Debevec Veronika, Srčič Stanko, Horvat Matej
a Sandoz Development Center , Lek Pharmaceuticals, d.d. , Ljubljana , Slovenia.
b Department of Pharmaceutical Technology, Faculty of Pharmacy , University of Ljubljana , Ljubljana , Slovenia.
Drug Dev Ind Pharm. 2018 Mar;44(3):349-364. doi: 10.1080/03639045.2017.1409755. Epub 2017 Dec 19.
The quality by design (QbD) paradigm guides the pharmaceutical industry towards improved understanding of products and processes, and at the same time facilitates a high degree of manufacturing and regulatory flexibility throughout the establishment of the design space. This review article presents scientific, statistical and regulatory considerations in design space development. All key development milestones, starting with planning, selection of factors, experimental execution, data analysis, model development and assessment, verification, and validation, and ending with design space submission, are presented and discussed. The focus is especially on frequently ignored topics, like management of factors and CQAs that will not be included in experimental design, evaluation of risk of failure on design space edges, or modeling scale-up strategy. Moreover, development of a design space that is independent of manufacturing scale is proposed as the preferred approach.
质量源于设计（QbD）范式引导制药行业更好地理解产品和工艺，同时在设计空间的建立过程中促进高度的制造和监管灵活性。本文综述了设计空间开发中的科学、统计和监管考量。介绍并讨论了从规划、因素选择、实验执行、数据分析、模型开发与评估、验证和确认，到设计空间提交的所有关键开发里程碑。重点尤其放在经常被忽视的主题上，例如不纳入实验设计的因素和关键质量属性的管理、设计空间边缘失败风险的评估或模型放大策略。此外，提出开发与制造规模无关的设计空间作为首选方法。
