Abstract：
The production of biopharmaceutical products carries an inherent risk of contamination by adventitious viruses. Historically, these manufacturing processes have incorporated a dedicated virus filtration step to ensure product safety. However, challenging process conditions can lead to passage of small viruses to the permeate pool and an overall decrease in the desired virus logarithmic reduction value (LRV) for the process. The implementation of serial virus filtration has improved the robustness of such processes, albeit concerns about increased operating times and process complexity have limited its implementation. This work focused on optimizing a serial filtration process and identifying process control strategies to provide maximum efficiency while ensuring proper controls for process complexity. Constant TMP was identified as the optimal control strategy, which combined with the optimal filter ratio, resulted in a robust and faster virus filtration process. To demonstrate this hypothesis, data with two filters connected in series (1:1 filter ratio) are presented for a representative non-fouling molecule. Similarly, for a fouling product, the optimal setup was a combination of a filter connected in series to two filters operated in parallel (2:1 filter ratio). The optimized filter ratios bring cost- and time-savings benefits to the virus filtration step, thereby offering improved productivity. The results of risk and cost analyses performed as part of this study combined with the control strategy, offer companies a toolbox of strategies to accommodate products with different filterability profiles in their downstream processes. This work demonstrates that the safety advantages of performing filters in series can be achieved with minimal increases in time, cost, and risk.
摘要：
生物制药产品的生产具有被外来病毒污染的固有风险。历史上,这些制造工艺已纳入专门的病毒过滤步骤，以确保产品安全。然而,具有挑战性的工艺条件可导致小病毒通过至渗透物池和用于该工艺的期望的病毒对数减少值(LRV)的总体降低。串行病毒过滤的实施提高了此类过程的鲁棒性，尽管对增加操作时间和过程复杂性的担忧限制了其实施。这项工作的重点是优化串行过滤过程和确定过程控制策略，以提供最大的效率，同时确保适当的控制过程的复杂性。恒定TMP被确定为最优控制策略，结合最佳过滤比，导致强大和更快的病毒过滤过程。为了证明这个假设，提供了具有两个串联连接的过滤器的数据（过滤器比率为1：1），用于代表性的防污分子。同样，对于污垢产品，最佳设置是串联连接的过滤器与并联运行的两个过滤器的组合（2:1过滤器比率）。优化的过滤比率为病毒过滤步骤带来了成本和时间的节省。从而提高生产率。作为本研究的一部分，结合控制策略进行的风险和成本分析的结果，为公司提供一个策略工具箱，以适应在下游过程中具有不同可过滤性的产品。这项工作表明，执行串联过滤器的安全优势可以实现最小的时间增加，成本,和风险。本文受版权保护。保留所有权利。
