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38 BioPharm International Quality and Regulatory Sourcebook eBook March 2022 www.biopharminternational.com comparability, proprietary vs. open- source soft ware, common terminol- ogy, and existing efforts in these areas, explains Kokai-Kun. Additional indus- try discussions since then have been ongoing. BioPharm International spoke with Kokai-Kun about these efforts. BENEFITS B ioP h a rm: W h at do you s e e a s the main advantages of implement- ing cont inuous ma nu fact u r ing for biologic drugs? Kokai-Kun (USP): Biopharmaceutical continuous manufact uring (BCM) represents a real opportunity for bio- pharmaceutical production because it has the potential to improve manufac- turing eff iciency, reduce production costs, and significantly reduce environ- mental footprints. Once implemented, there are also other benefits for devel- op er s /ma nu fac t u rer s of biolog ic s including: the ability to assess multiple process parameters during a single run, reduced dependence on skilled pro- duction workers (who require special- ized training), and less overall human interaction with the process. There is also the ability to increase process output by increasing run times rather than having to develop a larger scale of manufacturing, which can be espe- cially relevant when a product is tran- sitioning from the development scale into commercial production. BCM also holds promise for advanced therapies by streamlining the manufacturing process, including higher yields and more eff icient downstream processes of challenging products. BCM also a l lows for immediate feedback on process parameters to f ine-tune the process, allowing for products to be developed for individual patients. CHALLENGES BioPharm: What are the main barri- ers to processes that connect upstream and downstream manufacturing, and what is needed to overcome these? Kokai-Kun (USP): There are several cha l lenges to implementing BCM processes, including technical ones. W hile continuous perfusion biore- actors have been successfully imple- mented for cell growth/production in biologic processes, the transition from upstream to downstream processing has proven to be more challenging. Highly eff icient perfusion reactors can continuously produce large quan- tities of a biologic, but to transition that biologic product into the down- stream purif ication process requires harvest of the product from the cel- lular substrate, which can be chal- lenging in the BCM env ironment. Downstream processing of the prod- uct requires eff icient movement of solutions through various unit oper- ations that can have different scales and eff iciencies, and some of these (e.g., viral inactivation) are currently more amenable to static interactions than continuous f low. Many techni- cal innovations in BCM involve liq- uid handling and f luid dynamics to allow for continuous f low of the prod- uct through the process with smooth transitions between unit operations. A truly continuous process requires inline or at-line analytical capabilities for in-process analysis. These types of analyses represent a paradigm shift in analytical methodology over what is currently used for conventional pro- cess analysis. Managing and analyzing all the data generated by a BCM pro- cess are also challenging and require the addition of new types of technical specialties, such as data management, into the process design space. To develop truly continuous vial-to-vial processes will be highly challenging when it comes to including the final fill/finish operations into the process. For manufacturers contemplating use of BCM, other important consider- ations are evolving regulations, the cost of training new specialists, and the challenges associated with chang- ing an established process post-ap- prova l. There can be hesitanc y in changing an established process— even if it would benefit from BCM— because of perceived risks associated with the change. This is true for bio- simila rs that need to demonstrate comparabilit y to a reference prod- uct and batch processes for existing products where the perceived risk and regulatory uncertainty of making sub- stantial changes to the manufacturing process are considerable. As with any new technology, wider acceptance will need regulatory support to facilitate the adoption of the technology. Quality and Regulatory Sourcebook Compendial Compliance "Continuous manufacturing has the potential to improve manufacturing efficiency and reduce production costs," —John Kokai-Kun, USP "As with any new technology, wider acceptance will need regulatory support to facilitate the adoption of the technology." —John Kokai-Kun, USP