口服固体制剂的工艺研发方法应用—以利培酮片为例教程方案.docx

II 摘 要 本文总结了一个规格为 2mg 的仿制药利培酮片的开发，其参照药品（RLD）为 2mg 的品牌药维思通片。该参照药品是一种速释片剂，用于治疗非典型精神病。本次研究应 用了质量源于设计的理念来研发与参照药品具有同等疗效的仿制药利培酮速释片。 首先界定了目标产品的质量概况。这是基于原料药属性和参照药品产品的特性、 还考虑药品的说明书和预期的患者人群。在药品研发过程中，研究主要集中于那些会受 到药品处方和生产工艺变化影响的关键质量属性。对利培酮片，这些关键质量属性主要 是含量均匀度和溶出度。利培酮的水溶性差、渗透性高，是 BCSII 类化合物。因此，研 发的重点是仿制产品的溶出行为要与参照药品一致，从而最大程度的保证与参照药生物 等效。 通过风险评估及试验研究确定了原料药的粒度，粘合剂的种类、型号及用量，助 流剂的用量，两次物料混合时间为影响本产品质量的关键物料属性和关键工艺参数。针 对影响利培酮片质量的关键属性，制定了控制策略。最终提高了产品质量，及质量的可 控度。 关键词：利培酮片；溶出度；质量源于设计  PAGE 5 Process Developing Approach for Oral Solid Dose Drug Product Case study with Risperidone Tablets The thesis summarizes the development of generic risperidone oral tablet,2mg,a generic version of the reference listed drug(RLD), Risperdal tablet,2mg. The RLD is an immediate release (IR) tablet indicated for atypical psychotic disorder. Quality by Design was used to develop the generic risperidone IR tablet so that the end product is therapeutically equivalent to the RLD. Initially, the quality target product profile was defined based on the characterization of the properties of the RLD, and consideration of the RLD label and the intended patient population. In the process of the drug development, the investigation was focused on those Critical Quality Attributes that could be impacted by a realistic change to the drug product formulation or manufacturing process. For generic risperidone tablet, these CQAs include content uniformity and dissolution. Risperidone is a poorly soluble and highly permeable, BCS Class II compound. Therefore the generic drug development was focused on matching the dissolution of the RLD, in order to ensure bioequivalence (BE) with the RLD. By risk assessment and experimental studies, it was found that the API particle size, the binder type, grade and content, the glidant content, and twice blending time are critical material property and critical process parameters. A control strategy was developed for the critical quality attributes of risperidone generic oral tablet. Applic