THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
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Excerpt of Chapter 8

Steadily increasing business demands to reduce product development time and costs as well as expectations from the regulatory authorities for better process understanding and characterization are motivating companies to search for more efficient process development tools that help reduce development time while providing better process insight and understanding. Thus, in order to provide greater efficiencies in process development while reducing the costs and resources required to achieve a fully developed and optimized process as quickly as possible, new approaches and technologies for process development are being sought. One approach to reaching these goals is the use of high throughput or mini-system experimental technologies that rely on either significantly scaled-down experimental methods or on other miniaturized systems that can provide greater information about a particular unit operation in shorter periods of time while consuming less material. In most cases, a strategy that combines the use of high throughput methods with traditional larger scale development methods is likely to be the most appropriate means to ensure the generation of valid and useable data while maximizing productivity of process development resources. This combination of miniaturized, high throughput development technologies to rapidly and efficiently examine many process alternatives and variables combined with traditional laboratory scale process development to confirm the details of individual unit operations can expand the total knowledge base on which a monoclonal antibody manufacturing process is developed and increase process reliability, thereby leading to a more robust and fully controllable manufacturing process. High throughput techniques have been used in the small molecule drug discovery field for decades, but were not utilized in the field of biologic process development until the early 2000’s. The successful application of high throughput screening and mini-system experimental techniques have been reported in many areas related to the development of biomanufacturing processes, such as clone selection, optimization of upstream and development of downstream purification processes. The latter applications include solubility, partitioning, refolding, and chromatographic separations

A comprehensive example of the use of microtiter plate high throughput method for the development of a monoclonal antibody purification process has recently been reported by Lacki et al. One major objective of this study was the reduction in high molecular weight aggregate content in the final monoclonal antibody product from 15% in the bioreactor harvest used as starting material for purification to less than 1% in the final purified monoclonal antibody while still achieving high overall yields. This study included the testing of nine different chromatography resins and the evaluation of over 1,000 different operating conditions. All of the initial screening and optimization experiments were completed in 63 working days for one scientist, demonstrating the efficiency of the high throughput methodology.

… Mini-bioreactors and high throughput purification techniques can enable rapid and comprehensive development and characterization of many aspects of manufacturing processes for monoclonal antibody products. However, there are a number of challenges involved in making these techniques truly useful. For example, while mini-bioreactors are increasingly being used in cell culture process development, high throughput systems which take full advantage of the potential of these small scale bioreactors are expensive and not yet widely available. For purification development, there are challenges in optimizing chromatography protocols for accuracy and precision and in correlating the performance of the scale-down model systems with the manufacturing process at full scale and predicting where the models may break down. Also, the method qualification and validation studies necessary to create a high throughput development platform can be arduous and time-consuming but, once fully implemented, will enable much more rapid process development and will be a critical aspect of developing a full understanding of any manufacturing process. High throughput techniques can also generate new bottlenecks in experimental design, automation, analytics, and data evaluation for both cell culture and purification applications. High throughput systems can benefit significantly from the use of statistical design of experiments techniques to reduce the number of data points required and software to support this is available. Automation can be used for steps such as media preparation for cell culture studies or mixing of buffers on a well-by-well basis for purification studies and such automation can be quite involved and time-consuming to develop. These methods generate large numbers of samples to be analyzed and some of the typical analytical methods used (such as ELISA or size exclusion HPLC) can be slow and tedious.

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