Single Use Filtration and Processing
Pacific NW ISPE Disposables Technology
Conference
June 16th, 2011
Minh Tran
Mobius Technology Specialist
Single Use Processing
EDM Millipore
Outline
Preparing for the future with disposables technologies
Overview of Single Use Tool Chest
Achieving operational flexibility- Flexible filtration
Implementation case study
Summary
Preparing for the future with disposables
Past
Future
Leadership position with no
major competition
Increasing competition from CMOs,
generic manufacturers
Single product facilities
Multi-site, Multi-product facilities
Large-scale batches with no
variability
Small to large scale batches with
lot of variability
High volume-Low variety
formulations
Low volume-High variety
formulations
All Stainless Steel equipment
Mix of SS and single-use or all
single-use equipment
Less focus on cost control
and process improvement
Focus on Lean Process
Improvement
Minimal Tech Transfer
Increased Tech Transferconcurrent knowledge transfers
Drivers for disposables
Cost benefits:
Operational benefits:
Capital equipment
Increased flexibility
Validation
Increased capacity
Cleaning/ Maintenance
Reduced cross contamination
SIP/ Autoclaving
Reduced change over
WFI/ Utilities
Mobius product family
Mobius® Assemblies
Custom, easy to use single-use
containers, tubing, filters and connectors
Lynx® S2S Connectors
Truly sterile-to-sterile connectivity
Lynx® ST Connectors
Integrating stainless steel
with Mobius assemblies
Mobius® Mixers
Easy to use mixing systems with
single-use process containers
from 100 to 500 L
NovaSeal
Securely crimp and cut single-use
assembly into two sterile fluid paths
Mobius CellReady 3L
Bioreactor
Single-use stirred-tank bioreactor
Polyethylene Drums
Stainless Steel Bins
Drums to contain single-use
assemblies
Convenient handling and
flawless bag positioning
NovaSeptum Sampling System
Increase sampling productivity, while reducing set-up, cleaning and flushing
time
PureFlex Film
ULDPE fluid contacting layer
2D Bag Subassemblies
 50mL to 50L
3D Bag Subassemblies
 100L to 3500L
Validation Package: Leachables and
Extractables
Chemical Compatibility Data
Media/Buffer Preparation
Use of disposable mixing systems with liners or bags.
Bag with filter assemblies
Media addition assemblies
Filter Assembly with pre-use I.T
Transfer lines and manifolds
Addition assemblies
Intermediate 1000L bag with recirculation
loop
Configurable TFF Mix Bag Design
Operational flexibility
Validated systems with disposable flow paths
TFF (UF/DF)
Virus Filtration
Buffer & Media Preparation
Clarification
Achieving operational flexibility
Flexible filtration
Is this a good solution??
Complicated design and set-up
A EDM Millipore Solution:
Flexible Filtration Assemblies
Universal bag design
• Bag size selected based on the
smallest size requirement received
from various sites
• Bag tubing optimized for flow rate
and filling time requirements
• Two 1L sampling bags with
NovaSeal based on feedback from all
sites
• Smart-site sampling valve on one of
the top lines
• Lynx S2S connectors on the main
top and bottom lines
Modular Filtration Assemblies
WFI Filtration Assembly (Millipak 200)
Media Filtration Assembly (SHR)
Lynx S2S Cross Manifold
Buffer Filtration Assembly (SHF)
Hydroxide Filtration Assembly (SHF)
Case Study:
SS tanks to disposable assemblies
Steps
Current process with SS Tanks
Improved process with Mobius
Cleaning of 200L SS tank and
misc. tubing
20-30 minutes with 1-2 operators
Virtually eliminate all cleaning of SS tanks
using 200L HDPE drums
Cleaning supplies (DI,
Detergents, Labor, )
Need 350-500L with DI water. Keeping
cleaning records for tanks
Drastically reduce DI water use and
cleaning record keeping
Prepare SS tank for autoclaving,
vent filter and tubing
One vent filter at ~$120 per tank
Virtually eliminate total annual costs of vent
filters on SS tanks
10-15 minute to prep, 1 operator
600/yr x $120 each= $72,000
Autoclaving of 200L SS tanks
45-60 minutes per cycle, 2-4 SS tanks per
cycle, 1-2 operators
Greatly reduce demand for autoclave use
and time to sterilize SS tanks
Contamination Control
Poor drain ability of SS tanks may increase
risks of insufficient sterilization
Pre-sterilized 200L drum bags are readyto-use when needed.
Product Change Over
Traceability of product contact with tanks
and subsequent change over
No change over issues or questions with
single-use products
Storage of SS tanks
Limited space to keep tanks during use
and storage when empty
200L HDPE drums can be stacked during
storage when empty.
Process Simulation at Millipore’s Bioprocess
Science Training Center (BSTC)
The BSTC is a large Pilot Plant in Millipore’s Billerica facility that allows for
Process simulation at scale
Developed protocol and test plan to address robustness concerns of
proposed assemblies
Dedicated Applications Engineers to run customer process simulations
Process Simulation at Millipore’s Bioprocess
Science Technology Center (BSTC)
Assembly test set up and results
Run
Assembly Tested
1
Recirculation
2
Avg. Post
Avg.Tank
Avg.Delta Avg. Flow
Assembly
Avg.Transfer
Method of Air
Back
Pressure
P
Rate
Pressure
time @ 300L
Introduction pressure
PSI
PSI
PSI
L/min
min
Gradual
No
25.36
3.14
22.22
21.78
14.5
Transfer
Gradual
No
25.00
3.00
22.00
19.49
15.5
3
Recirculation
Gradual
Yes
25.50
14.73
10.78
15.13
20
4
Transfer
Gradual
Yes
25.29
12.16
13.13
15.02
20
5
Recirculation
Instantaneous
No
25.50
2.97
22.53
22.41
13.5
6
Transfer
Instantaneous
No
25.55
3.00
22.55
20.07
15
7
Transfer
Gradual
Yes
39.35
3.52
35.83
24.19
13
Other test notes:
•No leaks
•Suggestions for SOP
given
Extractable testing –Components
Part Numbers
Materials of Construction
Lynx® ST ½” HB x 1.5” TC
STC21THN10
Polyetherimide
Lynx S2S Female – ½” HB
SSCFHB2A24
Polysulfone
Lynx S2S Male – ½” HB
SSCMHB2A24
Polysulfone
Barbed Tee Hose Fitting ½”
P88185X9
Kynar
Tubing Silicone Pharma 50 ½” ID x
¾” OD x 60” LG
7486040801PU-14
Platinum Cured Silicone
Tee Reducer ½“ x ½“ x 1/8“
00104127PU
Polypropylene
Part Description
Extractable testing –Analytical Methods
Non-volatile Residue (NVR)
Total Organic Carbon (TOC)
Fourier Transform Infrared Spectroscopy (FTIR)
Reversed Phase High Performance Liquid Chromatography (RP-HPLC)
Gas chromatography-mass spectrometry (GC/MS)
Ion chromatography (IC)
Extractable testing –Results
Mobius Assembly Number MIL250ML089A
Part Description
Lynx S2S Male – ½”
HB
Pharma 50 Silicone
Tubing ½” ID x ¾”
OD x 60” LG
Pharma 50 Silicone
Tubing ½” ID x ¾”
OD x 12” LG
Pharma 50 Silicone
Tubing ½” ID x ¾”
OD x 6” LG
Pharma 50 Silicone
Tubing ½” ID x ¾”
OD x 4” LG
Pharma 50 Silicone
Tubing 3/8” ID x5/8”
OD x 112” LG
Pharma 50 Silicone
Tubing 3/8” ID x5/8”
OD x 4” LG
Barbed Tee Hose
Fitting ½”
Tee Reducer ½“ x ½“
x 1/8“
Conn, Apd. 3/8“ x ½“
Part Number
Quantity
Model Streams Applied
Worst-case Model Stream
Total Worst Case
Extractables Level
Expected for One
Component/Batch
SSCMHB2A24
1
Water, 25% EtOH, 0.5N NaOH
0.5N NaOH/TOC
0.28 mg C
7486040801PU-14
1
Water, 25% EtOH, 0.5N NaOH
0.5N NaOH/TOC
21.2 mg C
7486040801PU-14
1
Water, 25% EtOH, 0.5N NaOH
0.5N NaOH/TOC
4.3 mg C
7486040801PU-14
4
Water, 25% EtOH, 0.5N NaOH
0.5N NaOH/TOC
2.1 mg C
7486040801PU-14
2
Water, 25% EtOH, 0.5N NaOH
0.5N NaOH/TOC
1.4 mg C
7486040801PU-11
1
Water, 25% EtOH, 0.5N NaOH
0.5N NaOH/TOC
29.7 mg C
7486040801PU-11
1
Water, 25% EtOH, 0.5N NaOH
0.5N NaOH/TOC
1.0 mg C
P88185X9
1
Water, 25% EtOH, 0.5N NaOH
0.5N NaOH/TOC
0.07 mg C
00104127PU
5
Water, 25% EtOH, 0.5N NaOH
0.5N NaOH/TOC
0.21 mg C
1643121601PU
2
Water, 25% EtOH, 0.5N NaOH
0.5N NaOH/TOC
0.1 mg C
Based on the three model solvents and test conditions chosen by CUSTOMER in this extractables study the worst-case
average level of extractable substances were seen in each component in the 0.5N sodium hydroxide stream. The worst-case
average level of extractable substances from the Mobius Disposable Assembly catalog number MIL250ML089A
represented by the components and quantities listed above is expected to be 69.0 mg C.
Summary
Use of disposables technologies can help increase
operational flexibility and capacity
Validated hardware systems with disposable flow paths are
readily available
Flexible filtration can be successfully achieved at a large
scale
Implementation of disposable technologies is a multi-stage
process and vendor support is critical to overall success.
Back-up Slides
New Technologies
Mobius® CellReady Bioreactors
• Scalable cell culture from the bench top through manufacturing
• Market-driven innovation focused on delivering Flexibility, Confidence,
Ease of Use
• Millipore product quality and support
3L
Currently available
(Single use Sensors
in Development)
200L
50L
>1000L
The Mobius CellReady 50L and 200L Systems
Single-use, stirred tank bioreactors designed for pilot and clinical scale
cell culture available as a modular or turnkey systems
The fully Integrated Systems are:
 Bioreactor Cart
 Control Cart
 Automation by
– Delta V
– PC coming soon
 Single-use CellReady BPC
 SensorReady Assemblies
 Vent Assembly
Bioreactor Cart
(Artistic Rendering- not actual photo)
Controls
• Visible, easy access
• Compatible with all controllers
Vent Heater
• Primary & back-up vents
Work Surface
• Stainless steel construction
• Convenient work space
Jacketed Tank
• Heating and cooling
• Jacketed doors
Doors
• Simplifies bag installation
• Window for visibility
Temperature Control Unit
• On-board: saves floor space
• Can connect to house facilities
Levitronix Controls
• Impeller motor drive
SensorReady
• External sensor loop
• Positioned for easy access
Integrated Load Cells
• Precise level monitoring (bulk additions)
Control Cart
(Artistic Rendering- not actual photo)
Designed for Function
• Pumps, MFC conveniently located
• Cables off floor and routed to minimize
tangles
Media and Buffer Supply Rack
• Holds up to 4 x10L Bags
Organization
• “Tames the octopus”
• Storage for pumps and equipment
Controllers
• Automation supplied by Finesse
• On board
• Options for Delta V or PC based control
SensorReady
Increases process monitoring flexibility!
 External sensor and sampling loop
 Driven by low-shear, Levitronix blood pump
 Choice of Autoclavable or Single use Sensors, or a
combination of both
 Three versions available at launch
– Autoclavable- 2 x 12mm ports
– Autoclavable - 4 x 12mm Ports
– Finesse TruFluor™ pH and DO optical sensors
 Integrated sampling
– Weldable C-Flex® and Clave®
Confidential