arXiv subjects

Ellen Otte

Publications and source records attributed to Ellen Otte.

6 recordsLinked to original sources

arXiv2026

Multipath Adaptive Gated Bottleneck Latent ODE with Raman Data Fusion for Cell Culture Process Forecasting

Mammalian cell-culture processes underpin the manufacture of many biopharmaceuticals, yet keeping a run on track is hard: critical process parameters drift over days, and an off-specification trend is often confirmed too late to intervene. Early-stage, multi-day forecasts could enable timely adjustment of feeding, sampling, and control, but bioprocess forecasting is challenging because measurements are sparse and irregularly sampled, operating conditions are heterogeneous across cell lines and media, and runs with near-identical early behaviour can diverge into different futures. We propose an adaptive framework combining a Gated Bottleneck Latent Ordinary Differential Equation (GB-Latent ODE) with Multi-Path Just-In-Time Fine Tuning (MP-JIT-FT). The GB-Latent ODE augments the stan dard Latent ODE with learnable variable-wise gating and a mask-aware bottleneck that compress high-dimensional sparse inputs, improving learning under limited data. Given a partially observed run, MP-JIT-FT retrieves similar historical trajectories, clusters the local neighbourhood into candidate regimes, and fine-tunes a separate model per regime to produce multiple plausible paths, each with a reconstruction-based confidence score, not a single averaged forecast. We further fuse Raman spectroscopy data: a machine-learning soft sensor turns dense Raman spectra into pseudo-observations that enrich the sparse offline measurements for more robust training. On 38 fed-batch 5L bioreactor runs spanning 14 conditions, MP-JIT-FT with Raman fusion achieves the best average rank and outperforms a global Latent ODE baseline on 8 of 9 target variables. Using local-divergence metrics, we show the multi-path gains are largest when locally similar prefixes diverge, whereas Raman fusion helps most when early dynamics are representative of later behaviour.

cs.LG↗

arXiv2025

Learning From Limited Data and Feedback for Cell Culture Process Monitoring: A Comparative Study

In cell culture bioprocessing, real-time batch process monitoring (BPM) refers to the continuous tracking and analysis of key process variables such as viable cell density, nutrient levels, metabolite concentrations, and product titer throughout the duration of a batch run. This enables early detection of deviations and supports timely control actions to ensure optimal cell growth and product quality. BPM plays a critical role in ensuring the quality and regulatory compliance of biopharmaceutical manufacturing processes. However, the development of accurate soft sensors for BPM is hindered by key challenges, including limited historical data, infrequent feedback, heterogeneous process conditions, and high-dimensional sensory inputs. This study presents a comprehensive benchmarking analysis of machine learning (ML) methods designed to address these challenges, with a focus on learning from historical data with limited volume and relevance in the context of bioprocess monitoring. We evaluate multiple ML approaches including feature dimensionality reduction, online learning, and just-in-time learning across three datasets, one in silico dataset and two real-world experimental datasets. Our findings highlight the importance of training strategies in handling limited data and feedback, with batch learning proving effective in homogeneous settings, while just-in-time learning and online learning demonstrate superior adaptability in cold-start scenarios. Additionally, we identify key meta-features, such as feed media composition and process control strategies, that significantly impact model transferability. The results also suggest that integrating Raman-based predictions with lagged offline measurements enhances monitoring accuracy, offering a promising direction for future bioprocess soft sensor development.

q-bio.QM↗

arXiv2025

Lessons Learned from Deploying Adaptive Machine Learning Agents with Limited Data for Real-time Cell Culture Process Monitoring

This study explores the deployment of three machine learning (ML) approaches for real-time prediction of glucose, lactate, and ammonium concentrations in cell culture processes, using Raman spectroscopy as input features. The research addresses challenges associated with limited data availability and process variability, providing a comparative analysis of pretrained models, just-in-time learning (JITL), and online learning algorithms. Two industrial case studies are presented to evaluate the impact of varying bioprocess conditions on model performance. The findings highlight the specific conditions under which pretrained models demonstrate superior predictive accuracy and identify scenarios where JITL or online learning approaches are more effective for adaptive process monitoring. This study also highlights the critical importance of updating the deployed models/agents with the latest offline analytical measurements during bioreactor operations to maintain the model performance against the changes in cell growth behaviours and operating conditions throughout the bioreactor run. Additionally, the study confirms the usefulness of a simple mixture-of-experts framework in achieving enhanced accuracy and robustness for real-time predictions of metabolite concentrations based on Raman spectral data. These insights contribute to the development of robust strategies for the efficient deployment of ML models in dynamic and changing biomanufacturing environments.

q-bio.QM↗

arXiv2024

Uncertainty Quantification Using Ensemble Learning and Monte Carlo Sampling for Performance Prediction and Monitoring in Cell Culture Processes

Biopharmaceutical products, particularly monoclonal antibodies (mAbs), have gained prominence in the pharmaceutical market due to their high specificity and efficacy. As these products are projected to constitute a substantial portion of global pharmaceutical sales, the application of machine learning models in mAb development and manufacturing is gaining momentum. This paper addresses the critical need for uncertainty quantification in machine learning predictions, particularly in scenarios with limited training data. Leveraging ensemble learning and Monte Carlo simulations, our proposed method generates additional input samples to enhance the robustness of the model in small training datasets. We evaluate the efficacy of our approach through two case studies: predicting antibody concentrations in advance and real-time monitoring of glucose concentrations during bioreactor runs using Raman spectra data. Our findings demonstrate the effectiveness of the proposed method in estimating the uncertainty levels associated with process performance predictions and facilitating real-time decision-making in biopharmaceutical manufacturing. This contribution not only introduces a novel approach for uncertainty quantification but also provides insights into overcoming challenges posed by small training datasets in bioprocess development. The evaluation demonstrates the effectiveness of our method in addressing key challenges related to uncertainty estimation within upstream cell cultivation, illustrating its potential impact on enhancing process control and product quality in the dynamic field of biopharmaceuticals.

q-bio.QM↗

arXiv2023

Applications of Machine Learning in Biopharmaceutical Process Development and Manufacturing: Current Trends, Challenges, and Opportunities

While machine learning (ML) has made significant contributions to the biopharmaceutical field, its applications are still in the early stages in terms of providing direct support for quality-by-design based development and manufacturing of biopharmaceuticals, hindering the enormous potential for bioprocesses automation from their development to manufacturing. However, the adoption of ML-based models instead of conventional multivariate data analysis methods is significantly increasing due to the accumulation of large-scale production data. This trend is primarily driven by the real-time monitoring of process variables and quality attributes of biopharmaceutical products through the implementation of advanced process analytical technologies. Given the complexity and multidimensionality of a bioproduct design, bioprocess development, and product manufacturing data, ML-based approaches are increasingly being employed to achieve accurate, flexible, and high-performing predictive models to address the problems of analytics, monitoring, and control within the biopharma field. This paper aims to provide a comprehensive review of the current applications of ML solutions in a bioproduct design, monitoring, control, and optimisation of upstream, downstream, and product formulation processes. Finally, this paper thoroughly discusses the main challenges related to the bioprocesses themselves, process data, and the use of machine learning models in biopharmaceutical process development and manufacturing. Moreover, it offers further insights into the adoption of innovative machine learning methods and novel trends in the development of new digital biopharma solutions.

cs.LG↗

arXiv2022

Multi-fidelity Gaussian Process for Biomanufacturing Process Modeling with Small Data

In biomanufacturing, developing an accurate model to simulate the complex dynamics of bioprocesses is an important yet challenging task. This is partially due to the uncertainty associated with bioprocesses, high data acquisition cost, and lack of data availability to learn complex relations in bioprocesses. To deal with these challenges, we propose to use a statistical machine learning approach, multi-fidelity Gaussian process, for process modelling in biomanufacturing. Gaussian process regression is a well-established technique based on probability theory which can naturally consider uncertainty in a dataset via Gaussian noise, and multi-fidelity techniques can make use of multiple sources of information with different levels of fidelity, thus suitable for bioprocess modeling with small data. We apply the multi-fidelity Gaussian process to solve two significant problems in biomanufacturing, bioreactor scale-up and knowledge transfer across cell lines, and demonstrate its efficacy on real-world datasets.

cs.LG↗