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Biologics Processes

Industrial scale biologics facilities involve enormous capital investment, long seed train to product times, and highly integrated support areas such as CIP, buffer and media making, and quality control/quality assurance. As such there is an enormous value in being able to accurately model a biologics process to maximize production, have engineering projects achieve the intended results, and be able to accurately coordinate within the supply chain. However, biologics processes pose a host of challenges in the development of accurate models and in performing virtual process analysis. Biologics processes are particularly problematic for traditional modeling technologies. APC technology has been specifically developed to address biologic process complexity and APC has extensive experience in modeling, scheduling and optimization of biologics processes including major projects involving both fed batch and perfusion bioreactors. Customized VirtECS modules have been designed to handle the particular characteristics of each.

Fed Batch Reactors

Fed batch reactors are commonly used during the primary production steps in biologics processes, whether as a single stage or as part of a larger sequence of reactors. Complications in managing fed batch reactors arise from necessary operations such as the cleaning of the bioreactors between batches, coordinating the upstream seed train and media making, and anticipating the necessity of repacking downstream chromatography columns used in the separation stages of the process. The effect of such interruptions is not limited to a direct delay for the present batch. These delays often lead to additional ramifications due to the storage of the product material (frequently in the reactor itself) until it can enter the downstream separation system. Coordination with the separation system will sometimes delay the start of new batches and can result in the loss of the product if it is stored for a longer time than allowed by the appropriate regulations or procedures. Inherent variability in the process itself must also be considered because the exact yield and cycle time of each batch varies.

The complex nature of biologics processes limits the ability of simulation and other traditional approaches to produce realistic answers, but is well addressed by the mathematical programming approach used by VirtECS. A case study using VirtECS to produce a detailed schedule for a sample biologics manufacturing process can be found in the following two-part paper from Biopharm International (Part 1, Part 2). VirtECS routinely produces answers unachievable any other way.

Our module for fed batch reactors includes the following features:

  • multi-staged bioreactor trains
  • batch titre variability
  • titre dependent column repacking constraints
  • integrated buffer and media preparation
  • optimizaton of CIP and support operations

Perfusion Reactors

Perfusion reactors operate continuously over a fixed time period, usually several weeks. These reactors are both fed and harvested continuously. This presents a difficult challenge because perfusion reactors produce a different concentration of product every day over the life cycle of a campaign. In addition, limited storage available in the harvest tanks, results in the need for very tight control over inventory and harvest material properties.

Our module for perfusion reactors includes the following features:
  • time-dependent productivity profiles
  • customized management of harvest tanks
  • pooled and non-pooled stages
  • column repacking
  • buffer and media preparation
  • optimizaton of CIP and support operations
Advanced Process Combinatorics, Inc. - Scheduling, Optimization, Capacity Planning | 765.497.9969 | Contact Us

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