Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; Office of Research Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Int J Pharm. 2020 Oct 15;588:119761. doi: 10.1016/j.ijpharm.2020.119761. Epub 2020 Aug 12.
The quality of an ophthalmic suspension is crucial for its in vivo performance, and often impact product's effectiveness. An in-depth understanding of critical quality attributes (CQAs) of ophthalmic suspensions such as particle size distribution (PSD) and rheology, as well as the impact of these CQAs on product performance are important for successful product development, quality control, and regulatory approval. This study employed brinzolamide ophthalmic suspension, 1%, as a model ophthalmic product, and six batches were manufactured using an innovative planetary centrifugal milling (PCM) process. Three batches were manufactured to have distinctly different PSD. These three batches had qualitatively (Q1) and quantitatively (Q2) the same composition as the model drug product (i.e., Azopt), while the differences in PSD were introduced by changing only the manufacturing process parameters. On the other hand, changes in rheology were introduced by altering the input level of the viscosity enhancing polymer in the formulation. A systematic approach was employed to understand the relation between manufacturing process parameters, CQAs, and in vitro product performance. Among the evaluated CQAs, PSD, rheology, surface tension, and drug dissolution were found more sensitive to the changes in the manufacturing processes. Most notably, we developed a rapid dissolution method (completed within minutes) employing in-situ fiber optic UV dissolution system. This novel dissolution method mimics the environmental conditions of the eye such as dissolution under "non-sink" condition and under high shear (from blinking). The method was highly discriminatory to differences in the PSD in the suspension. This study also revealed an important relation between the PSD of the suspension and its rheology which originated as a result of an interaction at the molecular level between the solid drug particles and the viscosity enhancing polymers. These findings underscore the need to evaluate CQAs of the ophthalmic suspensions in concert rather than separately when comparing ophthalmic drug products and product performance.
混悬剂的质量对其体内性能至关重要，通常会影响产品的有效性。深入了解混悬剂的关键质量属性（CQAs），如粒径分布（PSD）和流变学，以及这些 CQAs 对产品性能的影响，对于成功的产品开发、质量控制和监管批准非常重要。本研究采用 1%布林佐胺滴眼剂作为模型眼用产品，采用创新的行星离心研磨（PCM）工艺生产了六批。其中三批的 PSD 明显不同。这三批在定性（Q1）和定量（Q2）上与模型药物产品（即 Azopt）相同，而 PSD 的差异仅通过改变制造工艺参数来引入。另一方面，通过改变配方中增粘聚合物的输入水平来引入流变学的变化。采用系统的方法来理解制造工艺参数、CQAs 和体外产品性能之间的关系。在所评估的 CQAs 中，PSD、流变学、表面张力和药物溶解更敏感于制造工艺的变化。值得注意的是，我们开发了一种快速溶解方法（在几分钟内完成），采用原位光纤紫外溶解系统。这种新的溶解方法模拟了眼睛的环境条件，如在“非溶出”条件下和高剪切（眨眼）下的溶解。该方法对混悬剂中 PSD 的差异具有高度鉴别力。本研究还揭示了混悬剂的 PSD 与其流变学之间的重要关系，这是由于固体药物颗粒和增粘聚合物之间在分子水平上的相互作用而产生的。这些发现强调了在比较眼科药物产品和产品性能时，需要协同评估而不是分别评估眼科混悬剂的 CQAs。
