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TideXcell ® Pilot Scale Bioreactor

The Gentle Giant of Adherent Bioprocessing
TideXcell® is a linearly scalable pilot bioreactor system that runs on Tide Motion principle. It is ideal for biomass expansion of adherent cells under single-use or multiple-use technologies. The pilot scale bioreactor is also integrated with desirable and advanced features such as pH and DO (Dissolved Oxygen) measurement capability, Siemens HMI or PLC-based monitoring and control system, compressed air path that comes with a double HEPA and VOC (volatile organic chemicals) filters as well as other accessories.
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TideXcell <sup>®</sup>

Tide Motion in TideXcell ®


Features

  • Adherent cell scale-up for up to 5,000L packed-bed volume (bio-equivalency of 50,000 L in suspension)

  • a 100% media exchange system ideal for continuous bioprocessing

  • Separation of the matrix and mixing vessel

    -permits dual temperature control process to produce higher virus titers
  • Built-in weighing platform and inhouse mixer

  • PLC based monitoring system

    - with simple, intuitive touchscreen runs on Wonderware SCADA
  • Can be connected to SCADA systems with DeltaV or Pcs7 controls

  • Dual redundant systems

    - for critical components such as PLC and pumps are catered
  • Provides an ultra-scale down process

    - and reduces costs by saving on media, labor, space, utilities, and most importantly, eliminates cross-contamination
  • Isolator capability

  • cGMP references

  • PAT/IPQC

Applications

  • Culture of anchorage-dependent cells with BioNOC™ || carriers
  • Cell mass train
  • Vaccine production
  • Recombinant protein and monoclonal antibody production
  • Biosimilars and biobetters
  • Transition from 2D system to closed 3D system
  • Continuous bioprocessing
  • Wild virus production
  • Cell therapy
  • Biologics for neglected tropical diseases and orphan diseases

Highlights

Uniform Seeding

TideXcell ® Matrix Bed is designed to cut the area into numerous small sections and force cells to flow in horizontal radial direction instead of vertical direction. The gradient effect during the seeding phase could be minimized.

A matrix cassette is packed with carriers configured in 3D for optimum cell growth. Cassettes are stacked inside the matrix vessel(2 L, 20 L, 100L) for uniform seeding of cells.

Uniform Seeding Principle

TideXcell ® Matrix Bed is designed to cut the area into numerous small sections and force cells to flow in horizontal radial direction instead of vertical direction. The gradient effect during the seeding phase could be minimized.

TideXcell ®-100 Packed with Matrix Cassettes
(Top View)

The concept is achieved by packing the matrix bed with porous cassettes with smaller diameter when matrixes are packed inside.

100% Media Exchange

Continuous harvesting can be done in the TideXcell system due to 100% media exchange. This process is beneficial when doing viral culture work for producing higher viral titers or for stem cell culture which requires switching to a different media for differentiation.

Due to the seperation of the matrix vessel (where cells reside) and the mixing vessel (where the mixing of the culture medium is happening), the system is capable of fully harvesting the waste or conditioned media and feeding in a 100% fresh culture medium afterwards without harming the cells being cultured.

Closed Sampling For Cell Monitoring

Closed system sampling can be done in the TideXcell ® system. Each vessel types have their own corresponding number of sampling port.

A matrix cassette is packed with carriers configured in 3D for optimum cell growth. Cassettes are stacked inside the matrix vessel (2 L, 20 L, 100 L) for uniform seeding of cells.

SCADA

TideXcell ® PLC-based monitoring and control structure runs on WonderWare SCADA. This provides a high-level process supervisory management and data acquisition. This software platform will ensure process control safety, will support control strategy, and will provide a remote method of capturing data and events (alarms) for monitoring the continuous process. SCADA platforms also provide functions for graphical displays, alarms, trends and historical storage of data.

TideXcell ® is the core of Esco Aster, a contract development manufacturing organization (CDMO) that uses single-use adherent bioreactors in bioprocessing needs. Esco Aster focuses on process development, commercialization of new translational drugs (NTDs) for both humans and animals, orphan drugs, as a CMO for partner TideXcell ® factories looking to gain access in the ASEAN, ANZ, African region.

Dimension Comparison

Frequently Asked Questions
All TideXcell systems can be equipped with on-line UPS (option) to avoid external interruption to the power supply.
All TideXcell™ systems are equipped with TideCommander and TideTracer. These user-friendly software offer a convenient way for parameter settings, profile check, and various feed/harvest strategies without any need of programming.
The TideXcell™ system controls the up and down speed of the medium in the matrix vessel, duration of aeration and nutrition, temperature, level, duration of each FEED/HARVEST cycle, pH, DO, CO2 concentration in the incubation chamber, valves for each gas, peristaltic pump speed, gas flow, and etc.
TideXcell can only monitor the value of DO. We can supply pure oxygen from the mixing tank and from the data, the DO could rise to 80% with a small amount of oxygen supply. That means the TideXcell could support most oxygen from the matrix side.
TideXcell™ system controls the pH either by introducing CO2 to the matrix vessel in the culture chamber or by loading NaOH or HCl solution to the medium mixing vessel (bag). NaHCO3 can be used as an alternative for NaOH, this will not become a problem in perfusion culture since the osmolarity will not accumulate.
The data from pH and DO can be collected and saved automatically and are traceable. They can be retrieved depending on the time (Year-Month-Day-Minute-Second) but cannot be modified, in accordance to regulation standards. RS485 communication protocol/pin-out definition can be provided. Real-time data can be printed on paper with the use of RS485 interface.
By air pressure. An air pump in the controller pump in and out of the air from the matrix vessel. When pumping filtered air into the matrix vessel, the medium will drain out to the external medium tank (bag); when pumping air out of the matrix vessel, the medium will fill(refill) into the matrix vessel.
Each scale of TideXcell system has a different range of flow rate setting: TideXcell-002: 0.8~1.8 L/min; TideXcell-010: 1.8~3.5 L/min; TideXcell-020: 3.5~5.0 L/min; TideXcell-100: 20~30 L/min. At the initial stage of the cell culture, you need to apply a somewhat lower flow rate in order to seed the cells on the BioNOC™ II matrices.
The purpose for sampling cells is to have an overall image about the cell viability and density daily. In the TideXcell matrix vessel, the sampling port with the matrix basket allows the user to get pieces of BioNOC™ II matrices for cell observation and quantification. The glucose consumption rate is another index to judge the cell growth.
It is a prerequisite for us to propose the layout as well as the 3D location and orientation of TideXcell systems on the customer site. It is part of URS.
The operator will define the feeding rate, and the autofeeder will pump in (the fresh medium) and pump out (the waste medium) automatically. For example, when we set the feeding rate is 2 L/hr, and 24 cycles/day (pump in and pump out 24 times a day, or once per hour), the autofeeder will pump out 2 L of waste medium first from the bioreactor to the waste line (or Harvest tank), and then pump in 2 L of fresh culture medium from the Feed tank to the bioreactor. The overall culture medium inside the bioreactor always keeps the same.

Cells are exposed to aeration during emerging and to nutrition during submerging and therefore vertically, cells may have different aeration and nutrition times. However, our findings show no disadvantage as long as the system can provide cells with sufficient oxygen and nutrients.

The real situation is that the cells are embedded inside the carriers and there is always a layer of culture medium absorbed by the carriers. Therefore, whether the system is in the aeration or nutrition phase, the cells are technically always in the liquid phase. The quantity of culture medium remaining on the carriers is 20% of the entire bed volume, which is sufficient to supply the nutrient to the cells. The tide movement is to maintain the supply of oxygen and nutrients and to remove waste, a very similar concept to roller bottles.

Most of our customers choose roller bottles as the seeding source. In addition to CelCradle™ System and smaller scale of TideXcell system, the customer can use any other bioreactors for seed preparation such as Cell Factory or microcarrier systems. Two CelCradle™ bottles can be used for the seed preparation for TideXcell-002 and ten CelCradle™ bottles can be used to seed TideXcell-010. Esco VacciXcell also provides TideXcell automatic Cell Harvest System to harvest cells from the TideXcell matrix vessel.
Inoculation
  • Clamp the tube between Matrix Vessel and Mixing Vessel.
  • Prepare at least 3x109 cells in pre-warmed 800 ml culture medium per L matrices.
  • Disconnect the air tube inside TideXcell Culture Chamber with the Matrix Vessel. Move the Matrix Vessel to the Biosafety cabinet.
  • Load the cells into the Matrix Vessel. Mix the cell containing culture medium together with the Matrixes by gently shaking the matrix vessel in a rotational manner by hand for 3 minutes.
  • Place the Matrix Vessel back to the Culture Chamber. Reconnect the air tube with the Matrix Vessel.
  • Remove the clamp on the tube between the Matrix Vessel and Mixing Vessel.
Currently, we only have closed sampling for single use system but we are developing a sampling mechanism for multiple use system. There is no need to open the matrix vessel during sampling. If you can imagine a “crane game” in arcades, the concept is similar to that one.
Model Vol. of BioNOC™ II Matrix volume Equivalence to Stirred Tank Bioreactors
1:10 Mixing Ratio 1:20 Mixing Ratio
TideXcell-002 110g 2000 ml 20L 40L
TideXcell-010 550g 10,000 ml 100L 200L
TideXcell-020 1100g 20,000 ml 200L 400L
TideXcell-100 5500g 100,000 ml 1000L 2000L
Model Cell Seeding (Recommended) Expected Resulting Cell Density
TideXcell-002 2x109 cells 2x1010 cells
TideXcell-010 1x1010 cells 1x1011 cells
TideXcell-020 2x1010 cells 2x1011 cells
TideXcell-100 1x1011 cells 1x1012 cells
This actually depends on the process. For rabies vaccine production, the proper volume ratio of matrix vessel to medium tank is 1:10.
It should be 220 V, 50/60 Hz, single phase. The UPS is highly recommended.
TideXcell pilot scale bioreactor system requires only electricity and compressed air. Three kinds of gases could be introduced in the system– air, CO2, and O2. For the area where electricity blackout occurs frequently, UPS is highly recommended.
Yes, the button of Emergency Stop is on an accessible area and independent for each major unit.
A floor load with 500 kg/m2 is enough.
The external surfaces of the TideXcell™ System are made of SS304L, while the internal surfaces are made of SS316L.

Yes, besides the function of "Emergency Stop", event and alarming messages provide operators real-time monitoring of process variables and historical data. All deviations and user control actions (e.g. log-in/off, door open) are listed in the record.

An optional alarming notification is through the SCADA system or mobile communication such as cell phones via e-mail.

Yes. We can provide a special monitor mount and keyboard/mouse, which are ergonomic, for the customer.

The validation of TideXcell system includes four major phases: DQ, IQ, OQ, and MQ. The validation may involve inspection, functional testing, and documentation review, verifying that the system can run appropriately at the customer site.

DQ, Design Qualification, defines the functional and operational specification of an instrument or system.

IQ, Installation Qualification, is the pre-installation detail that an instrument or system, its component parts and location, are fit for the purpose and satisfy the objectives or the user to carry out the intended function to expected standards.

OQ is Operation Qualification, demonstrating that an instrument or system will function according to its operational specification in the selected environment.

MQ is Maintenance Qualification, describing any maintenance required.

Yes, Esco VacciXcell offers Stainless Steel SIP stirred tank bioreactors and fermenters and Stainless Steel SIP solid state fermenters. Should the client require it, Esco VacciXcell can also provide stainless steel SIP mixing systems for the TideXcell™ System.

The commercial microcarrier system is a very difficult process. Though it is relatively easy in the small scale, scaling up to production scale is difficult and complex. The microcarrier system also incurs shear stress, foaming, and bubbling, which may all lead to cell death. Cell death not only decreases productivity but also increases downstream processing costs, due to increased cell debris.

Esco VacciXcell’s tide motion system is simple and applies a similar principle as that of the roller bottles. Most of our customers use roller bottles and transfer to our technology directly without any problems. Those that tried to use the microcarrier system failed and eventually switched to the tide motion system.

For contamination issues, it highly depends on how the customer controls the culture environment and operation. Customers seldom report contamination issues to us which we think is due to the fact that most contamination issues are due to their process and practices and is rarely due to the equipment itself. Using our single-use system would make contamination risk almost 0.

In terms of component failure, we have had some cases but it is quite rare, roughly 1% and all these cases are after warranty periods. Strictly following the maintenance schedule is very important to minimize or reduce the risk of system failure.

Product Specification

TideXcell ® Product Specifications

TideXcell ® Incubation and Control Unit
Construction External Carcass: 316 stainless steel
Dimension 125 (W) X 70 (D) X 115 (H) cm
Weight 240 kg
Electrical requirements AC 220V 20A, 50/60 Hz, Single phase
UPS (uninterrupted power supply) width 6kVA/4.2kW should be prepared by customers
Control Hardware (2-20L) Flexible PC-based/DAQ industrial control interface;
Solenoid valves/PID gauges/Pressure-vacuum motor
NDIR CO2 diffusion type sensor
Control Hardware (50-100 L) Siemens HMI/PLC based control structure
Solenoid valves/PID gauges/Pressure-vacuum motor
NDIR CO2 diffusion type sensor
Control Software Siemens PLC-based control and monitoring structure
Siemens HMI with 12.1" touchscreen
Development environment: TIA Protal V13 SP1
Incubator 0 - 20% CO2 PID Control
+8ºC~27ºC Operating Temperature
Front view window; LED inside lighting
Emergency power-off button
Connection CPC nickel-coated brass quick connectors
Electric connectors with locking-screw
Communication 9-pin Dsub RS-485 port : Modbus RTU protocol
2 USB Ports for import firmware / software upgrade and export trend data
Construction 264 W x 359 L X 170 H mm (10.4 x 14 x 6.7 inches)
Control Features Simple user's administration
Process page & Date viewer page
Data logging/Parameters logging/Events logging
Individual seed and amp
Cultivation conditions setting with default values
Automatic switch from seeding stage to cultivation stage up to 300 minutes
Automatic air refreshing mechanism
Tidal control 800 ~ 1, 800 mL/min
Gas flow rate 0.8 – 20 LPM (depends on system size)
Alkaline addition 80 mL/min at 100 rpm
Perfusion rate 80 mL/min at 100 rpm
File export Excel (.xlx)
pH control 4~10 ± 0.1
DO control 0%~100% ± 0.5%
CO2 control 0%~10% ± 0.3%
Protection Over pressure protection (max. 1 bar)
Liquid leaking protection
Over suction protection
Over time protection

TideXcell ® Mixing System

Magnetic Stirrer Mixing System Recirculation Thermostatic Mixing System Stir-tank Mixing System
Construction Magnetic stirrer
10 L, 20 L borosilicate glass vessel
with stir bar for mixing
Recirculation Mixing with magnetic driven
bearing-less impeller
Stir mixing with pre-installed impeller
Electrical Requirements Monophase 3-threads AC 220V ± 10V
5A max 50/60 Hz
Single phase, AC 220v,
9A max, 50/60 Hz
Three phase, 230 VAC, 50/60 Hz
Capacity 10 L and 20 L 50 L, 100 L 200 L, 500 L, 1,000 L 30 L, 50 L, 100 L, 200 L, 500 L, 1,000 L
Control 100 – 1,500 rpm stir rate
RT to +45°C temperature control
Pumping rate 0 – 21 LPM
RT to +50ºC temperature control
80 – 1,000 rpm stir rate
RT to +60ºC temperature control
SIP system (sterilization in place)

The following table shows cGMP compliant customers using TideCell in their projects. Company identities and some other information are hidden due to Non-disclosure agreement (NDA) between the company and VacciXcell

SECRETED VIRUS    

Country

Cell Line

Virus Strain

Cell Density
cells/mL

Virus Titer

cGMP

SCADA/DCS

Taiwan

VERO

Japanese Encephalitis virus

4.6 x107

109pfu/ml

Yes

-

China

VERO

Rabies virus

4.0 x107

108 IgLD50/ml

Yes

-

Taiwan

VERO

Enterovirus type 71

2.6 x107

107.8 TCID50/ml

Yes

-

Taiwan

MDCK

H5N1

2.3 x107

HA=1024~2048

Yes

SCADA

Taiwan

MDCK

A(H1N1)

2.2 x107

HA=512~1024

Yes

-

Taiwan

PK

Hog Cholera

3.7 x107

106.5pfu/ml

Yes

-

China

ST

Hog Cholera

2 x107

2 mil. RID/ml

Yes

-

China

BHK-21

Rabies

4.5x107

108.5 TCID50/ml

Yes

-

Japan

MDBK

(NDA) virus for Bovine vaccine

1.29x107

109.2 TCID50/ml

Yes

 

China

Marc145

PRRSV

1.16x107

108.29 TCID50/mL

Yes

-

Spain

NDA

(NDA) Virus of Bovine Vaccine

2.6 × 107

N/A

Yes

-

NON-SECRETED VIRUS      

Country

Cell Line

Virus Strain

Cell Density

Virus Titer

cGMP

SCADA/DCS

Japan

NDA

Hepatitis A

2×1011

N/A

Yes

SCADA