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High Productivity Harvest

High Productivity Harvest for Fed-Batch processes simplifies primary recovery and boosts production, eliminates centrifuge and depth filtration steps, and harvests material ready for processing on a capture column.

High Productivity Harvest

An innovative application of a cell retention device in the clarification step developed by Repligen, High Productivity Harvest for Fed-Batch processes has both productivity and process benefits.

Traditional Clarification

A traditional clarification process typically includes multi-stage harvest steps that are equipment-intensive and known to have high variability in processing. Because of the materials of construction used, extensive rinsing is needed causing large usage of buffer/WFI.

During centrifugation, there are no true linear scaling tools making it very labor-intensive. Lastly, traditional clarification processes are usually performed in an open system that is inherently non-sterile and not aligned with the industry trend to manufacture in closed system facilities.  

High Productivity Harvest

High Productivity Harvest uses an XCell™ ATF Cell Retention Device after peak density is achieved in a typical Fed-Batch process. Fresh media is added in a set flow rate while the harvesting of the product is initiated. This results in significant productivity and process gains.

Increase productivity

  • Generate up to 2X increase in protein production without additional time, OR
  • Harvest days earlier at the same titer, increasing throughput

Improve processes

  • Produce a healthier culture with lower process related impurities
  • Reduce number of unit operations and raw materials
  • Transition to a single-step 0.2µm filtered, closed system
  • Harvest material ready for downstream purification

HOW it Works

Step A
The fed-batch process is started inthe same way.  

Step B
Once the peak cell density is achieved, start to pump fresh media in at a set flow rate between 0.1 and 1 vvd.  As fresh media is pumped in, the harvesting of the product is initiated. In this example, the media exchange was started on Day 10, but this is flexible depending on the process.  

Step C
On the last day of the run, end addition of fresh media and start to draw down the volume in the reactor at 1-2 vvd.   Operating at 20LMH for a 1000L reactor, the reactor will be harvested in approximately 4 hours.  If a 2000L reactor it will take approximately 8 hours.

Step D
High Productivity Harvest is completed to match the original fed batch production timing.
 

Note: Above is an example. Number of days depends on user processes and facility constraints.

Typical Fed-Batch process

Start of High Productivity Harvest
~ 0.1 – 1 vvd

Start of Draw Down
~ 1 – 2 vvd
~ 20 LMH

Finish High Productivity Harvest and
Clarification

Matching typical Fed-Batch
Production Timing

High Impact Results

Harvest ready for purification

  • 2x total accumulated IgG
  • Harvested product is 0.2µm filtered and ready for purification, no centrifugation and no depth filtration required 
     

Higher viable cell density and viability

  • Viable cell density increased by more than 3-fold in fed-batch cultures using High Productivity Harvest compared to traditional FB
  • Viability in fed-batch cultures using High Productivity Harvest remained at >90% throughout run, a healthier environment for the cells and the product of interest
     

Higher product quality

  • HCP per mg of IgG is lower in both HP Harvest FB conditions compared to traditional FB harvest
  • Requirement for depth filtration eliminated

Advances in high productivity harvest

Alternating Tangential Flow (ATF) Filtration

An award-winning technology, ATF allows the removal of spent media while keeping cells in culture.  Applied using an XCell™ ATF device attached to a bioreactor, ATF minimizes cell shear and keeps cells in constant equilibrium with bioreactor contents. This results in faster cell growth at higher densities with higher productivity.  Today, the XCell™ ATF device, in single-use or reusable format, is the leading perfusion device for mAb and rProtein production.

Resources

Expand All

High Productivity Harvest - Intensify Harvest and Displace Depth Filtration in Fed Batch Cell Culture
John Bonham-Carter, November 2018

Filtration Primer - WIP

How Alternating Tangential Flow (ATF) works - WIP

XCell ATF from Repligen - WIP