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Tablets & Capsules May/June 2021 23 ferring from classic batch high-shear or fluid-bed granulation to continuous twin-screw granulation is difficult because these processes result in differences in end-product quality. What are the technical and regulatory challenges with converting a legacy batch process to continuous? Stuckwisch: Among the technical challenges in converting a legacy batch process to continuous manufacturing is the need for advanced systems to maintain process control during the long run duration. Conversion difficulties include different technologies used for PAT than for in-process testing. Also, sample timing and location may be different. The process parameter design space is typically different for a continuous process than for a batch-based process. While other justifications, such as containment of highly potent materials, are possible, products with high volumes, high forecast variability due to launch or generic compe- tition, and supply-chain risk often deliver the most return on investment from a batch-to-continuous conversion. Michaelis: The same rules apply for converting a legacy batch process to a continuous as converting from one batch process to another. Again, a risk-based approach is followed, evaluating all changes that might influence the product's qual- ity, safety, and efficacy. Changing the type of manufacturing process or even the formulation involves a high level of risk and might necessitate bioequivalence studies. We already know this from converting between batch processes such as from high-shear to fluid-bed granulation or vice versa. Why are regulatory authorities in favor of continuous manufacturing strategies? Michaelis: Authorities are interested in an efficient, agile, flexible manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight, and the idea is that continuous manufacturing can fulfill these interests. Again, a big gap still exists between the promise of continuous manufacturing and the status of the technology today, but an increased focus on quality and test strategy, increased process knowhow, and more QbD will definitely help to reach the goal. Stuckwisch: Regulatory authorities see the benefits of the degree of process monitoring that is needed for continuous manufacturing, which helps maintain a state of validation and process control. The ability to monitor quality using leading rather than lagging indicators provides improved process control and quality assurance, decreasing the like- lihood of batch loss or rejection and drug shortages. T&C Parsolex West Lafayette, IN 765 464 8414 www.parsolexinc.com Syntegon Pharma Technology Minneapolis, MN 763 424 4700 www.syntegon.com compared to manual cleaning by a trained operator. Devel- oping appropriate CIP processes for any new product takes time and effort but having a reproducible cleaning method helps facilitate cleaning validation efforts. Scholz: Syntegon does not consider any difference in the cleanability requirements between batch and contin- uous processes. Early machines developed for continu- ous manufacturing did not consider cleanability in their design, resulting in unacceptably long cleaning times and extremely complex cleaning validation and eliminating the cost-reduction benefits of continuous processing. The new generation of continuous systems, such as Xelum, incorporate automatic cleaning into their design, fulfilling the same cleaning requirements as batch equipment in addition to containment requirements. Do you anticipate that processes will be conceived only following a continuous approach, or will new product development always start with a batch strategy and convert established batch processes to continuous? David Engers, PhD, director, Parsolex: One advantage of continuous processing as stated by the FDA Center for Drug Evaluation and Research (CDER) is drug production tailored to meet the needs of precision medicine. While this ultimate goal to manufacture and release lifesaving medicines at the point of patient use is not yet fully real- ized, continuous manufacturing is gaining more interest from industry sponsors, contract development and manu- facturing organizations (CDMOs), and regulatory bodies for its ability to produce high-quality, safe, and effective pharmaceutical products. Continuous pharmaceutical processes are by nature more efficient than conventional batch processes, and considerable advances are being made. Today, quantities of clinical trial materials (CTM) required to support first-in-human studies rarely justify adopting a continuous approach during early clinical development. Therefore, batch and continuous processes can be developed in parallel to help inform the decision for which strategy to adopt during late-stage clin- ical development and commercial manufacturing. For new chemical entities (NCEs) pursuing a new drug application (NDA), this decision commonly occurs after completing piv- otal (Phase II) studies. For abbreviated new drug application (ANDA) products, continuous process development can be initiated at the start of product and process development. As the pharmaceutical industry strives to achieve lean production and six sigma operational efficiency, learning from and applying the best practices of other industries where continuous processes are well established will likely allow continuous manufacturing strategies to be adopted earlier in the product development lifecycle. Michaelis: Syntegon will not advise a complete switch in R&D to continuous, as the current solutions on the market are not flexible enough to cover all requirements. A better strategy for both brand owners and CDMOs would be to have hybrid solutions that can serve both batch and continuous to keep all manufacturing strategies open. For instance, trans-