatography can also yield a 3- to 5-fold increase in productivity compared to batch chromatography.
Multi-column chromatography is also configurable—column count can be modified to fit specific scales and processes, and even in large implementations, the system generally requires a smaller footprint than batch chromatography.
4. Precipitation and Crystallization
Speaking of chromatography efficiency, precipitation techniques ratchet downstream purification up a notch, enabling process intensification by eliminating multiple chromatography steps and reducing the number of unit operations. Precipitation lends to process intensification by facilitating continuous integrated processes (purification and isolation, for instance) by coupling with other operations like cell removal and viral inactivation.
Crystallization is another downstream purification and formulation step that, when executed in continuous fashion, supports process intensification. Compared to batch crystallization, continuous crystallization earns biopharma manufacturers a smaller footprint, reduced capital expense, and higher throughput.
5. Modular/Flexible Facilities
Particularly in response to the growing demand for personalized medicines and smaller batch sizes, biopharma manufacturers are increasingly investing in modular and flexible manufacturing facilities. These facilities are designed to accommodate rapid process changes, scale-up/down operations, and facilitate technology transfer across different product lines—a particularly important consideration for manufacturers who are anticipating a pivot. They also offer an attractive advantage to new builders, by many accounts cutting construction time by as much as 50 percent compared to fixed facilities.
Read more on facilities agility in this column from Bioprocess Online contributor Mark Witcher, Ph.D.
6. Single-Use Technologies
Speaking of agility, the widespread adoption of single-use technologies, such as previously mentioned disposable bioreactors and chromatography systems, unquestionably supports process intensification. They enable faster changeovers, reduce cleaning and validation requirements between batches by all but eliminating the risk of cross-contamination, and facilitate flexible manufacturing environments.
Single Use Systems claims that full adoption of these technologies can lower initial investment costs by 40 percent, reduce water and energy consumption by 46%, and yield a 35% improvement to a biopharma manufacturing facility’s CO2 footprint.
7. Bioprocessing 4.0 and Automation
It can be argued that, like many “industry 4.0” concepts, “bioprocessing 4.0” attempts to swallow an ocean where drinking from a water bottle might be more appropriate. At a high level, it encompasses digitization and automation of paper-based processes, digital data collection, digital analysis, digital process control, and IoT connected equipment and systems to enable real-time monitoring and autonomous operations in integrated software platforms. That’s all to underpin the application of advanced analytical tools and predictive modeling to optimize processes and, ultimately, inform product quality. We’ll not even get into the role of feedback loops and machine learning applications. It’s a lot to contemplate, much less invest in an overhaul. Bioprocess 4.0 is aspirational for many, if for no other reason than its implied benefits (there’s not much comprehensive or quantitative research available just yet), and its relationship to process intensification might be best described as mutually beneficial.
The good news is that getting to Bioprocess 4.0 is an incremental journey, and steps taken toward process intensification are taken in lockstep to that destination. The efficiencies facilitated by any and all of these process intensification strategies will set manufacturers up for better Bioprocess 4.0 inputs, and Bioprocess 4.0 outputs will inform more opportunities for process intensification. One is not necessarily prerequisite to the other, and there are myriad places to start.
On June 11 at 11 AM ET, we’ll explore those starting points, next steps, and real-world results in bioprocess intensification on Bioprocess Online Live. Stay tuned to this space for (free) registration information! Meanwhile, read more on continuous bioprocessing from Bioprocess Online contributor Priyanka Bhendale here.