Oberleitner Thomas, Zahel Thomas, Pretzner Barbara, Herwig Christoph
Competence Center CHASE GmbH, Ghegastraße 3, Top 3.2, 1030 Vienna, Austria.
Körber Pharma Austria GmbH, PAS-X Savvy, Mariahilferstraße 88A/1/9, 1070 Vienna, Austria.
Bioengineering (Basel). 2022 Nov 3;9(11):0. doi: 10.3390/bioengineering9110643.
Statistical experimental designs such as factorial, optimal, or definitive screening designs represent the state of the art in biopharmaceutical process characterization. However, such methods alone do not leverage the fact that processes operate as a mutual interplay of multiple steps. Instead, they aim to investigate only one process step at a time. Here, we want to develop a new experimental design method that seeks to gain information about final product quality, placing the right type of run at the right unit operation. This is done by minimizing the simulated out-of-specification rate of an integrated process model comprised of a chain of regression models that map process parameters to critical quality attributes for each unit operation. Unit operation models are connected by passing their response to the next unit operation model as a load parameter, as is done in real-world manufacturing processes. The proposed holistic DoE (hDoE) method is benchmarked against standard process characterization approaches in a set of in silico simulation studies where data are generated by different ground truth processes to illustrate the validity over a range of scenarios. Results show that the hDoE approach leads to a >50% decrease in experiments, even for simple cases, and, at the same time, achieves the main goal of process development, validation, and manufacturing to consistently deliver product quality.
统计实验设计，如析因设计、优化设计或确定性筛选设计，代表了生物制药工艺表征的最新技术水平。然而，仅靠这些方法并不能利用工艺作为多个步骤相互作用的这一事实。相反，它们旨在一次只研究一个工艺步骤。在此，我们希望开发一种新的实验设计方法，该方法旨在获取有关最终产品质量的信息，在正确的单元操作中进行正确类型的运行。这是通过最小化由一系列回归模型组成的集成过程模型的模拟不合格率来实现的，这些回归模型将每个单元操作的过程参数映射到关键质量属性。单元操作模型通过将其响应作为负载参数传递给下一个单元操作模型来连接，就像在实际制造过程中那样。在一组计算机模拟研究中，将所提出的整体实验设计（hDoE）方法与标准工艺表征方法进行了基准测试，在这些模拟研究中，数据由不同的真实过程生成，以说明该方法在一系列场景中的有效性。结果表明，即使对于简单的情况，hDoE方法也能使实验次数减少50%以上，同时实现工艺开发、验证和制造的主要目标，即始终如一地提供产品质量。
