Predictive chemometrics modelling for enhanced robustness of integrated continuous biomanufacturing processes

拟议的博士项目将解决为生物制药蛋白质（如双特异性抗体）的新模式开发强大的连续制造工艺的挑战。连续生物加工正在该行业内复苏。它有可能提高产品质量，并从根本上减少生产能力和设施占地面积的要求。此外，一些人认为，连续加工能够更好地应对市场需求的不确定性，并最大限度地减少技术转让风险。需要采用严格的方法来评估采用连续生物加工的产品对产品质量、工艺稳健性和产品组合管理的影响，以确定新模式商业化的最佳途径。UCL的生物化学工程系非常适合应对这一挑战，因为它率先开发了包括生物过程优化和化学计量学在内的决策工具。这些工具将使集成单元操作的超规模研究能够更好地模拟大规模连续生物过程，增强对这些过程的理解将解决有效的生物过程设计，投资组合管理和产能规划决策。该项目旨在创建实验和预测建模工具，以评估和优化生物制药端到端连续生物加工的新想法。MedImmune正在评估实验室规模的集成连续生物处理的潜力，ATF灌注培养连接到多柱连续色谱系统。开发与连续捕获色谱法相关的灌注培养集成规模缩小平台，将能够进行更高通量的实验，以探索连续上游和下游工艺步骤中关键工艺参数对质量和性能的影响。最初，将对现有灌注培养模拟物（例如，高通量微型生物反应器（例如ambr，Sartorius）和旋转管）和连续色谱模拟物（例如，1 ml色谱柱）的能力和局限性进行分析。这将形成缩小规模的模拟物的新设计的基础，这些模拟物克服了现有方法的限制，并且具有足够的传感器集成到装置中，例如用于细胞培养的pH和溶解氧。集成规模缩小平台的性能将通过与MedImmune连续色谱相关的实验室规模（5 L）灌注运行进行验证。集成连续生物过程的实验数据生成缩小规模的灌注模拟物将与连续捕获色谱模拟物相关联，以生成将细胞培养性能与下游性能相关联的实验数据。将使用风险分析确定灌注培养（例如进料流速）和连续色谱（例如停留时间、流速）中的关键工艺参数。将确定各实验中要测量的关键性能输出（例如生产率）和质量属性（例如糖基化、电荷亚型、产品相关杂质）。这些输入和输出将构成DoE实验的基础，该实验使用来自MedImmune的工业相关细胞系表达新型模式（例如双特异性抗体）。用于生物过程建模和连续过程控制的化学计量学实验数据将用于构建预测因果模型，该模型使用先进的化学计量学/多变量数据分析技术将关键过程参数（例如灌注进料流速）与关键质量属性（例如聚集体）和性能指标（例如灌注培养生产率，色谱产率）联系起来。将探讨连续运行的时间影响;

The proposed PhD project will address the challenge of developing robust continuous manufacturing processes for new modalities of biopharmaceutical proteins such as bispecific antibodies. Continuous bioprocessing is experiencing a resurgence within the sector. It has the potential to enhance product quality and radically reduce capacity and facility footprint requirements for manufacture. Furthermore, continuous processing is considered by some to be better able to address market demand uncertainties and minimise technology transfer risks. A rigorous approach to assessing the impact of introducing products adopting continuous bioprocessing on product quality, process robustness and portfolio management is required to determine the best route to commercialisation of new modalities. The department of Biochemical Engineering at UCL is well-placed to address this challenge as it has pioneered the development of decisional tools comprising bioprocess optimisation and chemometrics. These tools will enable ultrascale-down studies of integrated unit operations to better mimic large scale continuous bioprocesses, the enhanced understanding of which will address effective bioprocess design, portfolio management and capacity planning decisions.This project aims to create experimental and predictive modelling tools to assess and optimise novel ideas for end-to-end continuous bioprocessing of biopharmaceuticals. The potential of continuous processing to maintain and control product quality of biologics will be evaluated.MedImmune is evaluating the potential of integrated continuous bioprocessing at bench scale with ATF perfusion culture linked to multi-column continuous chromatography systems. The development of an integrated scale-down platform of perfusion culture linked to continuous capture chromatography will enable higher throughput experiments to be performed to explore the impact of critical process parameters in the continuous upstream and downstream processing steps on quality and performance. Initially, analysis of the capabilities and limitations of existing perfusion culture mimics (e.g. with high throughput mini-bioreactors (eg ambr, Sartorius) and spin tubes) and continuous chromatography mimics (e.g. 1ml columns) will be carried out. This will form the basis of novel designs of scale-down mimics that overcome limitations with existing methodologies and have sufficient sensors integrated into the devices for e.g. pH and dissolved oxygen for cell culture. The performance of the integrated scale-down platform will be validated with bench scale (5L) perfusion runs linked to continuous chromatography at MedImmune. Experimental data generation for integrated continuous bioprocessesThe scale down perfusion mimics will be linked to continuous capture chromatography mimics for experimental data generation linking cell culture performance with downstream performance. Key process parameters in perfusion culture (e.g. feed flowrates) and continuous chromatography (e.g. residence time, flowrates) will be identified using risk analysis. Key performance outputs (e.g. productivities) and quality attributes (e.g. glycosylation, charge isoforms, product-related impurities) to measure in each experiment will be identified. These inputs and outputs will form the basis for DoE experimentation using industrially relevant cell lines from MedImmune expressing novel modalities eg bispecific antibodies. Chemometrics for bioprocess modelling and control of continuous processesExperimental data will be used to build predictive cause-and-effect models that link critical process parameters (e.g. perfusion feed flowrates) to critical quality attributes (e.g. aggregates) and performance metrics (e.g. perfusion culture productivity, chromatography yield) using advanced chemometrics / multivariate data analysis techniques. The temporal impacts of continuous operation will be explored; m