Model-based development and scale-up of chromatographic separation processes

单克隆抗体、酶和干扰素等生物制药产品越来越多地加入到医生治疗癌症、心脏病和病毒感染等危及生命的疾病的救命药物清单中。与其他药物产品一样，这些产品需要以高度纯净的形式用于预期的治疗应用。由于开发和制造成本高以及相对较短的保质期等因素的综合作用，生物制药非常昂贵。对于典型的产品，如单克隆抗体，纯化成本几乎占总制造成本的60-80%。大多数生物药品是用柱或膜基色谱法纯化的。虽然色谱法在工业上得到了广泛的应用，但它很难规模化。这是由于任何色谱分离都涉及到吸附（即热力学）和物质的质量传递（即动力学）之间复杂的相互作用。不适当地扩大过程可能效率极低，这可能对过程经济产生不利影响。本项目的目的是了解热力学和动力学在单克隆抗体等生物药物的色谱纯化中的贡献。基于对这些个体因素的理解，将开发出这些产品的色谱纯化过程的放大模型。这些模型将有助于设计和开发具有成本效益的净化工艺，从而提高生物制药工业的制造效率。

Biopharmaceutical products such as monoclonal antibodies, enzymes and interferons are increasingly being added to the repertoire of life saving drugs available to physicians for treating life-threatening ailments such as cancer, cardiac diseases and viral infections. As with other pharmaceutical products, these need to be available in highly pure form for their intended therapeutic applications. Biopharmaceuticals are very expensive due to a combination of factors such as high development and manufacturing cost, and relatively low shelf-life. For a typical product such as a monoclonal antibody, purification cost accounts for almost 60-80% of the total manufacturing cost. Most biopharmaceuticals are purified using column or membrane-based chromatography. While chromatography is widely used in the industry, it is quite difficult to scale-up. This is due to the fact that any chromatographic separation involves the complex interplay between adsorption (i.e. thermodynamics) and mass transport of material (i.e. kinetics). Improperly scaled-up processes can be extremely inefficient and this can have a detrimental effect on process economics. The objective of this project is to understand the thermodynamic and kinetic contributions in chromatographic purification of biopharmaceuticals such as monoclonal antibodies. Based on an understanding of these individual contributing factors, models for scale-up of chromatographic purification processes for these products will be developed. Such models will be useful in designing and developing cost-effective purification processes and thereby increase manufacturing efficiency in the biopharmaceutical industry.