FDA Guidance on Continuous Manufacturing of Drug Substances and Drug Products

In March 2023, the FDA issued a final guidance, titled “Q13 Continuous Manufacturing of Drug Substances and Drug Products” that describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing (CM).” CM refers to “the continuous feeding of input materials into, the transformation of in-process materials within, and the concomitant removal of output materials from a manufacturing process.” The guidance applies to CM of drug substances and drug products for chemical entities and therapeutic proteins, including biosimilars, and the conversion of batch manufacturing to CM for existing products.

The guidance proposes strategies that account for scientific and regulatory considerations that impact CM. Under the scientific considerations, development of a CM should take into account process dynamics, material characterization, equipment design and system integration. Regulatory considerations include input material attributes, process monitoring and control, and drug stability in order to ensure quality product over time.

The last section of the guidance provides examples of how to implement CM of drug substances for chemical entities and therapeutic proteins and provides additional regulatory and scientific considerations and approaches for managing disturbances. For example, Annex III provides guidance on continuous manufacturing of therapeutic proteins. Figure 3 (reproduced below) “illustrates a continuous manufacturing process for therapeutic proteins that consists of unit operations characterized by a bioreactor compatible with a perfusion culture system, continuous capture chromatography, virus inactivation, and polishing purification chromatography columns, virus filtration, and buffer exchange and concentration through tangential flow filtration.” The guidance provides suggestions for process control strategies, equipment design, and process monitoring in real time.

According to the FDA’s news release about the guidance: “The FDA will continue taking necessary steps to facilitate the pharmaceutical industry’s implementation of CM and other emerging technologies that can improve product quality and help address many of the underlying causes of drug shortages and recalls.”