The question of whether a plant is capable of processing a given titer is, of course, an oversimplification. It is the rate of mass flow into the process that determines the ability of a downstream facility to purify the output of the reactors successfully. In this article, an example plant with fixed equipment was used to suggest where the limitations to plant throughput occur and how better process design and new methods have enabled improvements to be made over the last five years. The article also considers which technologies are, and in the future will, be available to push these limits still further.
It would be difficult to attend a conference or read an article on the development or production of monoclonal antibodies (MAbs) without being made aware of the predicted bottlenecks in the downstream processes handling the high-titer fermentations now being achieved. Facilities designed to purify the output of fermenters of a given size become unable to cope with the mass of product required of them. Where possible, increased column sizes and membrane areas can be used, but at the largest operational scales physical constraints and the prohibitively high costs of retrofitting mean that reducing the number of batches is the only realistic, though undesirable, option.
It may not be necessary to produce antibodies at such large volumes because the same amount of product mass can be obtained from a smaller plant, but from a historical perspective similar arguments have been used for the production of antibiotics and to satisfy the global requirement for Protein A in processes for the purification of MAbs.1–2 Therefore, this article will assume that there is, or will be, the need for high-titer, large-volume fermentations to supply the market for MAbs.
(LONZA, LTD., BASEL, SWITZERLAND)
Plant and Model Limitations
Models are useful tools to define process performance and gain insight into process fit in the confines of an existing plant. They are, of course, only an approximation—a model of the real situation limited by the information available for input. Models are as varied as their outputs, and are often constructed to answer a question or range of questions, which explains some of the variability seen in the conclusions reached in the literature.3
The goal of this model was to understand how changing titers affected a largely idealized production plant in its ability to match the purification output with that of the fermenters. This means that the numbers given in terms of fermenter titer represent the maximum that can be processed in the plant before the downstream operation limits the number of batches that can be produced per annum.
If we consider a plant constructed to produce MAbs for in-market supply and apply limitations to its operation, we can start to see where the bottlenecks occur, and begin to identify techniques and technologies to target the causes. In this case, the major limitations of the model are described in Table 1.
Table 1. Major assumptions of the model
Table 2 summarizes the evolution of the process, taking us from how processes were developed around five years ago, through today's modern processes, and how these might change in the future using some of the techniques that are beginning to be adopted by the industry.
Table 2. Explanation of process evolution