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Zeta Plus™ Depth Filtration and Alternative Technologies for Cell Culture Clarification

Production of therapeutics proteins is continuously advancing to meet the latest demands of increased cell densities, improved productivity; greater flexibility; lower manufacturing costs with improved yields.

Once the fermentation is complete the first purification step which separates the cell and or cell debris from extracellular produced proteins is critical and must be robust. Typically Zeta Plus Depth Filtration, Tangential Flow Filtration (TFF) and Centrifugation are considered.

These technologies need to show several key performance attributes:

3M™ Zeta Plus ranges

3M ™ Zeta Plus filter systems are available from 25cm2 (BC25) effective area capsules through to production scale 16” cartridges or to fully disposable3M™ Zeta Plus Encapsulated System (EZP).

Scale up experiments use constant flux (flow rate per unit area) which is subsequently scaled to full scale using similar conditions.

Tangential flow filtration systems can also be evaluated at small scale and data used to specify production size systems. In order to obtain accurate sizing for TFF systems, it is essential to use test filter devices with the same flow path length as will be used in production systems.

Centrifugation poses a more difficult scale up issue. In order to obtain accurate scale up information, the same g-force and flow path configuration device must be used.

3M™ Zeta Plus ranges

  • The quality of the cell separation step impacts the downstream processing.
  • Zeta Plus depth filters and TFF systems produce a high level of filtrate quality.
  • Centrifuges separate cell debris on the basis of density.
  • As density varies among whole cells, the quality can vary and often requires further clarification using a polishing filter.

3M™ Zeta Plus ranges

Yields will have a direct impact on costs. Both TFF systems and centrifuges can limit product yield. Centrifuges of solids ejecting type can mean the solid dryness is 50- 70%, reducing product yield by up to 30-50%. TFF systems are limited by volume concentration factor (VCF) giving a total yield of 90%, or product yield loss is 10%. Zeta Plus depth filtration systems are direct flow and any residual product flushed through in a recovery wash post filtration. The disposable 3M ™ Zeta Plus Encapsulated System (EZP) has a hold up volume of less than 100ml for 11m2 effective filter surface area to provide high yields and low hold up volumes.

3M™ Zeta Plus ranges

Zeta Plus depth filtration systems require only additional filter area to process larger volumes or take into account of fermentation variations and often used as the preferred platform technology.

TFF systems for cell separation are optimised and will need to be re-optimised for different processes and volumes. Centrifuge systems are also sized for specific process parameters. If batch size increases, centrifuge capacity cannot be added easily.

3M™ Zeta Plus ranges

Zeta Plus is very flexible available as traditional stainless steel housings or as fully disposable Zeta Plus Encapsulated Systems.

TFF are available in disposable systems but are typically limited to smaller volumes.

Disposable centrifuges are also restricted in the fermentation volumes they are capable of processing.

In summary: different technologies can be used for cell separation post fermentation

Table 1. below summarizes the comparisons made.

Issue Zeta Plus Depth Cartridges Disposable Zeta Plus Encapsulated system Depth Cartridges TFF Centrifuge
Scalability Yes, Linear Yes, Linear Yes, Linear Difficult
Effluent quality Excellent Excellent May need additional filtration Requires additional filtration
Yield Excellent >95% Excellent >95% Good, may need diafiltration Dependent on solid dryness
System flexibility Easy to size up & down Easy to size up & down Difficult to scale up None- fixed design
Fixed process design No No Yes Yes
Shear forces Low Low Moderate High
CIP Validation Yes None required Complex, membrane re-use Complex, may require disassembly
Cross Batch contamination No, single use filters No Yes, membrane re -use Yes, complex CIP
SIP Capability Yes No No Yes
Capital cost Low Low High High
Maintenance Cost Low Low Moderate High
Consumables Moderate filter Moderate Low/High dependent on membrane life Moderate power consumption
Disposable Systems No Yes, easy to use Yes Limited