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Tablets & Capsules May/June 2021 21 (CQA), requires greater effort to continuously monitor the process than a batch system. However, for Syntegon's Xelum continuous manufacturing process, the test strategy is less complex and more comparable to a batch process. Nathan Wade, PhD, MBA, senior managing chemist, analytical solutions, Parsolex: The testing strategy for a drug product manufactured by a continuous process does not necessarily need to differ from the testing strategy for the same drug product manufactured by a batch process. However, the inherent application of PAT and finer process controls within a continuous process may allow for some labora- tory-based test methods to be replaced with on-line or real-time analysis. On-line spectroscopic techniques may be equally effective as laboratory- based chromatographic and titration methods for the identification, assay, or water determination of the drug product. The dissolution test for tablets and capsules is an ardu- ous laboratory-based test method intended to predict the release rate of the drug under biorelevant conditions and serve as a quality control for the manufacturer. Potentially, even the traditional dissolution test could be replaced with real-time analysis. For example, control and on-line char- acterization of the particle size of the active component, at-line determination of tablet hardness, and on-line content uniformity determination for the drug product could provide product specifications that are as clinically relevant as the dissolution test. The concept that all product release tests could be performed in real time for a given drug product is intriguing from both a quality and cost benefit perspective. In practice, however, whether implementing a contin- uous or batch process, totally replacing laboratory-based methods with on-line or real-time analysis is a tough hill to climb. A number of product quality attributes are not conducive to on-line analysis, such as related impurities content, elemental impurities content, and microbiological content. Further, the same laboratory-based methods that one might hope to avoid in product release testing are still required for product stability testing. What analytical challenges might exist for a continuous manufacturing process as compared to a batch manufacturing process? Wade: Implementing PAT into a continuous manufac- turing process requires different technology and skills than the conventional off-line laboratory-based test methods required for a batch process. Spectroscopic tools, which are the most commonly used techniques to obtain data from PAT measurements, require significant amounts of data processing, data modeling, and statistical treatment that are less common for off-line test methods. Further, PAT tools often need to be custom fit to the continuous process equipment to ensure proper data acqui- sition and establish feedback control to the process. The analytical response and equipment operating conditions must remain synchronized, such that the analytical response for a specific time corresponds to the equipment parameters collected at that time, correcting for any lags in sampling and instrument measurements. Where appropriate, a continuous process can eliminate problems encountered during scale up of batch processes, as continuous processes do not involve discrete scale-up steps, but rather a clear production time variable that can be changed according to product demand. This offers the opportunity for savings during product development. Yield from continuous manufacturing is significantly better than from batch manufacturing, as continuous manufacturing integrates multiple processes into a single process with an overall yield and eliminates sublots. For example, when a batch-based tablet production process consists of four consecutive process steps (such as high- shear granulation, drying, tableting, and coating) and each step produces a yield of 97 percent, the overall yield for this batch is 88 percent. Production time is also significantly shorter for a contin- uous process, largely because it eliminates non- value-adding wait times between batch process stages (such as transfer, weighing, and calculation). In addition to the wait time between batch process stages, each stage requires manual product handling, which further increases production costs. A batch-based process is governed by the size of the equipment or container used during production, while a continuous process is governed by product flow rates. This allows for smaller equipment, which can reduce your manufacturing footprint. Continuous manufacturing also provides a means of getting closer to the factory of the future. Fritz-Martin Scholz, product manager, Syntegon Pharma Tech- nology: While the benefits have not yet been fully achieved in the market, continuous manufacturing promises reduced development time and cost; reduced manufacturing cost; and continuous, inline quality verification, leading to improved quality assurance and, eventually, real time release (RTR). Currently, however, continuous processes require more material and time for model development—process analytical testing (PAT) and residence time distribution (RTD)—qual- ification in R&D, and often also for production. By using compact, agile, fully automated equipment, continuous manufacturing promises flexible, one-step tablet produc- tion, with no intermediate storage and reduced floor space requirements and cost, but most systems currently on the market are complex, expensive, not agile, and difficult to clean. Inline quality verification with PAT tools can still be a challenge and requires intensive modeling for each product. Many continuous processes are sensitive and not robust, and generally, batch registration with release testing is still in place. How might the testing strategy for a drug product differ for a continuous manufacturing process compared to a batch manufacturing process? Dr. Marc Michaelis, head of pharma services, Syntegon Pharma Technology: The FDA and the International Council for Har- monisation (ICH) have provided guidance for developing and validating effective test methods based on a risk-based approach. The risk and the complexity of the manufacturing process define the testing strategy. A continuous manufacturing system, especially with RTR and an increased number of critical quality attributes