Among the many lessons learned during the COVID-19 pandemic is the need for large biopharma companies to be able to pivot quickly to meet emerging threats and demand for novel products. While this redirection typically costs time and money, there is significant room for efficiency if the right tools are in place. Many of these fall under the umbrella of Process Intensification (PI). While PI may not be the right decision for every company, we aim to provide some of the key considerations to determine if this is the right approach for you.
The Basics of Process Intensification
Process intensification is a holistic framework to maximize overall productivity. This can be done by increasing productivity through implementation of process changes, reducing timelines, decreasing footprints, decreasing costs, and improving flexibility. The concept is by no means a new one, but it has become increasingly popular in recent years, and we expect this trend to continue in 2021 as we see the need for fast and flexible bioprocesses increase.1
Clearly, creating a more efficient bioprocess is a positive thing, but the benefits get a little more granular than just saving time and money. They can also make the company more agile, which is increasingly important. The COVID-19 pandemic underscored the need to pivot quickly. Facilities that were making a whole host of other therapeutics must now manufacture vaccines against SARS-CoV-2. Process intensification can help make this redirection more realistic by not only allowing the biopharma to operate with more flexibility but also by offsetting the costs and time typically lost when straying from the original plan.
There are five main pillars of process intensification that we outline below.
Increased Productivity
This refers to making more of the product with a decreased or similar amount of a different metric, such as time, footprint, or cost. Productivity can be accomplished in many ways.
One key decision point is deciding on a bioreactor. There are fedbatch bioreactors (all materials are input and harvested at the same time) and perfusion bioreactors (actively replaces cell media and retains viable cells that allows product to be constantly harvested). Switching to a perfusion stage bioreactor can improve productivity three to tenfold.
Another important component is data modeling and analytics. Modeling can provide your team with quantitative insight about how decisions will improve processes, which helps teams understand what is worth the most investment. High-throughput data collection tools can help feed these models and allow them to provide better insight as well.
Reduced Timelines
To reduce timelines means to decrease the amount of time it takes to bring the product through the manufacturing cycle to market. This is especially important when companies are competing with others to be the first to market with a product for a new indication or for a product that is the first of its kind, like a biosimilar after a biologic’s patent has recently expired.
Timelines can be decreased by leveraging high density cell banks. This reduces the growth steps usually needed in a seed train. Another option is to add a perfusion bioreactor at the N-1 stage. This is just in the seed train before the production bioreactor. This method allows manufacturers to not completely switch over to perfusion bioreactors but instead implement a hybrid option that can still save days on production time. Compared to other options like dynamic perfusion, this is also much easier to implement. Additionally, timelines can be improved by transitioning from stainless steel bioreactors to single-use products. Along with added flexibility that makes it easier to switch more quickly to other products or batches, single-use technologies typically require much less downtime to operate and are quicker to scale up production.
Decreased Footprint
Footprint can be decreased by making changes to the layout, size and capabilities of a facility. These changes can decrease overhead costs and also expand potential capacity and revenue. A company’s footprint is usually a significant amount of its overhead costs, so changes here can have a huge payoff.
One method to decrease footprint is through continuous manufacturing. Here, materials are continuously added into the workflow in comparison to batch manufacturing where there are many discrete steps that are completed individually, ultimately creating a significant amount of start and stop time. Batch manufacturing has been a popular approach in the past because it allows manufacturers to pause the process at key points in the bioprocess if something is deemed off. Conversely, these interim pauses can lead to a lot of potentially wasteful downtime. If a facility is not able to create a fully continuous facility, it is still possible to be automate certain aspects of the bioprocess and reap many of the benefits.
Another way to decrease footprint is to increase cellular productivity, which will in turn allow you to decrease your bioreactor size without any associated productivity loss. With the decreased footprint, there is more room to increase the actual capacity of the facility or to maintain the same capacity with lower costs and less water and energy use.
Lowered Cost of Goods
In terms of PI, this means decreasing spend on input and manufacturing materials to ultimately decrease product cost and increase profit margins. Savings here can translate into a cheaper final product, which makes it more competitive and accessible within the market - a win for both the developer and the patient.
There are many technologies and approaches that can be switched out for an alternative to save costs. For example, implementing multi-column chromatography (MCC) is a great way to intensify downstream processes. This step is usually expensive because of resin costs. But with MCC, the amount of resin needed is decreased, which in turn lowers the overall cost. In addition, the operation time is decreased because it can semi-continuously process the material after it has been harvested.
Another way to lower good costs is to make sure materials are being used efficiently. Process modeling and analytics can be used to determine inefficiencies in areas like cell line development and media optimization.
Increased Flexibility
This refers to ensuring that the facility and the bioprocess are set up in a way that allows the biopharma to easily transition to new modalities and indications. This is crucial not only during times like the COVID-19 pandemic, but also just for facilities to be able to transition easily if a product does not make it through clinical trials.
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special offers
from Pharmaceutical Outsourcing – all delivered right to your inbox! Sign up now!
Intensifying a bioprocess will ultimately lead to producing the desired therapeutic more efficiently. These efficiencies can save the biopharma significant amounts of time and money, but they can also ensure that they are prepared to significantly ramp up production, pivot to a new indication, or accelerate the time-to-market if needed.
One way to increase flexibility is by implementing more single-use technologies. These help facilities more easily ramp up or downscale production and also allow for easier transitions between products because the strict cleaning protocols, typically associated with stainless steel products, are not needed with single-use technologies. While the majority of single-use products are for upstream processes, there are still some ways to implement this for downstream processing. For example, rapid cycle chromatography with single use membranes can be used to intensify the bioprocess during downstream processing.
The Decision to Implement Process Intensification
While there are many benefits, the decision to implement process intensification is not a straightforward one. It comes with tradeoffs and upfront investments that must be considered. Each company must determine whether it is the right move for their operations and site. Working with an experienced bioprocessing partner can help guide the critical decision process.
Training
First, it is crucial to make sure that there is a plan in place to ensure the company has the expertise to implement any new processes or provide training. While the investment in newer technologies may deliver an initial boost to workflows, companies need to make sure they are adequately staffed and trained in the new technologies to avoid long-term bottlenecks. This can specifically be a concern for smaller companies who often don’t have this level of expertise in house. If this is the case, it will be important to partner with those who have this expertise early on and even work with their technical teams to help build the internal knowledge within your team over time. Additionally, there are organizations promoting next-gen facilities, such as NIMBL and the BioPhorum Operations Group, that can provide extensive expertise on current approaches and emerging trends. Investing in memberships programs like this early on can greatly help set up teams for success.
Costs
The upfront cost of new equipment and training is a valid concern. Companies need to understand exactly how long it will take for the change to pay off before they decide to invest in tools and training. It is also wise to fully vet the credibility and capability of the supplier prior to investing in single-use technology. A break in the supply chain can significantly impact manufacturing in single-use facilities – more so than facilities using stainless steel equipment.
Tradeoffs
All these decisions come with tradeoffs as well. Something that may increase productivity may also increase footprint. For example, large media and buffer volumes are usually associated with perfusion bioreactors and continuous processes. While these are more productive, they may make it harder to reduce facility footprint. However, there are ways to reduce the amount of the tradeoff in many cases. For example, buying a premade solution. To make sure you are considering all the alternatives, it is important to be working with an experienced bioprocessing partner who can help provide this insight.
Industry Challenges
Ideally, an optimized bioprocess would be fully automated. But this can cause challenges. If the company chooses to implement automated technologies throughout the bioprocess, they will likely have issues integrating these solutions if they are from different vendors. The industry must focus on solutions, such as collaborations between vendors, that allow these technologies to communicate with each other if we are going to reap the full benefits of automation.
Regulatory
Companies may be hesitant to introduce process intensification into their manufacturing workflow because it could disrupt regulatory processes. If a company is in the late stages of clinical research and are making significant changes, this could mean major delays or complications with regulatory approvals while minor changes can be incorporated more seamlessly. However, if you have good reasoning and data to justify why the change was made, the FDA may be more open to working with your company to minimize regulatory disruptions. It also is important to weigh the savings because even if there are delays, there could still be long-term advantages that will make up for the initial loss. Recognizing the importance of process intensification and continuous manufacturing adoption, the FDA is dedicating resources to make sure that proper approval pathways are in place.2 They have also created an Emerging Technology Team that provides support for navigating the review process for newer methods, such as this. Ultimately, it pays to plan ahead and to understand how process intensification may impact your regulatory situation – but it’s not necessarily a dealbreaker.
The Future of Process Intensification
While it is clear that PI is becoming more widely adopted in the biopharma industry, each company must determine how exactly they can best implement these changes to their current processes. While there are many benefits, there are also initial upfront investments and regulatory concerns to factor in.
A good bioprocessing partner can help biomanufacturers understand if making major changes, introducing a few new technologies, or maintaining the current workflow is the best decision. A complete overhaul may not be necessary to receive some benefits. The partner will consider factors such as molecule, stage of the product, facility size, current facility setup, manufacturing capacity, currently available solutions, and timeline needs to help the biopharma make this decision. If deciding to only intensify one part of the bioprocess, it will also be important to understand how that change will impact the rest of the process and manufacturing network.
References
- Langer, E., 2021. Biomanufacturing: Demand for Continuous Bioprocessing Increasing - Bioprocess Development Forum. [online] Processdevelopmentforum.com. Available at: http://www.processdevelopmentforum.com/articles/biomanufacturing-demand-for-continuous-bioprocessing-increasing/
- U.S. Food and Drug Administration. 2019. FDA Statement On FDA’S Modern Approach To Advanced Pharmaceutical Manufacturing. [online] Available at: https://www.fda.gov/news-events/press-announcements/fda-statement-fdas-modern-approach-advanced-pharmaceutical-manufacturing
Author Biography
Priyanka Gupta has been working with Sartorius since 2007, where today, she is the Head of Market Entry Strategy for Protein Based Therapeutics. She holds a Master’s in Chemical Engineering from Florida State University in Tallahassee, FL. Most recently, she developed process models to understand the economic impact of implementing Process Intensification for various modalities and scales. Prior to that, she was a downstream application scientist. Before joining Sartorius, Gupta was a Process Development Scientist, Downstream at Amgen for more than four years.