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首页> 外文学位 >The application of first principle modeling in combination with empirical design of experiments and real-time data management for the automated control of pharmaceutical operations.
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The application of first principle modeling in combination with empirical design of experiments and real-time data management for the automated control of pharmaceutical operations.

机译：第一原理建模与实验的经验设计和实时数据管理相结合，可自动控制制药业务。

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摘要

The U.S. Food and Drug Administration has accepted the guidelines put forth by the International Conference on Harmonization (ICH-Q8) that allow for operational flexibility within a validated design space. These Quality by Design initiatives have allowed drug manufacturers to incorporate more rigorous scientific controls into their production streams.;Fully automated control systems can incorporate information about a process back into the system to adjust process variables to consistently hit product quality targets (feedback control), or monitor variability in raw materials or intermediate products to adjust downstream manufacturing operations (feedforward control). These controls enable increased process understanding, continuous process and product improvement, assurance of product quality, and the possibility of real-time release. Control systems require significant planning and an initial investment, but the improved product quality and manufacturing efficiency provide ample incentive for the expense.;The fluid bed granulation and drying unit operation was an excellent case study for control systems implementation because it is a complex unit operation with dynamic powder movement, high energy input, solid-liquid-gas interactions, and difficulty with scale-up development. Traditionally, fluid bed control systems have either used first principle calculations to control the internal process environment or purely empirical methods that incorporate online process measurements with process models. This dissertation was predicated on the development of a novel hybrid control system that combines the two traditional approaches.;The hybrid controls reduced the number of input factors for the creation of efficient experimental designs, reduced the variability between batches, enabled control of the drying process for a sensitive active pharmaceutical ingredient, rendered preconditioned air systems unnecessary, and facilitated the collection of data for the development of process models and the rigorous calculation of design spaces. Significant variably in the inlet airstream was able to be mitigated using feedforward controls, while process analytical technology provided immediate feedback about the process for strict control of process inputs. Tolerance surfaces provided the ideal tool for determining design spaces that assured the reduction of manufacturing risk among all future batches, and the information gained using small scale experimentation was leveraged to provide efficient scale-up, making these control systems feasible for consistent use.
机译：美国食品和药物管理局已经接受了国际协调会议（ICH-Q8）提出的指导原则，该指导原则允许在经过验证的设计空间内实现操作灵活性。这些“按质量设计”计划使药物制造商能够将更严格的科学控制方法纳入其生产流程。完全自动化的控制系统可以将有关过程的信息纳入系统，以调整过程变量以始终达到产品质量目标（反馈控制），或监视原材料或中间产品的变化以调整下游制造操作（前馈控制）。这些控件可以提高对流程的了解，对流程和产品的持续改进，对产品质量的保证以及实时发布的可能性。控制系统需要大量的规划和初期投资，但是改进的产品质量和制造效率为费用提供了充足的动力。；流化床造粒和干燥装置的操作是控制系统实施的一个很好的案例研究，因为它是一个复杂的装置操作具有动态粉末运动，高能量输入，固-液-气相互作用以及难以扩大规模的开发。传统上，流化床控制系统要么使用第一原理计算来控制内部过程环境，要么将在线过程测量与过程模型结合在一起的纯粹经验方法。本文基于结合两种传统方法的新型混合控制系统的开发。混合控制减少了用于创建有效实验设计的输入因子的数量，减少了批次之间的差异，实现了干燥过程的控制对于敏感的活性药物成分，无需使用预调节的空气系统，并有助于收集数据以开发过程模型和严格计算设计空间。使用前馈控制可以缓解进气流量的显着变化，而过程分析技术可提供有关过程的即时反馈，以严格控制过程输入。公差表面为确定设计空间提供了理想的工具，可确保减少所有未来批次的制造风险，并且利用小规模实验获得的信息可以有效地扩大规模，使这些控制系统对于一致使用是可行的。

著录项

  • 作者

    Zacour, Brian M.;

  • 作者单位

    Duquesne University.;

  • 授予单位 Duquesne University.;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 240 p.
  • 总页数 240
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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