Trends: Single-Use, Continuous, Modular Bioprocessing
Welcome folx!
Gm and welcome to BowTiedSkink’s third substack post.
In today’s post we will look at 3 industry trends you can discuss in an interview to show competency.
But first, a reminder as to what you can learn from this substack:
· WHO you need to become in order to excel, and WHO you can learn skills from
· WHAT Biotech Sales is and WHAT you need to know to win big
· WHEN to make the career switch
· WHY Biotech Sales is such a promising career path
· HOW to get the job and excel at it
Current trends – Single-Use, Continuous, Modular Bioprocessing
Last post we mentioned you should ask your interviewer their thoughts on industry trends. This helps convey competence. If you can have a detailed conversation about a niche subject in bioprocessing, then your interviewer will quickly see you as a peer rather than a clown.
In this section we will look at three industry trends: single-use, continuous, and modular systems.
Part 1: Single-use/consumables:
Traditionally, biologics were grown and processed in stainless-steel vessels. These are reusable and last a long time. However, they come with a massive labor, time and materials cost.
Because of FDA requirements, every process step must be recorded and verified in a batch record. Prior to starting a stainless-steel bioreactor process, you must:
1. CIP (Clean in Place) – hours of semi-automated-cleaning using multiple steps typically consisting of: rinse – base cleaner – rinse – acid cleaner – rinse – base cleaner – rinse – acid cleaner – rinse – rinse - rinse. Once complete, we sample some of the rinse and send it off for testing to ensure it is pure.
2. Pressure hold – hours of ensuring the vessel can hold ~30 psi of pressure to prevent contamination. Leaks happen often, and searching for the source can take hours, and potentially days to fix it.
3. Pre-use FIT (Filter Integrity Testing) – hours of preparing air filters, installing them into their housings, testing to ensure the filters hold ample pressure, and installing them onto the reactor.
4. Sensor calibration and installation – removal of each sensor from the reactor and calibrating them offline.
5. SIP (Sterilize in Place) – hours of shooting steam into the vessel to ensure any living thing has been eradicated.
These steps generally take at minimum two days to complete, as they must be done in series. It is also expensive – the WFI (Water for Injection) used for the rinse steps is expensive, the cleaning solution is expensive, the testing of the rinse is expensive. Validating these processes is expensive. Paying people to perform all these steps and the paperwork is expensive. Dealing with steam and high pressure can be dangerous and unnerving for operators. And every time a human performs a task there is risk of an error. One simple error can have catastrophic results.
Compare this with a single-use bioreactor (SUB):
· No CIP needed since the bioreactor consumable has never been used.
· Pressure hold takes ~15 minutes and if there is a leak, simply toss the old consumable and get a new one.
· No FIT required as all the filters are already attached and tested at the factory.
· Sensors come pre-installed and pre-calibrated.
· No SIP required since it comes gamma-irradiated from the factory.
The single-use bioreactor takes a few hours, rather than days to prepare. This allows for less downtime and higher production capacity. Reducing complexity and reducing process steps leads to fewer errors and less stress.
This example is just for one process step. Multiply the steps above for: Buffer prep, upstream storage, downstream storage, TFF, chrom, fill/finish. Switching to single-use saves hundreds of hours per batch, and thousands of gallons of cleaning liquids.
In sum, single-use is ultimately about *reducing operational cost and risk, and increasing efficiency*
The industry is clearly moving to a single-use standard, and has been for the last ten years or so, however, there are some things to consider:
· FDA approval is very complicated. Once a drug product is approved, it is extremely difficult and time-consuming to change any equipment/steps in the process. There are many top drugmakers still using stainless-steel process steps because of this. Their processes are sub-optimal, but they do work.
· Supplier quality is key for single-use processes. Companies become dependent on them. If a company gets in bed with a single-use supplier with quality issues, they can be forced to shut down because of poorly-built products.
· Similarly, extended lead times can shut a customer down. Once Covid began, demand for single-use materials skyrocketed, and the industry still has not caught up with the excess demand. Small companies are unable to leverage their buying power, and industry giants take precedence. Many companies with non-covid-related drugs have been forced to quit manufacturing because of their reliance on single-use and the suppliers’ inability to deliver.
· The size of single-use products generally max out at 3000-5000 Liters, whereas stainless steel has no practical size limitation.
· As a salesperson, you should usually want your customer to buy single-use equipment. Not only do the benefits outweigh the risks, but also you receive recurring revenue from the consumables.
Part 2: Continuous:
Traditionally, biologics were made in batch mode. And most still are. Batch mode means that each process step is performed in series. Thaw the cells. Grow the cells in scaling-up bioreactors. Harvest the cells. Isolate and purify the API (Active Pharmaceutical Ingredient). Add additional molecules. Pump into a vial. Repeat from step 1.
The whole process takes at least a month to complete. Of course you could produce many batches simultaneously if you have enough equipment and operators. But there is a better way.
Consider a batch TFF process. The liquid is placed into a vessel and pumped through the TFF cartridges over and over until the API is optimally isolated/concentrated. Then the product is removed, sent to the next step, and the TFF is cleaned and prepared for another batch. The TFF is only operating for 12 hours or less per batch – the majority of the time is spent being cleaned, preparing for the next batch, or sitting idle.
In a continuous process, instead of adding and removing the liquid all at once, there is a continuous stream into and out of the TFF.
Before, the TFF was in use for only 12 hours of the month-long batch. So it was actually only processing for 1/60th of the time of the batch. This vastly reduces the scale you must run at. Instead of a 1000L TFF skid for example, you could use a 20L continuous skid. This saves time, space, energy and labor.
In sum, continuous is ultimately about *automation and reducing downtime*
Whereas single-use has been trending up for ~10 years now, continuous is still a fairly new initiative. Here are some things to consider:
· A continuous input requires a continuous output from the previous process step for the greatest benefit. Remember how we mentioned how difficult it is to change one process step? It is multitudes harder to change the whole process at once. This is ideal for a clinical drug where the process has not been established yet.
· Some cells have poor productivity or API degradation when grown in batch mode. Continuous is ideal for these products.
· Continuous bioreactor processes (called perfusion) require A LOT of media. A cost-benefit analysis is pertinent.
· Redundancy is key. A continuous process cannot run forever. Maintenance needs to be performed, systems can have errors, filters can clog. There should be at least one (ideally two) other redundant system allowing for easy changeover.
· It takes serious expertise to run a continuous process. Especially with a lack of in-line real-time process monitoring, continuous is not friendly to inexperienced operator teams.
Part 3: Modular:
Building a new bioprocessing plant takes significantly longer than other types of factories. It takes at minimum two years after beginning construction of a new site before running a biologics process. Clean rooms in particular take a long time to build and validate, and tens to hundreds of millions of dollars. Every day that passes without manufacturing a biologic is another day that patients can’t receive treatment, and another day that competitors come closer to delivering a similar drug to market.
In response to a massive demand for new cleanrooms, many companies have started offering modular solutions. They build pre-manufactured cleanrooms in pieces. Upon order the pieces are shipped to their final destination and assembled in weeks as opposed to years.
It is important to note that >80% of drug candidates fail in clinical stage 2, and >40% fail in phase 3. By utilizing modular platforms, companies can delay large-scale capital expenses until they have the green (or more likely red) light from the FDA.
In the likely event that a drug fails in clinical trials, a modular facility can be quickly adapted to a new process. No need for large-scale construction. Just remove and/or add modules to fit the new process.
In sum, modular manufacturing is ultimately about *reducing time to market and lowering barriers to entry*
Conclusion: Synthesis:
Put single-use, continuous and modular trends together and what do you get? A true platform approach, where many promising drugs can be produced simultaneously, rapidly, and at scale. If a drug in the pipeline fails its clinical trial, companies can quickly swap production to a new target molecule. A new process no longer needs to be designed and built from scratch. This greatly reduces capex and time to market.
All of the top biotech players are building out teams to optimize based on these new trends. And of course development depends greatly on the capabilities of the products they are able to source.
It’s a rapidly growing and exciting space. Vendors are hungry for salespeople who understand and can apply these new trends. Become an expert salesperson in this space and not only will you be greatly rewarded monetarily, you will also have real influence on the future of the biotech industry.
Thanks for reading, and see ya next time
Nice write up skink! Who do you view as the top 3 companies in this space?