THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
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Excerpt of Chapter 3

The overall goal of a monoclonal antibody CMC development program is to develop a reliable, robust, and reproducible process to manufacture a monoclonal antibody product that is safe to administer to humans. The process which begins at small scale due to the relatively low demand for product should be scalable and in compliance with all relevant regulatory guidelines. As development of the monoclonal antibody product proceeds from pre-clinical testing through human clinical trials and ultimately to commercialization, the regulatory requirements increase in scope and depth. In conjunction with the development of this manufacturing process, suitable analytical methods should be developed that permit the full characterization of the monoclonal antibody product and provide appropriate in-process controls and quality control release specifications for the product…

…Selective, sensitive, and reproducible testing methods are critical tools used throughout the entire program, from initial process development through product release and characterization. At the initiation of the development program, some basic analytical methods must be in place to guide cell line selection and purification optimization so that the right product is produced and purified. As the program progresses, additional analytical methods must be developed to support process development, quality control testing and characterization of the bulk drug substance and to aid in demonstrating comparability of material produced as a result of future process scale-up, optimization, or improvement….

…A critical aspect of the development of any monoclonal antibody product is the development of a suitable genetically-modified, engineered cell line capable of producing the product at a sufficiently high titer. In addition to the production cell line, a suitable cell culture process that enables production of sufficient quantities of the monoclonal antibody product in an appropriate sized bioreactor must be developed. Upstream process development encompasses all of the activities related to the development of the DNA expression vector, the production cell line and the cell culture process for production of the monoclonal antibody product…The expression vector for a monoclonal antibody product is the DNA construct which is inserted into a suitable host cell line to enable the production of the monoclonal antibody of interest…. CHO cells are the dominant host cell line in use today for the production of monoclonal antibody products. …All approaches to upstream process development require systematic optimization of the growth and production medium and the bioreactor conditions over the course of the culture process to produce the maximum amount of active product of desired quality with the minimum amount of resource consumption (bioreactor volume, media and time)…. As the process is scaled up, additional process development may be required to solve problems that arise or to make process improvements. Following cell culture, the monoclonal antibody product produced by the production cell line in a suitable bioreactor must be separated from the cells, purified to remove impurities and potential contaminants to an acceptable level, formulated at the correct concentration with the proper excipients, and placed in storage in preparation for final formulation and drug product manufacturing. The downstream processing operations necessary to purify and formulate the bulk drug substance typically includes a step to remove the cells and cell debris, a capture step to selectively concentrate the monoclonal antibody product and remove the bulk of the impurities, one or more intermediate and polishing purification steps to remove the remaining impurities, and several steps to inactivate or remove endogenous or potential adventitious viruses.

… Managing the CMC activities of an antibody development program requires a coordinated and integrated project management approach that reaches back to the discovery function and forward to commercial manufacturing, and considers the requirements and impact of each activity as it relates to the timeline and dependencies of every other activity. Project management is essential in order to coordinate these numerous, interdependent activities and to ensure that the overall development program is consistent with the risk tolerance and strategic initiatives within the sponsor company. Certain development tasks are absolutely dependent on completion of previous activities whereas others can be initiated prior to finalization of previous steps or activities.

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