Robust Process Design in Pharmaceutical Manufacturing under Batch-to-Batch Variation

Abstract

Model-based concepts have been proven to be beneficial in pharmaceutical manufacturing, thus contributing to low costs and high quality standards. However, model parameters are derived from imperfect, noisy measurement data, which result in uncertain parameter estimates and sub-optimal process design concepts. In the last two decades, various methods have been proposed for dealing with parameter uncertainties in model-based process design. Most concepts for robustification, however, ignore the batch-to-batch variations that are common in pharmaceutical manufacturing processes. In this work, a probability-box robust process design concept is proposed. Batch-to-batch variations were considered to be imprecise parameter uncertainties, and modeled as probability-boxes accordingly. The point estimate method was combined with the back-off approach for efficient uncertainty propagation and robust process design. The novel robustification concept was applied to a freeze-drying process. Optimal shelf temperature and chamber pressure profiles are presented for the robust process design under batch-to-batch variation.Processes 2019, 7, 509 2 of 14 operating mode when producing active pharmaceutical ingredients (APIs) and drugs [18], i.e., all materials are charged before the start of processing and discharged at the end of processing. Thus, slight experimental deviations or the degradation of the process equipment might result in batch-to-batch variation [18][19][20]. The source of batch-to-batch variation is difficult to predict, but can be quantified with process analytical technology (PAT) and multivariate statistical analysis [19,20]. In the literature, it is well-known that batch-to-batch variation causes severe problems in pharmaceutical manufacturing, drug quality, clinical studies, and therapeutics [6,17,21,22]. To lower batch-to-batch variation in pharmaceutical, and to improve QbD measures, analyzing the effect of measurement noise and batch-to-batch variation is essential. The adverse effect of batch-to-batch variation in pharmaceutical manufacturing is studied experimentally for various processing steps, e.g., fermentation, crystallization, and (nanomaterial) formulation [17,19,23]. In model-based process design, in turn, recent studies try to analysis and control batch-to-batch variation effects too [24,25]. For instance, in the case of model-based process design, model parameters can be derived for each batch data set separately. When each batch run is fit individually, batch-to-batch variation leads to different sets of model parameter estimates and parameter uncertainties. Please note that the variability in the model parameters is not exclusively the result of measurement noise, but the joint effect of measurement errors and slight differences in the experimental settings and the raw materials of the batches [6,17]. Thus, simulation studies should consider imprecise uncertainties [26-28] as well. These imprecise uncertainties cannot be described via a single PDF, but via a set of PDFs that is known as the a...

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