Abstract—Monoclonal antibodies have emerged as a valuable class of therapeutic products. However, the industry still faces pertinent challenges with respect to product stability, particularly product aggregation that leads to toxicity and immunogenicity. The present project is an attempt to propose a kinetic model for the aggregation of monoclonal antibodies using the analysis of experiments that were performed for several different combinations of buffer type, temperature, pH and salt concentration pertaining to three types of chromatography – protein A chromatography, cation exchange chromatography and anion exchange chromatography. Modified Lumry Eyring model has been employed by taking into account the reversibility of each step in the aggregation process. MATLAB R2011b has been used to find the optimum values of the kinetic rate constants for the different cases. The model can go a long way in reducing the extent of aggregation by helping to accurately choose the experimental conditions with the minimum number of experiments. Index Terms—Aggregates, chromatography, Lumry Eyring model, monoclonal antibodies. I. INTRODUCTION Hundreds of monoclonal antibodies (mAbs) are either currently on the market or under development. They have been successfully introduced as therapies to a variety of diseases such as rheumatoid arthritis, multiple sclerosis and different forms of cancer. However, the industry still faces challenges with respect to product stability, particularly protein aggregation that is one of the major road barriers inhibiting the rapid commercialization of potential protein drug candidates. Aggregates can cause loss of activity as well as toxicity and immunogenicity. Because of their toxic potential, aggregates can cause an unwanted response or even overreaction of a patient's immune system. In fact, abnormal protein folding leading to its aggregation is very common in many human diseases resulting from various genetic as well as physical and chemical changes inside a cell [1]. Protein molecules can aggregate by physical association without any change in primary structure or by chemical bond formation and may lead to the formation of either soluble or insoluble aggregates. Aggregation can occur through a variety of mechanisms – Reversible association of the native monomer, aggregation of conformationally altered monomer, aggregation of chemically modified product, nucleation-controlled aggregation, surface induced aggregation etc. which are illustrated in Fig. 1 [2]. Manuscript received December 25, 2013; revised March 4, 2014. Ishan Arora, Rohit Bansal, Varsha Joshi, and Anurag S. Rathore are with the Department of Chemical Engineering, Indian Institute of Technology, Delhi, India (e-mail: amiarora2011@gmail.com). Fig. 1. Schematic illustration of common aggregation mechanisms [2]. The extent of aggregation depends on many factors which can be broadly classified as intrinsic (primary, secondary, tertiary or quaternary structure) or extrinsic (protein environment, processing conditions) [3]. Proteins in general are commonly known to aggregate under low pH conditions. During processing, there may be changes in protein environment such as changes in pH, buffer concentration, ionic concentration etc. The environmental factors affect at a molecular level the protein-protein and protein-salt interactions. It is extremely important to understand the mechanism of protein aggregation since the limited success in controlling aggregation is primarily due to the lack of a concrete understanding of the aggregation process. Kinetic studies and data curve fitting are keys to rigorous mechanistic studies [4]. When combined with experimental kinetic and thermodynamic data, models of aggregation kinetics can provide a unique and noninvasive way to gain qualitative and quantitative details about the aggregation mechanism and also help in the design of experiments and additives to more accurately predict or control aggregation rates [5]. The hold time of the monoclonal antibody in the buffer can be appropriately chosen depending on its aggregation behavior in order to minimize the formation of aggregates. The primary objective of this project was to use the experimental analysis together with the knowledge of chemical kinetics to build a kinetic model for protein aggregation and to correlate it with several key factors which influence aggregation such as buffer type, temperature, pH and salt concentration. The currently established purification platform for monoclonal antibodies Ishan Arora, Rohit Bansal, Varsha Joshi, and Anurag S. Rathore Aggregation Kinetics for Monoclonal Antibody Products International Journal of Chemical Engineering and Applications, Vol. 5, No. 5, October 2014 433 DOI: 10.7763/IJCEA.2014.V5.424