Abstract
Monoclonal antibodies are generally produced using a generic platform approach in which several chromatographic separations assure high purity of the product. Dimerization can occur during the fermentation stage and may occur also during the downstream processing. We present here simulations in which a traditional platform approach that consist of protein A capture, followed by cation-exchange and anion-exchange chromatography for polishing is compared to a continuous platform in which dimer removal and virus inactivation are carried out on a size-exclusion column. A dimerization model that takes pH, salt concentration and the concentration of antibodies into account is combined with chromatographic models, to be able to predicted both the separation and the degree to which dimers are formed. Purification of a feed composition that contained 1% by weight of dimer and a total antibody concentration of 1 g/L was modeled using both approaches, and the amount of antibodies in the continuous platform was at least 4 times lower than in the traditional platform. The total processing time was also lower, as the cation-exchange polish could be omitted.
Highlights
The use of monoclonal antibodies as biopharmaceuticals is becoming more popular [1,2], and antibody dimerization during preparation and the subsequent removal of aggregates are becoming increasingly studied areas
Dimerization that occurs during the upstream processing is, not a major purification problem, since the removal of such dimers is a straightforward problem in process design
Monoclonal antibodies are usually produced in a bioreactor, and a series of separation steps is subsequently used to isolate and purify the product [2,3,4]. This downstream processing normally consists of chromatographic purification steps that are run in batch mode, with storage tanks between each unit operation
Summary
The use of monoclonal antibodies as biopharmaceuticals is becoming more popular [1,2], and antibody dimerization during preparation and the subsequent removal of aggregates are becoming increasingly studied areas. Monoclonal antibodies are usually produced in a bioreactor, and a series of separation steps is subsequently used to isolate and purify the product [2,3,4] This downstream processing normally consists of chromatographic purification steps that are run in batch mode, with storage tanks between each unit operation. Borg et al [7] used modeling to study the effects of twelve process parameters on the separation process in a cation-exchange chromatography (CIEX) step. These models, do not include the dimerization that occurs during the separation steps. A batch-wise approach to antibody production is considered in which protein A is used as a capture step, followed by virus inactivation and cation-exchange chromatography. The dimerization occurring on the stationary phase is disregarded and the study focuses on dimerization in the mobile phase
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