Ask the Expert: BioSC Continuous Chromatography of MAbs, Process Design and Regulatory Considerations

with Vincent Monchois

In our September webcast, Vincent Monchois (biopharma strategic project director at Novasep) discussed continuous chromatography using BioSC technology. He included regulatory considerations and the challenges of viral clearance that arise when companies switch from batch to continuous processes.

Monchois’s Presentation
Users can apply BioSC multicolumn, continuous chromatography to standard capture steps such as ion-exchange or protein A chromatography. The main advantages are continuous operation and full access to the total static capacity of a resin. Other advantages include reduction of production costs (in terms of resins, buffers, volume, and footprint), a streamlined process, and increased productivity. Eluted product quality is the same as that from batch processing.

This technology works by repeating identical cycles, allowing for all columns to run an entire process. The key is to operate at a steady state, ensuring no change in critical attributes.

A batch is defined as a specific quantity with uniform characteristics. A lot is defined as an identifying portion of a batch produced either in a period of time or as a specific quantity. With those fully applicable definitions, no additional regulations or guidance is required with the BioSC operation. Companies must demonstrate that they can keep the critical attributes the same throughout a process.

For monoclonal antibody (MAb) manufacturing processes from Chinese hamster ovary (CHO) cell lines, viral clearance is often achieved through pH inactivation following protein A capture, nanofiltration, and ion-exchange chromatography. To demonstrate the efficiency of such viral clearance, users must first define and validate a scaleddown model, then perform spiking studies.

Novasep has developed an approach in which pH inactivation is a periodic process. This includes a sequential drum rotation in parallel with BioSC chromatography. In a case study, three protein A affinity columns were followed by an hour-long pH inactivation before anion-exchange chromatography. Users would have two options: either neutralization after pH inactivation or direct injection to the ion-exchange column(s).

Novasep has designed a scale-down model to show viral clearance. For ionexchange chromatography, the model uses the same linear flow rate and the same number of columns of the same bed height, but a reduced column diameter. It can mimic a steady state with a limited number of BioSC cycles. Because the start and end of a process are not part of that steady state, those parts of the process must be considered separately. This test can be completed in less than one day using the BioSC Lab mobile equipment.

Switching from batch to BioSC continuous processing is a straightforward adaptation of the batch procedure. The key is to design a process that will operate at a steady state. No specific new regulations apply beyond those for developing and validating batch processes. Users then validate their purification processes to show that the steady state is well controlled and appropriate viral clearance is achieved.

Questions and Answers
Because purified product is eluted in theory, how do you determine the inactivation time for pH inactivation? The time of inactivation remains the same at 60 minutes.

What are the main benefits of introducing batch stages in a continuous process? Doing so allows you to better control the process and, if problems arise, to put in place mitigation plans without jeopardizing a whole batch. Monchois believes that mixing a continuous chromatography process with periodic processes for steps that require higher levels of control (e.g., pH inactivation) is the right approach for a tight control of an overall downstream process.

Can column switching be driven by OLE for Process Control (OPC) or other management software to manage steady state? Yes. The BioSC system is equipped to support batch management. Upon request, we can connect the software to any OPCcompliant system. Novasep offers in-line detectors and also is working to implement advanced control methods. Your example was an antibody process.

Can we use BioSC chromatography for processes that need gradient elution? Yes. The BioSC system has binary gradient (linear and isocratic) capacities.

More Online
Click here to watch the recorded presentation of this webcast.