Simplifying Progress

Biostat STR® MO
Your solution for highly demanding microbial processes
Content

Introduction to Biostat STR® Microbial NEW PIC

 Sartorius microbial solutions
 Biostat STR® at a glance

The Biostat STR® Family

Biostat STR® Microbial Hardware Design
 Key features

Microbial Flexsafe® Bag Design

 Microbial Bag Features

Biobrain® Automation Platform

Please delete this box
System Performance
The images used for title and agenda slide are exemplary. They can be
 Case Studies changed. Depending on the topic of your presentation, please choose a
thematically appropriate image.

2
Introduction

3
Introduction

Sartorius Scalable Microbial Bioprocess Solutions from PD to CM

Scalable Bioprocess Technologies Solutions from PD to Manufacturing

Ambr® 250 Biostat® B-DCU Biostat® RM Biostat STR® 50 Microbial BioSMB Separation and FMT portfolio Flexact® Modular

Process Development, Upstream and Downstream Production

iQue®3 BioPAT® Toolbox Data Analytics Software Octet Systems BioPAT® MFCS 4

Analytical and Automation Services

4
Introduction

Biostat STR® Microbial | Established Stirred-Tank Design

Designed for high demanding microbial applications

Outstanding versatility, quality, and productivity

Working volume range: 11 L to 40 L

New industrial automation platform. Variable usage either with microbial or

cell culture bag holder

Key performance  kLa 675 h-1  Stir speed 500 rpm

indicators:  OD600: 140 to 300  Gassing rate: 1.5 vvm

5
Introduction

Biostat STR® Microbial

Microbial Single-use Fermenter supported by Biobrain® | For Product Development and Commercial Manufacturing

Gen3 Design & Automation Industrial Standards

Biostat STR® control tower design is Machine Safety Nema4x/IP66

independent of bag holder size/type (e.g. EN 60204) enclosure

Biobrain® automation supports standalone Redundant pH Traffic

GMP installation and DO sensors warning lights

SCADA & DCS connectivity possible … plus, Gen2 innovation carried forward
via OPC UA
Full jacketed bag Rigid-mounted
Flexibility for easy exchange of bag holders holder for superior motor and drain
and upgrade of peripherals like pumps temperature control conus enhances
and sensors bag reliability
3-gas, digital
wide-range MFCs
Foam sensor with High Foam New heat exchanger
alarm functionality design for connection
Integrated to pressurized
Load Cells cooling

6
Introduction

More Control, Better Organization, Faster Setup for Microbial

Applications
Smaller footprint with flexible design MFCs & motor servo drive
Control Tower
& layout options With max. configuration Integrated into bag holder
Removable (fits to any bagholder type and size)
Sensor & actuator field
document tray

Sensor &
actuator
field

Cable &
tube
organizer
Microbial Gassing box &
Supply box

7
The Biostat STR ® Family

8
The Biostat STR® Family

Biostat STR®-Family

The Biostat STR® Microbial is the newest

addition to the Biostat STR® product family
for cell culture and microbial applications. Biostat Biostat
STR® 50 CC STR® 50 MO
The systems feature …
Outstanding versatility, quality, and productivity

Biostat
Working volume range: 12.5 L to 2000 L STR® 200 – 2,000 L CC
for cell culture systems | 11 L to 40 L for
microbial systems

Industrial automation platform

Proven stirred tank design

9
The Biostat STR® Family

Biostat STR® Microbial | Offering the Flexibility and Scalability You Need

 Conventional stirred-tank bioreactor design in single-use for predictable results

Engineered for a multitude  Conserved geometry from Ambr® 250 to Biostat STR® 50 Microbial for easy scalability
of microbial applications
 Proven process transfer from multi-use to single-use
at any stage of your process
 Working volume range: 11 L to 40 L

Synchronized hardware | software | consumables concept:

 Biobrain® industrial controller with modern, intuitive HMI
 Bagholder with integrated temperature, gassing, and sensor control
 Flexsafe STR® bags with a stirrer and sparger design optimized for
predictable mixing and gassing performance in microbial applications Example picture of Flexsafe STR® bag

10
Microbial Hardware Design

11
Biostat STR® Microbial Hardware Design

Biostat STR® Microbial

12
Biostat STR® Microbial Hardware Design

Microbial Single-Use Design

Dead end pressure controller for

higher gassing rates

Large motor for higher torque and

stirring speed up to 500 rpm

Decoupling tool Temperature modules

Safely decouple Flexsafe® bag  208 V and 400 V version
Special magnetic coupling for from magnetic head plate  Heat exchanger and
higher torque transmission to piping designed for
the bag’s internal stirrer shaft higher cooling rates

Gassing module Baffles

 Gassing box for larger MFC gas flow Two tank baffles
to improve mixing Bag mounting
with baffles
 Reduced amount of parts adapted
to MO applications (3x gas in – 1x
gas out)

13
Biostat STR® Microbial Hardware Design

Accessories

Mains cable tray Signal tower

Mounting kit Xgas Cable hook

Filter holder Cable manager

Chiller for Holder for

single-use single-use Document tray
exhaust cooler exhaust cooler
Probe clamp
Tube holder
for reusable probes

Autoclave tray for

reusable probes Probe holder

14
Microbial Flexsafe ® Bag Design

15
Microbial Flexsafe® Bag Design

Unlock the Full Potential of Single-Use Fermentation with Flexsafe® STR®

Microbial Bags
New BioPAT® Sensor Automation
 Advanced sensors pair with advanced control within the Biostat STR®
 BioPAT® Foam, single-use foam interlock
 Turbidity (Hamilton® Dencytee Arc)
 Sensor redundancy
 BioPAT ® Trace MeOH induction
 Single-use electrochemical pH sensor for full range measurement

New Flexsafe STR® Microbial

 Robust bag design developed for high demanding microbial applications Single-use exhaust cooler is
composed of a polycarbonate
 2 x 6-blade Rushton impeller and ring-sparger Aseptiquik® & exhaust cooler cassette, Si(Pt)
 6 Flexsafe® STR® Microbial bag designs with Opta® and AseptiQuik® connectors Opta® tube, and either Sartorius Opta®
connections or AseptiQuik® sterile connectors
 Y-tube line for a 2nd backup filter connected to the SU exhaust cooler Expanded Single-use
and BioPAT® Xgas sensor configs and multi-
 MTS bag for fast delivery available for CM sensor ports

16
Microbial Flexsafe® Bag Design

Six Standard Bag Designs Available

KPC port
Bag Impeller Sampling Optical DO pH electrode Sterile
Sparger Temp. (for multi-use
reference configuration line (single-use) (single-use) connector
electrodes)

FRS313532 2x Rushton Ring 1x 1x 2x 1x - Opta®

FRS313533 2x Rushton Ring 1x 1x 2x - 4x Opta®

FRS313534 2x Rushton Ring 1x 1x 2x 2x 2x Opta®

FRS313536 2x Rushton Ring 1x 1x 2x 1x - AseptiQuik®

FRS313537 2x Rushton Ring 1x 1x 2x - 4x AseptiQuik®

FRS313538 2x Rushton Ring 1x 1x 2x 2x 2x AseptiQuik®

MTS Bag design

17
Microbial Flexsafe® Bag Design

Exhaust Line – Challenges of Microbial Cultivations

Microbial processes demand higher oxygen input provided through higher gas flow rates and mixing. This
increases the risk of foaming events and the transport of moisture/foam, particles and cell debris through
the exhaust line, eventually leading to a filter blockage and the preliminary end of a batch.

Various solutions to mitigate the risk of filter blockage on Flexsafe STR® bags are available. A heater
jacket embracing the exhaust filter reduces the relative humidity of the condensate. Together with
a 2nd backup filter it is increasing the process robustness.

However, a traditional filter heater alone cannot ensure safe high demanding microbial processes
where high flow rates are required. Additionally, Sartorius is offering a powerful exhaust cooler
(condenser) ensuring reliable and robust processes.

To keep foaming events under control, BioPAT® Foam, a single-use foam sensor, is supervising
the buildup of foam and interrupts the process until measures have been taken to reduce the
foam formation.

18
Microbial Flexsafe® Bag Design

Exhaust Concept

Microbial processes are requiring additional

measures to avoid filter clogging. The single-use
exhaust cooler is used to remove the condensate
from the exhaust gas stream.

Efficient exhaust performance, Single-use exhaust cooler is composed of

avoid filter blockages a polycarbonate exhaust cooler cassette, Si(Pt) tube,
and either Sartorius Opta® or AseptiQuik® sterile connectors

Assurance of safety for longer

process periods

Single-use exhaust solution with Single-use exhaust cooler schematic describing

recirculation of condensate water back Transfer line with OPTA®
or AseptiQuik®
External chiller device
connected to single-use
the components setup and exhaust gas flow.

to bag chamber avoiding media losses sterile connector exhaust cooler.

19
Biobrain ® Automation Platform
Empowering Biostat STR® Gen3 2.1 MO

20
Biobrain® Automation Platform

Biobrain® Platform Brings Key Industrial Automation Requirements to Instruments

21
Biobrain® Automation Platform

Biobrain® Automation Platform Focuses on Commercial Customer Needs

 Modern & common user interface  cGMP Standalone ready

across Biostat® STR & Biostat® RM
Biobrain®  Industry Standards
 Flexibility of configurations
 Local Recipe execution and PAT
Features  Life-cycle
 Secured Remote Access for
 OPC-UA Connectivity service & Antivirus support

 Decrease training effort and risk  Short time-to-facility

of errors
 Support fast & secure process
 Increased reliability, maintenance changes configured vs.
Customer and confidence engineered
 Future proof automation software  Process Automation, Advanced
Benefits Innovation & IT requirements automation & control
 Enable Integration into customers  Increased system availability
Historian, DCS & BioPAT ® MFCS

cGMP current Good Manufacturing Practice

DCS Distributed Control System
OPC UA Open platform communication; latest version UA – Unified Architecture
PAT Process Analytical Tools

22
Biobrain® Automation Platform

Modern and Easy to Use Interface – Increase Operator Efficiency

Same User Experience for Biostat STR® and Biostat® RM

Ease process monitoring and control of key parameters
Access historical batch data for batch review

23
Biobrain® Automation Platform

Accelerate Process Implementation In Commercial Manufacturing

Features to support standalone unit execution for ….enabled by following

customers in GMP environment… GAMP5 standards and 21 CFR Part 11.

User Management Archiving

& Audit trail Management

Local Historization
Local Recipe Control &
(1 year) Configurable Data Batch Reporting
Storage 21CFR Part 11
assessment report

No mandatory need for timely installation of complex higher systems (e.g., Distributed Control Systems – DCS)

GAMP5 Good Automated Manufacturing Practice Version 5

24
Biobrain® Automation Platform

Remote Support With Biobrain® | Secured & Supporting GMP

 Remote access can be configured and activated on the instrument (dedicated

2 1 privilege)
 Passwords settings can be defined (expiration, new password) as well as an
option to close remote server automatically with user log off

 Sartorius Service or internal Customer support* can access remotely the

2 instrument (e.g : from outside the clean room) but on customer network
 Access from outside the customer network can be granted if customer enables
access from remote (access runs via customer’s PC)
 Remote access is only possible if server is started, and password known
 Access is done through Ultra VNC Viewer
3
1  An Operator must be in front of the instrument during the remote operation
3  Activation or de-activation of remote server is audit trailed
 An active remote connection is indicated with a yellow wrench color icon so an
Operator Operator can easily identify it in the screen and disconnect by simple click

Operator must Remote server Remote server status is visible from

acknowledge remote activation&configuration monitoring screen and can
server activation is tracked in Audit trail disconnect simply

*only trained user are allowed to use remote access for support activities and only if an operator is in front of the instrument | Activities performed remotely are under customer responsibilities

25
Biobrain® Automation Platform

Local Recipe Execution With Biobrain®

 Biobrain® Recipe editor* (based on BioPAT® MFCS4) enables edition

1 of simple recipes (sequencing instrument phases) on a separate
computer.
 Editing can be done off-line and support multiple Biobrain®
instruments
 A customized recipe service is also available
 Biobrain® Recipe Editor can be upgraded easily to a complete
BioPAT MFCS 4 to bring additional functionalities (centralized recipe
execution, Batch comparison, Multi-instrument view, remote access,
etc.)

Recipes can be transferred to the instrument

2 ( Import from USB or shared folder)

Batch can be locally executed on the instrument based on

3 the imported recipe
*Available starting September 2022

26
Biobrain® Automation Platform

Biobrain® - OPC UA Interface Supports Integration Needs

Supported by our OPC UA server and complete

documentation; Biostat STR® powered by Biobrain can be
connected to a Data Historian or DCS
 Access process data, parameter values and alarms & conditions
 Remote control of equipment phase, as well as acknowledgement of
alarms by higher level systems (e.g. DCS)

Data Historian OPC UA Server

(e.g. OSI PI)

or DCS
(e.g. Siemens PCS7 or Emerson DeltaV)

Configuration Specific
OPC UA report, ~170 p.
Biostat® STR3 R2

27
Biobrain® Automation Platform

Biobrain® - Native Connectivity to BioPAT® MFCS 4

Easily connect Biobrain® Instruments to BioPAT®

Central Monitoring Batch Comparison
MFCS4 SCADA for additional functionalities :
 Remote control, Multi-unit View, Central Monitoring &
Control, Batch comparison, Advanced recipes, SIMCA®
connectivity, etc.

+ OPC UA Server

BioPAT® MFCS4

Biostat® STR R2

28
BioPAT® MFCS 4 – Sartorius Scada

1. MFCS Server application deployed on a

Sartorius Applications on Customer Infrastructure Customer Applications & Infrastructure customer hosted virtual server
2. MFCS client(s) deployed on customer PC’s
or accessing server by Remote Desktop
3. SIMCA/ SIMCA online connected using
SimApi (part of MFCS core)
4. MFCS needs OPC UA client module
Historian Domain Backup Building Mgmt. Time 5. MFCS needs OPC UA Server module
SIMCA® & BioPAT® MFCS 4 user BioPAT® MFCS Interface Controller6 Server for System (e.g. Synchronisation 6. MFCS needs User Management Module
access via Client(s) or (e.g. OSI SQL Iconics/ Server 7. Ambr 250 needs Kepware OPC UA Server
SIMCA® -online3 Production Server1
PI, etc.) 5 Wonderware)5 8. Cubis® balance line via OPC DA Server
RDP session2
(part number VF4844)

Connected PAT
Sartorius Technology/ Sensors
Connect up to 32 Unit
Remote Operations BioPAT® Flow, BioPAT® Fundalux
Support Biobrain, DCU, Ambr BioPAT® Pressure, BioPAT® Trace
2507, 3rd Party Unit BioPAT® Viamass, BioPAT® Xgas
Cubis® Balance Line8
Operations4
Kaiser Raman
3rd Party Instruments/ Sensors4

29
Biobrain® Automation Platform

Flexibility in Process Adaptation Is Key in Process Development

and Small-Scale Production Flexibility

Configure your process - instead of engineering it

 E.G: Flexibility to add new sensors ( BioPAT® Trace), or bag holder
afterwards

Minimizing instrument re-qualification need for pre-qualified &

approved configurations

Safe & secure change-over enabled by management of

defined configurations

Batch MO Fed-Batch for MO

All screenshots are examples and actual implementation can vary based on the options selected by and the activated sensors and actuators

30
Biobrain® Automation Platform

Biobrain® Supports Flexibility

From Standard Batch to Fed Batch

To support flexible manufacturing, Biobrain® control

towers supports multiple software configurations for
different process control settings or even different
Batch

process modes.

Process change-over therefore can be done with a few

clicks, so one control tower can be used for different
processes with minimal change-over risk and time.
Fed Batch

 Configurations can be approved and locked

 Change of configurations is logged in the audit trail
 Loading a new configuration depends on user privilege

31
Biobrain® Automation Platform

Biobrain®- Batch Operation

e.g. in regular Seed Train use case

In case of Standard Batch (e.g for regular seed train use):

Only the relevant basic control loops and elements are
activated (sensors, actuators, controllers).
Batch

e.g: Optical DO, Electrochemical pH, Stirrer, Vessel Weight,

Foam Control, Gassing…

Stirrer ® Foam
Fed Batch

BioPAT

Designedmeasurement,
Capacity to allow suspension ofpatch
flexible particles at
a low stirringbyspeed
positioning anduser
the end withand
minimal power
input. with positioning
available
recommendations.

32
Biobrain® Automation Platform

Biobrain®- Fed Batch Operation

(e.g. in final production bioreactor)

Using the same control tower for Fed Batch operation can be done by
simply selecting a pre-configured Fed-Batch configuration which will
activate the relevant additional control loops and elements :
Batch

e.g:
 Additional feeds (8) to support Fed batch processes
 CO2 and O2 exhaust gas sensors
 Activation of second filter heater if needed

BioPAT® Xgas
Fed Batch

Oxygen-carbon dioxide sensor featuring

automatic compensation of humidity
and pressure.

33
System Performance

34
System Performance

Demonstrating Biostat STR® Microbial Capabilities KPIs

Criteria Results
WCW (g/L) >400
OD600 >280
Process engineering characterization: kLa 675 h-1
Oxygen Transfer Rate
Peak OUR >500 mmol*(L*h)-1
Cooling Power Up to 34 K*h-1 with water
~21 K*h-1 in our E. coli model process conditions  Velocity of final cooling depends on the
remaining cellular metabolic heat (Organism, Cell Density, Growth Characteristics, etc.)
Exhaust System Pressure limit (50 mbar) not exceeded
Performance Combination of exhaust cooler and two filter/filter heater accommodates high cell density
microbial processes

Our results reveal that even highly demanding and exponentially growing high cell density E. coli fed-batch processes can be
accommodated and operated securely and robustly in the Biostat STR® Microbial fermenter

35
System Performance

Successful System Trials

The usage of single-use equipment for microbial applications is thought to be very

challenging. Demonstrating single-use bioreactor capabilities is key.

Performance & Transferability. Customers expecting to easily transfer their

processes from stainless steel fermenter

Scalability in single-use. Proof scaling from multi-parallel or bench-top instrument

to Biostat STR® Microbial

Robustness. Automation platform must be capable of controlling key process

parameters like temperature and foaming

Analytical tools. Advanced sensors improve process knowledge and controllability,

leading to higher productivity and better product quality.

Several successful trials with E. coli and P. pastoris. Culture growth comparable
to stainless steel fermenter. No process adaptation necessary.

36
System Performance

Seamless Scalability Based on Geometric Similarity

Classic Stirred Tank Design

From Ambr® 250 to Biostat STR® Microbial, Sartorius vessels maintain geometric similarity to
ensure consistent mixing and oxygen transfer

Simplified technology
transfer between cultivation
scales

Ratio Ambr® 250 STR® 50 Microbial

Vessel Height | Diameter 2 1.8

Impeller Diameter | Vessel Diameter 0.42 0.36

37
System Performance

Successful Process Transfer

Biostat STR® Microbial provided sufficient mixing and mass transfer, while operating
successfully at high gas flow rates with sufficient cooling capacity to allow effective
fermentation temperature control.

Cooling capacity of the Temperature Control Unit allows effective fermentation

and temperature control for high demanding microbial processes (OD600: 200,
>251 mmol/L*h, dry cell weight >60 g/L)

The Biostat STR® Microbial provided sufficient mixing and mass transfer to produce
comparable dry cell weights using a traditional SIP vessel

The system operated successfully at high gas flow rates (1.5 vvm) without
filter clogging

“The combination of the Biostat STR® Microbial, E. coli pAVEway strain, and
fermentation process provided a highly effective strategy for production of a
model His-tagged protease inhibitor protein.”

38
 Thank you.

Dr. Jens Rupprecht

Product Manager Biostat STR Microbial
Product Management Manufacturing Bioreactors
CCT
[email protected]
+49 176 10562224