Shifting from batch processes to continuous manufacturing has long been a goal for biologics manufacturers, especially as small molecule drug producers have increasingly shifted towards continuous processes. But to date, these processes have largely been limited to clinical products among biologics, due to challenges scaling up and improved yields and productivity from batch processes. However, biologics have a very short history without patent-protected pricing power, and the growing market for biosimilars promises to put new pressure on unit cost reductions. As a result of the traditionally limited price pressure in the industry, some process innovation might have stagnated. To quote Bill Kelly from Bioinformatics “Despite its high-technology reputation, the manufacture of therapeutic proteins is decades behind production systems for potato chips and cement in terms of continuous manufacturing”.
Continuous biomanufacturing is advancing, but not at the pace some had hoped for. The first mAb made by a completely continuous process was developed last year in Australia, but only for a Phase 1 trial. A recent GEN article discusses how manufacturing facilities for particular niches, such as exosomes, are starting to embrace continuous processing, but for large scale CDMOs and biomanufacturers, there are more than just technical challenges. Sanofi, for example, built a continuous manufacturing facility last year outside Boston, but found that there were far fewer GMP compliant off-the-shelf components available than for a standard batch plant.
Much of the development of continuous processes is split between upstream and downstream manufacturing. Within upstream cycles, the industry is trying to take advantage of single use bioreactors, which are already used in many batch processes, but combining them with cell perfusion technologies which replace the waste during fermentation, cutting off the normal death cycle that follows stabilization. While in downstream cycles, the focus is on continuous chromatography, which reduces the requirements for expensive resins used in standard chromatography.
Greater productivity in upstream batch processes has also greatly slowed development of continuous biomanufacturing. Expression levels have increased from being measured in milligrams per liter to grams per liter. This in turn has allowed manufacturers to get the same productivity from smaller and single use bioreactors they once got out of 10,000 L+ stainless steel systems. While the term “batch” sounds dated, the industry has been able to innovate within its unit-by-unit processes.
Sanofi's built plant in Massachusetts embraces continuous manufacturing, but it doesn't focus on either upstream or downstream processing as many others have done, but instead on integrating the two. Additionally, maintaining quality control and quality assurance is still a new area for continuous bioprocessing, and this required the company to make a significant investment in software and monitoring systems. The company claims that this new facility produces 770 million data points a day.
While the implementation of continuous biomanufacturing is occurring slowly, it does not appear to be stopping. However, Sanofi’s investments in IT indicate that a shift away from batch processes will require not just new perfusion or purification methods, but an entirely different approach to measuring and managing biologics production.