最近星辰君一直在写关于质量源于设计（QbD）的内容，尽管QbD是未来生物药物研发和生产的一个趋势，但是如果QbD应用的不好，也是会导致被退审的，下面就是这样的一个例子。
2012年9月，EMA给Inspiration Biopharmaceuticals申报的重组凝血因子IX发布了退审报告，主要原因是在其申报资料的审评中存在着重大缺陷项（major objections）。其中一个就是与QbD相关，另一个则是与宿主细胞蛋白含量的控制相关。
Major Objection 1
第一个major objection是在质量部分，原液相关的生产工艺控制章节（Control of manufacturing process）：
The general approach to assure a consistent and reliable manufacturing process is in compliance with ICHQ6B. However, the control strategy was not sufficiently defined for themanufacturing of DS. This was regarded as a major objection at D120. TheCompany hasdetermined the controlsteps according to quality by design (QbD) principles without applying QbD.
确保一致并且可靠的生产工艺的一个通用方法是符合ICH Q6B的要求。但是，DS的生产并不能充分的定义控制策略。这被认为是D120的主要缺陷项。本公司根据质量源于设计（QbD）的原则确定了控制步骤，但是却没有很好的应用QbD。
Theperformance parameters are categorized into in-process controls, in-processlimits, and in-process specifications. Based on an FMEA risk assessment, eachprocess parameter was ranked from 1-10 on the severity, probability of occurrence,and the ability to detect an excursion and/or the impact of an excursionoutside of the normal operating range (NOR). The categorization of a processparameter as critical or non-critical followed a riskbased approach without aproper argumentation of the criticality of the parameters and this was not considered appropriate.
工艺性能参数分类为工艺内控制，工艺限值和工艺标准。根据FMEA风险评估，每一个工艺参数在严重度、发生频率和超出正常操作范围（NOR）的偏移和/或偏移影响能力的可探测度上，分别赋予1-10分的分值。基于风险评估的方法，工艺参数分类为关键工艺参数和非关键工艺参数，但是却没有合适的依据证明其关键性，因此认为这是不合适的。
Major Objection 2
第二个major objection是在质量部分，原液相关的杂质部分（Impurities）：
The data indicate that IB1001 has a low level of process-related impurities, withthe exception of residual HCP present in DS and DP. In the Response to the Day120 LoQ the applicant reports that HCP impurities are present in IB1001 DS at acertain level, when measured with a more IB1001-specific HCP-ELISA. The levelof HCP in all GMP lots (pre-clinical and clinal lots) is higher, compared tothe data obtained with a previous, non-specific commercial assay (data providedin original submission). The high level of HCP in IB1001 DP is not acceptable.Major Objection).
