Process intensification is a discipline in the field of process engineering with a goal to increase production efficiency. As Stankiewicz and Moulijn describe, any engineering development “that leads to a substantially smaller, cleaner, and more energy efficient technology is process intensification.”
In this blog, we’ll look at process intensification in the context of biopharmaceutical manufacturing, some examples of process biointensification, the importance of process intensification in the biopharmaceutical industry, and how single-use products can impact process intensification.
In the 1970s, Colin Ramshaw, at the British chemical company Imperial Chemical Industries (ICI), first applied the concepts of process intensification to pharmaceutical manufacturing in an attempt to reduce the size and cost of new chemical plants.
Due to financial concerns, ICI needed to reduce the cost of new plants without sacrificing output. Based on their financial calculations, they sought to reduce the volume of a plant by 100-1,000 fold. The task would require non-incremental reductions in the size of multiple systems. Colin Ramshaw’s work focused on the distillation process. At the time, chemical plants used expensive and large (skyscraper-sized) distillation columns. By combining findings in other fields, Ramshaw developed what would be known as HiGee distillation, which uses a rotating packed bed to perform distillation instead of relying on gravity over a tall column. Critically, the HiGee distillation apparatus was significantly smaller.
This innovative step in reducing the size, and related cost, of the chemical plant is the first example of process intensification in the chemical industry. Process intensification continues in pharmaceutical chemical manufacturing and manufacturers are now applying the same approach in biopharmaceutical development and the production of larger molecules.
Process Intensification in Upstream and Downstream Biopharmaceutical Processing
Biopharmaceutical manufacturing processes can be divided into two categories — upstream and downstream. Upstream processes create the raw materials needed to produce biopharmaceuticals. This can involve growing large vats of Chinese hamster ovary cells or E. coli. In comparison, downstream processes take these raw materials and turn them into the final products, such as proteins or antibodies. Let’s look at examples of process intensification in both upstream and downstream processes.
Upstream Process: Continuous Culturing
A bioreactor is an apparatus used in upstream biopharmaceutical processing. These typically large vessels are used to grow host organisms (cell lines or bacteria) which produce a product of interest.
Traditionally, bioreactors were fed-batch. In this paradigm, the organisms receive nutrients throughout a culture cycle that typically lasts between 7 and 21 days. Over time, the number of organisms increases, as does the product of interest and waste products. When the culture cycle is complete and operators empty the bioreactor, the product of interest is separated from the organisms and other products.
In contrast to fed-batch, continuous culturing uses a perfusion reactor with several key differences. Continuous culturing keeps the organisms in the bioreactor vessel (or they are removed and returned) throughout the culture cycle. A continuous culture cycle can last many months. During this time, operators continuously harvest the media (including the product of interest and any other waste products) while the organisms receive a constant supply of fresh media.
Continuous culturing produces a significantly higher concentration of the product of interest, typically around 10-30-fold. Therefore, a 10,000-liter fed-batch bioreactor can be replaced with a 1,000-liter perfusion bioreactor without sacrificing productivity.
Another important aspect of continuous culturing is that it lends itself to continuous manufacturing. Instead of manufacturing batches, or specific quantities, of a drug, the entire manufacturing process becomes a single fully integrated flow. With continuous culturing, bioreactors produce a steady stream of media, potentially for months. This media is directly filtered continuously, providing an ongoing source of the product.
Downstream Process: Separation
Separation technologies play a significant role in the downstream processing of biopharmaceuticals. The product of interest, a protein or antibody, for example, must be separated and purified from the media harvested from bioreactors.
Resin-packed columns have been the established method for filtration and purification in biopharmaceutical manufacturing. This method depends on selecting an appropriate resin that will bind to the product of interest and packing it into a column. Operators load an impure mixture that includes the product of interest into the column. After loading, the column is washed to remove any molecules not bound to the resin. The pH is then changed to allow bound products to be released, allowing the collection of the product of interest.
Biomanufacturers have applied process intensification to increase the efficiency of purification processes. Reusing resin columns, as is typical, requires extensive cleaning and validation of clean conditions between uses. Moving to a single-use paradigm avoids these steps. With this approach, a dedicated purpose-built resin-packed column can be purchased, used, and then discarded. While the initial cost of single-use resin columns is generally higher than the reusable unit, the overall cost can be significantly lower by eliminating the cleaning and validation steps.
Another approach is to use alternative filtration methods. Membrane adsorbers are structured as stacks of porous membranes with functional groups that bind to the product of interest. Operators force an impure mixture through the porous membranes, allowing all molecules not meant to be captured to pass along. The stacking of membranes dramatically increases the surface area exposed to the liquid and permits membrane adsorber filters to process the same volumes with a significantly smaller apparatus footprint.
Reducing the cost of operation and decreasing the size of an apparatus are examples of process intensification in downstream biopharmaceutical processing.
Single-Use Technology as a Form of Process Biointensification
As we discussed above, incorporating single-use products can lead to overall cost reductions. Single-use products eliminate the time, labor, and costs involved with cleaning and validating the cleanliness of a reusable apparatus.
The sterility of an apparatus is vital for producing sterile drugs and biological products. If a reusable resin-packed filter contains products from the last run, then the new product may be contaminated with an unwanted drug. The FDA has issued a “Guidance for Industry” that reviews the best practices to ensure that sterility is maintained and validated so that produced drugs are sterile. The Guidance document is typically referred to in applications for new drugs destined for the market, and the sterilization process is an essential element considered for final approval.
The rise of single-use technology is fueled, in part, by the desire to eliminate the potential for contamination. The process of sterilizing a stainless-steel column and resin and then validating that they are sterile is costly and has the potential to fail. Instead of performing these cleaning and validating steps, a new single-use apparatus is deployed for each run. A single-use approach therefore constitutes process intensification due to the associated reduction in costs and time.
The Importance of Process Intensification in Biopharmaceuticals
The push for process intensification in biopharmaceutical manufacturing has been ongoing for the last few decades and will continue into the foreseeable future.
The high cost of drugs is frequently a significant bottleneck in healthcare since a large population cannot afford prescribed medications. Reducing costs by incorporating single-use equipment or reducing the size of facilities can make life-saving therapies more affordable.
Process intensification is also important in the trend toward personalized medicine. Traditionally, all patients with a particular condition received the same drug. Personalized medicine is disrupting this by instead carefully considering the characteristics present in each patient and deploying specific medications designed to be maximally effective. This trend has created a demand for a larger number of medications produced in smaller volumes. The cost savings and efficiency gains from process intensification become increasingly valuable in this paradigm of more, but smaller, production lines.
Another factor driving the need for process intensification is the increasing use of biologics, or biopharmaceutical products. While small molecules produced through pharmaceutical manufacturing have been around for decades, there is a burgeoning need for larger and more targeted biologics. With biologics’ market size expected to double in the next 10 years, investors have ample incentive to support novel bioengineering technologies such as single-use bioprocessing solutions.
That’s a Wrap!
In summary, process intensification can increase the efficiency of manufacturing pharmaceutical and biopharmaceutical drugs. After being applied for more than 50 years in small molecule manufacturing, process intensification is on the rise in biologics biomanufacturing. With the biologics market share growing at levels outpacing the small molecule market, there is a need and an ability to invest in increasing biomanufacturing efficiency. Ultimately, the lower biomanufacturing costs enabled by process intensification should lead to lower consumer costs, making life-saving drugs more accessible.