The misconceptions about disposable bioreactors' lifecycle are gone; the era of hard-piped, giant, stainless-steel tanks for biosimilar development is history now, according to Sarfaraz K. Niazi, PhD, in his latest column.
The days of giant bioreactors and billions of dollars of investment are gone. Now a small bioreactor, no more than 1,000 L, can produce a commercial supply of biologics in a continuous mode, a quest that has been in the works for several years.
In March 2023, the FDA sealed it in a detailed final guidance, addressing all validation and compliance issues, and details of lifecycle management. It applies to both chemical and biological products. Now all new biologics and biosimilars can be produced with the least capital expenditure and operating expenditure. This should encourage smaller entities to enter the biosimilars business.
In addition, it should be made clear that the Biologics Price Competition and Innovation Act restricts how a product is approved. For example, contiguous manufacturing applies to perfusion systems where proteins are secreted. In contrast, both eukaryotic and prokaryotic cells secrete, and continuous manufacturing is most suitable for eukaryotic systems that allow post-translational modification, such as significant dose antibodies.
Continuous manufacturing applies to any unit operation, such as a bioreactor, capture chromatography, virus filtration, virus inactivation, buffer exchange, and concentration through tangential flow chromatography. Each unit operation is integrated with adjacent unit operations, a surge line, or a tank connecting unit operations.
Using a surge line or tank allows continuous operations to accommodate differences in mass flow rates or process dynamics. It involves continuously feeding input materials into, transforming in-process materials within, and simultaneously removing output materials from a manufacturing process in an integrated system with 2 or more unit operations, regardless of their nature. Integrating the fill and finish unit operations is not too far, further reducing the cost. The idea of an integrated modular system from cell culture to vials and syringes is forthcoming; such an example has already been applied to messenger RNA production.
The batch testing cost is significantly reduced as continuous monitoring systems remove many testing requirements. Other high-cost components of at-scale process performance qualification lots are decreased substantially, and so is the time to file a biologics license application (BLA) since a single run can provide process and product validation. For analytical assessment in the development of biosimilars, samples drawn over the cycle period can be used to compare critical quality attributes, another significant saving to developers. I have filed my query in the comment section of the FDA portal.
The FDA has also listed additions to the Common Technical Document for the Registration of Pharmaceuticals for Human Use specific to continuous manufacturing BLA submissions, making it clear to developers what they need to submit.
The critical elements of the guideline include:
I do not see any reason why a biosimilar developer would not choose continuous manufacturing over batch manufacturing. Also, the approved biosimilars can be switched over to secure better profit margins as the competition heats up.
However, to reduce the time and cost of switchover, careful planning is required to minimize the switching cost. Setting up new manufacturing is more straightforward, and maximizing single-use technologies is recommended. The misconceptions about disposable bioreactors' lifecycle are gone. The era of hard-piped giant stainless-steel tanks, a darling of Big Pharma, is history now.
 National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Board on Chemical Sciences and Technology. Continuous Manufacturing for the Modernization of Pharmaceutical Production: Proceedings of a Workshop. Washington (DC): National Academies Press (US); January 30, 2019. Accessed April 12, 2023. https://pubmed.ncbi.nlm.nih.gov/30994997/