质量源于设计(QbD)在药物制剂工艺改进中的应用 —影响罗红霉素分散片分散均匀性的关键因素研究.doc

摘 要2010年版中国药典对片剂分散均匀性的检查方法与2005年版药典相比，发生了较大的变化，新的方法不仅增加了测定用片数，而且规定了测定用容器由于检验方法的改变，我公司生产的罗红霉素分散片出现分散均匀性不合格的现象采用新的测定方法，分散片崩解后，一些较大的颗粒无法在规定的时间内完全分散或溶解由于罗红霉素分散片在市场和临床应用中占有重要的地位，其分散均匀性的问题亟需立即解决本论文的目的在于从产品的生产工艺出发，找出生产环节中影响分散均匀性的因素，包括操作人员水平、工艺参数与设备维护、物料性质、操作方法，关键工艺步骤和参数控制、生产环境控制等由于该产品已批准上市，为了保证市场上产品供应的连续性，产品质量问题的解决不能改变其处方，同时产品的优化工作必需局限于已批准的生产工艺范围内 面对挑战，本论文的研究根据质量源于设计（Quality by Design，QbD）的理念首先对上述各个因素用鱼骨图进行风险评估，对那些鉴定的潜在风险开展了科学、系统的实验研究，以确定影响产品分散均匀性的关键因素实验表明：制粒与整粒筛网的孔径，压片主压力对产品分散均匀度都着有显著的影响压片主压力大，分散片硬度就高，导致了崩解时间延长，而制粒与整粒的筛网孔径大会产生较多的大颗粒，这些因素都使得产品的分散性变差。

进一步应用统计实验的方法（Design of Experiment，DOE），对湿制粒单元操作中制粒与整粒筛网2个因素进行了优化并建立了设计空间通过这一系列的试验，我们充分理解了罗红霉素分散片可以通过控制制粒与整粒的筛网孔径和压片主压力来改变其分散性此外，对改进后的罗红霉素分散片进行稳定性研究，长期（1年）和加速（6个月）稳定性试验数据显示本产品各项质量指标也符合质量标准要求因此，改进的罗红霉素分散片分散性好，储存条件下长期稳定，产品质量符合中国药典2010版二部收载的质量标准的要求应用QbD理念来解决制药工艺相关的问题需要深入地理解生产工艺，制备方法，采用风险评估的手段同时，要能够找出关键控制步骤和对影响关键质量属性的因素加以控制，使产品符合质量标准在工艺改进中使用QbD是改变我们以往研究方式的有效工具如果使用得当，对产品工艺的改进起到事半功倍的作用关键词：罗红霉素分散片；质量源于设计；分散均匀性；质量标准；鱼骨图；设计空间Applying QbD Design to Dispersibility Improvdement of Roxithromycin Dispersible Tablets through Process Optimization Testing method of tablet dispersability in new version of China Pharmacopea (2010) has modified from the previous version. In the new method, more tablets are used and the testing device has been specified. Due to the change in the testing method, Roxithromycin dispersible tablets manufactured by our company have failed to meet the tablet dispersibility. Larger particles were observed after tablets were disintegrated, which could not be dispersed or dissolved within specified period of time. Because of clinical and commercial importance of the product, the dispersibility issue must be resolved immediately. The purpose of this thesis is to investigate manufacturing and processing factors that impact tablet dispersibility and to propose a solution to solve the issue. The factors investigated include operator’s competency, processing parameters, equipment maintenance, materials, unit operation, critical process steps and parameters, and environmental conditions. Considering continuous commercial supply and regulatory requirements, quality improvement is limited to optimization of process parameters within approved range. Especially, formulaiton composition must remain unchanged.First, the thesis applied QbD principles to conduct manufacturing risk analysis using fishbone diagram. Then, based on the potential risks identified, scientific studies are systemically performed to explore factors that significantly impact tablet dispersibility. It was found that wet and dry milling screen in granulation step as well as main compression force during tabletting are critical for tablet dispersibility. Higher main compression force causes higher tablet hardness, resulting in longer disintegrating time. On the other hand, larger openings of milling screen lead to larger granules, resulting in poor dispersibility. Futher, using design of experiment (DOE) approach, wet and dry milling screens selected were optimized for acceptable granule size and size distribution. As a result, a design space for wet and dry milling screen size has been established. These studies help us better understanding of critical factors that impact on tablet dispersibility. The results indicate that good tablet dispersibility can be achieved by controlling milling screens and main compression force. Finally, Roxithromycin dispersible tablets were manufactured using optimized process conditions and evaluated for product stability. The stability results indicate that no noticeable change in product quality attributes was observed during the period of the studythe and the produt is stable under 40C/75% RH for at least 6 months and under 25C/60% RH for at least one year. The product is acceptable per specification under China Pharmacopea version 2010.Application of QbD principles to process optimization requires an understanding of the process, unit operations, as well as tools for conducting risk assessment. To do this, one must also be able to identify the critical control steps and critical process parameters that aid in ensuring the finished product will meet its critical quality attributes. Applying QbD to pharmaceutical development is a useful tool to improve product quality efficiently and effectively during reaearch and investigation.Keywords: Roxithromycin Dispersible Tablets, Quality by Design,Dispersibility, specification, Fishbone diagram, Design space目　录第1章 引 言 1第2章 新版药典对罗红霉素分散片检测方法改变对上市产品的影响 4第3章 影响罗红霉素分散片分散均匀性因素分析及研究实验设计 113.1 罗红霉素分散片生产流程图 113.2 影响罗红霉素分散片分散均匀性的因素确认 123.3影响关键质量属性的关键因素控制策略及试验方案设计 173.4 试验材料与仪器设备 183.5 罗红霉素分散片分析方法 19第4章 单因素试验结果与讨论 204.1 原辅料预处理与颗粒粒度分布 204.2 操作方法对分散均匀性的影响 214.3 环境湿度对颗粒结块的影响 234.4 颗粒粒度分布对分散均匀性的影响 254.5 分散片硬度对分散均匀性的影响 314.6 关键因素单因素试验结果 33第5章 影响罗红霉素分散片关键因素的优化实验及改进效果确认 335.1 罗红霉素分散片制粒整粒筛网的优化实验 335.2 实验结论及关键因素控制参数的确认 385.3 关键因素控制参数优化后的罗红霉素分散片产品质量确认 。