应用QbD的方法解决地塞米松磷酸钠注射液的有关物质问题详细分解.docx

I 摘 要 地塞米松是肾上腺皮质激素类药，具有抗炎、抗过敏、抗风湿、免疫抑制作用， 其磷酸钠注射剂临床上具有广泛应用。2010 年国家对药典进行了升级，升级后的 2010 版药典要求检测该注射液的有关物质并制定了接受标准。我公司产品按照原工艺条 件，已不能生产出符合新版药典的地塞米松注射液产品，因此需对产品的处方和/或 工艺条件进行改进。但是由于重新注册需要两至三年的时间，停止生产将对病人的 需求产生一定的影响。 因此需要在不影响已批准的处方和工艺条件下，对生产工艺 进行优化改进，以生产出合格的地塞米松磷酸钠注射液。 本论文应用 QbD 的理念，从原辅料来源，生产工艺，贮存条件等方面对地塞米 松磷酸钠注射液进行了科学与系统的研究，在研究过程中充分考虑了该产品整个生 命周期内的质量问题，成功地解决了地塞米松磷酸钠药典升级后的杂质不合格问题。 通过研究发现，原辅料来源，生产工艺，贮存条件等因素对地塞米松磷酸钠注 射液中的有关物质有显著影响，尤其生产过程中的药液 pH 值，药液温度。在理解了 影响产品稳定性的关键工艺参数基础上，通过严格控制这些变异因素，使终产品的 有关物质符合新版药典的规定。此外，通过对地塞米松磷酸钠长期稳定性结果进行 研究，提出了地塞米松磷酸钠合适的贮存条件应为阴凉、避光条件。结果表明地塞 米松磷酸钠注射液能够在已批准的生产工艺范围内进行优化， 并且使用优化后的工 艺生产出的注射剂符合 2010 年版中国药典的质量标准。 关键词：地塞米松磷酸钠, 注射液, 有关物质, 稳定性, QbD II Studies on Related Substance of Dexamethasone Sodium Phosphate Injection Using QbD Approach Abstract Dexamethasone is acortiadrenal hormone drug which has been widely used in treatment of diseases associated with inflammation, hyper-sensitivity, rheumatoid, and immune-suppression. In 2010, new version of Chinese Pharmacopeia (CP) was published in which additional test on related substances for Dexamethasone Sodium Phosphate Injection is required. Our product manufactured by originally approved process could not meet acceptance criteria against new CP standards. Thus, formulation and/or process of dexamethasone sodium phosphate should be properly optimized. However, a post-approval supplement for change in formulation and process needs 2-3 years to receive an approval from SFDA, which may cause an issue on medical needs if supply of the product is interrupted. It is important that optimization of the product should be within approved range of formulation and manufacturing process. This thesis is to explore an impact of source of API, manufacturing process, and storage conditions for quality of dexamethasone sodium phosphate using QbD approach. Cause of unacceptable levels of related substances was investigated systematically and scientifically with consideration of product life-cycle, so that the related substan