CSL Bioplasma - The BioProcessing Network

Keeping ahead in biopharmaceutical manufacturing
Bioprocessing Network Annual Conference 2009
1st October 2009
Dr Owen Tatford
Process Development Manager
CSL Bioplasma
May 2009
Biostate Process Overview
1
Introduction
•! CSL Bioplasma has been the national
blood fractionator since 1952
•! Demand for plasma products,
particularly intravenous immunoglobulin
(IVIG) has risen globally
–! US market for IVIG has risen from US$437M
in 1997 to US$2,397M in 2008
•! A similar increase in demand has been
observed in Australia
–! The National Blood Authority has observed
14% growth/year in IVIG use for the last 10
years and predicts this will continue for the
foreseeable future
May 2009
Biostate Process Overview
CSL Bioplasma
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2006 Production volume and revenue map
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Biostate Process Overview
CSL Bioplasma
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CSL Bioplasma – Broadmeadows site
•! Completed and
commissioned
1995
•! Designed for 250 T
human plasma per
annum, with a view
to expand
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Biostate Process Overview
CSL Bioplasma
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IgG / Albumin
Process
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Biostate Process Overview
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Common problems in Bioprocessing
•!
Ever-changing requirement of production facilities
•!
Maintaining quality requires increasing effort and cost to meet regulatory
compliance
•!
Increasing production costs – energy, material, resources, wastage
•!
Production downtime and equipment under-utilisation
•!
Maintenance requirements
•!
Poor use of statistical control and capture of process data
! inability to understand causes of manufacturing problems
Our solution ! A philosophy of continuous improvement
May 2009
Biostate Process Overview
CSL Bioplasma
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Chromatography
optimisation
PAT
Process
modelling
Efficiencies
and
yield increases
New technology
May 2009
Quality by Design
Risk assessment
Biostate Process Overview
CSL Bioplasma
7
Chromatography
optimisation
PAT
Process
modelling
Efficiencies
and
yield increases
New technology
May 2009
Quality by Design
Risk assessment
Biostate Process Overview
CSL Bioplasma
8
Desired state of manufacturing environment
•! An efficient, agile, flexible pharmaceutical manufacturing
environment that reliably produces high-quality drug products
without extensive regulatory oversight
•! Use a risk based analysis to ensure efficiency and reliability of
process equipment and utilities
!! Provides direction for continuous improvement initiatives
!! Highlights that manufacturing quality is as essential as the
quality of the product and development process
May 2009
Biostate Process Overview
CSL Bioplasma
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Risk based analysis
•! We apply a hybrid method of:
Hazard and operability (HAZOP): process
Failure mode and effect analysis (FMEA) : equipment and
components
Fault tree analysis (FTA) : deviations
•! Analyses risks relating to:
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Design and installation
Software and process control
Validation activities
Routine QC testing
Process transfer
Preventative Maintenance (PM)
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Documentation
Production data
Project management
HSE
GMP
•! Chor Sing Tan’s Poster at BPN 2009
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Biostate Process Overview
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Risk analysis
Reliable, robust and high quality
utility or system
1
Risk 6Risk Risk
1
Risk 5
Item
Risk 4
Risk 2
Risk 3
Risk elimination
and
minimisation
Information
P&ID, SOP, validation files,
GMP guidelines, maintenance record,
site inspection and communication
with internal and external departments
Risk 1
Risk
Risk
1 1
Current
control
Risk assessment
Detection
May 2009
Recommendations
Reliability, efficiency
and robustness
Quality and
compliance
Product quality
Workplace HSE
Biostate Process Overview
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Case study
•! Risk assessed the impact of the removal of an unnecessary filtration
step on all steps of a process
Item
Issue
Problem
Control
Assigned risk Solution
Upstream
reagent
preparation
tanks
(prior to the
filtration)
Interchangeable
tanks are
plastic and
hard to clean
effectively
Potential of
Endotoxin
absorbs to
plastic
Manual
cleaning of
tank
HIGH
Designated
Stainless steel
tanks
introduced
Process and
product
transfer pumps
Pumps not
designed for
CIP
Flushing may
be insufficient
to remove
residual protein
Pumps
cleaned
manually
HIGH
CIP capable
pumps
installed with
scheduled PM
and inspection
May 2009
Cross
contamination
Biostate Process Overview
CSL Bioplasma
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Chromatography
optimisation
PAT
Process
modelling
Efficiencies
and
yield increases
New technology
May 2009
Quality by Design
Risk assessment
Biostate Process Overview
CSL Bioplasma
13
Quality by design
•! Building quality through understanding of the design space
Traditional design space
Limit of investigation
Process limits
Target range
Set point
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Biostate Process Overview
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Design of Experiments - 1
Design space is multidimensional and parameters are inter-related
•! Aim: Perform as few studies as possible to achieve optimal conditions
! Apply DOE principles
May 2009
Biostate Process Overview
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Design of Experiments - 2
•! Applied DOE to UF operations
! Determine conditions to achieve reduced diafiltration time
May 2009
Biostate Process Overview
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Chromatography
optimisation
PAT
Process
modelling
Efficiencies
and
yield increases
New technology
May 2009
Quality by Design
Risk assessment
Biostate Process Overview
CSL Bioplasma
17
Process modelling - 1
Important to have a swift process (Time = money)
•!
However
–! Biopharmaceutical processes consist of many steps
–! Not all steps take the same amount of time
–! Often operating batches back to back
•!
The key is to understand which steps are holding up your process
(bottlenecks)
•!
But the complexity of the process may obscure the bottlenecks
–! e.g. hard to fathom the utilisation of common tanks and equipment
Process Modelling overcomes this
•!
Generates data to show if a step
–! Affects other individual steps in the process
–! Impacts the process as a whole
–! Has a knock-on effect on other batches
May 2009
Biostate Process Overview
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Process modelling - 2
•!
Modelling is only as good the data provided
•!
Vital to accurately collate and assess process data
–! Avoid assumptions, averages: both may hide the real situation
–! Obtain first hand data from process sheets, batch records
•!
Identify source data and collate
–!
–!
–!
–!
•!
Resin binding capacity
Filtrate flux data
Mass balances
Process, wait and transfer times
Analyse data
–! Select suitable software to generate the required output
–! Generate a picture of the current situation
•!
Perform simulations
–! Change one step at a time to determine impact
–! Identify and prioritise changes
–! Utilise to justify engineering solutions
May 2009
Biostate Process Overview
CSL Bioplasma
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DBM2
T1001/T1003
SHARPLES
LF521/LF522
T501
T502
T503
T504
T505
T506
T507
T509
UF531
T621
T622
T623
F608
T625
T626
DEAE
UF596
T591
T592
MACROPREP
UF597
T593
T594
PV633
UF528
PV534
PV523
CM
UF618
T627
T628
S200
UF646
T630
UF620
PV631
PV635
PV636
Hours
Process modelling - 3
Equipment utilisation chart for one batch
140
120
100
May 2009
80
60
40
20
0
Biostate Process Overview
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Process modelling - 4
Utilisation chart for 7 batches during 5 day cycle operations
(targeting 85% utilisation)
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Biostate Process Overview
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Chromatography
optimisation
PAT
Process
modelling
Efficiencies
and
yield increases
New technology
May 2009
Quality by Design
Risk assessment
Biostate Process Overview
CSL Bioplasma
22
Chromatography
•! Two chromatography steps in Intragam P process
•! Three chromatography steps in Albumex process
•! Vital to have optimised chromatography operations as multiple column
cycles performed per batch
May 2009
Biostate Process Overview
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Chromatography optimisation - 1
•! Processing a batch requires many
repetitive column cycles
•! Determine optimal column size : resin
cost
•! Ensure each cycle is performed
! Quickly
! Reproducibly
! At highest sample load that allows
required separation
May 2009
Biostate Process Overview
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Chromatography optimisation - 2
Long periods taken performing non-product
contact steps
•!
Buffer flushes
–! Key was to target pH and conductivity not
column volumes or contact time
! Optimised to reduce time and buffer volumes
e.g. Macroprep column - 12 loads / 10T batch
Equilibration buffer was 1200L/cycle now 600kg
! Saving of 7200kg/batch (= 7 hours)
•!
Column monitoring
–! Separate HETP step for S200 column
–! Incorporation into equilibration cycles
! Saving 10 – 12 hours/ batch
May 2009
Biostate Process Overview
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Chromatography optimisation - 3
•! Improved cleaning regimes
•! Extensive R&D trials (building QbD)
–! Karl McCann’s presentation
! Optimised contact time
! Improved resin lifetime
! Consistently high binding capacity
! Improved column performance
! Less column downtime and re-packing
May 2009
Biostate Process Overview
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Chromatography
optimisation
PAT
Process
modelling
Efficiencies
and
yield increases
New technology
May 2009
Quality by Design
Risk assessment
Biostate Process Overview
CSL Bioplasma
27
New technology
•!
14 years full operation at Broadmeadows
–! Need to replace obsolete equipment
–! High cost of maintaining original equipment
•!
Improved technology now available
–! Higher yield demonstrated at pilot scale
–! Automation, process control and monitoring
•!
Requires careful management
–! Extensive R&D compatibility studies
! Demonstrate “like for like” to avoid clinical trials,
•! IgG subclass analysis, impurity levels
–! Develop engineering and regulatory justification : Improved cleaning validation,
reduced manual handling
May 2009
Biostate Process Overview
CSL Bioplasma
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Depth filtration
•!
•!
Moved from Lochem to filter press
! removed recirculation
! reduced flush volume
! faster, more consistent filtration
May 2009
Biostate Process Overview
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Updating ultrafiltration
•!
Spirals in use were made obsolete, forcing a switch
! Flat bed cassettes
! Reduced membrane area with higher permeate flux
! 24 hour operation to produce 7500kg permeate became 6hr
! Validated cleaning via cleaning station, not inline
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Biostate Process Overview
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UF automation
•! Minimal operator input
•! Set flow rate
•! TMP via control valve
•! Mass balance via load
cells
•! Stops automatically
•! Highly reproducible
operation
May 2009
Biostate Process Overview
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Chromatography technology - 1
•! New column technology
–! Reproducible packing at higher
pressure
–! Self packing / unpacking
–! Higher flow rates
–! Improved process consistency
May 2009
Biostate Process Overview
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Chromatography technology - 2
•! Many new chromatography resins available on the market
–! Offering higher flow rates, improved binding capacity with new ligands
offering more modes of separation
–! Tailored to specific requirements
–! Allows significant capacity improvements for limited capital expenditure
May 2009
Biostate Process Overview
33
Evaluation of GE’s CaptoDEAE
v DEAE Sepharose FF
% of total loaded
DEAE Sepharose
Fast Flow
Protein load (g/L)
May 2009
Biostate Process Overview
CSL Bioplasma
34
Chromatography
optimisation
PAT
Process
modelling
Efficiencies
and
yield increases
New technology
May 2009
Quality by Design
Risk assessment
Biostate Process Overview
CSL Bioplasma
35
Process Analytical Technology (PAT)
•! New philosophy
–! Real time monitoring
–! Feeding back data into batch process
–! For every batch, not just validation
•! Working towards PAT system
–! QC testing
•! Can still be considered PAT if data utilised in process
•! However testing and obtaining results can mean delays
! Working to improve all sample communications
–! First steps in process monitoring
•! Protein concentration
–! Switching from QC assays to UV280nm and density measurements
performed in the manufacturing plant
May 2009
Biostate Process Overview
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Process control technology
Siemens control
•! Full traceability
•! Process monitoring
•! Electronic batch records
•! CFR 21 part 11
compliance
•! Improved trending
May 2009
Biostate Process Overview
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Outcome
•! Doubled design capacity of 250T
–! 524T plasma was processed during 2008/09
–! Without changing site footprint
•! Shifted from 7 day to 5 day processing cycle
•! Yield improvements
May 2009
Biostate Process Overview
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IVIG Yield
CSL IVIG yield
2008
5.5
5.0
5.35
Intragam P
commenced
IVIG yield (g/L)
4.5
4.0
Estimated average
industry yield
3.5
3.0
2.5
2.0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
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Biostate Process Overview
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Current focus
•! Reduce cycle time further?
! Increased capacity
–! Focus on resin changes
•! Compatibility trials based protein purity
•! Without clinical trials?
! Encouraged by regulatory consultation (TGA)
May 2009
Biostate Process Overview
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