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Pharmaceutical Technology REGULATORY SOURCEBOOK DECEMBER 2019 15 Equipment advances drive DoE In the small-molecule world, a major advance was made in the 1990s when near-infrared (NIR) spec- trometers were made small and versatile enough to be used in the lab or on the production f loor. Pfizer and Carl Zeiss pioneered the first such PAT devices in the 1990s using a benchtop NIR device, a V-blender, and a rotator, and employing DoE to study solid dosage blends. Similar setups were later used by other companies for small-molecule solid dosage form testing. Not only did this approach allow the first new drug applications incorporating PAT methods to be submitted to FDA, it represented a break- through by allowing development and quality testing to be done continuously for batch prod- ucts using a multivariate approach to analyze data. Now that more companies are evaluating or using continuous processes to make solid dosage forms, applying DoE with PAT and QbD in continuous testing can eliminate the need for large and ex- pensive pilot plants, offering considerable savings, says Ciurczak. An analogous trend has been happening in up- stream biopharmaceutical process development, as equipment has been developed to facilitate the Design of experiments (DoE) can be used in applications ranging from pre-formulation and formulation to finished drug manufacturing, says Emil Ciurczak, process analytical technology (PAT) expert and spectroscopist, and principal of DoraMaxx Consulting. To give an example of how DoE can enrich understanding in preformulation, consider tests that might be designed to study the interaction between an API and a single excipient, and how they affect stability. Using a univariate method, without DoE, one could take a mixture of active ingredient and excipient and put it through different stability studies (i.e., exposing it to heat, cold, light, and other variables) and hold it for 4–20 weeks and look for the breakdown point. This would provide information on interactions between the API and excipient, Ciurczak explains, but only one combination could be tested at a time. The time required for testing would be significant, after which high-performance liquid chromatography (HPLC) and thin layer chromatography (TLC) testing would still be required, and, overall tests would take several months to complete. Using DoE, one could choose to consider the API, plus seven of the excipients that are most often used with that active, and test for eight different parameters, says Ciurczak. This would mean 8 times 7 mixtures, which would be put in vials in test tube racks. Near-infrared (NIR) or Raman spectroscopy could then be used to test these samples every day and to plot any changes. After that point, the vials would be tested with chromatography. Not only would this approach be much faster, it would be much more exact, and show clearly when each different combination of API and excipient reacted. In drug synthesis, where chemists look for the highest yield, the best chemical for increasing yield may also be the least stable, DoE could be used to select the most stable alternative with the highest yield. In formulation, DoE would help determine the best formulation based on stability and release pattern, Ciurczak explains. In pharmaceutical quality by design (QbD), DoE methods are used to define the design space for a product, correlating critical quality attributes and process parameters, allowing product quality to be optimized by staying within specific boundaries. For these tests, one would need to know the process parameters and to test a wide range of combinations of API with various excipients, disintegrants, lubricants, and other additives, and to use a full-sized batch for testing. As Ciurczak explains, the Plackett Burman approach (1) would often be used for the first phase of testing, to develop a matrix. Optimum levels would be set for each parameter, with a deviation of plus or minus 10%. The Partial Least Squares regression method would then be used to show whether deviation is positive or negative. A second stage of testing would then determine upper and lower limits to the design space, allowing formulators to tweak formulations and to ensure that variations in ingredients or raw materials (e.g., between different lots of the same excipient or excipients from different suppliers) did not have an impact on product quality. Not only could this approach allow testing to be accomplished in a few days, says Ciurczak, but results could be applied to optimization in other areas. For example, using DoE and stability data, product shelf life could be maximized to extend expiry dates and reduce costs, Ciurczak says. Reference 1. M. Jayakumar, "When and How to Use Plackett Bur- man Design," isixsigma.com, www.isixsigma.com/ tools-templates/design-of-experiments-doe/when-and- how-to-use-plackett-burman-experimental-design/ —Agnes Shanley Handling complexity faster: examples of DoE at work