Continuous Viral Vector Manufacturing based on Mechanistic Modeling and Novel Process Analytics

生物制药行业对可持续发展表现出了浓厚的兴趣 用于治疗性蛋白质生产的制造工艺。这在一定程度上是由于优势所致。 与补料分批生产方法相比，补料分批生产方法包括更高的生产率，更多的产品 质量，减少生物反应器的尺寸，以及潜在地更好地利用生产基础设施。 连续生产方法对于可能很困难的工艺具有明显的优势 在不引起治疗产品变化的情况下扩大规模。尽管取得了这一进展，但仍在继续 制造方法尚未应用于病毒载体的制造。正在生长的细胞 基因治疗行业有三个关键需求，可以通过持续生产来解决 病毒载体。首先，预期的全球对病毒载体的需求不可能得到满足。 使用当前的批量生产基础设施，需要使用新的和替代的 制造方法。其次，连续生产可能会使快速 生产大量载体，使临床试验能够更快地启动，从而 加快新型基因治疗产品的上市速度。第三，随着生物制品成为 更大和更复杂(细胞疗法比病毒疗法更复杂 比蛋白质复杂)，从临床规模扩大到商业规模制造 流程变得具有挑战性。规模扩大带来的制造变化(例如，从500L增加 到2000L以及随之而来的搅拌速度的变化)会导致意外的变化 产品质量和最终临床表现。因此，开发一种大规模的工艺， 产生可比较的产品，并证明可比性既耗时又 资源密集型。为了帮助应对这些挑战，麻省理工学院提议开发和 一个持续的上游病毒载体制造平台的示范。这将是 通过三个不同的目标来完成：第一，我们将发展一个基本的数学原理 连续病毒载体细胞培养单元操作流程设计模型；第二，我们将 展示新型分析技术在在线测量质粒转染率中的应用 和媒介生产参数；第三，我们将利用这些学习来演示 连续细胞培养生产病毒载体。在项目结束时，我们将展示 一种可应用于其他病毒的连续病毒载体制造的通用方法 用于生产基因或基因修饰细胞疗法的感兴趣的载体。

The biopharmaceutical industry has shown significant interest in developing continuous manufacturing processes for therapeutic protein production. This is partly due to advantages compared to fed-batch production methods, which include higher productivity, increased product quality, reduction in bioreactor sizes, and potentially better utilization of production infrastructure. Continuous manufacturing approaches have clear advantages for processes that may be difficult to scale up without inducing changes to the therapeutic product. Despite this progress, continuous manufacturing approaches have yet to be applied to viral vector manufacturing. The growing cell and gene therapy industry has three key needs that may be addressed by continuous manufacturing of viral vectors. First, the anticipated worldwide demand for viral vectors cannot feasibly be met using current batch production infrastructure, necessitating the use of new and alternative manufacturing approaches. Second, continuous manufacturing could potentially allow rapid production of quantities of vectors which would enable more rapid initiation of clinical trials, thus increasing speed to market for novel gene therapy products. Third, as biologic products become larger and more complex (with cell therapies being more complex than viral therapies being more complex than proteins), scaling up from clinical scale to commercial scale manufacturing processes becomes challenging. Manufacturing changes due to scale up (e.g. increasing from 500L to 2000L and the accompanying changes in agitation rate) can lead to unanticipated changes in the product quality and final clinical performance. Therefore, developing a large-scale process that produces a comparable product as well as proving that comparability is both time consuming and resource intensive. To help address these challenges, MIT is proposing the development and demonstration of a continuous upstream viral vector manufacturing platform. This will be accomplished through three distinct aims: first, we will develop a first principles mathematical model for continuous viral vector cell culture unit operation process design; second, we will demonstrate the application of novel analytics for the in-line measurement of plasmid transfection and vector production parameters; and third, we will leverage these learnings to demonstrate the continuous cell culture production of viral vectors. At the end of the project we will have exhibited a generic approach for continuous viral vector manufacturing that can be applied to other viral vectors of interest for the production of either gene or gene-modified cell therapies.