Real-time multivariate statistical monitoring of biopharmaceutical processes with no prior product-specific history

Abstract

Biologics drug substance manufacturing normally comprises several processing steps including cell culture, purification, etc. Real-time Multivariate Statistical Process Monitoring (RT-MSPM) is an integral need in order to achieve early fault detection and prevention to guarantee robust and efficient process performance. As a part of RT-MSPM framework, Batch Evolution Models (BEMs), which take into account the transient phase of a batch prior to reaching full maturity (steady state), are the standard methods for real-time early fault detection in batch processes. Prior product-specific knowledge and training dataset are critical in order to model time (batch maturity) dependencies. Unlike traditional settings, modern biopharmaceutical manufacturing and clinical facilities use modular designs to enable simultaneous production of multiple medicines and quickly pivot from producing one medicine to another where no prior product-specific historical data might be available. In this article, first, a framework is proposed to detect the steady state operation of a manufacturing scale cell culture bioreactor. This is critical to achieve the ultimate goal to demonstrate feasibility of developing a continuous statistical process monitoring framework to monitor the steady state operation of a batch with no prior product specific history. Steady state time series data from previous step are processed following a systematic approach. The requirements for statistical properties of the processed time series in order to leverage data from different products to monitor a new product are outlined. The new framework establishes a guideline to develop models using datasets from other products with different recipes to monitor new products with no prior product-specific history. A novel software product is developed to test the framework. The framework is successfully applied for real-time monitoring of fast-rate sensors of a manufacturing cell culture bioreactor.